TREATMENT OF MULTIPLE MYELOMA AND USE OF BIOMARKERS FOR 4-(4-(4-(((2-(2,6-DIOXOPIPERIDINE-3-YL)-1-OXOISOINDOLINE-4-YL)OXY)METHYL)BENZYL)-PIPERAZINE-1-YL)-3-FLUORBENZONITRILE

Description

1. FIELD

[0001] Disclosed herein, are methods of using certain biomarkers, such as CRBN, Aiolos (IKZF3), Ikaros (IKZF1), zinc finger protein 91 (ZFP91), c-Myc, interferon regulatory factor 4 (IRF4), tumor immunity markers (soluble CD25, cytokines; tumor-infiltrating lymphocytes (TILs); T-cell activation, T-cell receptor clonality), circulating tumor cells (CTCs), soluble BCMA (sBCMA), apoptosis markers (cleaved-Caspase-1, cleaved-Caspase-7, cleaved-Caspase-3, cleaved PARP, survivin, BCL-2 like protein 11 (BIM), TUNEL, free light chain (FLC)), and cell cycle markers (p21, p27, pRb1) in predicting and monitoring clinical sensitivity and therapeutic response to 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, or an enantiomer, a mixture of enantiomers, a tautomer, or a pharmaceutically acceptable salt thereof, and methods for treating, preventing or managing multiple myeloma using such. Also described herein is 4-(4-(4-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)oxy)methyl)benzyl)piperazin-1-yl)-3-fluorobenzonitrile, or an enantiomer, a mixture of enantiomers, a tautomer, or a pharmaceutically acceptable salt thereof for use in methods for treating, preventing or managing multiple myeloma. Also disclosed are methods of identifying a patient likely to be responsive, predicting the responsiveness of a patient, determining the dosage, or determining the efficacy of a compound in treating diseases.2. BACKGROUND

[0002] Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow. Normally, plasma cells produce antibodies and play a key role in immune function. However, uncontrolled growth of these cells leads to bone pain and fractures, anemia, infections, and other complications. Multiple myeloma is the second most common hematological malignancy, although the exact causes of multiple myeloma remain unknown. Multiple myeloma causes high levels of proteins in the blood, urine, and organs, including but not limited to M-protein and other immunoglobulins (antibodies), albumin, and beta-2-microglobulin, except in some patients (estimated at 1% to 5%) whose myeloma cells do not secrete these proteins (termed non-secretory myeloma). M-protein, short for monoclonal protein, also known as paraprotein, is a particularly abnormal protein produced by the myeloma plasma cells and can be found in the blood or urine of almost all patients with multiple myeloma, except for patients who have non-secretory myeloma or whose myeloma cells produce immunoglobulin light chains with heavy chain.

[0003] Skeletal symptoms, including bone pain, are among the most clinically significant symptoms of multiple myeloma. Malignant plasma cells release osteoclast stimulating factors (including IL-1, IL-6 and TNF) that cause calcium to be leached from bones, thereby causing lytic lesions; hypercalcemia is another symptom. The osteoclast stimulating factors, also referred to as cytokines, may prevent apoptosis, or death of myeloma cells. Fifty percent of patients have radiologically detectable myeloma-related skeletal lesions at diagnosis. Other common clinical symptoms for multiple myeloma include polyneuropathy, anemia, hyperviscosity, infections, and renal insufficiency.

[0004] Current multiple myeloma therapy may involve one or more of surgery, stem cell transplantation, chemotherapy, immune therapy, and / or radiation treatment to eradicate multiple myeloma cells in a patient. All of the current therapy approaches pose significant drawbacks for the patient.

[0005] In the last decade, novel therapeutic agents, in particular immunomodulatory drugs such as lenalidomide and pomalidomide, significantly increased the response rates and prolonged progression free survival (PFS) and overall survival (OS) in multiple myeloma patients. However, persistent levels of residual disease that are below the sensitivity of bone marrow (BM) morphology, protein electrophoresis with immunofixation, and light chain quantitation exists in some patients with multiple myeloma, even after these patients have achieved complete response (CR), and may eventually cause relapse of the disease.

[0006] There exists a significant need for safe and effective compounds and methods for treating, preventing and managing multiple myeloma, including for patients whose multiple myeloma is newly diagnosed or refractory to standard treatments, while reducing or avoiding the toxicities and / or side effects associated with the conventional therapies.3. SUMMARY OF THE INVENTION

[0007] In one aspect, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compund has been administered; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof: and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0008] In another aspect, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compund has been administered, and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0009] In yet another aspect, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) determining the level of a biomarker in the a sample obtained from a subject to whom the treatment compund has been administered; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0010] In some embodiments, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) administering the treatment compound to a sample; from the subject (b) determining the level of a biomarker in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof: , and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0011] In another embodiment, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) administering the treatment compound to a sample; from the subject (b) determining the level of a biomarker in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and <2>

[0012] In yet another embodiment, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) administering the treatment compound to a sample from the subject (b) determining the level of a biomarker in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0013] In some embodiments, provided herein are methods of identifying a subject having cancer who is likely to be responsive to a treatment compound, wherein the level of the biomarker in the sample is higher than the reference level of the biomarker. In other embodiments, provided herein are methods of identifying a subject having cancer who is likely to be responsive to a treatment compound, wherein the level of the biomarker in the sample is lower than the reference level of the biomarker

[0014] In some embodiments, provided herein is a treatment compound for use in a method of treating cancer, comprising: (a) determining the level of a biomarker in a sample; from a subject having the cancer; (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; and (d) administering a therapeutically effective amount of the treatment compound to the subject diagnosed as being likely to be responsive to the treatment compound; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0015] In another embodiment, provided herein is a treatment compound for use in a method of treating cancer, comprising: (a) determining the level of a biomarker in the sample from a subject having the cancer; (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; and (d) administering a therapeutically effective amount of the treatment compound to the subject diagnosed as being likely to be responsive to the treatment compound; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof: , and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0016] In yet another embodiment, provided herein is a treatment compound for use in a method of treating cancer, comprising: (a) determining the level of a biomarker in a sample from a subject having the cancer; (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; and (d) administering a therapeutically effective amount of the treatment compound to the subject diagnosed as being likely to be responsive to the treatment compound; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0017] In some embodiments, the level of the biomarker in the sample is higher than the reference level of the biomarker. In other embodiments, the level of the biomarker in the sample is lower than the reference level of the biomarker. Also provided herein are Compound 1, Compound 2 and / or Compound 3 for use in a method for treating cancer as described above.

[0018] In some embodiments, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compund has been administered, and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof: , and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0019] In another embodiment, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (e) (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compund has been administered; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0020] In yet another embodiment, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compund has been administered; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof: , and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0021] In another aspect, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) administering the treatment compound to a sample from the subject (b) determining the level of a biomarker in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof: , and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0022] In another embodiment, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) administering the treatment compound to a sample from the subject; (e) (b) determining the level of a biomarker in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0023] In yet another embodiment, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) administering the treatment compound to a sample from the subject; (e) (b) determining the level of a biomarker in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0024] In some embodiments, provided herein are methods of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, wherein the level of the biomarker in the sample is higher than the reference level of the biomarker. In other embodiments, provided herein are methods of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, wherein the level of the biomarker in the sample is lower than the reference level of the biomarker

[0025] In another aspect, provided herein is a method of monitoring the efficacy of a treatment compound in treating cancer in a subject, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compund has been administered; and (b) comparing the level of the biomarker in the sample with the level of the biomarker obtained from a reference sample, wherein a change in the biomarker level is indicative of the efficacy of the treatment compound in treating the cancer in the subject; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0026] In some embodiments, provided herein is a method of monitoring the efficacy of a treatment compound in treating cancer in a subject, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compund has been administered; and (b) comparing the level of the biomarker in the sample with the level of the biomarker obtained from a reference sample, wherein a change in the biomarker level is indicative of the efficacy of the treatment compound in treating the cancer in the subject; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof: , and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0027] In another embodiment, provided herein is a method of monitoring the efficacy of a treatment compound in treating cancer in a subject, comprising: (a) determining the level of a biomarker in the a sample obtained from a subject to whom the treatment compund has been administered; and (b) comparing the level of the biomarker in the sample with the level of the biomarker obtained from a reference sample, wherein a change in the biomarker level is indicative of the efficacy of the treatment compound in treating the cancer in the subject; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0028] In some embodiments, provided herein are methods of monitoring the efficacy of a treatment compound in treating cancer in a subject, wherein an increased level of the biomarker as compared to the reference level is indicative of the efficacy of the treatment compound in treating the cancer in the subject. In some embodiments, provided herein are methods of monitoring the efficacy of a treatment compound in treating cancer in a subject, wherein a decreased level of the biomarker as compared to the reference level is indicative of the efficacy of the treatment compound in treating the cancer in the subject.

[0029] In some embodiments of any one of the methods provided herein, the reference sample is obtained from the subject prior to administering the treatment compound to the subject, and wherein the reference sample is from the same source as the sample.

[0030] In some embodiments of any one of the methods provided herein, the reference sample is obtained from a healthy subject not having the cancer, and wherein the reference sample is from the same source as the sample.

[0031] In some embodiments of any one of the methods provided herein, the reference sample is obtained from a subject receiving an anti-cancer compound that is not said treatment compound, and wherein the reference sample is from the same source as the sample. In specific embodiments, the reference sample is obtained from a subject receiving an anti-cancer compound that is not the treatment compound, wherein the reference sample is from the same source as the sample, and the anti-cancer compound is selected from the group comprising lenalidomide, pomalidomide, or a derivative thereof.

[0032] In some embodiments of the methods provided herein, the cancer is multiple myeloma (MM). In some specific embodiments, the MM is relapsed, refractory, or resistant to conventional therapy. In one embodiment, the MM is lenalidomide-resistant MM. In another embodiment, the MM is pomalidomide-resistant MM. In some embodiments, the MM is newly diagnosed MM. In some embodiments, the MM is transplant-eligible MM. In other embodiments, the MM is non-transplant-eligible MM.

[0033] Disclosed herein is a bipmarker biomarker having a function in an apoptosis pathway a biomarker having a function in a cell cycle pathway a biomarker having a function in T-cell activation a biomarker being circulating tumor cells (CTCs) and a biomarker being tumor-infiltrating lymphocytes (TILs).

[0034] In some specific embodiments, the biomarker is IKZF1. In another embodiment, the biomarker is IKZF3. In yet another embodiment, the biomarker is ZFP91. In still another embodiment, the biomarker is c-MYC. In certain embodiments, the biomarker is IRF4.

[0035] The biomarker having a function in apoptosis may be selected from the group consisting of cleaved Caspase-1 (c-Caspase-1), cleaved Caspase-3 (c-Caspase-3), cleaved Caspase-7 (c-Caspase-7), cleaved PARP, survivin, BIM BCL-2 like protein 11 (BIM), and serum free light chain.

[0036] The biomarker having a function in apoptosis may be measured by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), by Annexin-V and 7- AAD, or by Annexin-V and propidium iodide (PI).

[0037] The biomarker having a function in cell cycle may be selected from the group consisting of cyclin-dependent kinase inhibitor 1 (p21), cyclin-dependent kinase inhibitor 1B (p27), and retinoblastoma protein (pRb 1).

[0038] The biomarker having a function in T-cell activation and may be selected from the group consisting of interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and T-cell receptor (TCR) clonality. T-cell receptor (TCR) clonality may be is measured by DNA sequencing of the TCR. The level of the T-cell activation may be measured by histology.

[0039] In some embodiments of the methods provided herein, the level of the biomarker is higher than a reference level.

[0040] In yet other embodiments of the methods provided herein, the level of the biomarker is lower than a reference level.

[0041] In some embodiments, provided herein is a method of identifying a subject with multiple myeloma that is relapsed, refractory, or resistant to conventional therapy who is likely to be responsive to a treatment compound, comprising: (a) determining the level of a biomarker in a sample from the subject; and (a) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is lower than a reference level of the biomarker; wherein the treatment compound is a compound of Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0042] In another embodiment, provided herein is a method of identifying a subject with multiple myeloma that is relapsed, refractory, or resistant to conventional therapy who is likely to be responsive to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compund has been administered; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is lower than a reference level of the biomarker; wherein the treatment compound is a compound of Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0043] In yet another embodiment, provided herein is a method of identifying a subject with multiple myeloma that is relapsed, refractory, or resistant to conventional therapy who is likely to be responsive to a treatment compound, comprising: (a) determining the level of a biomarker in a sample from the subject; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is lower than a reference level of the biomarker; wherein the treatment compound is a compound of Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0044] In some embodiments, provided herein is a method of predicting the responsiveness of a subject having multiple myeloma to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compund has been administered; and (e) (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is lower than a reference level of the biomarker; wherein the treatment compound is a compound of Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0045] In another embodiment, provided herein is a method of predicting the responsiveness of a subject having multiple myeloma to a treatment compound, comprising: (a) determining the level of a biomarker in sample from the subject; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is lower than a reference level of the biomarker; wherein the treatment compound is a compound of Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof: , and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0046] In yet another embodiment, provided herein is a method of predicting the responsiveness of a subject having multiple myeloma to a treatment compound, comprising: (a) determining the level of a biomarker in a sample from the subject; and (e) (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is lower than a reference level of the biomarker; wherein the treatment compound is a compound of Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0047] In specific embodiments of the methods of predicting the responsiveness of a subject having multiple myeloma to a treatment compound, the biomarker is CRBN. In certain embodiments of the methods of predicting the responsiveness of a subject having multiple myeloma to a treatment compound the methods comprise diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is detected and lower than the reference sample. In some embodiments of the methods of predicting the responsiveness of a subject having multiple myeloma to a treatment compound the methods comprise diagnosing the subject as being likely to be responsive to the treatment compound if the biomarker in the sample is detectable. In some specific embodiments, the MM is relapsed, refractory, or resistant to conventional therapy. In one embodiment, the MM is lenalidomide-resistant MM. In another embodiment, the MM is pomalidomide-resistant MM.

[0048] In some embodiments of any one of the methods provided herein, the level of the biomarker is measured by determining the protein level of the biomarker. In other embodiments of any one of the methods provided herein, the level of the biomarker is measured by determining the mRNA level of the biomarker. In yet further embodiments of any one of the methods provided herein, the level of the biomarker is measured by determining the cDNA level of the biomarker. In certain embodiments of any one of the methods provided herein, the biomarker is determined by DNA sequencing. In other embodiments of any one of the methods provided herein, the biomarker is determined by RNA-sequencing (RNA-seq).

[0049] In some embodiments, the level of the biomarker is measured by determining the protein level of the biomarker, comprising contacting proteins within the sample with a first antibody that immunospecifically binds to the biomarker protein. In other embodiments, the level of the biomarker is measured by determining the protein level of the biomarker, comprising contacting proteins within the sample with a first antibody that immunospecifically binds to the biomarker protein, further comprising: (a) contacting the biomarker protein bound to the first antibody with a second antibody with a detectable label, wherein the second antibody immunospecifically binds to the biomarker protein, and wherein the second antibody immunospecifically binds to a different epitope on the biomarker protein than the first antibody; (b) detecting the presence of the second antibody bound to the biomarker protein; and (c) determining the amount of the biomarker protein based on the amount of detectable label in the second antibody.

[0050] In yet another embodiment, the level of the biomarker is measured by determining the protein level of the biomarker, comprising contacting proteins within the sample with a first antibody that immunospecifically binds to the biomarker protein, further comprising: (a) contacting the first antibody bound to the biomarker protein with a second antibody with a detectable label, wherein the second antibody immunospecifically binds to the first antibody; (b) detecting the presence of the second antibody bound to the first antibody; and (c) determining the amount of the biomarker protein based on the amount of detectable label in the second antibody.

[0051] In certain embodiments, provided herein is a method of determining a dosage for treating a subject having multiple myeloma with a treatment compound comprising: determining the level of a biomarker in the one or more samples that have been obtained at different time points from the subject to whom a dosage of the treatment compound has been administered, and thereby determining if the dosage is appropriate or needs an adjustment; wherein the treatment compound is a compound of Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof: , and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0052] In another embodiment, provided herein is a method of determining a dosage for treating a subject having multiple myeloma with a treatment compound comprising: determining the level of a biomarker in the one or more sample that have been obtained at different time points from the subject to whom a dosage of the treatment compound has been administered, and thereby determining if the dosage is appropriate or needs an adjustment; wherein the treatment compound is a compound of Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0053] In yet another embodiment, provided herein is a method of determining a dosage for treating a subject having multiple myeloma with a treatment compound comprising: determining the level of a biomarker in the one or more samples that have been obtained at different time points from the subject to whom a dosage of the treatment compound has been administered, and thereby determining if the dosage is appropriate or needs an adjustment; wherein the treatment compound is a compound of Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0054] In some embodiments of the methods of determining a dosage for treating a subject having multiple myeloma with a treatment compound, the biomarker is selected from the group consisting of IKZF1, and IKZF3. In some specific embodiments of the methods of determining a dosage for treating a subject having multiple myeloma with a treatment compound, the biomarker is IKZF1. In yet another specific embodiment of the methods of determining a dosage for treating a subject having multiple myeloma with a treatment compound the biomarker is IKZF3.

[0055] In some embodiments of the compound for use in treating cancer, the method further comprises administering a therapeutically effective amount of a second active agent or a support care therapy. In certain embodiments, the methods of identifying a subject having cancer who is compound has been administered likely to respond to a treatment compound further comprises administering a therapeutically effective amount of the treatment compound to the subject diagnosed as being likely to be responsive to the treatment compound, and also further comprises administering a therapeutically effective amount of a second active agent or a support care therapy. In specific embodiments, the second active agent is selected from the group comprising large molecules, small molecules, or cell therapies, and the second active agent is optionally selected from a group comprising of melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, a proteasome inhibitor, a histone deacetylase inhibitor, a BET inhibitor, a BCL2 inhibitor, an MCL-1 inhibitor, a corticosteroid, dexamethasone, an antibody, a checkpoint inhibitor, and CAR cells.

[0056] In some embodiments provided herein, the Compounds provided herein may be used in any method for treating, preventing and / or monitoring any of the diseases provided herein.4. BRIEF DESCRIPTION OF THE FIGURES

[0057] FIG. 1 illustrates that Compound 2 and Compound 3 degraded Aiolos protein in a time and concentration dependent manner. DF15 cells expressing Enhanced ProLabel (ePL)-tagged Aiolos were incubated with Compound 2 (triangle) or Compound 3 (square) for 45 minutes, 90 minutes, or 3 hours at the indicated concentrations. Cell extracts were then generated and the amount of Aiolos-ePL protein was determined by ePL luminescence assay. FIG. 2 illustrates that Compound 2 degraded Aiolos and Ikaros, even in pomalidomide resistant cells, and synergizes with dexamethasone to degrade IRF4 and c-MYC. Pomalidomide-sensitive (OPM2) or resistant (OPM2-P1) cells were treated with vehicle control (DMSO), pomalidomide, or Compound 2 either alone or in combination with 10 or 100 nM dexamethasone for 72 hours. CRL4 CRBN< E3 ubiquitin ligase substrates Aiolos and Ikaros, and their downstream effectors c-Myc and IRF4 were measured. Tubulin is a loading control. FIG. 3 illustrates that Compound 2 degraded Aiolos and Ikaros, even in pomalidomide resistant cells, and synergizes with dexamethasone to induce apoptosis. Pomalidomide-sensitive (OPM2) or resistant (OPM2-P1) cells were treated with vehicle control (DMSO), pomalidomide, or Compound 2 either alone or in combination with 10 or 100 nM dexamethasone for 72 hours. CRL4 CRBN< E3 ubiquitin ligase substrates Aiolos and Ikaros, and induction of apoptotic pathway proteins BIM, cleaved PARP, cleaved caspase-3, and cleaved caspase-7 were measured. Tubulin is a loading control. FIG. 4 illustrates that Compound 2 induced the degradation of Ikaros, Aiolos, ZFP91, c-Myc, and IRF4, which correlates with induction of the apoptotic protein cleaved-Caspase 3, and the cell cycle arrest protein p21. Immunoblot analysis of OPM2 parental cells incubated with Compound 2 at the indicated concentrations is shown. Actin is a loading control. FIG. 5A illustrates that CRBN is required for Compound 2 mediated degradation of Ikaros and Aiolos. Shown are Cereblon, Ikaros, and Aiolos immunoblots of extracts from DF15R and DF15R-human CRBN WT< cells that were incubated with DMSO, pomalidomide, or Compound 2 at 0.1 µM for 4 hours. Tubulin is a loading control. FIG. 5B illustrates that Ikaros is required for Compound 2 mediated downregulation of c-Myc and IRF4, as well as induction of apoptosis. Shown are immunoblots of extracts from wild-type OPM2 cells or OPM2 cells overexpressing stabilized Ikaros-, Aiolos-, or ZFP91-mutants. Cells were incubated with DMSO, or the indicated concentration Compound 2 for five days. FIG. 6A and FIG. 6B illustrate that Compound 2 degraded Ikaros and Aiolos in a concentration dependent manner, which induced apoptosis and cell cycle arrest in pomalidomide-resistant multiple myeloma cells. Shown is immunoblot analysis of pomalidomide-resistant MM cells (H929-1051) incubated with Compound 2 for (FIG. 6A) 4 hours or (FIG. 6B) 72 hours. FIG. 7A and FIG. 7B illustrate that Compound 2 induces prolonged degradation of Aiolos and Ikaros. Aiolos and Ikaros degradation as a percentage of dimethyl sulfoxide (DMSO) control in (FIG. 7A) H929-1051and (FIG. 7B) OPM2-P10 cell models after a one-time continuous exposure to Compound 2 is shown. These data are from a single experiment with one sample per data point. FIG. 8 illustrates that Compound 2 induced prolonged degradation of Aiolos and Ikaros after 15 minutes of exposure. Compound 2 was incubated for 15 minutes with H929-1051 cells and degradation of Aiolos (left panel) and Ikaros (right panel) was measured. The data are from a single experiment with one sample per data point. The y-axis represents the amount of Aiolos or Ikaros expressed as a percentage of the level of the corresponding protein in the dimethyl sulfoxide (DMSO) control; the x-axis shows time in hours. FIG. 9 illustrates that recovery of Aiolos levels post-washout from 6 hour exposure to Compound 2 required nearly 160 hours. Compound 2 was incubated for 6 hours with H929-1051 cells and degradation of Aiolos was measured. These data are from a single experiment with one sample per data point. The vertical dotted blue line divides the data into Compound 2 on-treatment (left of the vertical line) and post-washout segments (right of the vertical line). Results are presented for Aiolos levels in OPM2-P10 cells (left) and H929-1051 cells (right) for a total of 160 hours including and following a 6-hour incubation with 0.01 (red) or 0.1 µM Compound 2 (blue). FIG. 10 illustrates that continuous, but not transient, exposure to Compound 2 induced apoptosis in multiple myeloma cells. Apoptosis induction by Compound 2 treatment in a lenalidomide-resistant MM cell model (H929-1051 [top row] and a pomalidomide-resistant MM cell model OPM2-P10 [bottom row]) is presented. These data are from a single experiment with one sample per data point. FIG. 11A and FIG. 11B illustrate that Compound 2, but not pomalidomide, exhibit antiproliferative activity in lenalidomide- and pomalidomide-resistant multiple myeloma cells lines, including those with low CRBN protein levels. Anti-proliferative effects on human multiple myeloma cell lines of acquired resistance with low CRBN are shown. Cell lines were treated with (FIG. 11A) Pomalidomide, or (FIG. 11B) Compound 2 for 5 days and IC 50 values were assessed using an ATP determination assay (CellTiter-Glo). Percent control was calculated by subtracting the background and normalizing to the DMSO control (100% of control). FIG. 12 illustrates that dexamethasone (DEX) + Compound 2 induces apoptosis. Induction of apoptosis after 72 hr treatment with dexamethasone alone or in combination with Compound 2, lenalidomide or pomalidomide in a lenalidomide-resistant multiple myeloma cell line (H929-1051) was measured using Caspase-Glo 3 / 7. FIG. 13 illustrates that short daily Compound 2 exposures, for up to three days, induces Ikaros degradation in CD34+ cells. Ikaros degradation following short daily exposure to Compound 2 was measured by flow cytometry. CD34+ cells derived from healthy donor bone marrow were exposed to Compound 2 for 2, 4, and 6 hours starting on Day 14 for 1 (Day 14), 2 (Day 15), or 3 (Day 16) consecutive days. Percentage of Ikaros content (normalized to the DMSO control) is presented. At the end of the exposure period, Compound 2 was removed and cells were incubated in the absence of Compound 2 (recovery period). Ikaros was measured by flow cytometry during recovery on Days 19, 21, and 23. Data are presented as the mean of results for two donors. FIG. 14 illustrates the degradation and recovery of Ikaros following three consecutive days of 6-hour exposures to Compound 2. CD34+ bone marrow-derived cells from healthy donors were exposed to Compound 2 on each of three consecutive days starting on Day 10 for 6 hours. Percentage of Ikaros inhibition compared with DMSO is shown. Cultures were incubated in the absence of Compound 2 from Day 13 through Day 22. Ikaros was measured by flow cytometry after completion of each exposure and every other day during recovery. FIG. 15 illustrates the degradation and recovery of Ikaros following five consecutive days of 6-hour exposures to Compound 2. CD34+ bone marrow-derived cells were exposed to Compound 2 on each of five consecutive days, starting on Day 10. Percentage of Ikaros inhibition compared to DMSO control is presented. Cultures were incubated in the absence of Compound 2 from Day 15 through Day 22. Ikaros was measured by flow cytometry after the completion of each exposure (Days 10 to 14) and every other day during recovery (Day 17, 20, and 22). FIG. 16A and FIG. 16B illustrate the treatment scheme, and correlation between Ikaros inhibition (dotted line) and neutrophil differentiation (solid line) after exposure to Compound 2. (FIG. 16A) CD34 +< bone marrow-derived cells from healthy donors were cultured ex vivo and stimulated to develop into Stage IV mature neutrophils. (FIG. 16B) The cultures were exposed to different concentrations of Compound 2 for 6 hours on each of three days (Day 10, 11, and 12) and then cultured without further exposure to Compound 2 until Day 22. Percentage of Ikaros inhibition compared with DMSO control (circle) following 1 nM (square), 10 nM (upward triangle), and 100 nM (downward triangle) of Compound 2 exposure is shown on the right y-axis (dashed lines). The percentage of Stage IV cells is shown on the left y-axis (solid lines). The shaded area represents the 3 days with exposures to Compound 2. FIG. 17A and FIG. 17B illustrate that Compound 2 directly activated human Peripheral Blood Mononuclear Cells (PBMCs) to lyse K562 erythromyelocytic leukemia cells in a concentration-dependent manner. (FIG. 17A) Representative fluorescence-activated cell sorting plots of K562 cells co-cultured with human PBMCs that had been preincubated with Compound 2 or DMSO. (FIG. 17B) Apoptosis response in K562 cells after co-culture with Compound 2 treated PBMCs. Apoptosis was measured by PI and Annexin V staining in K562 cells after 24 hour of co-culture with PBMCs that were treated with Compound 2 for 72 hours. Data are presented as mean with error bars representing standard error of the mean. FIG. 18A and FIG. 18B illustrate that immune cells are directly activated by Compound 2 to lyse lenalidomide-sensitive and lenalidomide-resistant multiple myeloma cell lines. (FIG. 18A) Apoptosis response in NCI-H929 cells after 24-hour co-culture with PBMCs pretreated with Compound 2. (FIG. 18B) Apoptosis response in H929-1051 cells after 24-hour co-culture with PBMCs pretreated with Compound 2. FIG. 19A-FIG. 19D illustrate that compound-primed immune cells show enhanced tumor cell killing when multiple myeloma cells are pretreated with lenalidomide, pomalidomide, or Compound 2 prior to co-culture. Compound-primed immune cells show enhanced tumor cell killing in co-culture model (right) in (FIG. 19A) H929 cells, (FIG. 19B) H929-1051, (FIG. 19C) OPM2, and (FIG. 19D) OPM2 P10 cells, compared to the MM single cultures (left), and little effect on PBMC viability (middle). FIG. 20 illustrates that Compound 2 demonstrates greater potency for induction of Interleukin-2 production from anti-CD3 antibody bead-stimulated PBMCs than lenalidomide or pomalidomide at 72 hours. Induction of Interleukin-2 (IL-2) production from anti-CD3 antibody bead-stimulated PBMCs after treatment with Compound 2, lenalidomide (LEN), or pomalidomide (POM) for 72 hours. FIG. 21A-FIG. 21C illustrate that Compound 2 is a potent inducer of effector cytokines. Measurement of effector cytokine induction upon treatment with Compound 2, pomalidomide (POM), or lenalidomide (LEN) for 24 hours. (FIG. 21A) IL-2, (FIG. 21B) IFN-γ, and (FIG. 21C) TNF-α. Data shown are an average from three or four donors and are represented as fold change over DMSO control; error bars represent standard error of the mean (SEM). FIG. 22A-FIG. 22C illustrate that Compound 2 induces degradation of Ikaros in CD4+ T cells. Measurement of Ikaros degradation in CD4+ T-cells after treatment with Compound 2 (diamond), lenalidomide (LEN; circle), or pomalidomide (POM; square) for (FIG. 22A) 24 hours, (FIG. 22B) 48 hours, or (FIG. 22C) 72 hours. Data shown are an average from two donors and are represented as MFI normalized to DMSO control. FIG. 23A-FIG. 23C illustrate that dexamethasone (DEX) in combination with Compound 2 reduces Interleukin-2 (IL-2) production from anti-CD3 antibody-stimulated PBMCs. Interleukin-2 production from anti-CD3 antibody-stimulated PBMCs after (FIG. 23A) lenalidomide (LEN) alone or with dexamethasone, (FIG. 23B) pomalidomide (POM) alone or with dexamethasone, or (FIG. 23C) Compound 2 alone or with dexamethasone. FIG. 24A and FIG. 24B illustrate that Compound 2 induces Aiolos degradation in CD3+ T cells from peripheral blood of relapsed / refractory multiple myeloma patients after (FIG. 24A) the once daily (QD) 1-10, 15-24 / 28 schedule, or (FIG. 24B) the twice daily (BID) 1-3, 15-17 / 28 schedule. FIG. 25A and FIG. 25B illustrate that Compound 2 induced Ikaros degradation in CD3+ T cells from peripheral blood of relapsed / refractory multiple myeloma patients after (FIG. 25A) the once daily (QD) 1-10, 15-24 / 28 schedule, or (FIG. 25B) the twice daily (BID) 1-3, 15-17 / 28 schedule. FIG. 26A-FIG. 26E illustrate that the effect of Compound 2 on biomarker expression in CD138+ plasma cells from relapsed / refractory multiple myeloma patients. (FIG. 26A) Aiolos, (FIG. 26B) Ikaros, (FIG. 26C) ZFP91, (FIG. 26D) c-Myc, and (FIG. 26E) IRF4. FIG. 27 illustrates the effect of Compound 2 on soluble BCMA (sBCMA) expression in relapsed / refractory multiple myeloma patients. FIG. 28 illustrates the effect of Compound 2 on serum free light chain (sFLC) in relapsed / refractory multiple myeloma patients. 5. DETAILED DESCRIPTION OF THE INVENTION

[0058] The methods provided herein are based, in part, on the discovery that a changed level, e.g., an increased level and / or a decreased level, of certain molecules (e.g., mRNAs, cDNAs, or proteins) or malignant cells (e.g., circulating tumor cells (CTCs)) in a biological sample can be used to predict responsiveness of a subject having or suspected to have MM to a treatment compound (e.g., Compound 1, Compound 2, Compound 3, or an enantiomer, a mixture of enantiomers, tautomer, isotopolog or pharmaceutically acceptable salt thereof).5.1 Definitions

[0059] As used herein, the terms "comprising" and "including" can be used interchangeably. The terms "comprising" and "including" are to be interpreted as specifying the presence of the stated features or components as referred to, but does not preclude the presence or addition of one or more features, or components, or groups thereof. Additionally, the terms "comprising" and "including" are intended to include examples encompassed by the term "consisting of". Consequently, the term "consisting of" can be used in place of the terms "comprising" and "including" to provide for more specific embodiments of the invention.

[0060] The term "consisting of" means that a subject-matter has at least 90%, 95%, 97%, 98% or 99% of the stated features or components of which it consists. In another embodiment the term "consisting of" excludes from the scope of any succeeding recitation any other features or components, excepting those that are not essential to the technical effect to be achieved.

[0061] As used herein, the term "or" is to be interpreted as an inclusive "or" meaning any one or any combination. Therefore, "A, B or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B and C". An exception to this definition will occur only when a combination of elements, functions, steps or acts are in some way inherently mutually exclusive.

[0062] In general, the technical teaching of one embodiment can be combined with that disclosed in any other embodiments provided herein.

[0063] The references to the use of a product in a method of treatment in this description are to be interpreted as references to the products of the present invention for use in a method for treatment of the human (or animal) body by therapy.

[0064] As used herein, the term "cancer" includes, but is not limited to, solid cancer and blood borne cancer. The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A cancer can be a cancer of the hematopoietic and lymphoid tissue. A hematopoietic malignancy refers to a cancer that affects the blood, bone marrow, lymph, and lymphatic system.

[0065] As used herein "multiple myeloma" refers to hematological conditions characterized by malignant plasma cells and includes the following disorders: monoclonal gammopathy of undetermined significance (MGUS); low risk, intermediate risk, and high risk multiple myeloma; newly diagnosed multiple myeloma (including low risk, intermediate risk, and high risk newly diagnosed multiple myeloma); transplant eligible and transplant ineligible multiple myeloma; smoldering (indolent) multiple myeloma (including low risk, intermediate risk, and high risk smouldering multiple myeloma); active multiple myeloma; solitary plasmacytoma; extramedullary plasmacytoma; plasma cell leukemia; central nervous system multiple myeloma; light chain myeloma; non-secretory myeloma; Immunoglobulin D myeloma; and Immunoglobulin E myeloma; and multiple myeloma characterized by genetic abnormalities, such as Cyclin D translocations (for example, t(411;14)(q13;q32); t(6;14)(p21;32); t(12;14)(p13;q32)) or t(6,20)); MMSET translocations (for example, t(4;14)(p16;q32)); MAF translocations (for example, t(14;16)(q32;q32); t(20;22); t(16;22)(q11;q13); or t(14;20)(q32;q11)); or other chromosome factors (for example, deletion of 17p13, or chromosome 13; del(17 / 17p), nonhyperdiploidy, and gain(1q)).

[0066] As used herein and unless otherwise indicated, the terms "treat," "treating" and "treatment" refer to alleviating or reducing the severity of a symptom associated with the disease or condition being treated, for example, multiple myeloma.

[0067] The term "prevention" includes the inhibition of a symptom of the particular disease or disorder, for example multiple myeloma. In some embodiments, patients with familial history of multiple myeloma are candidates for preventive regimens. Generally, the term "preventing" refers to administration of the drug prior to the onset of symptoms, particularly to patients at risk of multiple myeloma.

[0068] As used herein and unless otherwise indicated, the term "managing" encompasses preventing the recurrence of the particular disease or disorder, such as multiple myeloma, in a patient who had suffered from it, lengthening the time a patient who had suffered from the disease or disorder remains in remission, reducing mortality rates of the patients, and / or maintaining a reduction in severity or avoidance of a symptom associated with the disease or condition being managed.

[0069] As used herein, "subject" or "patient" is an animal, typically a mammal, including a human, such as a human patient.

[0070] As described herein, the term "healthy subject" is any individual that does not have multiple myeloma. In some embodiments, the "healthy subject" has no pre-existing medical conditions.

[0071] As used herein, and unless otherwise specified, the terms "therapeutically effective amount" and "effective amount" of a compound refer to an amount sufficient to provide a therapeutic benefit in the treatment, prevention and / or management of a disease, for example multiple myeloma, or to delay or minimize one or more symptoms associated with the disease or disorder to be treated. The terms "therapeutically effective amount" and "effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

[0072] The term "responsiveness" or "responsive" when used in reference to a treatment refers to the degree of effectiveness of the treatment in lessening or decreasing the symptoms of a disease, e.g., MM, being treated. For example, the term "increased responsiveness" when used in reference to a treatment of a cell or a subject refers to an increase in the effectiveness in lessening or decreasing the symptoms of the disease compared to a reference treatment (e.g., of the same cell or subject, or of a different cell or subject) when measured using any methods known in the art. In certain embodiments, the increase in the effectiveness is at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%.

[0073] The term "sensitivity" or "sensitive" when made in reference to treatment with compound is a relative term that refers to the degree of effectiveness of the compound in lessening or decreasing the progress of a tumor or the disease being treated. For example, the term "increased sensitivity" when used in reference to treatment of a cell or tumor in connection with a compound refers to an increase of, at least about 5%, or more, in the effectiveness of the tumor treatment.

[0074] The term "refractory" or "resistant" refers to a circumstance where patients, even after intensive treatment, have residual cancer cells (e.g., multiple myeloma cells) in their lymphatic system, blood, and / or blood forming tissues (e.g., marrow). In the context of multiple myeloma, the term "refractory or resistant" refers to a circumstance where patients, even after intensive treatment, have residual myeloma cells and / or reduced normal cells in the marrow. It is understood that a refractory disease is a disease that is nonresponsive on therapy (failure to achieve minimal response or development of progressive disease), or progresses within approximately 60 days of last dose.

[0075] The term "relapsed" refers to a situation where patients who have had a remission of cancer after therapy have a return of cancer cells (e.g., multiple myeloma cells) in their lymphatic system, blood, and / or blood forming tissues (e.g. marrow) and a decrease in normal blood cells.

[0076] An improvement in the cancer or cancer-related disease can be characterized as a complete (CR) or partial response (PR). "Complete response" refers to an absence of clinically detectable disease with normalization of any previously abnormal radiographic studies, bone marrow, and cerebrospinal fluid (CSF) or abnormal monoclonal protein measurements. "Partial response" refers to at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90% decrease in all measurable tumor burden (i.e., the number of malignant cells present in the subject, or the measured bulk of tumor masses or the quantity of abnormal monoclonal protein) in the absence of new lesions. The term "treatment" contemplates both a complete and a partial response.

[0077] In the context of a cancer, inhibition may be assessed by inhibition of disease progression, inhibition of tumor growth, reduction of primary tumor, relief of tumor-related symptoms, inhibition of tumor secreted factors, delayed appearance of primary or secondary tumors, slowed development of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased severity of secondary effects of disease, arrested tumor growth and regression of tumors, increased Time To Progression (TTP), increased Progression Free Survival (PFS), increased Overall Survival (OS), among others. OS as used herein means the time from treatment onset until death from any cause. TTP as used herein means the time from treatment onset until tumor progression; TTP does not include deaths. In one embodiment, PFS means the time from treatment onset until tumor progression or death. In one embodiment, PFS means the time from the first dose of compound to the first occurrence of disease progression or death from any cause. In one embodiment, PFS rates will be computed using the Kaplan-Meier estimates. Event-free survival (EFS) means the time from treatment onset until any treatment failure, including disease progression, treatment discontinuation for any reason, or death. In one embodiment, overall response rate (ORR) means the percentage of patients who achieve a response. In one embodiment, ORR means the sum of the percentage of patients who achieve complete and partial responses. In one embodiment, ORR means the percentage of patients whose best response ≥ partial response (PR), according to the IMWG Uniform Response Criteria. In one embodiment, duration of response (DoR) is the time from achieving a response until relapse or disease progression. In one embodiment, DoR is the time from achieving a response ≥ partial response (PR) until relapse or disease progression. In one embodiment, DoR is the time from the first documentation of a response until to the first documentation of progressive disease or death. In one embodiment, DoR is the time from the first documentation of a response ≥ partial response (PR) until to the first documentation of progressive disease or death. In one embodiment, time to response (TTR) means the time from the first dose of compound to the first documentation of a response. In one embodiment, TTR means the time from the first dose of compound to the first documentation of a response ≥ partial response (PR). In the extreme, complete inhibition, is referred to herein as prevention or chemoprevention. In this context, the term "prevention" includes either preventing the onset of clinically evident cancer altogether or preventing the onset of a preclinically evident stage of a cancer. Also intended to be encompassed by this definition is the prevention of transformation into malignant cells or to arrest or reverse the progression of premalignant cells to malignant cells. This includes prophylactic treatment of those at risk of developing a cancer.

[0078] In the context of multiple myeloma, response may be assessed using the International Myeloma Working Group (IMWG) consensus criteria for response and minimal residual disease assessment (Rajkumar et al., Blood, 2011, 117(18):4691-5; Kumar et al., Lancet Oncol., 2016,17(8):e328-e346). The criteria can be summarized as follows (with further details available in Lancet Oncol., 2016,17(8):e328-e346). Response Criteria MWG MRD criteria (requires a complete response as defined below) Sustained MRD-negativeMRD negativity in the marrow (NGF or NGS, or both) and by imaging as defined below, confirmed minimum of 1 year apart. Subsequent evaluations can be used to further specify the duration of negativity (eg, MRD-negative at 5 years)Flow MRD-negativeAbsence of phenotypically aberrant clonal plasma cells by NGF on bone marrow aspirates using the EuroFlow standard operation procedure for MRD detection in multiple myeloma (or validated equivalent method) with a minimum sensitivity of 1 in 10 5< nucleated cells or higherSequencing MRD-negativeAbsence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a clone is defined as less than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using the LymphoSIGHT platform (or validated equivalent method) with a minimum sensitivity of 1 in 10 5< nucleated cells or higherImaging plus MRD-negativeMRD negativity as defined by NGF or NGS plus disappearance of every area of increased tracer uptake found at baseline or a preceding PET / CT or decrease to less mediastinal blood pool SUV or decrease to less than that of surrounding normal tissueStandard IMWG response criteria Stringent complete responseComplete response as defined below plus normal FLC ratio and absence of clonal cells in bone marrow biopsy by immunohistochemistry (κ / λ ratio ≤4: 1 or ≥ 1:2 for κ and λ patients, respectively, after counting ≥100 plasma cells)Complete responseNegative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspiratesVery good partial responseSerum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level <100 mg per 24 hResponse Criteria Partial response≥50% reduction of serum M-protein plus reduction in 24 h urinary M-protein by ≥90% or to <200 mg per 24 h; If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved and uninvolved FLC levels is required in place of the M-protein criteria; If serum and urine M-protein are unmeasurable, and serumfree light assay is also unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, provided baseline bone marrow plasma-cell percentage was ≥30%. In addition to these criteria, if present at baseline, a ≥50% reduction in the size (SPD) of soft tissue plasmacytomas is also requiredMinimal response≥25% but ≤49% reduction of serum M-protein and reduction in 24-h urine M-protein by 50-89%. In addition to the above listed criteria, if present at baseline, a ≥50% reduction in the size (SPD) of soft tissue plasmacytomas is also requiredStable diseaseNot recommended for use as an indicator of response; stability of disease is best described by providing the time-to-progression estimates. Not meeting criteria for complete response, very good partial response, partial response, minimal response, or progressive diseaseProgressive diseaseAny one or more of the following criteria:Increase of 25% from lowest confirmed response value in one or more of the following criteria:Serum M-protein (absolute increase must be ≥0·5 g / dL);Serum M-protein increase ≥1 g / dL, if the lowest M component was ≥5 g / dL;Urine M-protein (absolute increase must be ≥200 mg / 24 h); In patients without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels (absolute increase must be >10 mg / dL);In patients without measurable serum and urine M-protein levels and without measurable involved FLC levels, bone marrow plasma-cell percentage irrespective of baseline status (absolute increase must be ≥10%);Appearance of a new lesion(s), ≥50% increase from nadir in SPD of >1 lesion, or ≥50% increase in the longest diameter of a previous lesion >1 cm in short axis;≥50% increase in circulating plasma cells (minimum of 200 cells per µL) if this is the only measure of diseaseClinical relapseClinical relapse requires one or more of the following criteria:Direct indicators of increasing disease and / or end organ dysfunction (CRAB features) related to the underlying clonal plasma-cell proliferative disorder. It is not used in calculation of time to progression or progression-free survival but is listed as something that can be reported optionally or for use in clinical practice;Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures do not constitute progression); Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and ≥1 cm) increase as measured serially by the SPD of the measurable lesion;Hypercalcaemia (>11 mg / dL);Decrease in haemoglobin of ≥2 g / dL not related to therapy or other non-myeloma-related conditions;Rise in serum creatinine by 2 mg / dL or more from the start of the therapy and attributable to myeloma;Hyperviscosity related to serum paraproteinRelapse from complete response (to be used only if the end point is disease-free survival)Any one or more of the following criteria:Reappearance of serum or urine M-protein by immunofixation or electrophoresis;Development of ≥5% plasma cells in the bone marrow; Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcaemia see above)Relapse from MRD negative (to be used only if the end point is disease-free survival)Any one or more of the following criteria:Loss of MRD negative state (evidence of clonal plasma cells on NGF or NGS, or positive imaging study for recurrence of myeloma);Reappearance of serum or urine M-protein by immunofixation or electrophoresis;Development of ≥5% clonal plasma cells in the bone marrow; Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcaemia)RD= minimal residual disease. NGF= next-generation flow. NGS= next-generation sequencing. FLC= free light chain. M-protein= myeloma protein. SPD= sum of the products of the maximal perpendicular diameters of measured lesions. CRAB features= calcium elevation, renal failure, anaemia, lytic bone lesions. FCM= flow cytometry. SUVmax= maximum standardised uptake value. 18< F-FDG PET= 18< F-fluorodeoxyglucose PET.

[0079] As used herein, "induction therapy" refers to the first treatment given for a disease, or the first treatment given with the intent of inducing complete remission in a disease, such as cancer. When used by itself, induction therapy is the one accepted as the best available treatment. If residual cancer is detected, patients are treated with another chemotherapy course, termed reinduction. If the patient is in complete remission after induction therapy, then additional consolidation and / or maintenance therapy is given to prolong remission or to potentially cure the patient.

[0080] As used herein, "consolidation therapy" refers to the treatment given for a disease after remission is first achieved. For example consolidation therapy for cancer is the treatment given after the cancer has disappeared after initial therapy. Consolidation therapy may include radiation therapy, stem cell transplant, or treatment with cancer drug therapy. Consolidation therapy is also referred to as intensification therapy and post-remission therapy.

[0081] As used herein, "maintenance therapy" refers to the treatment given for a disease after remission or best response is achieved, in order to prevent or delay relapse. Maintenance therapy can include chemotherapy, hormone therapy or targeted therapy.

[0082] As used herein, the term "reference level" is intended to mean a control level of a biomarker used to evaluate a test level of the biomarker in a sample from an individual. A reference level can be a normal reference level in a sample from a normal subject or a disease reference level from a disease-state subject. A normal reference level is an amount of expression of a biomarker in a non-diseased subject or subjects. A disease-state reference level is an amount of expression of a biomarker in a subject with a positive diagnosis for the disease or condition. A reference level also can be a stage-specific reference level. A stage-specific reference level refers to a level of a biomarker characteristic of a given stage of progression of a disease or condition. A reference level can also be an amount of expression of a biomarker prior to treatment, or at a different time during treatment. For example, a reference level can be the amount of expression of a biomarker in the bone marrow prior to treatment. In another example, a reference level may be the expression of a biomarker in the blood at some point during or after treatment.

[0083] The terms "likely" or "likelihood" generally refer to an increase in the probability of an event. The term "likely" when used in reference to the responsiveness of a patient generally contemplates an increased probability that the patient will be responsive to a treatment compound. The term "likely" when used in reference to the responsiveness of a patient can also generally mean the increase of biomarkers, such as mRNA or protein expression, that may evidence an increase in the probability that the patient will be responsive to a treatment compound.

[0084] The terms "predict" or "predicting," as used herein, generally mean to determine or tell in advance. When used to "predict" the responsiveness of a treatment, for example, the term "predicting" can mean that the likelihood of responding, or not responding, to the cancer treatment can be determined at the outset, before the treatment has begun, or before the treatment period has progressed substantially.

[0085] The terms "monitor" or "monitoring," as used herein, generally refer to the overseeing, supervision, regulation, watching, tracking, or surveillance of an activity. For example, the term "monitoring the effectiveness of a compound" refers to tracking the effectiveness in treating cancer in a patient or in a tumor cell culture. Similarly, the term "monitoring," when used in connection with patient compliance, either individually, or in a clinical trial, refers to the tracking or confirming that the patient is actually taking a drug being tested as prescribed. The monitoring can be performed, for example, by following the expression of mRNA or protein biomarkers.

[0086] As used herein, the terms "T-cell activation" and "activated T-cell" is intended to mean cellular activation of resting naive T-cells into effector T-cells that are capable of inducing tumor cell death. T-cell activation can be initiated by the interaction of the T-cell receptor (TCR) / CD3 complex with an antigen. An exemplarity activated T cell exhibits cell responses that include, but are not limited to, cell proliferation, cytokine secretion, and / or effector function. In the context of the present application, T-cell activation may be induced by treatment with Compound 1, Compound 2, or Compound 3.

[0087] As used herein, there term "T-cell activation associated cytokine" refers to any of the numerous factors that are secreted by activated T-cell, or whose secretion increases in activated T-cells, relative to resting naive T-cells. Non-limiting examples of T-cell activation associated cytokines include IL-2, IFNγ, and TNFα.

[0088] The term "regulate" as used herein refers to controlling the activity of a molecule or biological function, such as enhancing or diminishing the activity or function.

[0089] A "biological marker" or "biomarker" is a substance whose detection indicates a particular biological state, such as, for example, the presence of cancer. Exemplary biomarkers can be determined individually. It is understood that several biomarkers can be measured simultaneously. A person of ordinary skill would understand that a "biomarker" indicates a change in the level of mRNA expression that may correlate with the response to a treatment, or patient's likelihood of responding to a treatment. The biomarker can be a nucleic acid, such as mRNA or cDNA. The biomarker can also be a protein. A specific example of a biomarker is one or more tumor cells that are circulating in the peripheral blood (i.e., circulating tumor cells, CTCs). A biomarker can also be the changing of the structure or sequence of a gene, resulting in a variant form that is caused by the alteration of single base units in DNA, or the deletion, insertion, or rearrangement of larger sections of genes or chromosomes.

[0090] An additional exemplary "biomarker" is one that indicates a change in the level of polypeptide or protein expression that may correlate with the response to a treatment, or patient's likelihood of responding to a treatment. The biomarker can be a polypeptide or protein, or a fragment thereof. The relative level of specific proteins can be determined by methods known in the art. For example, antibody based methods, such as an immunoblot, enzyme-linked immunosorbent assay (ELISA), or other methods can be used.

[0091] The terms "polypeptide" and "protein," as used interchangeably herein, refer to a polymer of three or more amino acids in a serial array, linked through peptide bonds. The term "polypeptide" includes proteins, protein fragments, protein analogues, oligopeptides, and the like. The term "polypeptide" as used herein can also refer to a peptide. The amino acids making up the polypeptide may be naturally derived, or may be synthetic. The polypeptide can be purified from a biological sample. The polypeptide, protein, or peptide also encompasses modified polypeptides, proteins, and peptides, e.g., glycopolypeptides, glycoproteins, or glycopeptides; or lipopolypeptides, lipoproteins, or lipopeptides.

[0092] The term "antibody," "immunoglobulin," or "Ig" as used interchangeably herein, encompasses fully assembled antibodies and antibody fragments that retain the ability to specifically bind to the antigen. Antibodies provided herein include, but are not limited to, synthetic antibodies, monoclonal antibodies, polyclonal antibodies, recombinantly produced antibodies, multispecific antibodies (including bi-specific antibodies), human antibodies, humanized antibodies, chimeric antibodies, intrabodies, single-chain Fvs (scFv) (e.g., including monospecific, bispecific, etc.), camelized antibodies, Fab fragments, F(ab') fragments, disulfidelinked Fvs (sdFv), anti-idiotypic (anti-Id) antibodies, and epitope-binding fragments of any of the above. In particular, antibodies provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., antigen binding domains or molecules that contain an antigen-binding site that immunospecifically binds to CRBN antigen (e.g., one or more complementarity determining regions (CDRs) of an anti-CRBN antibody). Immunoglobulins can be composed of heavy chains and light chains. The antibodies provided herein can be of any class (e.g., IgG, IgE, IgM, IgD, and IgA) or any subclass (e.g., IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 , and IgA 2 ) of immunoglobulin molecule. In some embodiments, the anti-CRBN antibodies are fully human, such as fully human monoclonal CRBN antibodies. In certain embodiments, antibodies provided herein are IgG antibodies, or a subclass thereof (e.g., human IgG1 or IgG4). In other embodiments, the antibodies provided herein include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., antigen binding domains or molecules that contain an antigen-binding site that immunospecifically binds to Aiolos, Ikaros, c-MYC, IRF4, Caspase-3, BCMA, free kappa light chains, or free lambda light chains.

[0093] The terms "immunoglobulin light chain" or "light chain" refers to the small polypeptide subunit of an antibody. The light chain can be a lambda light chain or a kappa light chain. When the light chain is attached to a heavy chain, the light chains are termed "bound light chains". When the light chains are not attached to the heavy chain, they are termed "free light chains (FLC)". When the free light chains can be detected in the serum or plasma of a patient, they are termed "serum free light chains" or "plasma free light chains." It is further understood that "serum free light chains" can also be termed "soluble free light chains." It is understood by a person of average skill in the art that the amount of free light chain in the serum or plasma is proportional to the amount of disease burden, where the disease is multiple myeloma. It is also understood that the levels of free light chain, or the ratio of free light kappa to free light lambda can be used for the monitoring or diagnosis of myeloma. For example, a decrease in abnormally high levels of free light chain kappa to free light chain lambda in the serum of a patient with multiple myeloma that is being treated with Compound 2, can be used to monitor the efficacy of treatment with Compound 2. Similarly, an increase in free light chains in a patient being treated with a different compound, such as lenalidomide, can indicate resistance to treatment and can serve as a predictor of response to Compound 1, Compound 2, or Compound 3.

[0094] The terms "antigen binding domain," "antigen binding region," "antigen binding fragment," and similar terms refer to the portion of an antibody that comprises the amino acid residues that interact with an antigen and confer on the binding agent its specificity and affinity for the antigen (e.g., the CDR). The antigen binding region can be derived from any animal species, such as rodents (e.g., rabbit, rat, or hamster) and humans. In some embodiments, the antigen binding region is of human origin.

[0095] The term "epitope" as used herein refers to a localized region on the surface of an antigen that is capable of binding to one or more antigen binding regions of an antibody, that has antigenic or immunogenic activity in an animal, such as a mammal (e.g., a human), and that is capable of eliciting an immune response. An epitope having immunogenic activity is a portion of a polypeptide that elicits an antibody response in an animal. An epitope having antigenic activity is a portion of a polypeptide to which an antibody immunospecifically binds as determined by any method well known in the art, for example, by the immunoassays described herein. Antigenic epitopes need not necessarily be immunogenic. Epitopes usually consist of chemically active surface groupings of molecules, such as amino acids or sugar side chains, and have specific three dimensional structural characteristics as well as specific charge characteristics. A region of a polypeptide contributing to an epitope may be contiguous amino acids of the polypeptide, or the epitope may come together from two or more non-contiguous regions of the polypeptide. The epitope may or may not be a three-dimensional surface feature of the antigen.

[0096] The terms "cereblon" or "CRBN" and similar terms refers to the polypeptides ("polypeptides," "peptides," and "proteins" are used interchangeably herein) comprising the amino acid sequence of any CRBN, such as a human CRBN protein (e.g., human CRBN isoform 1, GenBank Accession No. NP_057386; or human CRBN isoforms 2, GenBank Accession No. NP_001166953), and related polypeptides, including SNP variants thereof. Related CRBN polypeptides include allelic variants (e.g., SNP variants), splice variants, fragments, derivatives, substitution variant, deletion variant, insertion variant, fusion polypeptides, and interspecies homologs, which, in certain embodiments, retain CRBN activity and / or are sufficient to generate an anti-CRBN immune response.

[0097] As used herein, the term "cereblon-associated protein" or "CAP" refers to a protein that interacts with or binds to cereblon (CRBN) directly or indirectly. For example, the term refers to any protein that directly binds to cereblon, as well as any protein that is an indirect downstream effector of CRBN pathways. An exemplary CAP is a substrate of CRBN, for example, a protein substrate of the E3 ubiquitin ligase complex involving CRBN, such as IKZF1, IKZF3, ZFP91, or the downstream effector proteins thereof, such as c-Myc, or IRF4. In the context of the presemtly claimed invention, the term cereblon-associated protein (CRBN-associated protein; CAP) refers only to IKZF1, IKZF3, ZFP91, c-MYC, or IRRF4

[0098] As used herein, the term "cereblon modulator compound" refers to compound that binds to CRBN and alters it activity or substrate specificity. For example, binding of a cereblon modulator compound can increase the degradation of IKZF1, IKZF3, ZFP91, IRF4, or c-MYC. Exemplary cereblon modulator compounds can be, but are not limited to, lenalidomide, pomalidomide, or a similar compound.

[0099] As used herein, the term "mutation" refers to any changing of the structure of a gene, resulting in a variant (also called "mutant") form. Mutations in a gene may be caused by the alternation of single base in DNA, or the deletion, insertion, or rearrangement of larger sections of genes or chromosomes. In some embodiments, the mutation can affect the function or the resulting protein. For example, a mutation in a single nucleotide of DNA (i.e. point mutation) in the coding region of a protein can result in a codon that codes for a different amino acid (i.e. missense mutation). This different amino acid can alter the structure of the protein, such that a compound or its derivatives cannot bind and / or inhibit the protein

[0100] The term "T-cell receptor (TCR) clonality" refers to the somatic alteration of the germline configuration of the T-cell receptor genes to a unique configuration, in order to permit development of a clone of T cells with a T-cell receptor specific to a given antigen. The T-cell receptor genes (alpha, beta, delta, and gamma) can be somatically rearranged to produce heterodimeric cell surface T-cell receptors. The somatic TCR-gene rearrangements can result in expansion of diverse clones (polyclonal), or monoclonal expansion of a T-cell population with a single TCR-rearrangement pattern. The TCR clonality can be determined by standard molecular biology techniques such as PCR, Southern blotting, or sequencing of the TCR (e.g. next-generation sequencing).

[0101] The term "soluble" refers to forms of a biological molecule that are in the extracellular space (e.g. serum) and not on the surface of a cell. The term "soluble B-cell maturation antigen," "soluble BCMA (sBCMA)," "soluble CD25," or "soluble IL-2 receptor (sIL-2R)" refer to soluble proteins that are a released form of the proteins and are present in the sera.

[0102] The term "expressed" or "expression" as used herein refers to the transcription from a gene to give an RNA nucleic acid molecule at least complementary in part to a region of one of the two nucleic acid strands of the gene. The term "expressed" or "expression" as used herein also refers to the translation from the RNA molecule to give a protein, a polypeptide, or a portion thereof.

[0103] The term "level" refers to the amount, accumulation, or rate of a biomarker molecule. A level can be represented, for example, by the amount or the rate of synthesis of a messenger RNA (mRNA) encoded by a gene, the amount or the rate of synthesis of a polypeptide or protein encoded by a gene, or the amount or the rate of synthesis of a biological molecule accumulated in a cell or biological fluid. The term "level" refers to an absolute amount of a molecule in a sample or a relative amount of the molecule, determined under steady-state or non-steady-state conditions.

[0104] An mRNA that is "upregulated" is generally increased upon a given treatment or condition. An mRNA that is "downregulated" generally refers to a decrease in the level of expression of the mRNA in response to a given treatment or condition. In some situations, the mRNA level can remain unchanged upon a given treatment or condition. An mRNA from a patient sample can be "upregulated" when treated with a drug, as compared to a non-treated control. This upregulation can be, for example, an increase of about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 200%, about 300%, about 500%, about 1,000%, about 5,000%, or more of the comparative control mRNA level. Alternatively, an mRNA can be "downregulated", or expressed at a lower level, in response to administration of certain compounds or other agents. A downregulated mRNA can be, for example, present at a level of about 99%, about 95%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 10%, about 1%, or less of the comparative control mRNA level.

[0105] Similarly, the level of a polypeptide or protein biomarker from a patient sample can be increased when treated with a drug, as compared to a non-treated control. This increase can be about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 200%, about 300%, about 500%, about 1,000%, about 5,000%, or more of the comparative control protein level. Alternatively, the level of a protein biomarker can be decreased in response to administration of certain compounds or other agents. This decrease can be, for example, present at a level of about 99%, about 95%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 10%, about 1%, or less of the comparative control level of a polypeptide or protein.

[0106] In addition, the level of CTCs from a patient sample can be decreased in response to administration of certain compounds or other agents. This decrease can be, for example, present at a level of about 99%, about 95%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 10%, about 1%, or less of the comparative control level of CTCs.

[0107] The DNA sequence of the TCR, or the TCR clonality, can also be increased when treated with a drug, as compared to a non-treated control. The somatic TCR-gene rearrangements can result in expansion of diverse clones (polyclonal), or monoclonal expansion of a T-cell population with a single TCR-rearrangement pattern. This increase in specific clones can be about 5%, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 200%, about 300%, about 500%, about 1,000%, about 5,000%, or more of the comparative control TCR clonality.

[0108] The terms "determining," "measuring," "evaluating," "assessing," and "assaying" as used herein generally refer to any form of measurement, and include determining whether an element is present or not. These terms include quantitative and / or qualitative determinations. Assessing may be relative or absolute. "Assessing the presence of" can include determining the amount of something present, as well as determining whether it is present or absent.

[0109] The terms "nucleic acid" and "polynucleotide" are used interchangeably herein to describe a polymer of any length composed of nucleotides, e.g., deoxyribonucleotides or ribonucleotides, or compounds produced synthetically, which can hybridize with naturally occurring nucleic acids in a sequence specific manner analogous to that of two naturally occurring nucleic acids, e.g., can participate in Watson-Crick base pairing interactions. As used herein in the context of a polynucleotide sequence, the term "bases" (or "base") is synonymous with "nucleotides" (or "nucleotide"), i.e., the monomer subunit of a polynucleotide. The terms "nucleoside" and "nucleotide" are intended to include those moieties that contain not only the known purine and pyrimidine bases, but also other heterocyclic bases that have been modified. Such modifications include methylated purines or pyrimidines, acylated purines or pyrimidines, alkylated riboses or other heterocycles. In addition, the terms "nucleoside" and "nucleotide" include those moieties that contain not only conventional ribose and deoxyribose sugars, but other sugars as well. Modified nucleosides or nucleotides also include modifications on the sugar moiety, e.g., wherein one or more of the hydroxyl groups are replaced with halogen atoms or aliphatic groups, or are functionalized as ethers, amines, or the like. "Analogues" refer to molecules having structural features that are recognized in the literature as being mimetics, derivatives, having analogous structures, or other like terms, and include, for example, polynucleotides incorporating non-natural nucleotides, nucleotide mimetics such as 2'-modified nucleosides, peptide nucleic acids, oligomeric nucleoside phosphonates, and any polynucleotide that has added substituent groups, such as protecting groups or linking moieties.

[0110] The term "complementary" refers to specific binding between polynucleotides based on the sequences of the polynucleotides. As used herein, a first polynucleotide and a second polynucleotide are complementary if they bind to each other in a hybridization assay under stringent conditions, e.g., if they produce a given or detectable level of signal in a hybridization assay. Portions of polynucleotides are complementary to each other if they follow conventional base-pairing rules, e.g., A pairs with T (or U) and G pairs with C, although small regions (e.g., fewer than about 3 bases) of mismatch, insertion, or deleted sequence may be present.

[0111] "Sequence identity" or "identity" in the context of two nucleic acid sequences refers to the residues in the two sequences that are the same when aligned for maximum correspondence over a specified comparison window, and can take into consideration of additions, deletions, and substitutions.

[0112] The term "substantial identity" or "homologous" in their various grammatical forms in the context of polynucleotides generally means that a polynucleotide comprises a sequence that has a desired identity, for example, at least 60% identity, at least 70% identity, at least 80% identity, at least 90% identity, and at least 95% identity, compared to a reference sequence. Another indication that nucleotide sequences are substantially identical is if two molecules hybridize to each other under stringent conditions.

[0113] The terms "isolated" and "purified" refer to isolation of a substance (such as mRNA, DNA, or protein) such that the substance comprises a substantial portion of the sample in which it resides, i.e., greater than the portion of the substance that is typically found in its natural or un-isolated state. Typically, a substantial portion of the sample comprises, e.g., greater than 1%, greater than 2%, greater than 5%, greater than 10%, greater than 20%, greater than 50%, or more, usually up to about 90%-100% of the sample. For example, a sample of isolated mRNA can typically comprise at least about 1% total mRNA. Techniques for purifying polynucleotides are well known in the art and include, for example, gel electrophoresis, ion-exchange chromatography, affinity chromatography, flow sorting, and sedimentation according to density.

[0114] As used herein, the term "bound" indicates direct or indirect attachment. In the context of chemical structures, "bound" (or "bonded") may refer to the existence of a chemical bond directly joining two moieties or indirectly joining two moieties (e.g., via a linking group or any other intervening portion of the molecule). The chemical bond may be a covalent bond, an ionic bond, a coordination complex, hydrogen bonding, van der Waals interactions, or hydrophobic stacking, or may exhibit characteristics of multiple types of chemical bonds. In certain instances, "bound" includes embodiments where the attachment is direct and embodiments where the attachment is indirect.

[0115] The term "sample" as used herein relates to a material or mixture of materials, typically, although not necessarily, in fluid form, containing one or more components of interest.

[0116] "Biological sample" as used herein refers to a sample obtained from a biological subject, including a sample of biological tissue or fluid origin, obtained, reached, or collected in vivo or in situ. A biological sample also includes samples from a region of a biological subject containing precancerous or cancer cells or tissues. Such samples can be, but are not limited to, organs, tissues, and cells isolated from a mammal. Exemplary biological samples include but are not limited to cell lysate, a cell culture, a cell line, a tissue, oral tissue, gastrointestinal tissue, an organ, an organelle, a biological fluid, a blood sample, a urine sample, a skin sample, and the like. Preferred biological samples include, but are not limited to, whole blood, partially purified blood, PBMC, tissue biopsies, including bone marrow core biopsy, bone marrow aspirate, isolated bone marrow mononuclear cells, circulating tumor cells and the like.

[0117] The term "circulating tumor cell (CTC)" as used herein refers to multiple myeloma cells detected in the peripheral blood that have shed off from the tumor cells in the bone marrow. In some embodiments, CTCs can serve as a biomarker for response and prognosis. In other embodiments, the mutational landscape of CTCs in MM can be a biomarker.

[0118] The term "analyte" as used herein refers to a known or unknown component of a sample.

[0119] The term "capture agent" as used herein refers to an agent that binds an mRNA or protein through an interaction that is sufficient to permit the agent to bind and to concentrate the mRNA or protein from a heterogeneous mixture.

[0120] The term "probe" as used herein refers to a capture agent that is directed to a specific target mRNA biomarker sequence. Accordingly, each probe of a probe set has a respective target mRNA biomarker. A probe / target mRNA duplex is a structure formed by hybridizing a probe to its target mRNA biomarker.

[0121] The term "nucleic acid probe" or "oligonucleotide probe" refers to a nucleic acid capable of binding to a target nucleic acid of complementary sequence, such as the mRNA biomarkers provided herein, usually through complementary base pairing by forming hydrogen bond. As used herein, a probe may include natural (e.g., A, G, C, or T) or modified bases (7-deazaguanosine, inosine, etc.). In addition, the bases in a probe may be joined by a linkage other than a phosphodiester bond, so long as it does not interfere with hybridization. It will be understood by one of skill in the art that probes may bind target sequences lacking complete complementarity with the probe sequence depending upon the stringency of the hybridization conditions. The probes are preferably directly labeled with tags, for example, chromophores, lumiphores, chromogens, or indirectly labeled with biotin to which a streptavidin complex may later bind. By assaying for the presence or absence of the probe, one can detect the presence or absence of a target mRNA biomarker of interest.

[0122] The term "stringent assay conditions" refers to conditions that are compatible to produce binding pairs of nucleic acids, e.g., probes and target mRNAs, of sufficient complementarity to provide for the desired level of specificity in the assay while being generally incompatible to the formation of binding pairs between binding members of insufficient complementarity to provide for the desired specificity. The term "stringent assay conditions" generally refers to the combination of hybridization and wash conditions.

[0123] A "label" or "detectable moiety" in reference to a nucleic acid refers to a composition that, when linked with a nucleic acid, renders the nucleic acid detectable, for example, by spectroscopic, photochemical, biochemical, immunochemical, or chemical means. Exemplary labels include, but are not limited to, radioactive isotopes, magnetic beads, metallic beads, colloidal particles, fluorescent dyes, enzymes, biotin, digoxigenin, haptens, and the like. A "labeled nucleic acid or oligonucleotide probe" is generally one that is bound, either covalently through a linker or a chemical bond, or noncovalently through ionic bonds, van der Waals forces, electrostatic attractions, hydrophobic interactions, or hydrogen bonds, to a label such that the presence of the nucleic acid or probe can be detected by detecting the presence of the label bound to the nucleic acid or probe.

[0124] The term "polymerase chain reaction" or "PCR" as used herein generally refers to a procedure wherein small amounts of a nucleic acid, RNA and / or DNA, are amplified as described, for example, in U.S. Patent No. 4,683,195. Generally, sequence information from the ends or beyond of the region of interest needs to be available, such that oligonucleotide primers can be designed; these primers will be identical or similar in sequence to opposite strands of the template to be amplified. The 5' terminal nucleotides of the two primers may coincide with the ends of the amplified material. PCR can be used to amplify specific RNA sequences, specific DNA sequences from total genomic DNA, and cDNA transcribed from total cellular RNA, bacteriophage, or plasmid sequences, etc. See generally Mullis et al., Cold Spring Harbor Symp. Quant. Biol. 1987, 51:263-273; PCR Technology (Stockton Press, NY, Erlich, ed., 1989).

[0125] The term "cycle number" or "C T " when used herein in reference to PCR methods, refers to the PCR cycle number at which the fluorescence level passes a given set threshold level. The C T measurement can be used, for example, to approximate levels of mRNA in an original sample. The C T measurement is often used in terms of "dC T " or the "difference in the C T " score, when the C T of one nucleic acid is subtracted from the C T of another nucleic acid.

[0126] As used herein, the terms "compound" and "treatment compound" are used interchangeably, and include Compound 1, Compound 2, Compound 3, or an enantiomer, a mixture of enantiomers, tautomer, isotopolog or pharmaceutically acceptable salt thereof.

[0127] "Tautomer" as used herein refers to isomeric forms of a compound that are in equilibrium with each other. The concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution, pyrazoles may exhibit the following isomeric forms, which are referred to as tautomers of each other:

[0128] As used herein and unless otherwise indicated, the term "pharmaceutically acceptable salt" includes, but is not limited to, amine salts, such as but not limited to N,N'-dibenzylethylenediamine, chloroprocaine, choline, ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1'-ylmethyl- benzimidazole, diethylamine and other alkylamines, piperazine and tris(hydroxymethyl)aminomethane; alkali metal salts, such as but not limited to lithium, potassium and sodium; alkali earth metal salts, such as but not limited to barium, calcium and magnesium; transition metal salts, such as but not limited to zinc; and other metal salts, such as but not limited to sodium hydrogen phosphate and disodium phosphate; and also including, but not limited to, salts of mineral acids, such as but not limited to hydrochlorides and sulfates; and salts of organic acids, such as but not limited to acetates, lactates, malates, tartrates, citrates, ascorbates, succinates, butyrates, valerates, fumarates and organic sulfonates.

[0129] Unless specifically stated otherwise, where a compound may assume alternative tautomeric, regioisomeric and / or stereoisomeric forms, all alternative isomers are intended to be encompassed within the scope of the claimed subject matter. For example, where a compound can have one of two tautomeric forms, it is intended that both tautomers be encompassed herein.

[0130] Thus, the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures. As used herein and unless otherwise indicated, the term "stereomerically pure" means a composition that comprises one stereoisomer of a compound and is substantially free of other stereoisomers of that compound. For example, a stereomerically pure composition of a compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure composition of a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. A stereomerically pure compound as used herein comprises greater than about 80% by weight of one stereoisomer of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound, even more preferably greater than about 95% by weight of one stereoisomer of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound. As used herein and unless otherwise indicated, the term "stereomerically enriched" means a composition that comprises greater than about 60% by weight of one stereoisomer of a compound, preferably greater than about 70% by weight, more preferably greater than about 80% by weight of one stereoisomer of a compound. As used herein and unless otherwise indicated, the term "enantiomerically pure" means a stereomerically pure composition of a compound having one chiral center. Similarly, the term "stereomerically enriched" means a stereomerically enriched composition of a compound having one chiral center. As used herein, stereoisomeric or diastereomeric mixtures means a composition that comprises more than one stereoisomer of a compound. A typical stereomeric mixture of a compound comprises about 50% by weight of one stereoisomer of the compound and about 50% by weight of other stereoisomers of the compound, or comprises greater than about 50% by weight of one stereoisomer of the compound and less than about 50% by weight of other stereoisomers of the compound, or comprises greater than about 45% by weight of one stereoisomer of the compound and less than about 55% by weight of the other stereoisomers of the compound, or comprises greater than about 40% by weight of one stereoisomer of the compound and less than about 60% by weight of the other stereoisomers of the compound, or comprises greater than about 35% by weight of one stereoisomer of the compound and less than about 65% by weight of the other stereoisomers of the compound.

[0131] It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to administration of the compound in its (S) form.

[0132] Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as chromatography on a chiral stationary phase.

[0133] In the description herein, if there is any discrepancy between a chemical name and chemical structure, the structure controls.

[0134] It should also be noted compounds can contain unnatural proportions of atomic isotopes at one or more of the atoms. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3< H), iodine-125 ( 125< I), sulfur-35 ( 35< S), or carbon-14 ( 14< C), or may be isotopically enriched, such as with deuterium ( 2< H), carbon-13 ( 13< C), or nitrogen-15 ( 15< N). As used herein, an "isotopolog" or "isotopologue" is an isotopically enriched compound. The term "isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. The term "isotopic composition" refers to the amount of each isotope present for a given atom. Radiolabeled and isotopically enriched compounds are useful as therapeutic agents, e.g., cancer and inflammation therapeutic agents, research reagents, e.g., binding assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds as described herein, whether radioactive or not, are intended to be encompassed within the scope of the embodiments provided herein. In some embodiments, there are provided isotopologs of the compounds, for example, the isotopologs are deuterium, carbon-13, or nitrogen-15 enriched compounds. In some embodiments, isotopologs provided herein are deuterium enriched compounds. In some embodiments, isotopologs provided herein are deuterium enriched compounds, where the deuteration occurs on the chiral center. In some embodiments, provided herein are isotopologs of the compounds of Compound 1, where deuteration occurs on the chiral center. In some embodiments, provided herein are isotopologs of Compound 2, where deuteration occurs on the chiral center. In some embodiments, provided herein are isotopologs of Compound 3, where deuteration occurs on the chiral center.

[0135] It should be noted that if there is a discrepancy between a depicted structure and a name given to that structure, the depicted structure is to be accorded more weight. In addition, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.

[0136] As described herein, the term "second active agent" refers to any additional treatment that is biologically active. It is understood that the second active agent can be a hematopoietic growth factor, cytokine, anti-cancer agent, antibiotic, cox-2 inhibitor, immunomodulatory agent, immunosuppressive agent, corticosteroid, therapeutic antibody that specifically binds to a cancer antigen or a pharmacologically active mutant, or derivative thereof.

[0137] The term "supportive care agent" refers to any substance that treats, prevents or manages an adverse effect from treatment with Compound 1, Compound 2 or Compound 3, or an enantiomer or a mixture of enantiomers, tautomers, isotopolog or a pharmaceutically acceptable salt thereof. It is understood that the term "support care therapy" is refers to any therapeutic agent that is mainly directed to sustaining the strength and / or comfort of the patient. Exemplary support care therapies include, but are not limited to, therapies for pain control, intravenous fluids, and electrolyte support, such as isotonic saline, glucose saline, or balanced crystalloid solutions.

[0138] The term "biological therapy" refers to administration of biological therapeutics such as cord blood, stem cells, growth factors and the like.

[0139] The terms "co-administration" and "in combination with" include the administration of one or more therapeutic agents (for example, a compound provided herein and another anti-multiple myeloma agent, cancer agent or supportive care agent) either simultaneously, concurrently or sequentially with no specific time limits. In one embodiment, the agents are present in the cell or in the patient's body at the same time or exert their biological or therapeutic effect at the same time. In one embodiment, the therapeutic agents are in the same composition or unit dosage form. In another embodiment, the therapeutic agents are in separate compositions or unit dosage forms.

[0140] As used herein, the terms "immunospecifically binds," "immunospecifically recognizes," "specifically binds," and "specifically recognizes" are analogous terms in the context of antibodies and refer to molecules that bind to an antigen / epitope as such binding is understood by one skilled in the art. Antibodies that specifically bind to a target structure, or subunit thereof, do not cross-react with biological molecules that are outside the target structure family. In some embodiments, an antibody or antibody fragment binds to a selected antigen with a specific affinity of greater than 10 -7< M, 10 -8< M, 10 -9< M, 10 -10< M, or 10 -11< M, between 10 -8< M and 10 -11< M, between 10 -9< M and 10 -10< M, or between 10 -10< M and 10 -11< M. For example, a molecule (e.g., an antibody) that specifically binds to an antigen may bind to other peptides or polypeptides, generally with lower affinity as determined by, e.g., immunoassays, or other assays known in the art. In a specific embodiment, molecules that specifically bind to an antigen do not cross react with other proteins.

[0141] As described herein, the term "detectable label" refers to the attachment of a specific tag to an antibody to aid in the detection or isolation / purification of a protein. Examples of types of labels include, but are not limited to, a radioisotope, a fluorophore (e.g., fluorescein isothiocyanate (FITC), phycoerythrin (PE)), chemiluminescence, enzyme reporters, and element particles (e.g., gold particles). Detection can be direct or indirect. Optical methods include microscopy (both confocal and non-confocal), imaging methods and non-imaging methods. Electrochemical methods include voltammetry and amperometry methods. Radio frequency methods include multipolar resonance spectroscopy.

[0142] The term "about" or "approximately" means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0143] The practice of the embodiments provided herein will employ, unless otherwise indicated, conventional techniques of molecular biology, microbiology, and immunology, which are within the skill of those working in the art. Such techniques are explained fully in the literature. Examples of particularly suitable texts for consultation include the following: Sambrook et al., Molecular Cloning: A Laboratory Manual (2d ed. 1989); Glover, ed., DNA Cloning, Volumes I and II (1985); Gait, ed., Oligonucleotide Synthesis (1984); Hames & Higgins, eds., Nucleic Acid Hybridization (1984); Hames & Higgins, eds., Transcription and Translation (1984); Freshney, ed., Animal Cell Culture: Immobilized Cells and Enzymes (IRL Press, 1986); Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); Scopes, Protein Purification: Principles and Practice (Springer Verlag, N.Y., 2d ed. 1987); and Weir & Blackwell, eds., Handbook of Experimental Immunology, Volumes I-IV (1986).5.2 Biomarkers and Methods of Use Thereof

[0144] The methods provided herein are based, in part, on the finding that detectable increase or decrease in certain biomarkers upon compound treatment are observed in subjects with MM, who are responsive to a given treatment, e.g., a compound, such as Compound 1, Compound 2, or Compound 3, or an enantiomer, a mixture of enantiomers, tautomer, isotopolog or pharmaceutically acceptable salt thereof as described in Section 5.7 below, and that the levels of these biomarkers may be used for predicting the responsiveness of the subjects to the treatment. In some embodiments, the levels of biomarkers can be predictive of response to Compound 1, Compound 2, or Compound 3. In some embodiments, the compound is as described herein. In certain embodiments, the compound is Compound 1, Compound 2, or Compound 3. In one embodiment, the compound is Compound 1. In another embodiment, the compound is Compound 2. In yet another embodiment, the compound is Compound 3.

[0145] According to one aspect, the invention is directed to Compound 1, Compound 2 or Compound 3 for use in a method of treating, preventing and / or managing the diseases as provided herein.

[0146] As described in the Examples in Section 6, and shown in the figures, the levels of certain proteins, molecules, mRNAs, or cell composition change in response to treatment with Compound 1, Compound 2, or Compound 3. These biomarkers include CRBN, IKZF1, IKZF3, ZFP91, c-Myc, IRF4, Caspase-1, Caspase-3, Caspase-7, PARP, survivin, Bcl-2 like protein 11 (BIM), serum free light chain (sFLC), p21, p27, pRb1, IL-2, TNFα, IFNγ, tumor infiltrating lymphocytes (TILs), T-cell antigen receptor (TCR) clonality, and circulating tumor cells (CTCs). In addition, the Examples and figures show that the expression of certain proteins change after treatment with Compound 1, Compound 2, or Compound 3, and can serve as biomarkers for predicting response to treatment and / or selecting patients likely to respond to treatment with Compound 1, Compound 2, or Compound 3. These biomarkers include CRBN. The biomarker provided herein is selected from the group consisting of CRBN, IKZF1, IKZF3, ZFP91, c-Myc, IRF4, Caspase-1, Caspase-3, Caspase-7, PARP, survivin, Bcl-2 like protein 11 (BIM), serum free light chain (sFLC), p21, p27, pRb1, IL-2, TNFα, IFNγ, tumor infiltrating lymphocytes (TILs), T-cell antigen receptor (TCR) clonality, and circulating tumor cells (CTCs). Each of the biomarkers provided herein includes various isoforms, phosphorylated forms, cleaved forms, modified forms, and splicing variants thereof. For example, Caspase-3 includes the cleaved form of Caspase-3, Caspase-1 includes cleaved Caspase-1, Caspase-7 includes cleaved Caspase-7, PARP includes cleaved PARP, and pRb1 includes phosphorylated pRb1. Thus, sometimes the levels of the isoforms, phosphorylated forms, cleaved forms, modified forms, and / or splicing variants of these biomarkers increase or decrease in response to the compound treatment, and thus these isoforms, phosphorylated forms, cleaved forms, modified forms, and / or splicing variants of the biomarkers can be used to predict a patient's response.

[0147] IKAROS Family Zinc Finger 1 (IKZF1, also known as Ikaros) and IKAROS Family Zinc Finger 3 (IKZF3, also known as Aiolos) are hematopoietic-specific transcription factors involved in the regulation of lymphocyte development. The expression of IKZF1 and IKZF3 are restricted to the fetal and adult hemo-lymphopoietic system, and function as regulators of lymphocyte differentiation. Regulation of gene expression involves Ikaros homodimers, Ikaros / Aiolos heterodimers, and Aiolos homodimers. Multiple isoforms of human Ikaros and Aiolos have been found in both normal and leukaemic B cells. Non-DNA-binding isoforms are largely found in the cytoplasm, and are thought to function as dominant-negative factors. Overexpression of some dominant-negative isoforms has been associated with B-cell malignancies, such as acute lymphoblastic leukemia (ALL).

[0148] Caspase-1, -3, and -7 are members of the caspase family. Caspase-3 cleaves and activates Caspase-7, as well as Caspase-6, and -9. Cleavage of Caspase 7 occurs upon cell death stimuli and induces apoptosis. Caspase-3 itself is processed by Caspase-8, -9, and -10. The effector caspases, Caspase-3, -6, and -7 proteolytically degrade a host of intracellular proteins to carry out cell apoptosis. Caspase-3 has virtually no activity until it is cleaved by an initiator caspase after apoptotic signaling events have occurred. Similarly, Pro-Caspase-1 is converted to an active Caspase-1 upon cleavage, and Caspase-1 is also involved in some forms of apoptosis. In addition, poly(ADP-ribose) polymerase (PARP) can be cleaved by caspases. For example, PARP is known to be cleaved by Caspase-3 during apoptosis. PARP is a family of proteins involved in regulating various important cellular processes such as differentiation, proliferation, and tumor transformation. PARP also regulates the molecular events involved in cell recovery from DNA damage. Caspase activation can be inhibited by survivin, thereby preventing apoptosis. Another protein involved in promoting apoptosis is Bcl-2 like protein 11 (BIM). Apoptosis can also be promoted by serum free light chain (sFLC). Thus, in some embodiments cleaved-Caspase-1 (c-Caspase-1), cleaved-Caspase-3 (c-Caspase-3), cleaved-Caspase-7 (c-Caspase-7), cleaved PARP, survivin, BIM, and serum free light chain (sFLC) are biomarkers that are indicative of apoptosis.

[0149] In certain embodiments of the various methods provided herein, the biomarker is a protein that is directly or indirectly affected by cereblon (CRBN), for example through protein-protein interactions (e.g., certain CRBN substrates or downstream effectors thereof), or through various cellular pathways (e.g., signal transduction pathways). In specific embodiments, the biomarker is a CRBN-associated protein (CAP). In some embodiments, the biomarker is mRNA of a protein that is directly or indirectly affected by CRBN. In other embodiments, the biomarker is cDNA of a protein that is directly or indirectly affected by CRBN. At least two isoforms of the protein CRBN exist, which are 442 and 441 amino acids long, respectively.

[0150] As described in the Examples, treatment with Compounds 1-3 decrease the levels of Aiolos, Ikaros, ZFP91, c-Myc, and IRF4 (e.g., FIG. 4). Therefore, detecting the level of CRBN-associated proteins can be instrumental in monitoring the efficacy, predicting response, identifying a subject having cancer who is likely to be responsive, treating cancer, identifying a subject having multiple myeloma who is likely to be response to a treatment compound, and determining or adjusting a dose for treating a subject having multiple myeloma with a treatment compound. Therefore, in some embodiments, the biomarker is a CRBN-associated protein and the treatment compound is Compound 1. In other embodiments, the biomarker is a CRBN-associated protein and the treatment compound is Compound 2. In still other embodiments, in some embodiments, the biomarker is a CRBN-associated protein and the treatment compound is Compound 3. In certain embodiments, the biomarker is a CRBN-associated protein selected from the group consisting of Aiolos, Ikaros, ZFP91, c-Myc, and IRF4. In certain specific embodiments, the biomarker is a CRBN-associated protein selected from the group consisting of Aiolos, Ikaros, ZFP91, c-Myc, and IRF4, and the treatment compound is Compound 1. In certain specific embodiments, the biomarker is a CRBN-associated protein selected from the group consisting of Aiolos, Ikaros, ZFP91, c-Myc, and IRF4, and the treatment compound is Compound 2. In certain specific embodiments, the biomarker is a CRBN-associated protein selected from the group consisting of Aiolos, Ikaros, ZFP91, c-Myc, and IRF4, and the treatment compound is Compound 3.

[0151] In some embodiments, the biomarker is an IKAROS Family member zinc-finger transcription factor, such as IKZF1 or IKZF3. In a specific embodiment, the biomarker is IKZF1 and the treatment compound is Compound 1. In another specific embodiment, the biomarker is IKZF1 and the treatment compound is Compound 2. In another specific embodiment, the biomarker is IKZF1 and the treatment compound is Compound 3. In a specific embodiment, the biomarker is IKZF3 and the treatment compound is Compound 1. In another specific embodiment, the biomarker is IKZF3 and the treatment compound is Compound 2. In another specific embodiment, the biomarker is IKZF3 and the treatment compound is Compound 3. In a specific embodiment, the biomarker is ZFP91 and the treatment compound is Compound 1. In another specific embodiment, the biomarker is I ZFP91 and the treatment compound is Compound 2. In another specific embodiment, the biomarker is ZFP91 and the treatment compound is Compound 3. In yet another specific embodiment, the biomarker is c-Myc and the treatment compound is Compound 1. In another specific embodiment, the biomarker is c-Myc and the treatment compound is Compound 2. In another specific embodiment, the biomarker is c-Myc and the treatment compound is Compound 3. In another specific embodiment, the biomarker is IRF4 and the treatment compound is Compound 1. In another specific embodiment, the biomarker is IRF4 and the treatment compound is Compound 2. In another specific embodiment, the biomarker is IRF4 and the treatment compound is Compound 3. In other embodiments, the biomarker is a binding partner of, downstream effector thereof, or a factor in a cellular pathway affected by IKZF1, IKZF3, ZFP91, c-Myc, or IRF4.

[0152] As described in the Examples, the levels of the proteins in the apoptosis pathway, such as Caspase-1, Caspase-3, Caspase-7, PARP, survivin, BIM, and sFLC change with treatment Compounds 1-3. For example, treatment with Compounds 1-3 can increase the levels of c-Caspase-3, c-Caspase-1, c-Caspase-7, cleaved-PARP, BIM, and sFLC in multiple myeloma cells, thereby indicating apoptosis. Treatment with Compounds 1-3 can also decrease the levels of survivin, thereby indicating apoptosis. Detecting apoptosis can be instrumental in monitoring the efficacy, predicting response, identifying a subject having cancer who is likely to be responsive, treating cancer, identifying a subject having multiple myeloma who is likely to be response to a treatment compound, and determining or adjusting a dose for treating a subject having multiple myeloma with a treatment compound. Therefore, disclosed is a biomarker having a function in an apoptosis pathway.

[0153] The biomarker having a function in an apoptosis pathway may be selected from the group consisting of cleaved caspase 1 (c-caspase 1), cleaved caspase 3 (c-caspase 3), cleaved caspase 7 (c-caspase 7), cleaved PARP, survivin, BIM BCL-2 like protein 11 (BIM), and serum free light chain. The levels of serum free light chain (sFLC), and CTCs may change with treatment Compounds 1-3. For example, treatment with Compounds 1-3 can decrease the amount of sFLC detected in the blood or serum / plasma. Similarly, treatment with Compounds 1-3 can decrease the amount of CTCs that are detected in the peripheral blood. Treatment with Compounds 1-3 can also decrease the amount of soluble BCMA (sBCMA) that are detected in the serum from multiple myeloma patients.

[0154] Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) is a method for detecting DNA fragmentation by labeling the 3'- hydroxyl termini in the double-strand DNA breaks generated during apoptosis. It is a common method known in the art (Darzynkiewicz et al., Methods, 2008, 44(3): 250-254). Thus, sometimes the biomarker is the detection of apoptosis by TUNEL and the treatment compound is Compound 1. Sometimes the biomarker is the detection of apoptosis by TUNEL and the treatment compound is Compound 2. Sometimes the biomarker is the detection of apoptosis by TUNEL and the treatment compound is Compound 3.

[0155] Apoptosis can also be measured by Annexin-V and 7-AAD or Annexin-V and propidium iodide (PI). Annexin V (or Annexin A5) is a member of the annexin family of intracellular proteins that binds to phosphatidylserine (PS) in a calcium-dependent manner. PS is normally only found on the intracellular leaflet of the plasma membrane in healthy cells, but during early apoptosis, membrane asymmetry is lost and PS translocates to the external leaflet. Fluorochrome-labeled Annexin V can then be used to specifically target and identify apoptotic cells. Annexin V binding alone cannot differentiate between apoptotic and necrotic cells. To help distinguish between the necrotic and apoptotic cells 7-amino-actinomycin D (7-AAD) or PI solution can be used. Early apoptotic cells will exclude 7-AAD and PI, while late stage apoptotic cells and necrotic cells will stain positively, due to the passage of these dyes into the nucleus where they bind to DNA.

[0156] Detecting modulation of the immune response can be instrumental in monitoring the efficacy, predicting response, identifying a subject having cancer who is likely to be responsive, treating cancer, identifying a subject having multiple myeloma who is likely to be responsive to a treatment compound, and determining or adjusting a dose for treating a subject having multiple myeloma with a treatment compound. For example, the Examples in Section 6 below describe enhanced T-cell mediated tumor cell lysis in a co-culture model (Example 11), activation of effector T cells (Example 12), the activation and proliferation of T-cells (Example 16) with treatment Compounds 1-3. Therefore, sometimes T-cell activation can be a biomarker for treatment with Compound 1. sometimes T-cell activation can be a biomarker for treatment with Compound 2. sometimes T-cell activation can be a biomarker for treatment with Compound 3.

[0157] It is disclosed herein that T-cell activation can be a biomarker for treatment with a treatment compound, and the biomarker is selected from the group consisting of interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and T-cell receptor (TCR) clonality.

[0158] Further, the release of cytokines is centrally important to many aspects of T cell function. For example, IL-2 is a potent T cell growth factor that is essential for the long-term proliferation of activated T cells. Secretion of other cytokines, such as TNFα and IFNγ, can facilitate the effector T-cell function in killing tumor cells. Therefore, detecting cytokines can indicate T-cell activation.

[0159] Circulating tumor cells (CTCs) are prognostic in multiple myeloma and characterization of CTCs, including identifying relevant mutations, from peripheral blood can indicate disease burden, and may predict response to treatment (Mishima et al., Cell Rep., 2017, 19(1):218-224; Lohr et al., Sci Transl Med., 2016, ;8(363):363ra147). Therefore, sometimes CTCs in the peripheral blood can be a biomarker and the treatment compound is Compound 1, Compound 2, or Compound 3. The mutational profile of CTCs can also be a biomarker for predicting response to treatment with Compound 1, Compound 2, or Compound 3.

[0160] Inhibiting the progression of the cell cycle in a cancer cell can be an effective means of preventing the progression of a cancer. As described in Example 6, Compound 2 can induce G1 cell cycle arrest and apoptosis in multiple myeloma cells. Detecting members of the cell cycle pathway can be instrumental in monitoring the efficacy, predicting response, identifying a subject having cancer who is likely to be responsive, treating cancer, identifying a subject having multiple myeloma who is likely to be response to a treatment compound, and determining or adjusting a dose for treating a subject having multiple myeloma with a treatment compound. Therefore, the biomarker may have a function in a cell cycle pathway.

[0161] The biomarker having a function in a cell cycle pathway, may be selected from the group consisting of cyclin-dependent kinase inhibitor 1 (p21), cyclin-dependent kinase inhibitor 1B (p27), and retinoblastoma protein (pRb1).

[0162] As described in the Examples in Section 6, the treatment compounds can inhibit proliferation of multiple myeloma cells with acquired resistance to cereblon modulators, such as lenalidomide and pomalidomide, even if the cells have reduced, but detectable, levels of CRBN (Example 8). Therefore, in some embodiments, reduced levels of CRBN is a biomarker for diagnosing the subject as being likely to be responsive to the treatment compound and the treatment compound is Compound 1. In other embodiments, reduced levels of CRBN is a biomarker for diagnosing the subject as being likely to be responsive to the treatment compound and the treatment compound is Compound 2. In yet another embodiment, reduced levels of CRBN is a biomarker for diagnosing the subject as being likely to be responsive to the treatment compound and the treatment compound is Compound 3. In some embodiments of the methods of predicting the responsiveness of a subject having multiple myeloma to a treatment compound the methods comprise diagnosing the subject as being likely to be responsive to the treatment compound if the biomarker in the sample is detectable. In some specific embodiments, the MM is relapsed, refractory, or resistant to conventional therapy. In one embodiment, the MM is lenalidomide-resistant MM. In another embodiment, the MM is pomalidomide-resistant MM.

[0163] Biomarkers can also be useful for determining or adjusting dosage for treating a subject having multiple myeloma with a treatment compound. For example, detecting an increase in a biomarker, such as IKZF1, after treatment with a treatment compound can indicate that a subject requires more frequent dosing, or treatment for an extended period. Therefore, in some embodiments, the biomarker is for determining dosage for treating a subject having multiple myeloma with a treatment compound and is selected from the group consisting of IKZF1 and IKZF3. In specific embodiments, the biomarker is selected from the group consisting of IKZF1 and IKZF3, and the treatment compound is Compound 1. In another specific embodiment, the biomarker is selected from the group consisting of IKZF1 and IKZF3, and the treatment compound is Compound 2. In yet another specific embodiment, the biomarker is selected from the group consisting of IKZF1 and IKZF3, and the treatment compound is Compound 3. In certain embodiments, the biomarker is IKZF1 and the treatment compound is Compound 1. In certain embodiments, the biomarker is IKZF1 and the treatment compound is Compound 2. In certain embodiments, the biomarker is IKZF1 and the treatment compound is Compound 3. In some embodiments, the biomarker is IKZF3 and the treatment compound is Compound 1. In other embodiments, the biomarker is IKZF3 and the treatment compound is Compound 2. In still other embodiments, the biomarker is IKZF3 and the treatment compound is Compound 3.

[0164] In some embodiments, the biomarker measured comprises one biomarker. In some embodiments, the biomarker measured comprises one or more biomarker. In certain embodiments, the biomarkers measured comprise two biomarkers. In some embodiments, the biomarker measured comprises two or more biomarker. In other embodiments, the biomarkers measured comprise three biomarkers. In some embodiments, the biomarker measured comprises three or more biomarker. In certain embodiments, the biomarkers measured comprise four biomarkers. In some embodiments, the biomarker measured comprises four or more biomarker. In some embodiments, the biomarkers measured comprise five biomarkers. In some embodiments, the biomarker measured comprises five or more biomarker. In other embodiments, the biomarkers measured comprise six biomarkers. In some embodiments, the biomarker measured comprises six or more biomarker. In yet other embodiments, the biomarkers measured comprise seven biomarkers. In some embodiments, the biomarker measured comprises seven or more biomarker. In certain embodiments, the biomarkers measured comprise eight biomarkers. In some embodiments, the biomarker measured comprises eight or more biomarker. In other embodiments, the biomarkers measured comprise nine biomarkers. In some embodiments, the biomarker measured comprises nine or more biomarker. In another embodiment, the biomarkers measured comprise ten or more biomarkers.

[0165] Also provided herein are methods for the management of cancer using a biomarker, e.g., Aiolos, Ikaros, CRBN, ZFP91, c-MYC, IRF4, as a predictive or prognostic factor for the compounds provided herein. In certain embodiments, provided herein are methods for screening or identifying multiple myeloma patients for treatment with a compound using the level of one or more biomarkers provided herein, wherein one biomarker is Aiolos, Ikaros, CRBN, ZFP91, c-MYC, IRF4, and a further biomarker is c-Caspase 1, c-Caspase-3, c-Caspase 7, cleaved-PARP, survivin, BIM, sFLC, p21, p27, pRB1, soluble BCMA, CTCs, TILs, IL-2, IFNγ, TNFα, or TCR clonality, as a predictive or prognostic factor. In some embodiments, provided herein are methods for selecting patients having a higher response rate to therapy with a compound provided herein, using a biomarker (e.g., Aiolos, Ikaros, CRBN, ZFP91, c-MYC) level as a predictive or prognostic factor. In certain embodiments, the treatment compound is Compound 1, Compound 2, or Compound 3. In one embodiment, the treatment compound is Compound 1. In another embodiment, the compound is Compound 2. In another embodiment, the treatment compound is Compound 3.

[0166] In one aspect, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) determining the level of a biomarker in a sample, obtained from a subject to whom the treatment compound has been administered and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0167] In another aspect, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (e) (a) determining the level of a biomarker in a sample, obtained from a subject to whom the treatment compound has been administered and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP391, c-MYC, or IRF4.

[0168] In another aspect, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (e) (a) determining the level of a biomarker in a sample, obtained from a subject to whom the treatment compound has been administered and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP391, c-MYC, or IRF4.

[0169] In another aspect of the invention the method of identifying a subject having cancer who is likely to be responsive to a treatment compound, which has been administered to the subject, comprising: (a) determining the level of a biomarker in a sample obtained from the subject; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 1, Compound 2 or Compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0170] In another aspect, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) administering the treatment compound to a sample from the subject; (b) determining the level of a biomarker in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0171] In another aspect, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) administering the treatment compound to a sample from the subject, (b) determining the level of a biomarker in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0172] In another aspect, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: administering the treatment compound to a sample from the subject, determining the level of a biomarker in the sample; and diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0173] In another aspect, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) administering the treatment compound to a sample obtained from the subject; (c) determining the level of a biomarker in the sample; and (d) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 1, Compound 2 or Compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZf3, ZFP91, c-MYC, or IRF4.

[0174] Thus, in some embodiments, provided herein is a treatment compound for use in a method of treating cancer, comprising: (a) determining the level of a biomarker a the sample from a subject having cancer; (b) (e) diagnosing the subject as being likely to be responsive to a treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; and (d) administering a therapeutically effective amount of the treatment compound to the subject; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0175] In some embodiments, provided herein is treatment compound for use in a method of treating cancer, comprising: (a) determining the level of a biomarker in a sample; from a subject having cancer; (b) diagnosing the subject as being likely to be responsive to a treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; and (d) administering a therapeutically effective amount of the treatment compound to the subject; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0176] In some embodiments, provided herein is a treatment compound for use in a method of treating cancer, comprising: (a) determining the level of a biomarker in a sample from a subject having cancer; (b) diagnosing the subject as being likely to be responsive to a treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; and (d) administering a therapeutically effective amount of the treatment compound to the subject; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0177] In some embodiments, provided herein is Compound 1, Compound 2 or Compound 3 or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof for use in a method of treating cancer, comprising: (a) obtaining a sample from a subject having the cancer; (b) determining the level of a biomarker in the sample; (c) diagnosing the subject as being likely to be responsive to a treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; and (d) administering a therapeutically effective amount of the treatment compound to the subject, wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0178] In other embodiments, provided herein is the treatment compound for use in methods for selectively treating a patient selected using the methods provided herein.

[0179] One embodiment of the above methods comprises treating the multiple myeloma patient that is selected based on the biomarkers described herein, comprising administering to a patient Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0180] Another embodiment of the above methods further comprises a method of treating the multiple myeloma patient that is selected based on the level of the biomarkers described herein, comprising administering to a patient Compound 2, or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0181] In yet another embodiment of the above methods further comprises a method of treating the multiple myeloma patient that is selected based on the level of the biomarkers described herein, comprising administering to a patient Compound 3, or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0182] Further disclosed is method of preventing multiple myeloma in a patient selected based on the level of the biomarkers described herein, which comprises administering to a patient a compound provided herein, e.g., Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0183] Further disclosed is a method of managing multiple myeloma based on the level of the biomarkers described herein, which comprises administering to a patient a compound provided herein, e.g., Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0184] One embodiment of the compound for use provided herein, further comprises methods for inducing a therapeutic response assessed with the International Uniform Response Criteria for Multiple Myeloma (IURC) (see Durie BG, et al., Leukemia, 2006, 20(9):1467-73) of a patient based on the level of the biomarkers described herein, comprising administering an effective amount of a compound described herein, e.g., Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, to a patient having multiple myeloma. Another embodiment, comprises methods for achieving a stringent complete response, complete response, or very good partial response, as determined by the International Uniform Response Criteria for Multiple Myeloma (IURC) in a patient, comprising administering an effective amount of a compound described herein, e.g., Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, to patient having multiple myeloma. Another embodiment comprises are methods for achieving an increase in overall survival, progression-free survival, event-free survival, time to progression, or disease-free survival in a patient, comprising administering an effective amount of a compound described herein, e.g., Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, to patient having multiple myeloma. Another embodiment, comprises methods for achieving an increase in overall survival in a patient, comprising administering an effective amount of a compound described herein, e.g., Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, to patient having multiple myeloma. Another embodiment comprises methods for achieving an increase in progression-free survival in a patient, comprising administering an effective amount of a compound described herein, e.g., Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, to patient having multiple myeloma. Another embodiment comprises methods for achieving an increase in event-free survival in a patient, comprising administering an effective amount of a compound described herein, e.g., Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, to patient having multiple myeloma. Another embodiment comprises methods for achieving an increase in time to progression in a patient, comprising administering an effective amount of a compound described herein, e.g., Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, to patient having multiple myeloma. Another embodiment comprises methods for achieving an increase in disease-free survival in a patient, comprising administering an effective amount of a compound described herein, e.g., Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, to patient having multiple myeloma.

[0185] Another embodiment of the compounds for use comprises treating patients who have been previously treated for multiple myeloma but are non-responsive to standard therapies, as well as those who have not previously been treated. Another embodiment comprises treating patients who have undergone surgery in an attempt to treat multiple myeloma, as well as those who have not. Another embodiment comprises treating patients who have been previously undergone transplant therapy, as well as those who have not.

[0186] Some embodiments of the compounds for use provided herein further comprise treatment of multiple myeloma that is relapsed, refractory or resistant. The methods disclosed herein include prevention of multiple myeloma that is relapsed, refractory or resistant. The methods within the context of the compounds for use include management of multiple myeloma that is relapsed, refractory or resistant. In some such embodiments, the myeloma is primary, secondary, tertiary, quadruply or quintuply relapsed multiple myeloma. In one embodiment, the methods reduce, maintain or eliminate minimal residual disease (MRD). In one embodiment, methods encompass treating, preventing or managing various types of multiple myeloma, such as monoclonal gammopathy of undetermined significance (MGUS), low risk, intermediate risk, and high risk multiple myeloma, newly diagnosed multiple myeloma (including low risk, intermediate risk, and high risk newly diagnosed multiple myeloma), transplant eligible and transplant ineligible multiple myeloma, smoldering (indolent) multiple myeloma (including low risk, intermediate risk, and high risk smouldering multiple myeloma), active multiple myeloma, solitary plasmacytoma, extramedullary plasmacytoma, plasma cell leukemia, central nervous system multiple myeloma, light chain myeloma, non-secretory myeloma, Immunoglobulin D myeloma, and Immunoglobulin E myeloma, by administering a therapeutically effective amount of a compound described herein. In another embodiment, the methods encompass treating, preventing or managing multiple myeloma characterized by genetic abnormalities, such as Cyclin D translocations (for example, t(411;14)(q13;q32); t(6;14)(p21;32); t(12;14)(p13;q32); or t(6;20)); MMSET translocations (for example, t(4;14)(p16;q32)); MAF translocations (for example, t(14;16)(q32;q32); t(20;22); t(16; 22)(q11;q13); or t(14;20)(q32;q11)); or other chromosome factors (for example, deletion of 17p13, or chromosome 13; del(17 / 17p), nonhyperdiploidy, and gain(1q)), by administering a therapeutically effective amount of a compound described herein. In one embodiment, the methods comprise administering a therapeutically effective amount of Compound 1, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof. In another embodiment, the methods comprise administering a therapeutically effective amount of Compound 2, or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof. In another embodiment, the methods comprise administering a therapeutically effective amount of Compound 3, or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0187] In one embodiment, the high risk multiple myeloma is multiple myeloma that is relapsed within 12 months of first treatment. In yet another embodiment, the high risk multiple myeloma is multiple myeloma that is characterized by genetic abnormalities, for example, one or more of del(17 / 17p and t(14;16)(q32;q32).

[0188] In some such embodiments, the multiple myeloma is transplant eligible newly diagnosed multiple myeloma. In another embodiment, the multiple myeloma is transplant ineligible newly diagnosed multiple myeloma. In yet other embodiments, the multiple myeloma is characterized by early progression (for example less than 12 months) following initial treatment. In still other embodiments, the multiple myeloma is characterized by early progression (for example less than 12 months) following autologous stem cell transplant. In another embodiment, the multiple myeloma is refractory to pomalidomide. In some such embodiments, the multiple myeloma is predicted to be refractory to pomalidomide (for example, by molecular characterization). In another embodiment, the multiple myeloma is relapsed or refractory to 3 or more treatments and was exposed to a proteasome inhibitor (for example, bortezomib, carfilzomib, ixazomib, oprozomib, or marizomib) and an immunomodulatory compound (for example thalidomide, lenalidomide, and pomalidomide), or double refractory to a proteasome inhibitor and an immunomodulatory compound. In still other embodiments, the multiple myeloma is relapsed or refractory to 3 or more prior therapies, including for example, a CD38 monoclonal antibody (CD38 mAb, for example, daratumumab or isatuximab), a proteasome inhibitor (for example, bortezomib, carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound (for example thalidomide, lenalidomide, and pomalidomide) or double refractory to a proteasome inhibitor or immunomodulatory compound and a CD38 mAb. In still other embodiments, the multiple myeloma is triple refractory, for example, the multiple myeloma is refractory to a proteasome inhibitor (for example, bortezomib, carfilzomib, ixazomib, oprozomib or marizomib), an immunomodulatory compound (for example thalidomide, lenalidomide, and pomalidomide), and one other active agent, as described herein.

[0189] Certain embodiments of the compounds for use provided herein further comprise methods of treating, preventing, and / or managing multiple myeloma, including relapsed / refractory multiple myeloma in patients with impaired renal function or a symptom thereof, comprising administering a therapeutically effective amount of Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof to a patient having relapsed / refractory multiple myeloma with impaired renal function.

[0190] Certain embodiments of the compounds for use herein further comprise methods of treating, preventing, and / or managing multiple myeloma, including relapsed or refractory multiple myeloma in frail patients or a symptom thereof, comprising administering a therapeutically effective amount of Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof to a frail patient having multiple myeloma. In some such embodiments, the frail patient is characterized by ineligibility for induction therapy, or intolerance to dexamethasone treatment. In some such embodiment the frail patient is elderly, for example, older than 65 years old.

[0191] In certain embodiments, a therapeutically or prophylactically effective amount of the compound is from about from about 0.01 to about 25 mg per day, from about 0.01 to about 10 mg per day, from about 0.01 to about 5 mg per day, from about 0.01 to about 2 mg per day, from about 0.01 to about 1 mg per day, from about 0.01 to about 0.5 mg per day, from about 0.01 to about 0.25 mg per day, from about 0.1 to about 25 mg per day, from about 0.1 to about 10 mg per day, from about 0.1 to about 5 mg per day, from about 0.1 to about 2 mg per day, from about 0.1 to about 1 mg per day, from about 0.1 to about 0.5 mg per day, from about 0.1 to about 0.25 mg per day, from about 0.5 to about 25 mg per day, from about 0.5 to about 10 mg per day, from about 0.5 to about 5 mg per day, from about 0.5 to about 2 mg per day, from about 0.5 to about 1 mg per day, from about 1 to about 25 mg per day, from about 1 to about 10 mg per day, from about 1 to about 5 mg per day, from about 1 to about 2.5 mg per day, or from about 1 to about 2 mg per day. In one embodiment, a therapeutically or prophylactically effective amount of Compound 1, Compound 2 or Compound 3 is from about 0.1 mg per day to about 0.4 mg per day.

[0192] In certain embodiments, the therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, or about 25 mg per day. In some such embodiments, the therapeutically or prophylactically effective amount is about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6 or about 0.7 mg per day.

[0193] In one embodiment, the recommended daily dose range of Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, for the conditions described herein lie within the range of from about 0.1 mg to about 25 mg per day, preferably given as a single once-a-day dose, or in divided doses throughout a day. In other embodiments, the dosage ranges from about 0.1 to about 10 mg per day. Specific doses per day include 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mg per day. More specific doses per day include 0.1, 0.2, 0.3, 0.4, or 0.5 mg per day.

[0194] In a specific embodiment, the recommended starting dosage may be 0.1, 0.2, 0.3, 0.4, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, or 25 mg per day. In another embodiment, the recommended starting dosage may be 0.1, 0.2, 0.3, 0.4, or 0.5, mg per day. The dose may be escalated to 1, 2, 3, 4, or 5 mg per day.

[0195] In certain embodiments, the therapeutically or prophylactically effective amount is from about 0.001 to about 5 mg / kg / day, from about 0.001 to about 4 mg / kg / day, from about 0.001 to about 3 mg / kg / day, from about 0.001 to about 2 mg / kg / day, from about 0.001 to about 1 mg / kg / day, from about 0.001 to about 0.05 mg / kg / day, from about 0.001 to about 0.04 mg / kg / day, from about 0.001 to about 0.03 mg / kg / day, from about 0.001 to about 0.02 mg / kg / day, from about 0.001 to about 0.01 mg / kg / day, or from about 0.001 to about 0.005 mg / kg / day.

[0196] The administered dose can also be expressed in units other than mg / kg / day. For example, doses for parenteral administration can be expressed as mg / m 2< / day. One of ordinary skill in the art would readily know how to convert doses from mg / kg / day to mg / m 2< / day given either the height or weight of a subject or both (see, www.fda.gov / cder / cancer / animalframe.htm). For example, a dose of 1 mg / kg / day for a 65 kg human is approximately equal to 38 mg / m 2< / day.

[0197] In certain embodiments, the patient to be treated with one of the methods provided herein has not been treated with multiple myeloma therapy prior to the administration of Compound 1, Compound 2 or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof. In certain embodiments, the patient to be treated with one of the methods provided herein has been treated with multiple myeloma therapy prior to the administration of Compound 1, Compound 2 or Compound 3 provided herein or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof. In certain embodiments, the patient to be treated with one of the methods provided herein has developed drug resistance to the anti-multiple myeloma therapy. In some such embodiments, the patient has developed resistance to one, two, or three anti-multiple myeloma therapies, wherein the therapies are selected from a CD38 monoclonal antibody (CD38 mAb, for example, daratumumab or isatuximab), a proteasome inhibitor (for example, bortezomib, carfilzomib, ixazomib, or marizomib), and an immunomodulatory compound (for example thalidomide, lenalidomide, and pomalidomide).

[0198] The compounds for use herein encompass treating a patient regardless of patient's age. In some embodiments, the subject is 18 years or older. In other embodiments, the subject is more than 18, 25, 35, 40, 45, 50, 55, 60, 65, or 70 years old. In other embodiments, the subject is less than 65 years old. In other embodiments, the subject is more than 65 years old. In one embodiment, the subject is an elderly multiple myeloma subject, such as a subject older than 65 years old. In one embodiment, the subject is an elderly multiple myeloma subject, such as a subject older than 75 years old.

[0199] Depending on the state of the disease to be treated and the subject's condition, Compound 1 or compound 2 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or local) routes of administration. Compound 1, Compound 2 or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, may be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles, appropriate for each route of administration.

[0200] In one embodiment, Compound 1, Compound 2 or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, is administered orally. In another embodiment, the compound of Compound 1, Compound 2 or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, is administered parenterally. In yet another embodiment, the compound of Compound 1, Compound 2 or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, is administered intravenously.

[0201] Compound 1, Compound 2 or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time, such as, e.g., continuous infusion over time or divided bolus doses over time. The compounds as described herein can be administered repeatedly if necessary, for example, until the patient experiences stable disease or regression, or until the patient experiences disease progression or unacceptable toxicity. Stable disease or lack thereof is determined by methods known in the art such as evaluation of patient symptoms, physical examination, visualization of the tumor that has been imaged using X-ray, CAT, PET, or MRI scan and other commonly accepted evaluation modalities.

[0202] Compound 1, Compound 2 or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, can be administered once daily (QD), or divided into multiple daily doses such as twice daily (BID), three times daily (TID), and four times daily (QID). In addition, the administration can be continuous (i.e., daily for consecutive days or every day), intermittent, e.g., in cycles (i.e., including days, weeks, or months of rest without drug). As used herein, the term "daily" is intended to mean that a therapeutic compound, such as Compound 1, Compound 2 or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, is administered once or more than once each day, for example, for a period of time. The term "continuous" is intended to mean that a therapeutic compound, such as Compound 1, Compound 2 or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, is administered daily for an uninterrupted period of at least 7 days to 52 weeks. The term "intermittent" or "intermittently" as used herein is intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of Compound 1, Compound 2 or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, is administration for one to six days per week, administration in cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days. The term "cycling" as used herein is intended to mean that a therapeutic compound, such as Compound 1, Compound 2 or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, is administered daily or continuously but with a rest period. In some such embodiments, administration is once a day for two to six days, then a rest period with no administration for five to seven days.

[0203] In some embodiments, the frequency of administration is in the range of about a daily dose to about a monthly dose. In certain embodiments, administration is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks. In one embodiment, Compound 1, Compound 2 or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, is administered once a day. In another embodiment, Compound 1, Compound 2 or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, is administered twice a day. In yet another embodiment, Compound 1, Compound 2 or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, is administered three times a day. In still another embodiment, Compound 1, Compound 2 or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, is administered four times a day.

[0204] In one embodiment, a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 is administered in a treatment cycle which includes an administration period of up to 20 days followed by a rest period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 is administered in a treatment cycle which includes an administration period of up to 15 days followed by a rest period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 is administered in a treatment cycle which includes an administration period of up to 10 days followed by a rest period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 is administered in a treatment cycle which includes an administration period of up to 7 days followed by a rest period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 is administered in a treatment cycle which includes an administration period of up to 5 days followed by a rest period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 is administered in a treatment cycle which includes an administration period of up to 4 days followed by a rest period. In one embodiment, a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 is administered in a treatment cycle which includes an administration period of up to 3 days followed by a rest period.

[0205] In one embodiment, the treatment cycle includes an administration period of up to 14 days followed by a rest period. In one embodiment, the treatment cycle includes an administration period of up to 10 days followed by a rest period. In one embodiment, the treatment cycle includes an administration period of up to 7 days followed by a rest period. In one embodiment, the treatment cycle includes an administration period of up to 5 days followed by a rest period. In one embodiment, the treatment cycle includes an administration period of up to 4 days followed by a rest period. In one embodiment, the treatment cycle includes an administration period of up to 3 days followed by a rest period.

[0206] In one embodiment, the rest period is from about 2 days up to about 11 days. In one embodiment, the rest period is from about 2 days up to about 10 days. In one embodiment, the rest period is about 2 days. In one embodiment, the rest period is about 3 days. In one embodiment, the rest period is about 4 days. In one embodiment, the rest period is about 5 days. In one embodiment, the rest period is about 6 days. In another embodiment, the rest period is about 7 days. In another embodiment, the rest period is about 8 days. In another embodiment, the rest period is about 9 days. In another embodiment, the rest period is about 10 days. In another embodiment, the rest period is about 11 days.

[0207] In one embodiment, the treatment cycle includes an administration period of up to 15 days followed by a rest period from about 2 days up to about 10 days. In one embodiment, the treatment cycle includes an administration period of up to 10 days followed by a rest period from about 2 days up to about 10 days. In one embodiment, the treatment cycle includes an administration period of up to 7 days followed by a rest period from about 2 days up to about 10 days. In one embodiment, the treatment cycle includes an administration period of up to 5 days followed by a rest period from about 2 days up to about 10 days. In one embodiment, the treatment cycle includes an administration period of up to 3 days followed by a rest period from about 10 days up to about 15 days. In one embodiment, the treatment cycle includes an administration period of up to 3 days followed by a rest period from about 3 days up to about 15 days.

[0208] In one embodiment, the treatment cycle includes an administration period of up to 15 days followed by a rest period of 7 days. In one embodiment, the treatment cycle includes an administration period of up to 10 days followed by a rest period of 5 days. In one embodiment, the treatment cycle includes an administration period of up to 10 days followed by a rest period of 4 days. In one embodiment, the treatment cycle includes an administration period of up to 10 days followed by a rest period of 3 days. In one embodiment, the treatment cycle includes an administration period of up to 10 days followed by a rest period of 2 days. In one embodiment, the treatment cycle includes an administration period of up to 7 days followed by a rest period of 7 days. In one embodiment, the treatment cycle includes an administration period of up to 5 days followed by a rest period of 5 days. In one embodiment, the treatment cycle includes an administration period of up to 3 days followed by a rest period of 11 days. In another embodiment, the treatment cycle includes an administration period of up to 5 days followed by a rest period of 9 days. In another embodiment, the treatment cycle includes an administration period of up to 5 days followed by a rest period of 2 days. In another embodiment, the treatment cycle includes an administration period of up to 3 days followed by a rest period of 4 days.

[0209] In one embodiment, the treatment cycle includes an administration of a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 on days 1 to 5 of a 28 day cycle. In another embodiment, the treatment cycle includes an administration of Compound 1, Compound 2 or Compound 3 on days 1 to 10 of a 28 day cycle. In one embodiment, the treatment cycle includes an administration of a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 on days 1 to 21 of a 28 day cycle. In another embodiment, the treatment cycle includes an administration of a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 on days 1 to 5 of a 7 day cycle. In another embodiment, the treatment cycle includes an administration of a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 on days 1 to 7 of a 7 day cycle. In one embodiment, the treatment cycle includes an administration of a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 on days 1 to 10 and days 15 to 24 of a 28 day cycle. In one embodiment, the treatment cycle includes an administration of a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 on days 1 to 3 and days 15 to 18 of a 28 day cycle. In one embodiment, the treatment cycle includes an administration of a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 on days 1 to 7 and days 15 to 21 of a 28 day cycle. In one embodiment, the treatment cycle includes an administration of a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 on days 1 to 5 and days 15 to 19 of a 28 day cycle. In one embodiment, the treatment cycle includes an administration of a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 on days 1 to 3 and days 15 to 17 of a 28 day cycle.

[0210] In one embodiment, the treatment cycle includes an administration of a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 on days 1 to 14 of a 21 day cycle. In another embodiment, the treatment cycle includes an administration of Compound 1, Compound 2 or Compound 3 on days 1 to 4 and 8 to 11 of a 21 day cycle. In one embodiment, the treatment cycle includes an administration of a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 on days 1 to 5 and 8 to 12 of a 21 day cycle. In another embodiment, the treatment cycle includes an administration of a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 on days 1 to 5 and 11 to 15 of a 21 day cycle. In another embodiment, the treatment cycle includes an administration of a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 on days 1 to 5, 8 to 12 and 15 to 19 of a 21 day cycle. In another embodiment, the treatment cycle includes an administration of a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 on days 1 to 4, 8 to 11 and 15 to 18 of a 21 day cycle. In another embodiment, the treatment cycle includes an administration of a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 on days 1 to 4, 8 to 10 and 15 to 17 of a 21 day cycle. In another embodiment, the treatment cycle includes an administration of a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 on days 1 to 3, and 8 to 11 of a 21 day cycle. In another embodiment, the treatment cycle includes an administration of a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 on days 1 to 3 and 11 to 13 of a 21 day cycle.

[0211] Any treatment cycle described herein can be repeated for at least 2, 3, 4, 5, 6, 7, 8, or more cycles. In certain instances, the treatment cycle as described herein includes from 1 to about 24 cycles, from about 2 to about 16 cycles, or from about 2 to about 4 cycles. In certain instances a treatment cycle as described herein includes from 1 to about 4 cycles. In certain embodiments, cycle 1 to 4 are all 28 day cycles. In some embodiments, a therapeutically effective amount of Compound 1, Compound 2 or Compound 3 is administered for 1 to 13 cycles of 28 days (e.g. about 1 year). In certain instances, the cycling therapy is not limited to the number of cycles, and the therapy is continued until disease progression. Cycles can in certain instances include varying the duration of administration periods and / or rest periods described herein.

[0212] In one embodiment the treatment cycle includes administering Compound 1, Compound 2 or Compound 3 at a dosage amount of about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, 0.8 mg / day, 0.9 mg / day, 1.0 mg / day, 5.0 mg / day, or 10 mg / day, administered once per day. In one embodiment the treatment cycle includes administering Compound 1, Compound 2 or Compound 3 at a dosage amount of about 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg / day, 0.6 mg / day, 0.7 mg / day, or 0.8 mg / day, administered once per day. In some such embodiments, the treatment cycle includes administering Compound 1, Compound 2 or Compound 3 once a day at a dosage amount of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on days 1 to 10 of a 28 day cycle. In some such embodiments, the treatment cycle includes administering Compound 1, Compound 2 or Compound 3 once a day at a dosage amount of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on days 1 to 10 and 15 to 24 of a 28 day cycle. In some such embodiments, the treatment cycle includes administering Compound 1, Compound 2 or Compound 3 once a day at a dosage amount of about 0.1 mg on days 1 to 10 and 15 to 24 of a 28 day cycle. In other embodiments, the treatment cycle includes administering Compound 1, Compound 2 or Compound 3 twice a day at a dosage amount of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on days 1 to 3 of a 28 day cycle. In other embodiments, the treatment cycle includes administering Compound 1, Compound 2 or Compound 3 twice a day at a dosage amount of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on days 1 to 3 and 15 to 19 of a 28 day cycle. In other embodiments, the treatment cycle includes administering Compound 1, Compound 2 or Compound 3 twice a day at a dosage amount of about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg on days 1 to 3 and 15 to 17 of a 28 day cycle. In other embodiments, the treatment cycle includes administering Compound 1, Compound 2 or Compound 3 twice a day at a dosage amount of about 0.2 mg on days 1 to 3 and 15 to 17 of a 28 day cycle. In one such embodiment, the compound is administered on days 1 to 3 (morning and evening), day 14 (evening only), days 15 and 16 (morning and evening), and day 17 (morning only) in Cycle 1.

[0213] In some embodiments, provided herein is a method of identifying a subject with multiple myeloma that is relapsed, refractory, or resistant to conventional therapy who is likely to be responsive to a treatment compound, comprising: (a) determining the level of a biomarker in a sample from the subject, and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is lower than a reference level of the biomarker; wherein the treatment compound is a compound of Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0214] In another embodiment, provided herein is a method of identifying a subject with multiple myeloma that is relapsed, refractory, or resistant to conventional therapy who is likely to be responsive to a treatment compound, comprising: (a) determining the level of a biomarker in a sample from the subject, and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is lower than a reference level of the biomarker; wherein the treatment compound is a compound of Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0215] In yet another embodiment, provided herein is a method of identifying a subject with multiple myeloma that is relapsed, refractory, or resistant to conventional therapy who is likely to be responsive to a treatment compound, comprising: (a) (b) determining the level of a biomarker in a sample from the subject, and (b) (e) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is lower than a reference level of the biomarker; wherein the treatment compound is a compound of Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0216] In some embodiments, provided herein is a method of identifying a subject with multiple myeloma that is relapsed, refractory, or resistant to conventional therapy who is likely to be responsive to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from the subject; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is lower than a reference level of the biomarker; wherein the treatment compound is a compound of Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0217] In another aspect, provided herein is a method of predicting the responsiveness of a subject having multiple myeloma to a treatment compound, comprising: (a) determining the level of a biomarker in a sample from the subject, and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is lower than a reference level of the biomarker; wherein the treatment compound is a compound of Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0218] In another embodiment, provided herein is a method of predicting the responsiveness of a subject having multiple myeloma to a treatment compound, comprising: (a) (b) determining the level of a biomarker in a sample from the subject, and (b) (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is lower than a reference level of the biomarker; wherein the treatment compound is a compound of Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0219] In yet another embodiment, a method of predicting the responsiveness of a subject having multiple myeloma to a treatment compound, comprising: (a) determining the level of a biomarker in a sample from the subject, and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is lower than a reference level of the biomarker; wherein the treatment compound is a compound of Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0220] In another aspect, provided herein is a method of predicting the responsiveness of a subject having multiple myeloma to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is lower than a reference level of the biomarker; wherein the treatment compound is a compound of Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0221] It is understood, but not claimed, the dosing regimen can be adjusted to a patient's response, or lack thereof, according to the level of a biomarker. For example, the dosage can be adjusted if a patient is neutropenic or if the patient does not respond. Therefore, disclosed herein is a method of determining or adjusting a dosage for treating a subject having multiple myeloma with a treatment compound comprising: determining the level of a biomarker in the one or more samples that have been obtained at different time points from the subject to whom a dosage of the treatment compound has been administered, and thereby determining if the dosage is appropriate or needs an adjustment; wherein the treatment compound is a compound of Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof: , and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0222] In another embodiment, provided herein is a method of determining a dosage for treating a subject having multiple myeloma with a treatment compound comprising: determining the level of a biomarker in the one or more sample that have been obtained at different time points the subject to whom a dosage of the treatment compound has been administered, and thereby determining if the dosage is appropriate or needs an adjustment; wherein the treatment compound is a compound of Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof , and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0223] In yet another embodiment, provided herein is a method of determining a dosage for treating a subject having multiple myeloma with a treatment compound comprising: determining the level of a biomarker in the one or more samples that have been obtained at different time points from the subject to whom a dosage of the treatment compound has administered, and thereby determining if the dosage is appropriate or needs an adjustment wherein the treatment compound is a compound of Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYc, or IRF4.

[0224] In yet another embodiment, provided herein is a method of determining a dosage for treating a subject having multiple myeloma with a treatment compound, wherein the compound has been admisnitered to the subject, comprising: (a) determining the level of a biomarker in one or more samples obtained from the subject, and thereby determining if the dosage is appropriate or needs an adjustment wherein the treatment compound is a compound of Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0225] In some embodiments, the different time points can include a reference sample obtained prior to treatment with a treatment compound, and one or more samples obtained from the subject at different times during treatment with a treatment compound. In other embodiments, the different time points can include a reference sample obtained during treatment, and one or more samples taken at a later time during treatment with a treatment compound. In yet another embodiment, the different time points can include a reference sample taken prior to treatment, and a sample taken after treatment.

[0226] Also provided herein are methods for predicting or monitoring the responsiveness of a patient to a treatment compound, or efficacy of a treatment compound, using a biomarker (e.g., Aiolos, Ikaros, CRBN, ZFP91, c-MYC, IRF4, ). In certain embodiments, provided herein are methods for predicting the responsiveness of a subject having or suspected of having cancer (e.g., multiple myeloma), to a treatment compound, using a predictive or prognostic factor, such as Aiolos, Ikaros, CRBN, ZFP91, c-MYC, IRF4. In some embodiments, provided herein are methods for monitoring the efficacy of a treatment of cancer (e.g., multiple myeloma) in a subject with a treatment compound using a biomarker (e.g., Aiolos, Ikaros, CRBN, ZFP91, c-MYC, IRF4) level as a predictive or prognostic factor. The treatment compound is Compound 1, Compound 2, or Compound 3. In one embodiment, the treatment compound is Compound 1. In another embodiment, the compound is Compound 2. In another embodiment, the treatment compound is Compound 3.

[0227] Thus, in some aspects, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compound has been administered, and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 1: or an enantiomer, a mixture of enantiomers, tautomer, isotopolog, pharmaceutically acceptable salt, or a polymorph thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0228] In another aspect, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compound has been administered, and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0229] In yet another aspect, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compound has been administered, and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or a pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0230] In another aspect, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, which has been administered to the subject, comprising: (a) determining the level of a biomarker in a sample obtained from the subject; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or a pharmaceutically acceptable salt thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0231] In yet another aspect, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) administering the treatment compound to a sample from the subject; (b) determining the level of a biomarker in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 1: or an enantiomer, a mixture of enantiomers, tautomer, isotopolog, pharmaceutically acceptable salt, or a polymorph thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0232] In yet another aspect, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) administering the treatment compound to a sample from the subject; (b) determining the level of a biomarker in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, pharmaceutically acceptable salt, or a polymorph thereof, and wherein the bimarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0233] In yet another aspect, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) administering the treatment compound to a sample from the patient; (b) (e) determining the level of a biomarker in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, pharmaceutically acceptable salt, or a polymorph thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0234] In yet another aspect, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) administering the treatment compound to a sample obtained from the subject; (b) determining the level of a biomarker in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, pharmaceutically acceptable salt, or a polymorph thereof, and wherein the bimarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0235] In some embodiments of the various methods provided herein, the level of the biomarker in the sample is higher than the level of the biomarker obtained from the reference sample. In other embodiments of the various methods provided herein, the level of the biomarker in the sample is lower than the level of the biomarker obtained from the reference sample.

[0236] In yet another aspect, provided herein is a method of monitoring the efficacy of a treatment of cancer in a subject with a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compound has been administered, and (b) comparing the level of the biomarker in the sample with the level of the biomarker obtained from a reference sample, wherein a change in the biomarker level is indicative of the efficacy of the treatment compound in treating the cancer in the subject; wherein the treatment compound is Compound 1: or an enantiomer, a mixture of enantiomers, tautomer, isotopolog, pharmaceutically acceptable salt, or a polymorph thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0237] In yet another aspect, provided herein is a method of monitoring the efficacy of a treatment of cancer in a subject with a treatment compound, comprising: (a) determining the level of a biomarker in a sample obteined from a subject to whom the treatment compound has been administered, and (b) comparing the level of the biomarker in the sample with the level of the biomarker obtained from a reference sample, wherein a change in the biomarker level is indicative of the efficacy of the treatment compound in treating the cancer in the subject; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, pharmaceutically acceptable salt, or a polymorph thereof , and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0238] In yet another aspect, provided herein is a method of monitoring the efficacy of a treatment of cancer in a subject with a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compound has been administered,, and (b) comparing the level of the biomarker in the sample with the level of the biomarker obtained from a reference sample, wherein a change in the biomarker level is indicative of the efficacy of the treatment compound in treating the cancer in the subject; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, pharmaceutically acceptable salt, or a polymorph thereof , and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0239] In yet another aspect, provided herein is a method of monitoring the efficacy of a treatment of cancer in a subject with a treatment compound, which has been administered to the subject, comprising: (a) determining the level of a biomarker in a sample obtained from the subject; and (b) comparing the level of the biomarker in the sample with the level of the biomarker obtained from a reference sample, wherein a change in the biomarker level is indicative of the efficacy of the treatment compound in treating the cancer in the subject; wherein the treatment compound is Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, pharmaceutically acceptable salt, or a polymorph thereof, and wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

[0240] In some cases, an increased level as compared to the reference level is indicative of the efficacy of the treatment compound in treating the cancer in the subject. For example, an increase in c-Caspase-3, c-Caspase 1, c-Caspase 7, cleaved-PARP, BIM, TUNEL, Annexin-V / 7-AAD, Annexin-V / PI, p21, p27, free light chain, IL-2, TNFα, IFNγ, or TCR clonality, relative to a reference, is indicative of the efficacy of the treatment compound in treating the multiple myeloma in the subject. In other cases, a decreased level as compared to the reference level is indicative of the efficacy of the treatment compound in treating the cancer in the subject. For example, a decrease in Aiolos (IKZF3), Ikaros (IKZF1), CTC, ZFP91, c-MYC, IRF4, phospho-Rb1, relative to a reference, is indicative of the efficacy of the treatment compound in treating the multiple myeloma in the subject.

[0241] It is understood that the level of a biomarker will be relative to the reference level. Therefore, in some cases, decreased level as compared to the reference level is indicative of the efficacy of the treatment compound in treating the cancer in the subject. For example, an decrease in c-Caspase-3, c-Caspase 1, c-Caspase 7, cleaved-PARP, BIM, TUNEL, Annexin-V / 7-AAD, Annexin-V / PI, p21, p27, free light chain, IL-2, TNFα, IFNγ, or TCR clonality from a healthy patient, relative to a reference from a multiple myeloma patient, is indicative of the efficacy of the treatment compound in treating the multiple myeloma in the subject. In other cases, an increased level as compared to the reference level is indicative of the efficacy of the treatment compound in treating the cancer in the subject. For example, an increase in Aiolos (IKZF3), Ikaros (IKZF1), CTC, ZFP91, c-MYC, IRF4, phospho-Rb1 from a healthy patient, relative to a reference from a multiple myeloma patient, is indicative of the efficacy of the treatment compound in treating the multiple myeloma in the subject.

[0242] As discussed elsewhere herein, encompassed herein is a method of reducing, treating and / or preventing adverse or undesired effects associated with conventional therapy including, but not limited to, surgery, chemotherapy, radiation therapy, biological therapy and immunotherapy. A compound provided herein, e.g., Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and other active ingredient can be administered to a patient identified using the biomarkers described herein prior to, during, or after the occurrence of the adverse effect associated with conventional therapy.

[0243] Compound 1, Compound 2 or Compound 3 provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, can also be combined or used in combination with other therapeutic agents useful in the treatment and / or prevention of multiple myeloma described herein.

[0244] In some embodiments of the various methods provided herein, the method comprises administering to a patient Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, in combination with one or more second active agents, and optionally in combination with radiation therapy, blood transfusions, or surgery.

[0245] As used herein, the term "in combination" includes the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term "in combination" does not restrict the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a patient with a disease or disorder. A first therapy (e.g., a prophylactic or therapeutic agent such as a compound provided herein, e.g., Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent) to the subject. Triple therapy is also contemplated herein, as is quadruple therapy. In one embodiment, the second therapy is dexamethasone.

[0246] Administration of Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and one or more second active agents to a patient can occur simultaneously or sequentially by the same or different routes of administration. The suitability of a particular route of administration employed for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without decomposing prior to entering the blood stream).

[0247] The route of administration of Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, is independent of the route of administration of a second therapy. In one embodiment, Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, is administered orally. In another embodiment, Compound 1, Compound 2 or Compound 3 is administered intravenously. Thus, in accordance with these embodiments, Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, is administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form. In one embodiment, Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, and a second therapy are administered by the same mode of administration, orally or by IV. In another embodiment, Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, is administered by one mode of administration, e.g., by IV, whereas the second agent (an anti- multiple myeloma agent) is administered by another mode of administration, e.g., orally.

[0248] In one embodiment, the second active agent is administered intravenously or subcutaneously and once or twice daily in an amount of from about 1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. The specific amount of the second active agent will depend on the specific agent used, the type of multiple myeloma being treated or managed, the severity and stage of disease, and the amount of Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, provided herein and any optional additional active agents concurrently administered to the patient.

[0249] One or more second active ingredients or agents can be used together with Compound 1, Compound 2 or Compound 3 in the methods and compositions provided herein. Second active agents can be large molecules (e.g., proteins), small molecules (e.g., synthetic inorganic, organometallic, or organic molecules), or cell therapies (e.g., CAR cells).

[0250] Examples of second active agents that can be used in the methods and compositions described herein include one or more of melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, a proteasome inhibitor (for example, bortezomib, carfilzomib, ixazomib, oprozomib or marizomib), a histone deacetylase inhibitor (for example, panobinostat, ACY241), a BET inhibitor (for example, GSK525762A, OTX015, BMS-986158, TEN-010, CPI-0610 , INCB54329, BAY1238097, FT-1101, C90010, ABBV-075, BI 894999, GS-5829, GSK1210151A (I-BET-151), CPI-203, RVX-208, XD46, MS436, PFI-1, RVX2135, ZEN3365, XD14, ARV-771, MZ-1, PLX5117, EP11313 and EP11336), a BCL2 inhibitor (for example, venetoclax or navitoclax), an MCL-1 inhibitor (for example, AZD5991, AMG176, MIK665, S64315, or S63845), a corticosteroid (for example, prednisone), dexamethasone; an antibody (for example, a CS1 antibody, such as elotuzumab; a CD38 antibody, such as daratumumab isatuximab; or a BCMA antibody or antibody-conjugate, such as GSK2857916 or BI 836909), a checkpoint inhibitor (as described herein), or CAR cells (as described herein).

[0251] In one embodiment, the second active agent used together with Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, in the methods and compositions described herein is dexamethasone.

[0252] In some embodiments, the dexamethasone is administered at a 4 mg dose on days 1 and 8 of a 21 day cycle. In some other embodiments, the dexamethasone is administered at a 4 mg dose on days 1, 4, 8 and 11 of a 21 day cycle. In some embodiments, the dexamethasone is administered at a 4 mg dose on days 1, 8, and 15 of a 28 day cycle. In some other embodiments, the dexamethasone is administered at a 4 mg dose on days 1, 4, 8, 11, 15 and 18 of a 28 day cycle. In some embodiments, the dexamethasone is administered at a 4 mg dose on days 1, 8, 15, and 22 of a 28 day cycle. In one such embodiment, the dexamethasone is administered at a 4 mg dose on days 1, 10, 15, and 22 of Cycle 1. In some embodiments, the dexamethasone is administered at a 4 mg dose on days 1, 3, 15, and 17 of a 28 day cycle. In one such embodiment, the dexamethasone is administered at a 4 mg dose on days 1, 3, 14, and 17 of Cycle 1.

[0253] In some other embodiments, the dexamethasone is administered at an 8 mg dose on days 1 and 8 of a 21 day cycle. In some other embodiments, the dexamethasone is administered at an 8 mg dose on days 1, 4, 8 and 11 of a 21 day cycle. In some embodiments, the dexamethasone is administered at an 8 mg dose on days 1, 8, and 15 of a 28 day cycle. In some other embodiments, the dexamethasone is administered at an 8 mg dose on days 1, 4, 8, 11, 15 and 18 of a 28 day cycle. In some embodiments, the dexamethasone is administered at an 8 mg dose on days 1, 8, 15, and 22 of a 28 day cycle. In one such embodiment, the dexamethasone is administered at an 8 mg dose on days 1, 10, 15, and 22 of Cycle 1. In some embodiments, the dexamethasone is administered at an 8 mg dose on days 1, 3, 15, and 17 of a 28 day cycle. In one such embodiment, the dexamethasone is administered at an 8 mg dose on days 1, 3, 14, and 17 of Cycle 1.

[0254] In some embodiments, the dexamethasone is administered at a 10 mg dose on days 1 and 8 of a 21 day cycle. In some other embodiments, the dexamethasone is administered at a 10 mg dose on days 1, 4, 8 and 11 of a 21 day cycle. In some embodiments, the dexamethasone is administered at a 10 mg dose on days 1, 8, and 15 of a 28 day cycle. In some other embodiments, the dexamethasone is administered at a 10 mg dose on days 1, 4, 8, 11, 15 and 18 of a 28 day cycle. In some embodiments, the dexamethasone is administered at a 10 mg dose on days 1, 8, 15, and 22 of a 28 day cycle. In one such embodiment, the dexamethasone is administered at a 10 mg dose on days 1, 10, 15, and 22 of Cycle 1. In some embodiments, the dexamethasone is administered at a 10 mg dose on days 1, 3, 15, and 17 of a 28 day cycle. In one such embodiment, the dexamethasone is administered at a 10 mg dose on days 1, 3, 14, and 17 of Cycle 1.

[0255] In some embodiments, the dexamethasone is administered at a 20 mg dose on days 1 and 8 of a 21 day cycle. In some other embodiments, the dexamethasone is administered at a 20 mg dose on days 1, 4, 8 and 11 of a 21 day cycle. In some embodiments, the dexamethasone is administered at a 20 mg dose on days 1, 8, and 15 of a 28 day cycle. In some other embodiments, the dexamethasone is administered at a 20 mg dose on days 1, 4, 8, 11, 15 and 18 of a 28 day cycle. In some embodiments, the dexamethasone is administered at a 20 mg dose on days 1, 8, 15, and 22 of a 28 day cycle. In one such embodiment, the dexamethasone is administered at a 20 mg dose on days 1, 10, 15, and 22 of Cycle 1. In some embodiments, the dexamethasone is administered at a 20 mg dose on days 1, 3, 15, and 17 of a 28 day cycle. In one such embodiment, the dexamethasone is administered at a 20 mg dose on days 1, 3, 14, and 17 of Cycle 1.

[0256] In some embodiments, the dexamethasone is administered at a 40 mg dose on days 1 and 8 of a 21 day cycle. In some other embodiments, the dexamethasone is administered at a 40 mg dose on days 1, 4, 8 and 11 of a 21 day cycle. In some embodiments, the dexamethasone is administered at a 40 mg dose on days 1, 8, and 15 of a 28 day cycle. In one such embodiment, the dexamethasone is administered at a 40 mg dose on days 1, 10, 15, and 22 of Cycle 1. In some other embodiments, the dexamethasone is administered at a 40 mg dose on days 1, 4, 8, 11, 15 and 18 of a 28 day cycle. In other such embodiments, the dexamethasone is administered at a 40 mg dose on days 1, 8, 15, and 22 of a 28 day cycle. In other such embodiments, the dexamethasone is administered at a 40 mg dose on days 1, 3, 15, and 17 of a 28 day cycle. In one such embodiment, the dexamethasone is administered at a 40 mg dose on days 1, 3, 14, and 17 of Cycle 1.

[0257] In another embodiment, the second active agent used together with Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, in the methods and compositions described herein is bortezomib. In yet another embodiment, the second active agent used together with Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, in the methods and compositions described herein is daratumumab. In some such embodiments, the methods additionally comprise administration of dexamethasone. In some embodiments, the methods comprise administration of Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, with a proteasome inhibitor as described herein, a CD38 inhibitor as described herein and a corticosteroid as described herein.

[0258] In certain embodiments, Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, is administered in combination with checkpoint inhibitors. In one embodiment, one checkpoint inhibitor is used in combination with Compound 1, or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, in connection with the methods provided herein. In another embodiment, two checkpoint inhibitors are used in combination with Compound 1, or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof, in connection with the methods provided herein. In yet another embodiment, three or more checkpoint inhibitors are used in combination with Compound 1, Compound 2 or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, in connection with the methods provided herein.

[0259] As used herein, the term "immune checkpoint inhibitor" or "checkpoint inhibitor" refers to molecules that totally or partially reduce, inhibit, interfere with or modulate one or more checkpoint proteins. Without being limited by a particular theory, checkpoint proteins regulate T-cell activation or function. Numerous checkpoint proteins are known, such as CTLA-4 and its ligands CD80 and CD86; and PD-1 with its ligands PD-Ll and PD-L2 (Pardoll, Nature Reviews Cancer, 2012, 12, 252-264). These proteins appear responsible for co-stimulatory or inhibitory interactions of T-cell responses. Immune checkpoint proteins appear to regulate and maintain self-tolerance and the duration and amplitude of physiological immune responses. Immune checkpoint inhibitors include antibodies or are derived from antibodies.

[0260] In one embodiment, the checkpoint inhibitor is a CTLA-4 inhibitor. In one embodiment, the CTLA-4 inhibitor is an anti-CTLA-4 antibody. Examples of anti-CTLA-4 antibodies include, but are not limited to, those described in US Patent Nos: 5,811,097; 5,811,097; 5,855,887; 6,051,227; 6,207,157; 6,682,736; 6,984,720; and 7,605,238, all of which are incorporated herein in their entireties. In one embodiment, the anti-CTLA-4 antibody is tremelimumab (also known as ticilimumab or CP-675,206). In another embodiment, the anti-CTLA-4 antibody is ipilimumab (also known as MDX-010 or MDX-101). Ipilimumab is a fully human monoclonal IgG antibody that binds to CTLA-4. Ipilimumab is marketed under the trade name Yervoy ™< .

[0261] In one embodiment, the checkpoint inhibitor is a PD-1 / PD-L1 inhibitor. Examples of PD-1 / PD-L1 inhibitors include, but are not limited to, those described in US Patent Nos. 7,488,802; 7,943,743; 8,008,449; 8,168,757; 8,217,149, and PCT Patent Application Publication Nos. WO2003042402, WO2008156712, WO2010089411, WO2010036959, WO2011066342, WO2011159877, WO2011082400, and WO2011161699, all of which are incorporated herein in their entireties.

[0262] In one embodiment, the checkpoint inhibitor is a PD-1 inhibitor. In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody. In one embodiment, the anti-PD-1 antibody is BGB-A317, nivolumab (also known as ONO-4538, BMS-936558, or MDX1106) or pembrolizumab (also known as MK-3475, SCH 900475, or lambrolizumab). In one embodiment, the anti-PD-1 antibody is nivolumab. Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody, and is marketed under the trade name Opdivo ™< . In another embodiment, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized monoclonal IgG4 antibody and is marketed under the trade name Keytruda ™< . In yet another embodiment, the anti-PD-1 antibody is CT-011, a humanized antibody. CT-011 administered alone has failed to show response in treating acute myeloid leukemia (AML) at relapse. In yet another embodiment, the anti-PD-1 antibody is AMP-224, a fusion protein. In another embodiment, the PD-1 antibody is BGB-A317. BGB-A317 is a monoclonal antibody in which the ability to bind Fc gamma receptor I is specifically engineered out, and which has a unique binding signature to PD-1 with high affinity and superior target specificity.

[0263] In one embodiment, the checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment, the PD-L1 inhibitor is an anti-PD-L1 antibody. In one embodiment, the anti-PD-L1 antibody is MEDI4736 (durvalumab). In another embodiment, the anti-PD-L1 antibody is BMS-936559 (also known as MDX-1105-01). In yet another embodiment, the PD-L1 inhibitor is atezolizumab (also known as MPDL3280A, and Tecentriq ®< ).

[0264] In one embodiment, the checkpoint inhibitor is a PD-L2 inhibitor. In one embodiment, the PD-L2 inhibitor is an anti-PD-L2 antibody. In one embodiment, the anti-PD-L2 antibody is rHIgM12B7A.

[0265] In one embodiment, the checkpoint inhibitor is a lymphocyte activation gene-3 (LAG-3) inhibitor. In one embodiment, the LAG-3 inhibitor is IMP321, a soluble Ig fusion protein (Brignone et al., J. Immunol., 2007, 179, 4202-4211). In another embodiment, the LAG-3 inhibitor is BMS-986016.

[0266] In one embodiment, the checkpoint inhibitor is a B7 inhibitor. In one embodiment, the B7 inhibitor is a B7-H3 inhibitor or a B7-H4 inhibitor. In one embodiment, the B7-H3 inhibitor is MGA271, an anti-B7-H3 antibody (Loo et al., Clin. Cancer Res., 2012, 3834).

[0267] In one embodiment, the checkpoint inhibitors is a TIM3 (T-cell immunoglobulin domain and mucin domain 3) inhibitor (Fourcade et al., J. Exp. Med., 2010, 207, 2175-86; Sakuishi et al., J. Exp. Med., 2010, 207, 2187-94).

[0268] In one embodiment, the checkpoint inhibitor is an OX40 (CD134) agonist. In one embodiment, the checkpoint inhibitor is an anti-OX40 antibody. In one embodiment, the anti-OX40 antibody is anti-OX-40. In another embodiment, the anti-OX40 antibody is MEDI6469.

[0269] In one embodiment, the checkpoint inhibitor is a GITR agonist. In one embodiment, the checkpoint inhibitor is an anti-GITR antibody. In one embodiment, the anti-GITR antibody is TRX518.

[0270] In one embodiment, the checkpoint inhibitor is a CD137 agonist. In one embodiment, the checkpoint inhibitor is an anti-CD137 antibody. In one embodiment, the anti-CD137 antibody is urelumab. In another embodiment, the anti-CD137 antibody is PF-05082566.

[0271] In one embodiment, the checkpoint inhibitor is a CD40 agonist. In one embodiment, the checkpoint inhibitor is an anti-CD40 antibody. In one embodiment, the anti-CD40 antibody is CF-870,893.

[0272] In one embodiment, the checkpoint inhibitor is recombinant human interleukin-15 (rhIL-15).

[0273] In one embodiment, the checkpoint inhibitor is an IDO inhibitor. In one embodiment, the IDO inhibitor is INCB024360. In another embodiment, the IDO inhibitor is indoximod.

[0274] In certain embodiments, the combination therapies provided herein include two or more of the checkpoint inhibitors described herein (including checkpoint inhibitors of the same or different class). Moreover, the combination therapies described herein can be used in combination with one or more second active agents as described herein where appropriate for treating diseases described herein and understood in the art.

[0275] In certain embodiments, Compound 1, Compound 2 or Compound 3 can be used in combination with one or more immune cells expressing one or more chimeric antigen receptors (CARs) on their surface (e.g., a modified immune cell). Generally, CARs comprise an extracellular domain from a first protein (e.g., an antigen-binding protein), a transmembrane domain, and an intracellular signaling domain. In certain embodiments, once the extracellular domain binds to a target protein such as a tumor-associated antigen (TAA) or tumor-specific antigen (TSA), a signal is generated via the intracellular signaling domain that activates the immune cell, e.g., to target and kill a cell expressing the target protein.

[0276] Extracellular domains: The extracellular domains of the CARs bind to an antigen of interest. In certain embodiments, the extracellular domain of the CAR comprises a receptor, or a portion of a receptor, that binds to said antigen. In certain embodiments, the extracellular domain comprises, or is, an antibody or an antigen-binding portion thereof. In specific embodiments, the extracellular domain comprises, or is, a single chain Fv (scFv) domain. The single-chain Fv domain can comprise, for example, a V L linked to V H by a flexible linker, wherein said V L and V H are from an antibody that binds said antigen.

[0277] In certain embodiments, the antigen recognized by the extracellular domain of a polypeptide described herein is a tumor-associated antigen (TAA) or a tumor-specific antigen (TSA). In various specific embodiments, the tumor-associated antigen or tumor-specific antigen is, without limitation, Her2, prostate stem cell antigen (PSCA), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen-125 (CA-125), CA19-9, calretinin, MUC-1, B cell maturation antigen (BCMA), epithelial membrane protein (EMA), epithelial tumor antigen (ETA), tyrosinase, melanoma-24 associated antigen (MAGE), CD19, CD22, CD27, CD30, CD34, CD45, CD70, CD99, CD117, EGFRvIII (epidermal growth factor variant III), mesothelin, PAP (prostatic acid phosphatase), prostein, TARP (T cell receptor gamma alternate reading frame protein), Trp-p8, STEAPI (six-transmembrane epithelial antigen of the prostate 1), chromogranin, cytokeratin, desmin, glial fibrillary acidic protein (GFAP), gross cystic disease fluid protein (GCDFP-15), HMB-45 antigen, protein melan-A (melanoma antigen recognized by T lymphocytes; MART-I), myo-D1, muscle-specific actin (MSA), neurofilament, neuron-specific enolase (NSE), placental alkaline phosphatase, synaptophysis, thyroglobulin, thyroid transcription factor-1, the dimeric form of the pyruvate kinase isoenzyme type M2 (tumor M2-PK), an abnormal ras protein, or an abnormal p53 protein. In certain other embodiments, the TAA or TSA recognized by the extracellular domain of a CAR is integrin αvβ3 (CD61), galactin, or Ral-B.

[0278] In certain embodiments, the TAA or TSA recognized by the extracellular domain of a CAR is a cancer / testis (CT) antigen, e.g., BAGE, CAGE, CTAGE, FATE, GAGE, HCA661, HOM-TES-85, MAGEA, MAGEB, MAGEC, NA88, NY-ES0-1, NY-SAR-35, OY-TES-1, SPANXBI, SPA17, SSX, SYCPI, or TPTE.

[0279] In certain other embodiments, the TAA or TSA recognized by the extracellular domain of a CAR is a carbohydrate or ganglioside, e.g., fuc-GMI, GM2 (oncofetal antigen-immunogenic-1; OFA-I-1); GD2 (OFA-I-2), GM3, GD3, and the like.

[0280] In certain other embodiments, the TAA or TSA recognized by the extracellular domain of a CAR is alpha-actinin-4, Bage-1, BCR-ABL, Bcr-Abl fusion protein, beta-catenin, CA 125, CA 15-3 (CA 27.29\BCAA), CA 195, CA 242, CA-50, CAM43, Casp-8, cdc27, cdk4, cdkn2a, CEA, coa-1, dek-can fusion protein, EBNA, EF2, Epstein Barr virus antigens, ETV6-AML1 fusion protein, HLA-A2, HLA-All, hsp70-2, KIAA0205, Mart2, Mum-1, 2, and 3, neo-PAP, myosin class I, OS-9, pml-RARα fusion protein, PTPRK, K-ras, N-ras, triosephosphate isomerase, Gage 3,4,5,6,7, GnTV, Herv-K-mel, Lage-1, NA-88, NY-Eso-1 / Lage-2, SP17, SSX-2, TRP2-Int2, gp100 (Pmel17), tyrosinase, TRP-1, TRP-2, MAGE-1, MAGE-3, RAGE, GAGE-1, GAGE-2, p15(58), RAGE, SCP-1, Hom / Mel-40, PRAME, p53, HRas, HER-2 / neu, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, human papillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, MAGE-5, MAGE-6, p185erbB2, p180erbB-3, c-met, nm-23H1, PSA, TAG-72-4, CA 19-9, CA 72-4, CAM 17.1, NuMa, K-ras, 13-Catenin, Mum-1, p16, TAGE, PSMA, CT7, telomerase, 43-9F, 5T4, 791Tgp72, 13HCG, BCA225, BTAA, CD68\KP1, C0-029, FGF-5, G250, Ga733 (EpCAM), HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB\70K, NY-C0-1, RCAS1, SDCCAG16, TA-90, TAAL6, TAG72, TLP, or TPS.

[0281] In various specific embodiments, the tumor-associated antigen or tumor-specific antigen is an AML-related tumor antigens, as described in S. Anguille et al., Leukemia (2012), 26, 2186-2196.

[0282] Other tumor-associated and tumor-specific antigens are known to those in the art.

[0283] Receptors, antibodies, and scFvs that bind to TSAs and TAAs, useful in constructing chimeric antigen receptors, are known in the art, as are nucleotide sequences that encode them.

[0284] In certain specific embodiments, the antigen recognized by the extracellular domain of a chimeric antigen receptor is an antigen not generally considered to be a TSA or a TAA, but which is nevertheless associated with tumor cells, or damage caused by a tumor. In certain embodiments, for example, the antigen is, e.g., a growth factor, cytokine or interleukin, e.g., a growth factor, cytokine, or interleukin associated with angiogenesis or vasculogenesis. Such growth factors, cytokines, or interleukins can include, e.g., vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF), or interleukin-8 (IL-8). Tumors can also create a hypoxic environment local to the tumor. As such, in other specific embodiments, the antigen is a hypoxia-associated factor, e.g., HIF-1α, HIF-1β, HIF-2α, HIF-2β, HIF-3α, or HIF-3β. Tumors can also cause localized damage to normal tissue, causing the release of molecules known as damage associated molecular pattern molecules (DAMPs; also known as alarmins). In certain other specific embodiments, therefore, the antigen is a DAMP, e.g., a heat shock protein, chromatin-associated protein high mobility group box 1 (HMGB 1), S100A8 (MRP8, calgranulin A), S100A9 (MRP14, calgranulin B), serum amyloid A (SAA), or can be a deoxyribonucleic acid, adenosine triphosphate, uric acid, or heparin sulfate.

[0285] In certain embodiments, the extracellular domain of the CAR is joined to the transmembrane domain of the polypeptide by a linker, spacer or hinge polypeptide sequence, e.g., a sequence from CD28 or a sequence from CTLA4. The transmembrane domain can be obtained or derived from the transmembrane domain of any transmembrane protein, and can include all or a portion of such transmembrane domain. In specific embodiments, the transmembrane domain can be obtained or derived from, e.g., CD8, CD16, a cytokine receptor, and interleukin receptor, or a growth factor receptor, or the like.

[0286] In certain embodiments, the intracellular domain of a CAR is or comprises an intracellular domain or motif of a protein that is expressed on the surface of T cells and triggers activation and / or proliferation of said T cells. Such a domain or motif is able to transmit a primary antigen-binding signal that is necessary for the activation of a T lymphocyte in response to the antigen's binding to the CAR's extracellular portion. Typically, this domain or motif comprises, or is, an ITAM (immunoreceptor tyrosine-based activation motif). ITAM-containing polypeptides suitable for CARs include, for example, the zeta CD3 chain (CD3ζ) or ITAM-containing portions thereof. In a specific embodiment, the intracellular domain is a CD3ζ intracellular signaling domain. In other specific embodiments, the intracellular domain is from a lymphocyte receptor chain, a TCR / CD3 complex protein, a Fe receptor subunit or an IL-2 receptor subunit. In certain embodiments, the CAR additionally comprises one or more co-stimulatory domains or motifs, e.g., as part of the intracellular domain of the polypeptide. The one or more co-stimulatory domains or motifs can be, or can comprise, one or more of a co-stimulatory CD27 polypeptide sequence, a co-stimulatory CD28 polypeptide sequence, a co-stimulatory OX40 (CD134) polypeptide sequence, a co-stimulatory 4-1BB (CD137) polypeptide sequence, or a co-stimulatory inducible T-cell costimulatory (ICOS) polypeptide sequence, or other costimulatory domain or motif, or any combination thereof.

[0287] The CAR may also comprise a T cell survival motif. The T cell survival motif can be any polypeptide sequence or motif that facilitates the survival of the T lymphocyte after stimulation by an antigen. In certain embodiments, the T cell survival motif is, or is derived from, CD3, CD28, an intracellular signaling domain of IL-7 receptor (IL-7R), an intracellular signaling domain of IL-12 receptor, an intracellular signaling domain of IL-15 receptor, an intracellular signaling domain of IL-21 receptor, or an intracellular signaling domain of transforming growth factor β (TGFβ) receptor.

[0288] The modified immune cells expressing the CARs can be, e.g., T lymphocytes (T cells, e.g., CD4+ T cells or CD8+ T cells), cytotoxic lymphocytes (CTLs) or natural killer (NK) cells. T lymphocytes used in the compositions and methods provided herein may be naive T lymphocytes or MHC-restricted T lymphocytes. In certain embodiments, the T lymphocytes are tumor infiltrating lymphocytes (TILs). In certain embodiments, the T lymphocytes have been isolated from a tumor biopsy, or have been expanded from T lymphocytes isolated from a tumor biopsy. In certain other embodiments, the T cells have been isolated from, or are expanded from T lymphocytes isolated from, peripheral blood, cord blood, or lymph. Immune cells to be used to generate modified immune cells expressing a CAR can be isolated using art-accepted, routine methods, e.g., blood collection followed by apheresis and optionally antibody-mediated cell isolation or sorting.

[0289] The modified immune cells are preferably autologous to an individual to whom the modified immune cells are to be administered. In certain other embodiments, the modified immune cells are allogeneic to an individual to whom the modified immune cells are to be administered. Where allogeneic T lymphocytes or NK cells are used to prepare modified T lymphocytes, it is preferable to select T lymphocytes or NK cells that will reduce the possibility of graft-versus-host disease (GVHD) in the individual. For example, in certain embodiments, virus-specific T lymphocytes are selected for preparation of modified T lymphocytes; such lymphocytes will be expected to have a greatly reduced native capacity to bind to, and thus become activated by, any recipient antigens. In certain embodiments, recipient-mediated rejection of allogeneic T lymphocytes can be reduced by co-administration to the host of one or more immunosuppressive agents, e.g., cyclosporine, tacrolimus, sirolimus, cyclophosphamide, or the like.

[0290] T lymphocytes, e.g., unmodified T lymphocytes, or T lymphocytes expressing CD3 and CD28, or comprising a polypeptide comprising a CD3ζ signaling domain and a CD28 co-stimulatory domain, can be expanded using antibodies to CD3 and CD28, e.g., antibodies attached to beads; see, e.g., U.S. Patent Nos. 5,948,893; 6,534,055; 6,352,694; 6,692,964; 6,887,466; and 6,905,681.

[0291] The modified immune cells, e.g., modified T lymphocytes, can optionally comprise a "suicide gene" or "safety switch" that enables killing of substantially all of the modified immune cells when desired. For example, the modified T lymphocytes, in certain embodiments, can comprise an HSV thymidine kinase gene (HSV-TK), which causes death of the modified T lymphocytes upon contact with gancyclovir. In another embodiment, the modified T lymphocytes comprise an inducible caspase, e.g., an inducible caspase 9 (icaspase9), e.g., a fusion protein between caspase 9 and human FK506 binding protein allowing for dimerization using a specific small molecule pharmaceutical. See Straathof et al., Blood 1 05(11):4247-4254 (2005). In certain embodiments, Compound 1, compound 2 or Compound 3 as provided herein is administered to patients with various types or stages of multiple myeloma in combination with chimeric antigen receptor (CAR) T-cells. In certain embodiments the CAR T cell in the combination targets B cell maturation antigen (BCMA), and in more specific embodiments, the CAR T cell is bb2121 or bb21217. In some embodiments, the CAR T cell is JCARH125.

[0292] In some embodiments of the various methods provided herein, the reference sample is obtained from the subject prior to administering the treatment compound to the subject, and the control sample is from the same source as the sample. In other embodiments of the various methods provided herein, the reference sample is obtained from a healthy subject not having cancer, and the control sample is from the same source as the sample.

[0293] In some embodiments of the various methods provided herein, the cancer is a blood borne cancer. In certain embodiments, the blood borne cancer is metastatic. In some embodiments of the various methods provided herein, the cancer is multiple myeloma.

[0294] Some embodiments of the compounds for use provided herein encompass treating, preventing, or managing various types of cancers. One embodiment, encompasses treating, preventing, or managing multiple myeloma by administering a therapeutically effective amount of Compound 1, or enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof. One embodiment, encompasses treating, preventing, or managing multiple myeloma by administering a therapeutically effective amount of Compound 2, or a tautomer, One isotopolog, or pharmaceutically acceptable salt thereof. One embodiment, encompasses treating, preventing, or managing multiple myeloma by administering a therapeutically effective amount of Compound 3, or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0295] Certain embodiments, encompass treating, preventing, or managing cancer in patients with impaired renal function. Certain embodiments, encompass providing appropriate dose adjustments for patients with impaired renal function due to, but not limited to, disease, aging, or other patient factors.

[0296] Certain embodiments, encompass treating, preventing, or managing MM, including relapsed / refractory MM in patients with impaired renal function or a symptom thereof, comprising administering a therapeutically effective amount of Compound 1, Compound 2, or Compound 3, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, to a patient having relapsed / refractory MM with impaired renal function alone or in combination with a second active agent. Some embodiments, comprise the step of administering to the subject a compound provided herein, or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof, in combination with a second active agent in amounts effective to treat, prevent, or manage relapsed / refractory MM in patients with impaired renal function. In certain embodiments, the compound is Compound 1. In certain embodiments, the compound is Compound 2. In certain embodiments, the compound is Compound 3.

[0297] In some embodiments, the level of the biomarker decreases with the compound treatment. In some embodiments, the biomarker is selected from the group consisting of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, IRF4, pRB1, and the level of the biomarker decreases as compared to a reference level prior to treatment with a treatment compound.

[0298] The level of the biomarker may increase with the compound treatment. In some examples, the biomarker is selected from the group consisting of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, and TCR clonality and the level of the biomarker increases as compared to a reference level prior to treatment with a treatment compound.

[0299] In certain embodiments of the various methods provided herein, the biomarker is a protein that is directly or indirectly affected by CRBN, for example through protein-protein interactions (e.g., certain CRBN substrates or downstream effectors thereof), or through various cellular pathways (e.g., signal transduction pathways). In specific embodiments, the biomarker is a CRBN-associated protein (CAP). In some embodiments, the biomarker is mRNA of a protein that is directly or indirectly affected by CRBN. In other embodiments, the biomarker is cDNA of a protein that is directly or indirectly affected by CRBN.

[0300] Thus, in some embodiments, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compound has been administered, wherein the biomarker is a CAP; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0301] In another embodiment, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compound has been administered, wherein the biomarker is a CAP; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0302] In yet another embodiment, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compound has been administered, wherein the biomarker is a CAP; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0303] In another embodiment, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, which has been administered to the subject, comprising: (a) determining the level of a biomarker in a sample obtained from the subject, wherein the biomarker is a CAP; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0304] In some embodiments, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) administering the treatment compound to a sample; from the subject; (b) determining the level of a biomarker in the sample, wherein the biomarker is a CAP; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0305] In some embodiments, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) (b) administering the treatment compound to a sample; from the subject; (b) (c) determining the level of a biomarker in the sample, wherein the biomarker is a CAP; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0306] In some embodiments, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) administering the treatment compound to a sample; from the subject; (b) determining the level of a biomarker in the sample, wherein the biomarker is a CAP; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0307] In some embodiments, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) administering the treatment compound to a sample obtained from the subject; (b) determining the level of a biomarker in the sample, wherein the biomarker is a CAP; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0308] In some embodiments, provided herein is a treatment compound for use in a method of treating cancer, comprising: (a) determining the level of a biomarker in a sample from a subject having the cancer wherein the biomarker is a CAP; (b) diagnosing the subject as being likely to be responsive to a treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; and (c) administering a therapeutically effective amount of the treatment compound to the subject; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0309] In some embodiments, provided herein is a treatment compund for use in a method of treating cancer, comprising: (a) determining the level of a biomarker in a sample from a subject having the cancer, wherein the biomarker is a CAP; (b) diagnosing the subject as being likely to be responsive to a treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; and (c) administering a therapeutically effective amount of the treatment compound to the subject; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0310] In some embodiments, provided herein is a treatment compund for use in a method of treating cancer, comprising: (a) determining the level of a biomarker in a sample from a subject having the cancer wherein the biomarker is a CAP; (b) diagnosing the subject as being likely to be responsive to a treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; and (c) administering a therapeutically effective amount of the treatment compound to the subject; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0311] In some embodiments, provided herein is Compound 1, Compound 2 or Compound 3 for use in a method of treating cancer, comprising: (a) determining the level of a biomarker in sample from a subject having the cancer wherein the biomarker is a CAP; (b) diagnosing the subject as being likely to be responsive to a treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; and (c) administering a therapeutically effective amount of the treatment compound to the subject; wherein the treatment compound is Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0312] In some embodiments, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) determining the level of a biomarker in sample obtained from a subject to whom the treatment compound has been administered, wherein the biomarker is a CAP; (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0313] In some embodiments, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compound has been administered, wherein the biomarker is a CAP; (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0314] In some embodiments, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compound has been administered, wherein the biomarker is a CAP; (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0315] In some embodiments, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, which has been administered to the subject, comprising: (a) determining the level of a biomarker in a sample, obtained from the subject, wherein the biomarker is a CAP; (d) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 1, Compound 3 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0316] In some embodiments, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) administering the treatment compound to a sample from the patient; (b) (e) determining the level of a biomarker in the sample, wherein the biomarker is a CAP; (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0317] In some embodiments, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) administering the treatment compound to a sample from the subject; (b) (e) determining the level of a biomarker in the sample, wherein the biomarker is a CAP; (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0318] In some embodiments, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) administering the treatment compound to a sample from the subject; (b) determining the level of a biomarker in the sample, wherein the biomarker is a CAP; (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0319] In some embodiments, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, which has been administered to the subject, comprising: (a) determining the level of a biomarker in a sample obtained from the subject, wherein the biomarker is a CAP; (d) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from the level of the biomarker obtained from a reference sample; wherein the treatment compound is Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0320] In some embodiments, provided herein is a method of monitoring the efficacy of a treatment of cancer in a subject with a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compound has been administered, wherein the biomarker is a CAP; (b) comparing the level of the biomarker in the sample with the level of the biomarker obtained from a reference sample, wherein a change in the biomarker level is indicative of the efficacy of the treatment compound in treating the cancer in the subject; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0321] In some embodiments, provided herein is a method of monitoring the efficacy of a treatment of cancer in a subject with a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compound has been administered, wherein the biomarker is a CAP; (b) comparing the level of the biomarker in the sample with the level of the biomarker obtained from a reference sample, wherein a change in the biomarker level is indicative of the efficacy of the treatment compound in treating the cancer in the subject; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0322] In some embodiments, provided herein is a method of monitoring the efficacy of a treatment of cancer in a subject with a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compound has been administered, wherein the biomarker is a CAP; (b) comparing the level of the biomarker in the sample with the level of the biomarker obtained from a reference sample, wherein a change in the biomarker level is indicative of the efficacy of the treatment compound in treating the cancer in the subject; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0323] In some embodiments, provided herein is a method of monitoring the efficacy of a treatment of cancer in a subject with a treatment compound, which has been administered to the subject, comprising: (a) determining the level of a biomarker in a sample obtained from the subject, wherein the biomarker is a CAP; (b) comparing the level of the biomarker in the sample with the level of the biomarker obtained from a reference sample, wherein a change in the biomarker level is indicative of the efficacy of the treatment compound in treating the cancer in the subject; wherein the treatment compound is Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0324] In some embodiments, the biomarker is a CAP selected from the group consisting of IKZF1, IKZF3, ZFP91, c-MYC, and IRF4. In some embodiments, the biomarker is an Ikaros family member, such as IKZF1 or IKZF3. In a specific embodiment, the biomarker is IKZF1. In another specific embodiment, the biomarker is IKZF3. In a specific embodiment, the biomarker is ZFP91. In some embodiments, the biomarker is a binding partner of, downstream effector of, or a factor in a cellular pathway impacted IKZF1, and IKZF3. For example, in some embodiments, the biomarker is a binding partner of, downstream effector of, or a factor in a cellular pathway impacted by IKZF1, or IKZF3. In a specific embodiment, the biomarker is a downstream effector of IKZF1, such as IRF4. In a specific embodiment, the biomarker is a downstream effector of IKZF3, such as IRF4. In a specific embodiment, the biomarker is a downstream effector of IKZF1, such as c-MYC. In a specific embodiment, the biomarker is a downstream effector of IKZF3, such as c-MYC.

[0325] As shown in the Examples, the level of a biomarker, such CRBN, IKZF1, IKZF3, CTC, soluble BCMA, survivin, serum free light chain, ZFP91, c-MYC, IRF4, pRB1, decreases as compared to a reference in response to Compound 1, Compound 2, or Compound 3 treatment. Accordingly, in some embodiments, the biomarker is selected from the group consisting of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, IRF4, and the level of the biomarker decreases in response to the Compound 1, Compound 2, or Compound 3 treatment. Thus, in some embodiments of the various methods provided herein, the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, IRF4, and wherein the level of the biomarker is lower than a reference level.

[0326] Thus, in some embodiments, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) determining the level of CRBN, IKZF 1, IKZF3, ZFP91, c-MYC, or IRF4, in a sample obtained from a subject to whom the treatment compound has been administered, and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC or IRF4, in a reference sample; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0327] In another embodiment, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) determining the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC or IRF4, in a sample obtained from a subject to whom the treatment compound has been administered, and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC or IRF4, in a reference sample; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0328] In yet another embodiment, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) determining the level of RBN, IKZF1, IKZF3, ZFP91, c-MYC or IRF4, pRB1 in a sample obtained from a subject to whom the treatment compound has been administered, and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN, IKZF1, IKZF3, c-MYC or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC or IRF4, in a reference sample; wherein the treatment compound is Compound 3; or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0329] In another embodiment, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, which has been administered to the subject, comprising: (a) determining the level CRBN, IKZF1, IKZF3, ZFP91, c-MYC or IRF4, in a sample obtained from the subject; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a reference sample; wherein the treatment compound is Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0330] In some embodiments, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) administering the treatment compound to a sample from the patient; (b) (e) determining the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC or IRF4, in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or RF4, in a reference sample; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0331] In some embodiments, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) administering the treatment compound to a sample from the patient; (b) (e) determining the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a reference sample; wherein the treatment compound is Compound 2: or tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0332] In some embodiments, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) administering the treatment compound to a sample; from the patient; (b)(e) determining the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level or CRBN, IKZF1, IKZF3, ZFP91, c-MYC, IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a reference sample; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0333] In some embodiments, provided herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) administering the treatment compound to a sample obtained from the subject; (b) determining the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level or CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a reference sample; wherein the treatment compound is Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0334] In some embodiments, provided herein is a treatment compund for use in a method of treating cancer, comprising: (a) determining the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a sample; from a subject having cancer (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4,-er-pRB4 in a reference sample; and (c) administering a therapeutically effective amount of the treatment compound to the subject; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0335] In some embodiments, provided herein is a treatment compund for use in a method of treating cancer, comprising: (a) determining the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a sample from a subject having the cancer; (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a reference sample; and (c) administering a therapeutically effective amount of the treatment compound to the subject; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0336] In some embodiments, provided herein is a treatment compound for use in a method of treating cancer, comprising: (a) determining the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a sample from a subject having the cancer; (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a reference sample; and (c) administering a therapeutically effective amount of the treatment compound to the subject; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0337] In some embodiments, provided herein is Compound 1, Compound 2 or Compound 3 for use in a method of treating cancer, comprising: (a) determining the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a sample from a subject having the cancer; (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a reference sample; and (c) administering a therapeutically effective amount of the treatment compound to the subject.

[0338] In some embodiments, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compound has been administered, wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a reference sample; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0339] In some embodiments, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) determining the level of a biomarker in a sample, obtained from a subject to whom the treatment compound has been administered, herein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or RF4, in a reference sample; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0340] In some embodiments, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compound has been administered, wherein the biomarker is CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or or IRF4, in the sample; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a reference sample; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0341] In some embodiments, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, which has been administered to the subject, comprising: (a) determining the level of a biomarker in a sample obtained from the subejct, wherein the biomarker is CRBN, IKZF1, IKZF3, c-MYC, or IRF4,in the sample; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a reference sample; wherein the treatment compound is Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0342] In some embodiments, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) administering the treatment compound to a sample from the subject; (b) determining the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a reference sample; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0343] In some embodiments, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) administering the treatment compound to a sample from the subject; (b) determining the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a reference sample; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0344] In some embodiments, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) obtaining a sample from the subject; (a) administering the treatment compound to a sample from the subject; (b) determining the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91,c-MYC, or IRF4, in a reference sample; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0345] In some embodiments, provided herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) administering the treatment compound to a sample obtained from the subject; (b) determining the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample is lower than the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a reference sample; wherein the treatment compound is Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0346] In some embodiments, provided herein is a method of monitoring the efficacy of a treatment of cancer in a subject with a treatment compound, comprising: (a) determining the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a sample obtained from a subject to whom the treatment compound has been administred, and (b) comparing the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample with the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, obtained from a reference sample, wherein a decrease in the level as compared to the reference level is indicative of the efficacy of the treatment compound in treating the cancer in the subject; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0347] In some embodiments, provided herein is a method of monitoring the efficacy of a treatment of cancer in a subject with a treatment compound, comprising: (a) determining the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a sample; obtained from a subject to whom the treatment compound has been administered and (b) comparing the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample with the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, obtained from a reference sample, wherein a decrease in the level as compared to the reference level is indicative of the efficacy of the treatment compound in treating the cancer in the subject; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0348] In some embodiments, provided herein is a method of monitoring the efficacy of a treatment of cancer in a subject with a treatment compound, comprising: (a) (e) determining the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in a sample obtained from a subject to whom the treatment compound has been administered, and (b) comparing the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample with the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, obtained from a reference sample, wherein a decrease in the level as compared to the reference level is indicative of the efficacy of the treatment compound in treating the cancer in the subject; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0349] In some embodiments, provided herein is a method of monitoring the efficacy of a treatment of cancer in a subject with a treatment compound, which has been administered to the subject, comprising: (a) determining the level of CRBN, IKZF1, IKZF3, c-MYC, or IRF4,-er--pRB4 in a sample obtained from the subject; and (b) comparing the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC, or IRF4, in the sample with the level of CRBN, IKZF1, IKZF3, ZFP91, c-MYC 4, or IRF4, obtained from a reference sample, wherein a decrease in the level as compared to the reference level is indicative of the efficacy of the treatment compound in treating the cancer in the subject; wherein the treatment compound is Compound 2, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0350] In specific embodiments of the methods described herein, the reference sample is a sample prior to treatment with the treatment compound.

[0351] In a specific embodiment, the biomarker is CRBN, and the cancer is multiple myeloma (MM). In a specific embodiment, the biomarker is CRBN, and the treatment compound is Compound 1, Compound 2, or Compound 3. In a specific embodiment, the treatment compound is Compound 1. In another specific embodiment, the treatment compound is Compound 2. In yet another specific embodiment, the treatment compound is Compound 3.

[0352] In a specific embodiment, the biomarker is IKZF1, and the cancer is multiple myeloma (MM). In a specific embodiment, the biomarker is IKZF1, and the treatment compound is Compound 1, Compound 2, or Compound 3. In a specific embodiment, the treatment compound is Compound 1. In another specific embodiment, the treatment compound is Compound 2. In yet another specific embodiment, the treatment compound is Compound 3.

[0353] In a specific embodiment, the biomarker is IKZF3, and the cancer is multiple myeloma (MM). In a specific embodiment, the biomarker is IKZF3, and the treatment compound is Compound 1, Compound 2, or Compound 3. In a specific embodiment, the treatment compound is Compound 1. In another specific embodiment, the treatment compound is Compound 2. In yet another specific embodiment, the treatment compound is Compound 3.

[0354] In a specific embodiment, the biomarker is ZFP91, and the cancer is multiple myeloma (MM). In a specific embodiment, the biomarker is ZFP91, and the treatment compound is Compound 1, Compound 2, or Compound 3. In a specific embodiment, the treatment compound is Compound 1. In another specific embodiment, the treatment compound is Compound 2. In yet another specific embodiment, the treatment compound is Compound 3.

[0355] In a specific embodiment, the biomarker is c-MYC, and the cancer is multiple myeloma (MM). In a specific embodiment, the biomarker is c-MYC, and the treatment compound is Compound 1, Compound 2, or Compound 3. In a specific embodiment, the treatment compound is Compound 1. In another specific embodiment, the treatment compound is Compound 2. In yet another specific embodiment, the treatment compound is Compound 3.

[0356] In a specific embodiment, the biomarker is IRF4, and the cancer is multiple myeloma (MM). In a specific embodiment, the biomarker is IRF4, and the treatment compound is Compound 1, Compound 2, or Compound 3. In a specific embodiment, the treatment compound is Compound 1. In another specific embodiment, the treatment compound is Compound 2. In yet another specific embodiment, the treatment compound is Compound 3.

[0357] In some embodiments, provided herein is a method of identifying a subject with multiple myeloma that is relapsed, refractory, or resistant to conventional therapy who is likely to be responsive to a treatment compound, comprising: (a) detecting the level of CRBN in a sample comprising a cancer cell from a subject; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN in the sample is detectable and lower than a reference level of CRBN; wherein the treatment compound is a compound of Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0358] In another embodiment, provided herein is a method of identifying a subject with multiple myeloma that is relapsed, refractory, or resistant to conventional therapy who is likely to be responsive to a treatment compound, comprising: (a) detecting the level of CRBN in a sample; comprising a cancer cell from a subject; and (b) (e) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN in the sample is detectable and lower than a reference level of CRBN; wherein the treatment compound is a compound of Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0359] In yet another embodiment, provided herein is a method of identifying a subject with multiple myeloma that is relapsed, refractory, or resistant to conventional therapy who is likely to be responsive to a treatment compound, comprising: (a) detecting the level of CRBN in a sample comprising a cancer cell from a subject, and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN in the sample is detectable and lower than a reference level of CRBN; wherein the treatment compound is a compound of Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0360] In some embodiments, provided herein is a method of identifying a subject with multiple myeloma that is relapsed, refractory, or resistant to conventional therapy who is likely to be responsive to a treatment compound, comprising: (a) detecting the level of CRBN in a sample obtained from a subejct; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN in the sample is detectable and lower than a reference level of CRBN; wherein the treatment compound is a compound of Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0361] In another aspect, provided herein is a method of predicting the responsiveness of a subject having multiple myeloma to a treatment compound, comprising: (a) detecting the level of CRBN in a sample comprising a cancer cell from a subject, and (b) (e) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN in the sample is detectable and lower than a reference level of CRBN; wherein the treatment compound is a compound of Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0362] In another embodiment, provided herein is a method of predicting the responsiveness of a subject having multiple myeloma to a treatment compound, comprising: (a) (b) detecting the level of CRBN in a sample comprising a cancer cell from a subject, and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN in the sample is detectable and lower than a reference level of CRBN; wherein the treatment compound is a compound of Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0363] In yet another embodiment, provided herein is a method of predicting the responsiveness of a subject having multiple myeloma to a treatment compound, comprising: (a) detecting the level of CRBN in a sample comprising a cancer cell from a subject, and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN in the sample is detectable and lower than a reference level of CRBN; wherein the treatment compound is a compound of Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0364] In another embodiment, provided herein is a method of predicting the responsiveness of a subject having multiple myeloma to a treatment compound, comprising: (a) detecting the level of CRBN in a sample obtained from the subject; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN in the sample is detectable and lower than a reference level of CRBN; wherein the treatment compound is a compound of Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0365] Thus, in some embodiments, provided herein is a method of detecting CRBN levels in a cancer cell and diagnosing the subject as being likely to be responsive to the treatment compound if the level of CRBN in the sample is detectable and lower than a reference level of CRBN. In some embodiments the MM is relapsed, refractory, or resistant to conventional therapy. In one embodiment, the MM is lenalidomide-resistant MM. In another embodiment, the MM is pomalidomide-resistant MM. As described in the Examples in Section 6, Compound 2 also has immunomodulatory properties in PBMCs, and CD4+ and CD8+ T-cells. Therefore, in one embodiment of the methods provided herein, CRBN is not detectable in the cancer cell and CRBN is detectable in the immune cell, and the patient is responsive to Compound 1. In another embodiment of the methods provided herein, CRBN is not detectable in the cancer cell and CRBN is detectable in the immune cell, and the patient is responsive to Compound 2. In yet another embodiment of the methods provided herein, CRBN is not detectable in the cancer cell and CRBN is detectable in the immune cell, and the patient is responsive to Compound 1.

[0366] In another aspect, provided herein is a method of determining a dosage for treating a subject having multiple myeloma with a treatment compound comprising: determining the level of IKZF1, IKZF3, or both in the one or more sample that have been obtained at different time points from the subject to whom a dosage of the treatment compound has been administered, and thereby determining if the dosage is appropriate or needs an adjustment; wherein the treatment compound is a compound of Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0367] In another embodiment, provided herein is a method of determining a dosage for treating a subject having multiple myeloma with a treatment compound comprising: determining the level of IKZF1, IKZF3, or both in the one or more samples that have been obtained at different time points from the subject to whom a dosage of the treatment compound has been administered, and thereby determining if the dosage is appropriate or needs an adjustment; wherein the treatment compound is a compound of Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0368] In yet another embodiment, provided herein is a method of determining a dosage for treating a subject having multiple myeloma with a treatment compound comprising: determining the level of IKZF1, IKZF3, or both in the one or more sample that have been obtained at different time points from the subject to whom a dosage of the treatment compound has been administered, and thereby determining if the dosage is appropriate or needs an adjustment wherein the treatment compound is a compound of Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0369] In another embodiment, provided herein is a method of determining a dosage for treating a subject having multiple myeloma with a treatment compound, which has been administered to the subject, comprising: (a) determining the level of IKZF 1, IKZF3, or both in one or more samples obtained from the subject, and thereby determining if the dosage is appropriate or needs an adjustment; wherein the treatment compound is a compound of Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0370] As disclosed herein the level of the biomarker may increase with the compound treatment. In some examples, the biomarker is selected from the group consisting of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, and TCR clonality and the level of the biomarker increases as compared to the level in a reference sample prior to treatment with a treatment compound. In some examples, the biomarker has a function in apoptosis, and the level of the biomarker increases as compared to the level in a reference sample prior to treatment with a treatment compound. In other examples, the biomarker has a function in T-cell activation and the level of the biomarker increases as compared to the level in a reference sample prior to treatment with a treatment compound.

[0371] Thus, disclosed herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) administering the treatment compound to the subject; (b) obtaining a sample from the subject; (c) determining the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; and (d) diagnosing the subject as being likely to be responsive to the treatment compound if the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0372] Disclosed herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) administering the treatment compound to the subject; (b) obtaining a sample from the subject; (c) determining the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; and (d) diagnosing the subject as being likely to be responsive to the treatment compound if the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0373] Disclosed herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) administering the treatment compound to the subject; (b) obtaining a sample from the subject; (c) determining the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; and (d) diagnosing the subject as being likely to be responsive to the treatment compound if the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; wherein the treatment compound is Compound 3; or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0374] Disclosed herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, which has been administered to the subject, comprising: (a) determining the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a sample obtained from the subject; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; wherein the treatment compound is Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0375] Disclosed herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) obtaining a sample from the subject; (b) administering the treatment compound to the sample; (c) determining the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; and (d) diagnosing the subject as being likely to be responsive to the treatment compound if the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0376] Disclosed herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) obtaining a sample from the subject; (b) administering the treatment compound to the sample; (c) determining the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; and (d) diagnosing the subject as being likely to be responsive to the treatment compound if the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0377] Disclosed herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) obtaining a sample from the subject; (b) administering the treatment compound to the sample; (c) determining the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; and (d) diagnosing the subject as being likely to be responsive to the treatment compound if the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0378] Disclosed herein is a method of identifying a subject having cancer who is likely to be responsive to a treatment compound, comprising: (a) administering the treatment compound to a sample obtained from the subject; (c) determining the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; and (d) diagnosing the subject as being likely to be responsive to the treatment compound if the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; wherein the treatment compound is Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0379] Disclosed herein is a method of treating cancer, comprising: (a) obtaining a sample from a subject having the cancer; (b) determining the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; and (d) administering a therapeutically effective amount of the treatment compound to the subject; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0380] Disclosed herein is a method of treating cancer, comprising: (a) obtaining a sample from a subject having the cancer; (b) determining the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; and (d) administering a therapeutically effective amount of the treatment compound to the subject; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0381] Disclosed herein is a method of treating cancer, comprising: (a) obtaining a sample from a subject having the cancer; (b) determining the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; and (d) administering a therapeutically effective amount of the treatment compound to the subject; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0382] Disclosed herein is Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof for use in a method of treating cancer, comprising: (a) obtaining a sample from a subject having the cancer; (b) determining the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; and (d) administering a therapeutically effective amount of the treatment compound to the subject.

[0383] Disclosed herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) administering the treatment compound to the subject; (b) obtaining a sample from the subject; (c) determining the level of a biomarker in the sample, wherein the biomarker is Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; and (d) diagnosing the subject as being likely to be responsive to the treatment compound if the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0384] Disclosed herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) administering the treatment compound to the subject; (b) obtaining a sample from the subject; (c) determining the level of a biomarker in the sample, wherein the biomarker is Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; and (d) diagnosing the subject as being likely to be responsive to the treatment compound if the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0385] Disclosed herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) administering the treatment compound to the subject; (b) obtaining a sample from the subject; (c) determining the level of a biomarker in the sample, wherein the biomarker is Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; and (d) diagnosing the subject as being likely to be responsive to the treatment compound if the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0386] Disclosed herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, which has been administered to the subject, comprising: (a) determining the level of a biomarker in a sample obtained from the subject, wherein the biomarker is Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; wherein the treatment compound is Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0387] Disclosed herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) obtaining a sample from the subject; (b) administering the treatment compound to the sample; (c) determining the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; and (d) diagnosing the subject as being likely to be responsive to the treatment compound if the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0388] Disclosed herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) obtaining a sample from the subject; (b) administering the treatment compound to the sample; (c) determining the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; and (d) diagnosing the subject as being likely to be responsive to the treatment compound if the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; wherein the treatment compound is Compound 2: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0389] Disclosed herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) obtaining a sample from the subject; (b) administering the treatment compound to the sample; (c) determining the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; and (d) diagnosing the subject as being likely to be responsive to the treatment compound if the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; wherein the treatment compound is Compound 3: or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0390] Disclosed herein is a method of predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) administering the treatment compound to a sample obtained from the subject; (b) determining the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound if the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in the sample is higher than the level of Caspase 1, Caspase-3, Caspase 7, PARP, IFNγ, TNFα, IL2, p21, p27, BIM, or TCR clonality in a reference sample; wherein the treatment compound is Compound 1, Compound 2 or Compound 3 or a tautomer, isotopolog, or pharmaceutically acceptable salt thereof.

[0391] Disclosed herein is a meth...

Claims

1. A method of identifying a subject having cancer who is likely to be responsive to a treatment compound or predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) determining the level of a biomarker in a sample obtained from a subject to whom the treatment compound has been administered; and (b) diagnosing the subject as being likely to be responsive to the treatment compound, if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; and wherein the biomarker is cereblon (CRBN), IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

2. A method of identifying a subject having cancer who is likely to be responsive to a treatment compound or predicting the responsiveness of a subject having or suspected of having cancer to a treatment compound, comprising: (a) administering the treatment compound to a sample from the subject; (b) determining the level of a biomarker in the sample; and (c) diagnosing the subject as being likely to be responsive to the treatment compound, if the level of the biomarker in the sample is different from a reference level of the biomarker; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; and wherein the biomarker is cereblon (CRBN), IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

3. A method of monitoring the efficacy of a treatment compound in treating cancer in a subject, comprising: (a) determining the level of a biomarker in a sample obtained from the subject to whom the compound has been administered; and (b) comparing the level of the biomarker in the sample with the level of the biomarker obtained from a reference sample, wherein a change in the biomarker level is indicative of the efficacy of the treatment compound in treating the cancer in the subject; wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; and wherein the biomarker is cereblon (CRBN), IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

4. The method of claim 3, wherein an increased level of the biomarker as compared to the reference level is indicative of the efficacy of the treatment compound in treating the cancer in the subject; or wherein a decreased level of the biomarker as compared to the reference level is indicative of the efficacy of the treatment compound in treating the cancer in the subject.

5. A treatment compound for use in a method of treating cancer in a subject, wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; and wherein the method comprises the steps defined in any one of claims 1 to 4 and further comprises administering a therapeutically effective amount of the treatment compound to the subject diagnosed as being likely to be responsive to the treatment compound.

6. A treatment compound for use in a method of treating cancer in a subject, wherein the treatment compound is Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; and wherein the method comprises: (a) determining the level of a biomarker in a sample obtained from the subject; (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is different from a reference level of the biomarker; and (c) administering a therapeutically effective amount of the treatment compound to the subject diagnosed as being likely to be responsive to the treatment compound, and wherein the biomarker is cereblon (CRBN), IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

7. The treatment compound for use of claim 5 or 6, further comprising administering a therapeutically effective amount of a second active agent or a support care therapy; optionally wherein the second active agent is selected from the group comprising large molecules, small molecules, or cell therapies, and the second active agent is optionally selected from a group comprising of melphalan, vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, a proteasome inhibitor, a histone deacetylase inhibitor, a BET inhibitor, a BCL2 inhibitor, an MCL-1 inhibitor, a corticosteroid, dexamethasone, an antibody, a checkpoint inhibitor, and CAR cells.

8. The method of any one of claims 1 to 4 or treatment compound for use of any one of claims 5 to 7, wherein the subject from whom the reference sample has been obtained is: (i) the subject prior to administration of the treatment compound, and wherein the reference sample is from the same source as the sample; (ii) a healthy subject not having the cancer, and wherein the reference sample is from the same source as the sample; or (iii) a subject receiving an anti-cancer compound that is not said treatment compound, and wherein the reference sample is from the same source as the sample.

9. The method or treatment compound for use of claim 8(iii), wherein said anti-cancer compound is lenalidomide or pomalidomide.

10. The method or treatment compound for use of any one of claims 1 to 9, wherein the cancer is multiple myeloma (MM); optionally wherein the MM is relapsed, refractory, or resistant to conventional therapy.

11. The method, or treatment compound for use of any one of claims 1 to 10, wherein the level of the biomarker is higher than a reference level; or wherein the level of the biomarker is lower than a reference level.

12. A method of identifying a subject with multiple myeloma that is relapsed, refractory, or resistant to conventional therapy who is likely to be responsive to a treatment compound or of predicting the responsiveness of a subject having multiple myeloma to a treatment compound, comprising: (a) determining the level of a biomarker in a sample from the subject; and (b) diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is lower than a reference level of the biomarker; wherein the treatment compound is a compound of Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; and wherein the biomarker is cereblon (CRBN), IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

13. The method of claim 12, comprising diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample is lower than the reference of the biomarker; or diagnosing the subject as being likely to be responsive to the treatment compound if the biomarker is detectable in the sample.

14. The method or treatment compound for use of any one of claims 1 to 13, wherein: the level of the biomarker is measured by determining: (i) the protein level of the biomarker; (ii) the mRNA level of the biomarker; or (iii) the cDNA level of the biomarker; or the biomarker is determined by: (iv) DNA sequencing; or (v) RNA-sequencing (RNA-seq).

15. The method or treatment compound for use of claim 14(i), wherein the method comprises contacting proteins within the sample with a first antibody that immunospecifically binds to the biomarker protein.

16. The method or treatment compound for use of claim 15, wherein the method further comprises: (a) (i) contacting the biomarker protein bound to the first antibody with a second antibody with a detectable label, wherein the second antibody immunospecifically binds to the biomarker protein, and wherein the second antibody immunospecifically binds to a different epitope on the biomarker protein than the first antibody; (ii) detecting the presence of the second antibody bound to the biomarker protein; and (iii) determining the amount of the biomarker protein based on the amount of detectable label in the second antibody; or (b) (i) contacting the first antibody bound to the biomarker protein with a second antibody with a detectable label, wherein the second antibody immunospecifically binds to the first antibody; (ii) detecting the presence of the second antibody bound to the first antibody; and (iii) determining the amount of the biomarker protein based on the amount of detectable label in the second antibody.

17. A method of determining a dosage of a treatment compound in a subject having multiple myeloma and undergoing treatment with said treatment compound comprising determining the level of a biomarker in one or more samples that have been obtained at different times from the subject to whom a dosage of the treatment compound has been administered, and thereby determining if the dosage is appropriate or needs an adjustment; wherein the treatment compound is a compound of Compound 1: or an enantiomer, mixture of enantiomers, tautomer, isotopolog, or pharmaceutically acceptable salt thereof; and wherein the biomarker is cereblon (CRBN), IKZF1, IKZF3, ZFP91, c-MYC, or IRF4.

18. The method, or treatment compound for use of any preceding claim, wherein the enantiomer is: or