Treatment of multiple myeloma and use of the biomarker 4-(4-(4-(((2-(2,6-dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)oxy)methyl)benzyl)piperazine-1-yl)-3-fluorobenzonitrile

Abstract

To provide a method of identifying a subject having cancer who is likely to be responsive to a treatment compound.SOLUTION: A method includes: administering the treatment compound to the subject having the cancer; obtaining a sample from the subject; determining the level of a biomarker in the sample from the subject; and diagnosing the subject as being likely to be responsive to the treatment compound if the level of the biomarker in the sample of the subject changes as compared to a reference level of the biomarker; wherein the treatment compound is Compound 1, Compound 2, or Compound 3.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] This invention is based on U.S. Provisional Application No. 62 / 675,732, filed on May 23, 2018, and And claiming the interests of U.S. Provisional Application 62 / 737,772 filed on September 27, 2018, These are incorporated herein by reference in their entirety.

[0002] 1. Technical field In some embodiments, what is provided herein is 4-(4-(4-(((2-( 2,6-Dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)Oxy Methyl benzyl piperazine-1-yl-3-fluorobenzonitrile, or Enantiomers, mixtures of enantiomers, tautomers, or pharmaceutically acceptable thereof When predicting and monitoring clinical sensitivity and treatment response to salts, CRBN, i Oros (IKZF3), Ikaros (IKZF1), Zinc Finger Protein 91 (Z FP91), c-Myc, interferon regulator 4 (IRF4), tumor immunomarkers (Soluble CD25, cytokine; tumor-infiltrating lymphocytes (TILs); T cell activation, T cells Receptor clonal), circulating tumor cells (CTCs), soluble BCMA (sBCMA), Apot - Systolic markers (cleavage caspase-1, cleavage caspase-7, cleavage caspase-3) , cleavage-type PARP, Survivin, BCL-2-like protein 11 (BIM), TUNEL, Free light chains (FLCs), and cell cycle markers (p21, p27, pRb1), etc. Methods using specific biomarkers, and using them to treat and predict multiple myeloma. This refers to methods for preventing or managing multiple myeloma. For use in methods for treatment, prevention or management, 4-(4-(4-(((2-( 2,6-Dioxopiperidine-3-yl)-1-oxoisoindorin-4-yl)Oxy Methyl benzyl piperazine-1-yl-3-fluorobenzonitrile, or The enantiomer, mixture of enantiomers, tautomers, or pharmaceutically acceptable It is a salt. Also, in certain embodiments, what is provided herein is a possible response Methods for identifying patients with high susceptibility, methods for predicting patient responsiveness, methods for determining medication dosage, This is a method for determining the effectiveness of a compound in treating a disease. [Background technology]

[0003] 2. Background technology Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow. Normally, plasma cells are immune to antibodies. They produce and play an important role in immune function. However, these cells are not controlled. Rapid growth can cause bone pain and fractures, anemia, infections, and other complications. Although multiple myeloma is the second most common hematological malignancy, the exact cause of multiple myeloma remains unknown. Multiple myeloma is characterized by the presence of M protein and other immunoglobulins in the blood, urine, and organs. This includes, but is not limited to, antibodies, albumin, and beta-2-microglobulin. It causes high levels of proteins that cannot be produced, but myeloma cells secrete these proteins. Except for a small percentage of patients (estimated 1%-5%) who do not have paraproteins (called non-secretory myeloma). M protein, an abbreviation for monoclonal protein also known as , is a myeloma phenotype. A particularly abnormal protein produced by cells, and presents in almost all individuals with multiple myeloma. It may be found in the patient's blood or urine, but in patients with non-secretory myeloma or in their bone marrow. Excluding patients in whom tumor cells produce immunoglobulin light chains along with heavy chains.

[0004] Skeletal symptoms, including bone pain, are one of the most clinically prominent symptoms of multiple myeloma. Osteoclasts are cells that cause calcium to leak out of the bone, thereby leading to lytic lesions. It releases stimulating factors (including IL-1, IL-6, and TNF). Hypercalcemia is also This is one of the symptoms. Osteoclast-stimulating factors, also called cytokines, are involved in apoptosis. In other words, it prevents the death of myeloma cells. 50% of patients have radiologically detectable bone marrow at the time of diagnosis. It has tumor-associated skeletal lesions. Other common clinical manifestations of multiple myeloma include polyneuropathy and adenoma. This includes blood, hyperviscosity, infection, and renal failure.

[0005] Current multiple myeloma therapy involves surgery to eradicate multiple myeloma cells in the patient, and stem cell surgery. This may include one or more of the following: cell transplantation, chemotherapy, immunotherapy, and / or radiotherapy. All current treatment approaches present significant drawbacks for the patient.

[0006] Over the past decade, new therapeutic agents have emerged, particularly immunomodulatory drugs such as lenalidomide and pomalidomide. The drug significantly improved the response rate in patients with multiple myeloma, and also improved progression-free survival (PFS) and It extended overall survival (OS). However, in some patients with multiple myeloma... Even after these patients achieved a complete response (CR), bone marrow (BM) morphology and immunofixation remained. Persistent levels of residual lesions below the sensitivity of protein electrophoresis and light chain quantification are present. This can ultimately lead to a relapse of the disease.

[0007] Multiple myeloma can be treated while reducing or avoiding the toxicity and / or side effects associated with conventional therapies. , treating multiple myeloma, including newly diagnosed patients or those whose condition is refractory to standard treatment. There is a significant need for safe and effective compounds and methods for prevention and control. do. [Overview of the project]

[0008] 3. Outline of the Invention In one embodiment, the herein provides a cancer that is likely to respond to a therapeutic compound. A method for identifying an object that possesses, (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Determining the level of biomarkers in the sample, (d) When the level of the biomarker in the sample differs from the reference level of the biomarker. This includes diagnosing the subject as likely to respond to therapeutic compounds, and the therapeutic compounds The substance is compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0009] In another embodiment, what is provided herein is likely to respond to therapeutic compounds, A method for identifying an object that possesses (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Determining the level of biomarkers in the sample, (d) When the level of the biomarker in the sample differs from the reference level of the biomarker. This includes diagnosing the subject as likely to respond to therapeutic compounds, and the therapeutic compounds The substance is compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0010] In yet another embodiment, what is provided herein is a compound that is highly likely to respond to therapeutic compounds. i. A method for identifying subjects who have cancer, (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Determining the level of biomarkers in the sample, (d) When the level of the biomarker in the sample differs from the reference level of the biomarker. This includes diagnosing the subject as likely to respond to therapeutic compounds, and the therapeutic compounds The substance is compound 3: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0011] In some embodiments, what is provided herein is the possibility of responding to therapeutic compounds. A method for identifying subjects with a high risk of cancer, (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Determining the level of biomarkers in the sample, (d) When the level of the biomarker in the sample differs from the reference level of the biomarker. This includes diagnosing the subject as likely to respond to therapeutic compounds, and the therapeutic compounds The substance is compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0012] In another embodiment, what is provided herein is likely to respond to therapeutic compounds. A method for identifying subjects who have cancer, (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Determining the level of biomarkers in the sample, (d) When the level of the biomarker in the sample differs from the reference level of the biomarker. This includes diagnosing the subject as likely to respond to therapeutic compounds, and the therapeutic compounds The substance is compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0013] In yet another embodiment, what is provided herein is the possibility of responding to therapeutic compounds. A method for identifying subjects with a high risk of cancer, (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Determining the level of biomarkers in the sample, (d) When the level of the biomarker in the sample differs from the reference level of the biomarker. This includes diagnosing the subject as likely to respond to therapeutic compounds, and the therapeutic compounds The substance is compound 3: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0014] In some embodiments, what is provided herein is the possibility of responding to therapeutic compounds. This is a method for identifying subjects with high levels of cancer, and the level of biomarkers in the sample is Higher than the reference level of the biomarker. In other embodiments, provided herein are This is a method for identifying cancer patients who are likely to respond to therapeutic compounds, and the sample The levels of the biomarkers inside are lower than the reference levels of the biomarkers.

[0015] In some embodiments, what is provided herein is a method for treating cancer, (a) Obtaining samples from subjects with cancer, (b) Determining the level of biomarkers in the sample, (c) When the level of the biomarker in the sample differs from the reference level of the biomarker. , to diagnose the subject as likely to respond to the therapeutic compound, (d) In subjects diagnosed as likely to respond to the therapeutic compound, a therapeutically effective amount of the This includes administering therapeutic compounds, The therapeutic compound is compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0016] In another embodiment, provided herein is a method for treating cancer, (a) Obtaining samples from subjects with cancer, (b) Determining the level of biomarkers in the sample, (c) If the level of the biomarker in the sample differs from the reference level of the biomarker, To diagnose the subject as likely to respond to the therapeutic compound, (d) In subjects diagnosed as likely to respond to the therapeutic compound, a therapeutically effective dose of the treatment. The administration of the compound, The therapeutic compound is compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0017] In yet another embodiment, provided herein is a method for treating cancer, (a) Obtaining samples from subjects with cancer, (b) Determining the level of biomarkers in the sample, (c) When the level of the biomarker in the sample differs from the reference level of the biomarker. , to diagnose the subject as likely to respond to the therapeutic compound, (d) In subjects diagnosed as likely to respond to the therapeutic compound, a therapeutically effective amount of the This includes administering therapeutic compounds, The therapeutic compound is compound 3: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0018] In some embodiments, what is provided herein is a method for treating cancer, and an experiment The level of the biomarker in the sample is higher than the reference level of the biomarker. Other implementations In this specification, the present invention provides a method for treating cancer, wherein a biomarker in a sample The level of - is lower than the reference level of the biomarker. Also, the level provided herein Compounds 1 and 2 and for use in methods for treating cancer as described above. It is compound 3.

[0019] In some embodiments, what is provided herein is a therapeutic compound for cancer A method for predicting the responsiveness of a subject who has cancer or is suspected of having cancer, (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Determining the level of biomarkers in the sample, (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If it differs from Bell's, the subject should be diagnosed as likely to respond to the therapeutic compound, Including, The therapeutic compound is compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0020] In another embodiment, provided herein are therapeutic compounds for cancer A method for predicting the responsiveness of a subject or a subject suspected of having cancer, (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Determining the level of biomarkers in the sample, (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If it differs from Bell's, the subject should be diagnosed as likely to respond to the therapeutic compound, Including, The therapeutic compound is compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0021] In yet another embodiment, what is provided herein is a therapeutic compound for cancer A method for predicting the responsiveness of a subject who has cancer or is suspected of having cancer, (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Determining the level of biomarkers in the sample, (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If it differs from Bell's, the subject should be diagnosed as likely to respond to the therapeutic compound, Including, The therapeutic compound is compound 3: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0022] In another embodiment, the foregoing provides for therapeutic compounds for subjects with cancer. or a method for predicting the responsiveness of a subject suspected of having cancer, (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Determining the level of biomarkers in the sample, (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If it differs from Bell's, the subject should be diagnosed as likely to respond to the therapeutic compound, Including, The therapeutic compound is compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0023] In another embodiment, provided herein are therapeutic compounds for cancer A method for predicting the responsiveness of a subject or a subject suspected of having cancer, (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Determining the level of biomarkers in the sample, (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If it differs from Bell's, the subject should be diagnosed as likely to respond to the therapeutic compound, Including, The therapeutic compound is compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0024] In yet another embodiment, what is provided herein is a therapeutic compound for cancer A method for predicting the responsiveness of a subject who has cancer or is suspected of having cancer, (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Determining the level of biomarkers in the sample, (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If it differs from Bell's, the subject should be diagnosed as likely to respond to the therapeutic compound, Including, The therapeutic compound is compound 3: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0025] In some embodiments, what is provided herein is a therapeutic compound for cancer A method for predicting the responsiveness of subjects who have cancer or are suspected of having cancer, in the sample In other embodiments, the biomarker level is higher than the reference level of the biomarker. Provided herein are therapeutic compounds for subjects having cancer or cancer This is a method for predicting the responsiveness of a suspected subject, and the level of biomarkers in the sample is It is lower than the reference level of the biomarker.

[0026] In another aspect, what is provided herein is the treatment of cancer in a subject A method for monitoring the effectiveness of therapeutic compounds, (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Determining the level of biomarkers in the sample, (d) The level of the biomarker in the sample is compared to the level of the biomarker obtained from the reference sample. The comparison is with Bell, and changes in biomarker levels indicate that cancer is being treated in the subjects. This includes demonstrating the effectiveness of therapeutic compounds in doing so, and making comparisons. The therapeutic compound is compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0027] In some embodiments, what is provided herein is a method for treating cancer in a subject. A method for monitoring the effectiveness of therapeutic compounds in and (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Determining the level of biomarkers in the sample, (d) The level of the biomarker in the sample is compared to the level of the biomarker obtained from the reference sample. The comparison is with Bell, and changes in biomarker levels indicate that cancer is being treated in the subjects. This includes demonstrating the effectiveness of therapeutic compounds in doing so, and making comparisons. The therapeutic compound is compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0028] In another embodiment, provided herein is a method for treating cancer in a subject. A method for monitoring the effectiveness of a therapeutic compound, (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Determining the level of biomarkers in the sample, (d) The level of the biomarker in the sample is compared to the level of the biomarker obtained from the reference sample. The comparison is with Bell, and changes in biomarker levels indicate that cancer is being treated in the subjects. To demonstrate the effectiveness of therapeutic compounds in doing so, to compare and include therapeutic compounds However, compound 3: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0029] In some embodiments, what is provided herein is a method for treating cancer in a subject. This is a method for monitoring the effectiveness of therapeutic compounds in and compared to a reference level. Increased levels of biomarkers indicate therapeutic use in treating cancer in the target population. The effectiveness of the compound is demonstrated. In some embodiments, the subject odor is provided herein. This is a method for monitoring the effectiveness of therapeutic compounds in treating cancer, and The decreased level of biomarkers compared to the illumination level indicates that the cancer in the subject was treated. This demonstrates the efficacy of therapeutic compounds in [the relevant context].

[0030] In some embodiments, subjects with cancer who are likely to respond to therapeutic compounds are selected. The identification method involves identifying subjects diagnosed as likely to respond to therapeutic compounds, and then determining if they are therapeutically effective. Further comprising administering a certain amount of the therapeutic compound. In additional embodiments, the therapeutic compound A method for predicting the response of subjects with cancer or suspected of having cancer. This involves administering a therapeutically effective amount of the therapeutic compound to subjects diagnosed as likely to respond to the therapeutic compound. This further includes administering the compound.

[0031] In some embodiments of any one of the methods provided herein, the reference sample is compared to The reference sample was obtained from the subject before administering the therapeutic compound to the elephant, and the reference sample was obtained from the same source as the sample. It is.

[0032] In some embodiments of any one of the methods provided herein, the reference sample is The sample was obtained from a healthy subject free of the disease, and the reference sample was from the same source as the sample.

[0033] In any one of the embodiments of the methods provided herein, the reference sample is the The sample was obtained from a subject receiving an anticancer compound that is not a therapeutic compound, and the reference sample was the same as the sample. It originates from the same source. In certain embodiments, the reference sample is an antimicrobial agent that is not a therapeutic compound. The sample is obtained from a subject receiving cancer compounds, and the reference sample is from the same source as the sample. The anticancer compounds include lenalidomide, pomalidomide, or derivatives thereof. Selected.

[0034] In some embodiments of the methods provided herein, cancer is multiple myeloma (MM) In some specific embodiments, MM is used for relapsed, refractory, or conventionally treated conditions. In contrast, it is resistant. In one embodiment, MM is lenalidomide-resistant MM. In some embodiments, MM is pomalidomide-resistant MM. In some embodiments, M M is a newly diagnosed MM. In some embodiments, MM is a transplant-eligible MM. Yes. In other embodiments, MM is an unsuitable MM for transplantation.

[0035] In certain embodiments of the methods provided herein, the biomarker is cereblon (CRBN). In some embodiments of the methods provided herein, biomer Kerr is a CRBN-related protein.

[0036] In some embodiments of the methods provided herein, the biomarker is apotosis It functions in the pathway. In yet another embodiment of the method provided herein, Iomarkers have function in the cell cycle pathway. Some of the methods provided herein In some embodiments, the biomarker has a function in T cell activation. In some embodiments of the method provided, the biomarker is circulating tumor cells (CTCs). )

[0037] In some embodiments of the methods provided herein, the biomarker is a tumor infiltration marker. It is a lymphocyte (TIL).

[0038] In some specific embodiments, the biomarker is a CRBN-related protein. Selected from the group consisting of IKZF1, IKZF3, ZFP91, c-MYC, and IRF4. In some specific embodiments, the biomarker is IKZF1. Morphologically, the biomarker is IKZF3. In yet another embodiment, the biomarker The car is ZFP91. In yet another embodiment, the biomarker is c-MYC. Yes, in certain embodiments, the biomarker is IRF4.

[0039] In other embodiments, the biomarker has a function in apoptosis and cleavage type caspase-1 (c-caspase-1), cleavage-type caspase-3 (c-caspase-3), cleavage Dissecting caspase-7 (c-caspase-7), dissecting PARP, Survivin, BIM B It is selected from the group consisting of CL-2-like protein 11 (BIM) and serum free light chains. In a particular embodiment, the biomarker is cleavage caspase-3 (c-caspase-3) ) In some embodiments, the biomarker is cleavage caspase-1 (c-ca In another embodiment, the biomarker is a cleavage caspase. -7 (c-caspase-7). In another embodiment, the biomarker is cleaved PA It is RP. In yet another embodiment, the biomarker is survivalin. In one embodiment, the biomarker is Survivin. In another embodiment, the biomarker is The car is BCL-2-like protein 11 (BIM). In certain embodiments, The omarker is serum free light chain (sFLC).

[0040] In yet another embodiment, the biomarker has a function in apoptosis and terminal Deoxynucleotidyltransferase dUTP Nickel End Labeling (TUNE) Measured by L). In certain embodiments, the biomarker is used in apoptosis. It has function in and is measured by Annexin V and 7-AAD. Furthermore, other implementations In this state, the biomarker has a function in apoptosis, and annexin V and iodine It is measured by propidium (PI).

[0041] In other embodiments of the methods provided herein, the biomarker is used in the cell cycle. It has the function of cyclin-dependent kinase inhibitor 1 (p21), cyclin-dependent kinase Select from the group consisting of enzyme inhibitor 1B (p27) and retinoblastoma protein (pRb1). Selected. In some embodiments, the biomarker is p21. In a particular implementation Morphologically, the biomarker is p27. In yet another embodiment, the biomarker This is pRb1.

[0042] In some embodiments of the methods provided herein, the biomarker is T cell activity It has a function in the transformation of interleukin-2 (IL-2) and tumor necrosis factor alpha (T). NFα, interferon-gamma (IFNγ), and T cell receptor (TCR) clones Selected from the group consisting of sex. In other specific embodiments, the biomarker is IL-2. Yes. In yet another embodiment, the biomarker is TNFα. In this case, the biomarker is IFNγ. In some embodiments, the biomarker It is T cell receptor (TCR) clonal. In certain embodiments, the biomarker is The T cell receptor (TCR) is clonal, and the biomarker is determined by the DNA sequence of the TCR. It is measured by a certain method. In some specific embodiments, the biomarker is T cell activity It has a function in chemical processes, and the level of the biomarker is measured by tissue imaging.

[0043] In some embodiments of the methods provided herein, the level of the biomarker is, It's higher than the illumination level.

[0044] In yet another embodiment of the method provided herein, the level of the biomarker is, It's lower than the illumination level.

[0045] In some embodiments, the herein provides for recurrent, refractory, or conventional Patients with multiple myeloma that are resistant to therapy and are likely to respond to therapeutic compounds. A method for identifying elephants, (a) Obtaining a sample from the subject, (b) Determining the level of biomarkers in the sample, (c) When the level of the biomarker in the sample is lower than the reference level of the biomarker This includes diagnosing the subject as likely to respond to the therapeutic compound, The therapeutic compound is compound 1: [ka] Compounds thereof, or their enantiomers, mixtures of enantiomers, tautomers, isopropyl alcohols The method involves a polog, or a pharmaceutically acceptable salt.

[0046] In another embodiment, provided herein are treatments for relapsed, refractory, or conventionally treated conditions. In contrast, we specifically target patients with resistant multiple myeloma who are highly likely to respond to therapeutic compounds. A method of determination, (a) Obtaining a sample from the subject, (b) Determining the level of biomarkers in the sample, (c) When the level of the biomarker in the sample is lower than the reference level of the biomarker This includes diagnosing the subject as likely to respond to the therapeutic compound, The therapeutic compound is compound 2: [ka] The compound, or its tautomer, isotopolog, or pharmaceutically acceptable salt thereof That is the method.

[0047] In yet another embodiment, the herein provides for recurrent, refractory, or conventional Patients with multiple myeloma that are resistant to therapy and are likely to respond to therapeutic compounds. A method for identifying elephants, (a) Obtaining a sample from the subject, (b) Determining the level of biomarkers in the sample, (c) When the level of the biomarker in the sample is lower than the reference level of the biomarker This includes diagnosing the subject as likely to respond to the therapeutic compound, The therapeutic compound is compound 3: [ka] The compound, or its tautomer, isotopolog, or pharmaceutically acceptable salt thereof That is the method.

[0048] In some embodiments, the present invention provides for multiple occurrences of therapeutic compounds. A method for predicting the responsiveness of a subject with myeloma, (a) Obtaining a sample from the subject, (b) Determining the level of biomarkers in the sample, (c) When the level of the biomarker in the sample is lower than the reference level of the biomarker This includes diagnosing the subject as likely to respond to the therapeutic compound, The therapeutic compound is compound 1: [ka] Compounds thereof, or their enantiomers, mixtures of enantiomers, tautomers, isopropyl alcohols The method involves a polog, or a pharmaceutically acceptable salt.

[0049] In another embodiment, the present invention provides a therapeutic compound for multiple myeloma. A method for predicting the responsiveness of an object having the following characteristics: (a) Obtaining a sample from the subject, (b) Determining the level of biomarkers in the sample, (c) When the level of the biomarker in the sample is lower than the reference level of the biomarker This includes diagnosing the subject as likely to respond to the therapeutic compound, The therapeutic compound is compound 2: [ka] The compound, or its tautomer, isotopolog, or pharmaceutically acceptable salt thereof That is the method.

[0050] In yet another embodiment, the present invention provides for multiple occurrences of therapeutic compounds. A method for predicting the responsiveness of a subject with myeloma, (a) Obtaining a sample from the subject, (b) Determining the level of biomarkers in the sample, (c) When the level of the biomarker in the sample is lower than the reference level of the biomarker This includes diagnosing the subject as likely to respond to the therapeutic compound, The therapeutic compound is compound 3: [ka] The compound, or its tautomer, isotopolog, or pharmaceutically acceptable salt thereof That is the method.

[0051] Specific implementation of a method for predicting the response to therapeutic compounds in subjects with multiple myeloma. Morphologically, the biomarker is CRBN. A therapeutic compound for patients with multiple myeloma. In one particular embodiment of a method for predicting responsiveness to a substance, the method involves the biomass in the sample. If the ker level is detected and is lower than that of the reference sample, the subject is considered to be in response to the therapeutic compound. This includes diagnosing that there is a high probability of having the disease. Regarding therapeutic compounds for subjects with multiple myeloma. In some embodiments of a method for predicting responsiveness, the method involves a biomarker in the sample. If detectable, this includes diagnosing the subject as likely to respond to the therapeutic compound. In some specific embodiments, MM is used to treat relapsed, refractory, or conventional therapies. It is resistant. In one embodiment, MM is lenalidomide-resistant MM. Another embodiment Morphologically, MM is pomalidomide-resistant MM.

[0052] In some embodiments of any one of the methods provided herein, a biomarker The level is measured by determining the protein level of the biomarker. In any other embodiment of the method provided in the specification, the level of the biomarker is It is measured by determining the mRNA level of the biomarker. Provided herein In any further embodiment of the method, the level of the biomarker is bio It is measured by determining the cDNA level of the marker. The method provided herein In one particular embodiment of the law, the biomarker is determined by DNA sequencing. This is determined. In any other embodiment of the methods provided herein, biomass The maker is determined by RNA sequencing (RNA-seq).

[0053] In some embodiments, the level of the biomarker is the protein level of the biomarker. It is measured by determining the bell, and the proteins in the sample are identified as biomarker proteins. This involves contacting the substance with a first antibody that binds immunospecifically to it. In other embodiments, Omarker levels are measured by determining the protein levels of the biomarker. The first method involves immunospecifically binding the proteins in the sample to the biomarker protein. This includes contact with the antibody, (a) The biomarker protein bound to the first antibody is subjected to a detectable label. This involves contacting the second antibody with the biomarker protein, which has immunological properties. Heteroplasty occurs, and the second antibody binds to a different biomarker protein than the first antibody. Immunospecific binding to the tope, and contact with it. (b) Detecting the presence of a second antibody bound to a biomarker protein, (c) Based on the amount of detectable label in the second antibody, the amount of biomarker protein This includes determining and further including

[0054] In yet another embodiment, the level of the biomarker is the level of the biomarker protein It is measured by determining the bell, and the proteins in the sample are identified as biomarker proteins. This involves contacting the substance with a first antibody that binds immunospecifically, (a) A first antibody bound to a biomarker protein, having a detectable label. The process involves contacting the first antibody with the second antibody, so that the second antibody binds immunospecifically to the first antibody. , making contact, (b) To detect the presence of a second antibody bound to the first antibody, (c) Based on the amount of detectable label in the second antibody, the amount of biomarker protein This includes determining and further including

[0055] In certain embodiments, what is provided herein is a method for treating subjects having multiple myeloma. A method for determining or adjusting the dosage of a therapeutic compound for treatment, (a) administering a certain dose of a therapeutic compound to the subject, (b) Obtaining one or more samples from the subject at different time points, (c) Determine the level of biomarkers in one or more samples, and thereby determine the dosage. This includes determining whether it is appropriate or whether adjustments are needed. The therapeutic compound is compound 1: [ka] Compounds thereof, or their enantiomers, mixtures of enantiomers, tautomers, isopropyl alcohols The method involves a polog, or a pharmaceutically acceptable salt.

[0056] In another embodiment, provided herein is a therapeutic application for subjects having multiple myeloma. A method for determining or adjusting the dosage of medication for treatment with a compound, (a) administering a certain dose of a therapeutic compound to the subject, (b) Obtaining one or more samples from the subject at different time points, (c) Determine the level of biomarkers in one or more samples, and thereby determine the dosage. This includes determining whether it is appropriate or whether adjustments are needed. The therapeutic compound is compound 2: [ka] The compound, or its tautomer, isotopolog, or pharmaceutically acceptable salt thereof That is the method.

[0057] In yet another embodiment, the present invention provides a method for treating subjects having multiple myeloma. A method for determining or adjusting the dosage of a therapeutic compound for treatment, (a) administering a certain dose of a therapeutic compound to the subject, (b) Obtaining one or more samples from the subject at different time points, (c) Determine the level of biomarkers in one or more samples, and thereby determine the dosage. This includes determining whether it is appropriate or whether adjustments are needed. The therapeutic compound is compound 3: [ka] The compound, or its tautomer, isotopolog, or pharmaceutically acceptable salt thereof That is the method.

[0058] To determine or adjust the dosage of therapeutic compounds for treating patients with multiple myeloma. In some embodiments of the method, the biomarkers consist of IKZF1 and IKZF3. Selected from the group. Dosage for treating a subject with multiple myeloma with a therapeutic compound. In some specific embodiments of the method for determining or adjusting, the biomarker is IKZ It is F1. The dosage of therapeutic compounds to treat patients with multiple myeloma is determined. Or, in yet another specific embodiment of the method of adjustment, the biomarker is IKZF3 ru.

[0059] In some embodiments, a method for treating cancer involves administering a therapeutically effective amount of another second active agent. or further comprising administering support care therapy. In certain embodiments, therapeutic A method for identifying cancer patients who are likely to respond to a compound is to identify patients who are likely to respond to a therapeutic compound. Administering a therapeutically effective amount of the therapeutic compound to subjects diagnosed as likely to respond. Furthermore, it may include administering a therapeutically effective amount of a second active agent or supportive care therapy. This further includes the following. In additional embodiments, the therapeutic compound is used to target a subject with cancer or A method for predicting the responsiveness of subjects suspected of having cancer is a method for predicting the response to therapeutic compounds. This further includes administering a therapeutically effective amount of a therapeutic compound to subjects diagnosed with a high risk of infection. Furthermore, administering a therapeutically effective amount of a second active agent or supportive care therapy may be further indicated. Includes. In certain embodiments, the second activator consists of large molecules, small molecules, or cell therapies. Selected from the group, the second active agent is optionally melphalan, vincristine, or cyclophosphone. Famide, etoposide, doxorubicin, bendamustine, proteasome inhibitors, his Tondeacetylase inhibitors, BET inhibitors, BCL2 inhibitors, MCL-1 inhibitors, cortisol Includes costeroids, dexamethasone, antibodies, checkpoint inhibitors, and CAR cells. Selected from the group.

[0060] In some embodiments provided herein, the compounds provided herein are as described herein. Any treatment, prevention and / or monitoring of any of the diseases provided in the details. It can be used in this way. [Brief explanation of the drawing]

[0061] 4. Brief explanation of the drawing [Figure 1] This document illustrates how compounds 2 and 3 degraded the 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) at the indicated concentrations for 45 minutes, 90 minutes, or 3 hours. Cell extracts were then prepared, and the amount of Aiolos-ePL protein was determined by an ePL luminescence assay.

[0062] [Figure 2]This study exemplifies how compound 2 degrades Aiolos and Ikaros, even in pomalidomide-resistant cells, and, in synergy with dexamethasone, degrades IRF4 and c-MYC. Pomalidomide-sensitive (OPM2) or resistant (OPM2-P1) cells were treated for 72 hours with a vehicle control (DMSO), pomalidomide, or compound 2 alone or in combination with 10 or 100 nM dexamethasone. CRL4CRBN E3 ubiquitin ligase substrates, Aiolos and Ikaros, as well as their downstream effectors, c-Myc and IRF4, were measured. Tubulin was used as a loading control.

[0063] [Figure 3] This study exemplifies how compound 2 degrades Aiolos and Ikaros, even in pomalidomide-resistant cells, and synergistically induces apoptosis with dexamethasone. Pomalidomide-sensitive (OPM2) or resistant (OPM2-P1) cells were treated for 72 hours with a vehicle control (DMSO), pomalidomide, or compound 2 alone or in combination with 10 or 100 nM dexamethasone. Induction of Aiolos and Ikaros, which are CRL4CR BN E3 ubiquitin ligase substrates, as well as apoptotic pathway proteins BIM, cleaved PARP, cleaved caspase-3, and cleaved caspase-7, was measured. Tubulin was used as a loading control.

[0064] [Figure 4] The study exemplifies that compound 2 induced the degradation of Ikaros, Aiolos, ZFP91, c-Myc, and IRF4, which correlates with the induction of the apoptotic protein cleavage 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 the loading control.

[0065] [Figure 5A]This illustrates the requirement of CRBN for compound 2-mediated degradation of Ikaros and Aiolos. Shown are immunoblots of cerebron, Ikaros, and Aiolos from extracts of DF15R and DF15R-human CRBNWT cells incubated with DMSO, pomalidomide, or compound 2 at 0.1 μM for 4 hours. Tubulin is a loading control.

[0066] [Figure 5B] This study exemplifies that Ikaros is required for compound 2-mediated downregulation of c-Myc and IRF4, as well as for the induction of apoptosis. The images show immunoblots of extracts from wild-type OPM2 cells or OPM2 cells overexpressing stabilized Ikaros, Aiolos, or the ZFP91 mutant. Cells were incubated with DMSO or compound 2 at the indicated concentrations for 5 days.

[0067] [Figure 6] This example illustrates how compound 2 degrades Ikaros and Aiolos in a concentration-dependent manner, inducing apoptosis and cell cycle arrest in pomalidomide-resistant multiple myeloma cells. Shown are immunoblot analyses of pomalidomide-resistant MM cells (H929-1051) incubated with compound 2 for 4 hours (Figure 6A) or 72 hours (Figure 6B).

[0068] [Figure 7] This illustrates how compound 2 induces prolonged degradation of Aiolos and Ikaros. The degradation of Aiolos and Ikaros as a percentage of dimethyl sulfoxide (DMSO) control in (Figure 7A) H929-1051 and (Figure 7B) OPM2-P10 cell models after a single sustained exposure to compound 2 is shown. These data are from a single experiment using one sample per data point.

[0069] [Figure 8]It is exemplified that compound 2 induced an extended degradation of Aiolos and Ikaros after 15 minutes of exposure. Compound 2 was incubated with H929-1051 cells for 15 minutes, and the degradation of Aiolos (left panel) and Ikaros (right panel) was measured. The data are from a single experiment using 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 indicates time in hours.

[0070] [Figure 9] It is exemplified that approximately 160 hours were required for the recovery of Aiolos levels after washout from a 6-hour exposure to compound 2. Compound 2 was incubated with H929-1051 cells for 6 hours, and the degradation of Aiolos was measured. These data are from a single experiment using one sample per data point. The vertical blue dotted line divides the data into compound 2 on-treatment (left of the vertical line) and post-washout segments (right of the vertical line). The results are shown for Aiolos levels in OPM2-P10 cells (left) and H929-1051 cells (right) for a total of 160 hours following a 6-hour incubation with 0.01 (red) or 0.1 μM compound 2 (blue).

[0071] [Figure 10] It is exemplified that a sustained but not transient exposure to compound 2 induced apoptosis in multiple myeloma cells. Induction of apoptosis by compound 2 treatment in lenalidomide-resistant MM cell models (H929-1051 [upper panel] and pomalidomide-resistant MM cell model OPM2-P10 [lower panel]) is shown. These data are from a single experiment using one sample per data point.

[0072] [Figure 11]Rather than pomalidomide, Compound 2 is exemplified to exhibit anti-proliferative activity in lenalidomide- and pomalidomide-resistant multiple myeloma cell lines, including those with low CRBN protein levels. An anti-proliferative effect against acquired resistance human multiple myeloma cell lines with low CRBN is shown. Cell lines were treated with (Figure 11A) pomalidomide or (Figure 11B) Compound 2 for 5 days, and IC50 values were evaluated using an ATP determination assay (CellTiter-Glo). The control ratio was calculated by subtracting the background and normalizing to the DMSO control (100% of the control).

[0073] [Figure 12] Exemplified is that dexamethasone (DEX) + Compound 2 induces apoptosis. In a lenalidomide-resistant multiple myeloma cell line (H929-1051), induction of apoptosis after 72-hour treatment with dexamethasone alone or in combination with Compound 2, lenalidomide, or pomalidomide was measured using Caspase-Glo 3 / 7.

[0074] [Figure 13] Exemplified is that short daily exposure to Compound 2 for up to 3 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 on consecutive 1-day (day 14), 2-day (day 15), or 3-day (day 16) starting on day 14. The percentage of Ikaros content (normalized to the DMSO control) is shown. At the end of the exposure period, Compound 2 was removed and the 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 shown as the average of results from two donors.

[0075] [Figure 14]The degradation and recovery of Ikaros following 6-hour exposure to compound 2 for three consecutive days is illustrated. CD34+ bone marrow-derived cells from healthy donors were exposed to compound 2 for 6 hours each of three consecutive days, starting on day 10. The percentage of Ikaros inhibition compared to DMSO is shown. Cultures were incubated in the absence of compound 2 from day 13 to day 22. Ikaros was measured by flow cytometry after the completion of each exposure and every other day during recovery.

[0076] [Figure 15] The degradation and recovery of Ikaros following 6-hour exposure to compound 2 for 5 consecutive days is illustrated. CD34+ bone marrow-derived cells were exposed to compound 2 for 5 consecutive days, starting on day 10. The percentage of Ikaros inhibition compared to DMSO control is shown. Cultures were incubated in the absence of compound 2 from day 15 to day 22. Ikaros was measured by flow cytometry after the completion of each exposure (days 10–14) and every other day during recovery (days 17, 20, and 22).

[0077] [Figure 16] The treatment scheme and the correlation between Ikaros inhibition (dotted line) and neutrophil differentiation (solid line) after exposure to compound 2 are illustrated. (Figure 16A) CD34+ bone marrow-derived cells from healthy donors were cultured ex vivo and stimulated to develop into mature neutrophils in stage IV. (Figure 16B) The cultures were exposed to different concentrations of compound 2 for 6 hours on each of the three days (days 10, 11, and 12), and then cultured until day 22 without further exposure to compound 2. The percentage of Ikaros inhibition compared to DMSO control (circle) following exposure to 1 nM (square), 10 nM (upward-pointing triangle), and 100 nM (downward-pointing triangle) of compound 2 is shown on the right y-axis (dashed line). The percentage of stage IV cells is shown on the left y-axis (solid line). The shaded area represents the three days with exposure to compound 2.

[0078] [Figure 17]This example illustrates how compound 2 directly activates human peripheral blood mononuclear cells (PBMCs) to lyse K562 erythromyelocytic leukemia cells in a concentration-dependent manner. (Figure 17A) Representative fluorescence-activated cell sorting plot of K562 cells co-cultured with human PBMCs pre-incubated with compound 2 or DMSO. (Figure 17B) Apoptotic response in K562 cells after co-culture with PBMCs treated with compound 2. Apoptosis was measured in K562 cells by PI and annexin V staining after co-culture for 24 hours with PBMCs treated with compound 2 for 72 hours. Data are shown as means, and error bars represent the standard error of the mean.

[0079] [Figure 18] This illustrates how immune cells are directly activated by compound 2 to lyse lenalidomide-sensitive and lenalidomide-resistant multiple myeloma cell lines. (Figure 18A) Apoptotic response in NCI-H929 cells after 24 hours of co-culture with PBMCs previously treated with compound 2. (Figure 18B) Apoptotic response in H929-1051 cells after 24 hours of co-culture with PBMCs previously treated with compound 2.

[0080] [Figure 19] This example illustrates that when multiple myeloma cells are pre-treated with lenalidomide, pomalidomide, or compound 2 before co-culture, pre-stimulated immune cells with the compound exhibit enhanced tumor cell death. Pre-stimulated immune cells with the compound showed enhanced tumor cell death in co-culture models (right) of H929 cells (Figure 19A), H929-1051 cells (Figure 19B), OPM2 cells (Figure 19C), and OPM2 P10 cells (Figure 19D), compared to MM single culture (left), with little effect on PBMC survival rate (center).

[0081] [Figure 20]This example illustrates that compound 2 demonstrates greater efficacy than lenalidomide or pomalidomide in inducing interleukin-2 production from anti-CD3 antibody bead-stimulated PBMCs at 72 hours. Induction of interleukin-2 (IL-2) production from anti-CD3 antibody bead-stimulated PBMCs after 72 hours of treatment with compound 2, lenalidomide (LEN), or pomalidomide (POM).

[0082] [Figure 21] This illustrates that compound 2 is a potent inducer of effector cytokines. Measurement of effector cytokine induction during 24-hour treatment with compound 2, pomalidomide (POM), or lenalidomide (LEN). (Figure 21A) IL-2, (Figure 21B) IFN-γ, and (Figure 21C) TNF-α. The data shown are averages from three or four donors and are expressed as a percentage change relative to the DMSO control. Error bars represent the standard error (SEM) of the mean.

[0083] [Figure 22] This illustrates how compound 2 induces Ikaros degradation in CD4+ T cells. Measurements of Ikaros degradation in CD4+ T cells after treatment with compound 2 (diamond), lenalidomide (LEN, round), or pomalidomide (POM, square) at (Figure 22A) 24 hours, (Figure 22B) 48 hours, or (Figure 22C) 72 hours. The data shown are mean values ​​from two donors and are expressed as MFI normalized against DMSO control.

[0084] [Figure 23] This example illustrates how dexamethasone (DEX) combined with compound 2 reduces interleukin-2 (IL-2) production from anti-CD3 antibody-stimulated PBMCs. (Figure 23A) Interleukin-2 production from anti-CD3 antibody-stimulated PBMCs after lenalidomide (LEN) alone or in combination with dexamethasone, (Figure 23B) after pomalidomide (POM) alone or in combination with dexamethasone, or (Figure 23C) after compound 2 alone or in combination with dexamethasone.

[0085] [Figure 24] Compound 2 is exemplified to induce Aiolos degradation in CD3+ T cells from the peripheral blood of relapsed / refractory multiple myeloma patients after a schedule of once daily (QD) 1-10, 15-24 / 28 (Figure 24A) or twice daily (BID) 1-3, 15-17 / 28 (Figure 24B).

[0086] [Figure 25] Compound 2 is exemplified to induce Ikaros degradation in CD3+ T cells from the peripheral blood of relapsed / refractory multiple myeloma patients after a schedule of once daily (QD) 1-10, 15-24 / 28 (Figure 25A) or twice daily (BID) 1-3, 15-17 / 28 (Figure 25B).

[0087] [Figure 26] The effect of Compound 2 on biomarker expression in CD138+ plasma cells from relapsed / refractory multiple myeloma patients is exemplified. (Figure 26A) Aiolos, (Figure 26B) Ikaros, (Figure 26C) ZFP91, (Figure 26D) c-Myc, and (Figure 26E) IRF4.

[0088] [Figure 27] The effect of Compound 2 on soluble BCMA (sBCMA) expression in relapsed / refractory multiple myeloma patients is exemplified.

[0089] [Figure 28] The effect of Compound 2 on serum free light chain (sFLC) in relapsed / refractory multiple myeloma patients is exemplified.

MODE FOR CARRYING OUT THE INVENTION

[0090] 5. DETAILED DESCRIPTION OF THE INVENTION The methods provided herein are, in part, directed to certain molecules (e.g., mR) in a biological sample (NA, cDNA, or proteins) or malignant cells (e.g., circulating tumor cells (CTCs)) )) changed levels, for example, increased levels and / or decreased levels, therapeutic Compounds (e.g., compound 1, compound 2, compound 3, or their enantiomers, enantiomers) (Omer mixtures, tautomers, isotopologs or pharmaceutically acceptable salts) It can be used to predict the responsiveness of subjects who have or are suspected of having MM. Based on the discovery.

[0091] 5.1 Definition As used herein, "comprising" and "incl." The term "comprising" can be used interchangeably. The terms "including" and "contains" indicate the presence of the described features or components. This is interpreted as specifying that one or more features or components should be referenced, This does not prevent the existence or addition of that group. Additionally, "includes (compris The terms "ing)" and "including" mean "consisting of It is intended to include examples encompassed by the term "sting of". The term "consisting of" is more specific to this invention. To provide embodiments, "comprising" and "incl." This term can be used instead of "ding."

[0092] The term "consisting of" means that the objects that make up the object at least 90%, 95%, 97%, 98%, or 99% of the listed characteristics or components It means having a portion. In another embodiment, it means "consisting of The term "of)" is used for any postscript, except for those that are not essential to the technical effect achieved. Exclude any other features or components from the scope of the enumeration.

[0093] As used herein, the term "or" means any one or any combination of It is interpreted as a comprehensive "or" meaning "A, B, or C " is one of the following: "A, B, C, A and B, A and C, B and C, A, B and C" This means that an exception to this definition is a combination of elements, functions, steps, or actions. It only occurs when they are essentially mutually exclusive in some form.

[0094] In general, the technical teachings of one embodiment are not disclosed in any other embodiments provided herein. It can be combined with other things.

[0095] As used herein, the term "cancer" includes solid tumors and blood-derived cancers. However, it is not limited to these. The terms "cancer" and "cancerous" are not strictly defined. This refers to or describes a physiological state in mammals that is typically characterized by vesicular growth. Cancer can be cancer of the hematopoietic and lymphoid tissues. Hematopoietic malignancies include cancers of the blood, bone marrow, and lymphatic tissue. This refers to cancers that affect the blood vessels and lymphatic system.

[0096] As used herein, "multiple myeloma" refers to a hematological condition characterized by malignant plasma cells. This refers to the following disorder: monoclonal gammaglobulinemia of unspecified significance (MGUS); Low-risk, intermediate-risk, and high-risk multiple myeloma; newly diagnosed multiple myeloma (low-risk) Including newly diagnosed multiple myeloma at high risk, intermediate risk, and high risk); transplant eligibility and Multiple myeloma unsuitable for transplantation; smoldering (painless) multiple myeloma (low-risk, intermediate-risk) , and including high-risk smoldering multiple myeloma; active multiple myeloma; solitary phenotypic multiple myeloma. Cytoplasma; Extramedullary plasmacytoma; Plasma cell leukemia; Multiple myeloma of the central nervous system; Light chain myeloma; Non-segmental Urinary myeloma; immunoglobulin D myeloma; and immunoglobulin E myeloma; and cyclitis Multiple myeloma characterized by genetic abnormalities such as the đn-D translocation (e.g., t(411;14)(q 13;q32);t(6;14)(p21;32);t(12;14)(p13;q32 )) or t(6,20));MMSET translocation (e.g., t(4;14)(p16;q3 2)) MAF translocation (for example, t(14;16)(q32;q32);t(20;22) ;t(16;22)(q11;q13); or t(14;20)(q32;q11)) ; or other chromosomal factors (e.g., deletion of 17p13 or chromosome 13; del(17 / 17p), non-high diploidy, and gain(1q)).

[0097] As used herein, unless otherwise indicated, “to treat,” “to treat,” and The term "treatment" refers to the disease or condition being treated, for example, the symptoms associated with multiple myeloma. This refers to reducing or mitigating the severity of a condition.

[0098] The term "prevention" refers to inhibiting the symptoms of a specific disease or disorder, such as multiple myeloma. Includes. In some embodiments, patients with a family history of multiple myeloma are included in the prophylactic regimen. It is a candidate. Generally, the term "prevention" is used, especially when referring to the risk of multiple myeloma. This refers to administering medication to a patient before symptoms appear.

[0099] As used herein, unless otherwise indicated, the term “to control” means multiple To prevent the recurrence of certain diseases or disorders, such as myeloma, in patients suffering from them. This includes extending the time patients with disease or disability remain in remission and reducing patient mortality. To reduce and / or reduce the severity of symptoms associated with the disease or condition being managed. This includes maintaining avoidance.

[0100] As used herein, “subject” or “patient” means an animal, typically a human patient. This includes all mammals, including humans.

[0101] Where used herein, the term “healthy subject” means a subject who does not have multiple myeloma. It is an individual of intent. In some embodiments, a “healthy subject” has a pre-existing medical condition. do not have.

[0102] When used herein, unless otherwise specified, the “therapeutically effective amount” of the compound and "Effective dose" is the therapeutic dose used to treat, prevent and / or manage a disease, such as multiple myeloma. To provide benefits or to delay one or more symptoms associated with the disease or disorder being treated. This refers to an amount sufficient to either eliminate or minimize the effect. The terms "therapeutably effective amount" and "effective amount" are used interchangeably. The term refers to improving the overall treatment, reducing the symptoms or etiology of a disease or disorder, or This may include amounts that avoid or enhance the therapeutic effect of another therapeutic agent.

[0103] The terms "responsive" or "responsive" are used in reference to treatment, when treated. The degree of effectiveness of treatment in suppressing or reducing the symptoms of a disease, for example, MM. This refers to the term "increased responsiveness," for example, used in relation to the treatment of cells or subjects. If measured using any method known in the art, the reference treatment (e.g., The symptoms of the disease, compared to the same cells or subjects, or different cells or subjects. This refers to an increase in effectiveness in suppressing or reducing. In certain embodiments, effective The increase in sex is at least about 5%, at least about 10%, at least about 20%, at It is approximately 30%, at least about 40%, or at least about 50%.

[0104] "Sensitivity" when it is done with a compound or The term "sensitive" refers to the progression of the tumor or disease being treated. This is a relative term referring to the degree of effectiveness of a compound in suppressing or reducing a certain condition. For example, "increased sensitivity" when used in relation to the treatment of cells or tumors in connection with a compound. The term "increased effectiveness" refers to an increase of at least approximately 5% or more in the effectiveness of tumor treatment.

[0105] The terms "refractory" or "resistant" refer to cases where a patient's condition persists even after intensive treatment. Residual cancer cells in the lymphatic system, blood and / or hematopoietic tissue (e.g., bone marrow) (e.g., multiple bone marrow This refers to a condition where there are myeloma cells. In the context of multiple myeloma, it means "refractory or resistant." The term refers to the fact that, even after intensive treatment, the patient still has residual myeloma cells and / or residual cells in the bone marrow. This refers to a situation where normal cells are present. Intractable diseases are unresponsive to therapy (minimum response). Failure to achieve the goal, or onset of a progressive disease, or within approximately 60 days of the last dose. It is understood that this is a disease that progresses over time.

[0106] The term "recurrent" refers to a patient who has achieved cancer remission after therapy, but whose lymphatic system and blood... , and / or cancer cells in hematopoietic tissue (e.g., bone marrow) (e.g., multiple myeloma cells) This refers to a condition characterized by recurrence of ) and a decrease in normal blood cells.

[0107] Improvement in cancer or cancer-related disease is specifically defined as a complete response (CR) or partial response (PR). It can be marked by the presence of abnormalities in previously observed X-rays, bone marrow, and cerebrospinal fluid. "Complete remission" is indicated by the presence of abnormalities in previously observed X-rays, bone marrow, and cerebrospinal fluid. Clinically, with normalization of the CSF (Chemical Stomach Fluid) or abnormal monoclonal protein levels. This refers to the absence of detectable disease. "Partial response" means that no new lesions are present and all measurements are ineffective. Possible tumor volume (i.e., the number of malignant cells present in the subject, or the measured volume of the tumor mass) Or at least about 10%, about 20%, about 3% of the amount of abnormal monoclonal protein. This refers to a decrease of 0%, approximately 40%, approximately 50%, approximately 60%, approximately 70%, approximately 80%, or approximately 90%. The term "treatment" refers to both complete and partial responses.

[0108] In the context of cancer, inhibition is particularly important for inhibiting disease progression, inhibiting tumor growth, and inhibiting primary tumors. Reduction of ulcers, alleviation of tumor-related symptoms, inhibition of tumor-secreting factors, and prevention of the appearance of primary or secondary tumors. Delayed development, slowed development of primary or secondary tumors, decreased incidence of primary or secondary tumors, disease Delay in secondary effects of the disease or reduction in their severity, cessation of tumor growth and regression of the tumor, and no progression. Increased time to progression (TTP), increased progression-free survival (PFS), and increased overall survival (OS) Therefore, it can be evaluated. When used herein, OS refers to the period from the start of treatment to any cause. This refers to the time to death. When used herein, TTP means from the start of treatment. This refers to the time to tumor progression. TTP does not include death. In one embodiment, PFS is This refers to the time from the start of treatment to tumor progression or death. In one embodiment, PFS is, Time from the first administration of the compound to the first onset of disease progression or death from any cause. This means that, in one embodiment, the PFS rate is calculated using Kaplan-Meier estimation. Event-free survival (EFS) is defined as the period from the start of treatment to disease progression, discontinuation of treatment for any reason, and Or it means the time to any treatment failure, including death. In one embodiment, the overall response rate ( ORR refers to the percentage of patients who achieved a response. In one embodiment, ORR This refers to the total percentage of patients who achieved complete response and partial response. In this context, ORR is based on the IMWG Uniform Response Criteria. Therefore, it represents the percentage of patients whose best response is a partial response (PR) or better. In one embodiment, the duration of response (DoR) is defined as the period from achieving a response to relapse or disease progression. This is the time. In one embodiment, DoR is from the time when a response of partial response (PR) or better is achieved. This is the time to recurrence or disease progression. In one embodiment, DoR is defined as the time to response when first documented. This is the time between the initial recording and the first documented occurrence of a progressive disease or death. In terms of treatment methods, DoR progresses only after a partial response (PR) or better is first documented. This is the time until the first documented occurrence of a sexually transmitted disease or death. In one embodiment, the response The time to response (TTR) is the time from the first administration of the compound until the first documented response. It means the interval. In one embodiment, TTR is the period from the first dose of the compound to partial response (PR). This refers to the time until the above effects are first documented. In extreme cases, complete inhibition occurs. In this specification, the terms "prevention" and "chemoprevention" are used. In this context, the term "prevention" is used. This means completely preventing the development of clinically apparent cancer, or preclinically apparent status This includes any of the following: preventing the development of cancer. The intention is to prevent transformation into malignant cells, or the progression from pre-malignant cells to malignant cells. This is a stop or reversal of a line. This is a preventive treatment for those at risk of developing cancer. include.

[0109] In the context of multiple myeloma, response is measured in relation to response and minimal residual disease assessment. rnational Myeloma Working Group (IMWG) It can be evaluated using the NS criteria (Rajkumar et al., Blood, 2 011,117(18):4691-5, Kumar et al., Lancet O ncol.,2016,17(8):e328-e346). The criteria are summarized as follows: This is possible (for further details, see Lancet Oncol., 2016, 17(8):e3 (Available in 28-e346). [Table 1] TIFF0007853352000029.tif182170TIFF0007853352000030.tif151170TIFF0007853352000031.tif242170TIFF0007853352000032.tif102170RD=Minimal residual disease. NGF=Next-generation flow. NGS=Next-generation sequencing. FLC= Free light chain. M protein = myeloma protein. SPD = maximum vertical diameter of the lesion as measured. Product-to-product ratio. CRAB characteristics = elevated calcium, renal failure, anemia, lytic bone lesions. FCM = Flosa Itometry. SUVmax = maximum normalized ingestion value. 18 F-FDG PET = 18 F-Fluorodeoxyglucose PET.

[0110] As used herein, “induction therapy” refers to the first treatment given for a disease. Alternatively, it refers to the initial treatment given with the aim of inducing complete remission of a disease such as cancer. The law, when used alone, is accepted as the best available treatment. If residual cancer is detected, the patient will be treated with another course of chemotherapy called reinduction. If the patient is in complete remission after induction therapy, additional consolidation therapy and / or maintenance therapy may be administered. The law is granted to prolong remission or, as a possibility, cure the patient.

[0111] Where used herein, “consolidation therapy” refers to the treatment of a disease after remission has been initially achieved. This refers to the treatment given in response to cancer. For example, consolidation therapy for cancer is a treatment given after the initial treatment. This is the treatment given after the disease has disappeared. Consolidation therapy is radiation therapy, stem cell transplantation, or This may include treatment using cancer drug therapy. Consolidation therapy is also referred to as intensification therapy and post-remission therapy. To be called.

[0112] Where used herein, “maintenance therapy” refers to the treatment after remission or the best response has been achieved. This refers to treatment given to a disease to prevent or delay recurrence. Maintenance therapy may include chemotherapy, hormone therapy, or targeted therapy.

[0113] As used herein, the term “reference level” refers to the bio-intake of a sample from an organism. This refers to the control level of a biomarker used to evaluate the test level of a marker. It is intended that the reference level is the normal reference level in a sample from a normal subject, and This can be a disease reference level from a diseased state subject. The normal reference level is one non-disease subject. This refers to the expression levels of biomarkers in multiple subjects. The disease status reference level is the level of disease. This refers to the expression level of biomarkers in subjects diagnosed as positive for the condition. Bell can also be a stage-specific reference level. A stage-specific reference level is a disease Alternatively, it refers to the level of a biomarker characteristic of a given stage in the progression of a condition. Reference level The threshold could also be the expression level of a biomarker at different times before or during treatment. For example, the reference level could be the expression level of a biomarker in the bone marrow before treatment. In this example, the reference level is the level of biomarkers in the blood at some point during or after treatment. It is possible.

[0114] The terms "high probability" or "possibility" refer to an increase in the probability of an event. When used in relation to response, the term "likely" generally means that the patient is likely to be able to treat it. The aim is to increase the probability that the patient will respond to the compound. Used in relation to patient responsiveness. The term "likely" in this case also generally means that the patient will respond to the therapeutic compound. Biomarkers such as mRNA or protein expression can prove an increased probability of degeneration. This could mean an increase in -.

[0115] The terms “predict” or “predicting” are used herein in general terms. This means to decide or know in advance. For example, predicting the response to treatment. When used in the context of "predicting," the term "predicting" refers to responding to cancer treatment. Or, there is a possibility of no response at the start, before starting treatment, or the duration of treatment is substantial. This can mean that decisions can be made before the process actually proceeds.

[0116] The terms “monitoring” or “to monitor” are used herein. In general, this refers to monitoring, supervising, regulating, watching, tracking, or investigating activities. However, the term "monitoring the efficacy of a compound" is used when referring to patients or tumor cell cultures. This refers to tracking the effectiveness of cancer treatment. Similarly, "monitoring" The term "compliance" refers to patient compliance, either individually or in a clinical trial. When used in connection with, the patient actually takes the drug being tested as prescribed. It refers to tracking or confirming that something is happening. Monitoring, for example, mRNA or This can be done by tracking the expression of protein biomarkers.

[0117] As used herein, the terms “T cell activation” and “activated T cells” refer to tumors. Cell activation of resting naive T cells into effector T cells capable of inducing ulcer cell death. This is intended to mean transformation. T cell activation is caused by the T cell receptor (TCR) / CD3 complex. It can be initiated by interaction with antigens in the body. Exemplary activated T cells are cell proliferation, cytoplasmic Cellular responses including, but not limited to, tokine secretion and / or effector function. In the context of this application, T cell activation is exhibited by compound 1, compound 2, or compound 3. It can be induced by treatment at [location].

[0118] As used herein, the term “T cell activation-related cytokine” means activation Secreted by T cells, or the secretion of which is compared to that of dormant naive T cells, is secreted by activated T cells. This refers to one of many factors that increase cell count. (T cell activation-related cytokines) Non-limiting examples include IL-2, IFNγ, and TNFα.

[0119] When used herein, the term "modulate" means to enhance or increase activity or function. This refers to controlling the activity of molecules or biological functions, such as reducing them.

[0120] A "biological marker" or "biomarker" is a substance whose detection indicates, for example, the presence of cancer. These are substances that indicate specific biological conditions, such as those mentioned above. Exemplary biomarkers are individually determined. It is possible. It is understood that several biomarkers can be measured simultaneously. Those skilled in the art will understand. "Biomarkers" indicate a response to treatment, or the potential for a patient's response to treatment. It will be understood that this indicates a change in the level of mRNA expression that can be correlated. - can be nucleic acids such as mRNA or cDNA. Biomarkers can also be proteins. It can be of quality. A specific example of a biomarker is one or more tumor cells circulating in the peripheral blood. These are cells (i.e., circulating tumor cells, CTCs). Biomarkers also include the structure of genes. or a change in sequence, which is a modification of a single base unit in DNA, or a gene or Variance caused by deletion, insertion, or rearrangement of larger sections of a chromosome It produces an ant-like form.

[0121] Additional exemplary “biomarkers” include responses to treatment, or patients’ responses to treatment. This indicates changes in polypeptide or protein expression levels that may correlate with the likelihood of a response. Biomarkers can be polypeptides, proteins, or fragments thereof. The relative levels of specific proteins can be determined by methods known in the art. This can be done using antibody-based methods such as immunoblotting and enzyme-linked immunosorbent assay (ELISA). Method S or other methods may be used.

[0122] The terms “polypeptide” and “protein” are used interchangeably herein. A polymer of three or more amino acids in a continuous sequence, linked together by peptide bonds. The term "polypeptide" refers to a protein, protein fragment, or protein-like substance. This includes bodies, oligopeptides, etc. The term "polypeptide" is also used herein. In this case, it can refer to peptides. The amino acids that make up polypeptides are of natural origin. Polypeptides may be naturally occurring or may be synthetically produced. Polypeptides are purified from biological samples. Polypeptides, proteins, or peptides are also modified polypeptides. Proteins and peptides, for example, glycopolypeptides, glycoproteins or glycopeptides, This includes lipopeptides, lipoproteins, or lipopeptides.

[0123] The terms “antibody,” “immunoglobulin,” or “Ig” are used interchangeably in this specification. When used, it retains the ability to specifically bind to fully assembled antibodies and antigens. It includes body fragments. The antibodies provided herein include synthetic antibodies, monoclonal antibodies, and poly Clonal antibodies, recombinant antibodies, multispecific antibodies (including bispecific antibodies), human antibodies Humanized antibodies, chimeric antibodies, intrabodies, single-chain Fv(scFv) (e.g., single-specific antibodies) (including sex, bispecificity, etc.), camelized antibodies, Fab fragments, F(ab') fragments, disulf Id-conjugated Fv (sdFv), anti-idiotype (anti-Id) antibody, and any of the above. This includes, but is not limited to, the epitope-binding fragments provided herein. Antibodies are immunoglobulin molecules and the immunologically active portion of immunoglobulin molecules, i.e. , an antigen-binding domain containing an antigen-binding site that immune-specifically binds to the CRBN antigen or It contains molecules (e.g., one or more complementarity-determining regions (CDRs) of an anti-CRBN antibody). Immunoglobulins may consist of heavy and light chains. The antibodies provided herein are immunoglobulins. Any class of phosphorus molecule (e.g., IgG, IgE, IgM, IgD, and IgA), or any subclass (for example, IgG1, IgG2, IgG3, IgG4, IgA1, It may be an IgA2 antibody. In some embodiments, the anti-CRBN antibody is a complete hemoglobin. Tomonoclonal CRBN antibodies, etc., are fully human. In certain embodiments, this specification The antibodies provided in this book are IgG antibodies, or their subclasses (e.g., human IgG1 or ( is IgG4). In other embodiments, the antibody provided herein is immunoglobulin The immunologically active parts of molecules and immunoglobulin molecules, namely Aiolos, Ika ros, c-MYC, IRF4, caspase-3, BCMA, free kappa light chain, or free An antigen-binding domain or containing an antigen-binding site that binds immunologically to the released lambda light chain Contains molecules.

[0124] The term "immunoglobulin light chain" or "light chain" refers to the small polypeptide subchains of antibodies. This refers to a unit. The light chain can be a lambda light chain or a kappa light chain. The light chain is bonded to the heavy chain. If a light chain is not bonded to a heavy chain, it is called a "bonded light chain." These are called "free light chains (FLCs)." Free light chains are detected in the patient's serum or plasma. If possible, they are called "serum free light chains" or "plasma free light chains." It is further understood that "free light chains" are also called "soluble free light chains." (serum or plasma) The amount of free light chains in the substance is proportional to the disease burden when the disease is multiple myeloma. As understood by those skilled in the art, the level of free light chains, or free light cut relative to free light lambda. It is also understood that the P-ratio may be used for monitoring or diagnosing myeloma. For example, free light chains in the serum of a patient with multiple myeloma being treated with compound 2. The unusually high level of reduction in kappa versus free light chain lambda suggests that the effectiveness of treatment with compound 2 is being monitored. It can be used to treat. Similarly, it can be treated with different compounds such as lenalidomide. An increase in free light chains in patients may indicate resistance to treatment, compound 1, compound It can serve as a predictor of the response to substance 2 or compound 3.

[0125] The terms "antigen-binding domain," "antigen-binding region," and "antigen-binding fragment," and similar terms The term refers to an amino acid that interacts with an antigen and confers its specificity and affinity to the antigen to the binder. This refers to the part of the antibody containing an acid residue (e.g., CDR). The antigen-binding region is found in rodents (for example) It may originate from any animal species, such as rabbits, rats, or hamsters, and humans. In some embodiments, the antigen-binding region is of human origin.

[0126] When used herein, the term "epitope" refers to the binding of one or more antigens to an antibody. It can bind to a region and is antigenic in animals such as mammals (e.g., humans) or This refers to a localized area on the surface of an antigen that possesses immunogenic activity and can induce an immune response. Epitopes with immunogenic activity are polypeptides that induce an antibody response in animals. It is a part. An epitope having antigenic activity can be obtained by any method known in the art, for example, As determined by the immunoassay described herein, the antibody binds immunospecifically. This is the polypeptide portion. Antigenic epitopes do not necessarily need to be immunogenic. Epitopes are typically chemically active surface populations of molecules, such as amino acids or sugar side chains. It has specific three-dimensional structural characteristics and specific charge characteristics. The lipeptide region may be a sequence of amino acids in the polypeptide, or the epitope may be Epitopes can originate from two or more non-adjacent regions of a polypeptide. These may or may not be three-dimensional surface features.

[0127] The terms "Cereblon" or "CRBN," and similar terms, refer to human CRBN tannins. Proteins (for example, human CR, each incorporated herein by whole-word reference) BN isoform 1, GenBank accession number NP_057386, or Human CRBN isoform 2, GenBank accession number NP_001166 Polypeptides containing any CRBN amino acid sequence such as 953, etc. ("polypeptides") (The terms "peptide" and "protein" are used interchangeably in this specification) and their SN This refers to the related polypeptide containing the P variant, and the related CRBN polypeptide. In certain embodiments, it retains CRBN activity and / or anti-CRBN immunity. Allele variants (e.g., SNP variants) that are sufficient to generate a response, Supra variant, fragment, derivative, substitution variant, deletion variant, insertion variant, fusion Includes synthetic polypeptides and interspecies homologs.

[0128] As used herein, the terms "cereblon-related protein" or "CAP" are used in this specification. The word directly or indirectly interacts with cereblon (CRBN), or cereblon This refers to any protein that binds to cereblon. For example, this term could refer to any protein that directly binds to cereblon. Proteins, as well as any proteins that are indirect downstream effectors of the CRBN pathway. This refers to the following. Exemplary CAPs are substrates of CRBN, e.g., IKZF1, IKZF3, ZFP Protein substrates of E3 ubiquitin ligase complexes involved in CRBN, such as 91, or It is c-Myc, or a downstream effector protein such as IRF4.

[0129] As used herein, the term "cereblon modulator compound" is used with respect to CR This refers to compounds that bind to BN and modify its activity or substrate specificity. For example, cereblon. The modulator compounds bind to IKZF1, IKZF3, ZFP91, IRF4, and This may increase the degradation of c-MYC. An example of a cereblon modulator compound is Lena This may be, but is not limited to, lidomide, pomalidomide, or similar compounds. .

[0130] As used herein, the term "mutation" means variant (also called "mutant"). A gene mutation refers to any change in the structure of a gene that results in a mutation. A single nucleotide alteration, or deletion or insertion of a larger section of a gene or chromosome, if This can be caused by rearrangement. In some embodiments, the mutation may affect function or connection. This can affect the resulting protein. For example, the DN in the protein's coding region. A single nucleotide mutation in A (i.e., a point mutation) results in a nucleotide encoding a different amino acid. This can result in a missense mutation (i.e., a different amino acid). This different amino acid can result in a compound or The derivative cannot bind to the protein and / or inhibit the protein. Sea urchins can modify the structure of proteins.

[0131] The term "clonal T cell receptor (TCR)" refers to T cell receptors that are specific to a given antigen. To enable the development of clones of T cells with a reproductive function, the germline of the T cell receptor gene This refers to somatic cell modification to a unique configuration of the cellular lineage. (T cell receptor genes (alpha, beta)) The , delta, and gamma γ It can produce substances. Somatic cell TCR gene rearrangement produces diverse clones (polyclones). Monoclonal expansion of a T cell population having a single TCR rearrangement pattern, or monoclonal This can lead to expansion. TCR clonality can be determined by PCR, Southern blotting, or TCR Standard molecular biological techniques such as sequencing (e.g., next-generation sequencing) It can be decided.

[0132] The term "soluble" refers to organisms that are present in the extracellular space (e.g., serum) and not on the cell surface. This refers to the morphology of somatic molecules. Examples include "soluble B-cell maturation antigen" and "soluble BCMA (sBCMA)." The terms "soluble CD25" or "soluble IL-2 receptor (sIL-2R)" are used to describe... This refers to soluble proteins, which are the released form of proteins, and are present in serum.

[0133] The terms “expressed” or “expression” as used herein refer to two genes. This gives an RNA nucleic acid molecule that is at least partially complementary to one region of the nucleic acid strand. This refers to transcription from a gene. The terms "expressed" or "expressed" also apply to this specification. When used in writing, it provides a protein, polypeptide, or a part thereof, from an RNA molecule. This refers to the translation of [the original text].

[0134] The term "level" refers to the amount, accumulation, or rate of a biomarker molecule. For example, the amount of messenger RNA (mRNA) encoded by a gene or This refers to the synthesis rate, the amount of polypeptides or proteins encoded by genes, or Depending on the rate of synthesis, or the amount or rate of synthesis of biomolecules accumulated in cells or biological fluids It can be expressed as follows. The term "level" is determined under steady-state or transient conditions. This refers to the absolute or relative amount of molecules in a sample.

[0135] mRNA that is "upregulated" generally increases under a given treatment or condition. The mRNA that is "regulated" is generally mRNA expression that responds to a given treatment or condition. This refers to a decrease in bells. In some situations, mRNA levels are lower when a given treatment or condition is met. It may remain unchanged. mRNA from patient samples may be different from untreated samples if treated with drugs. Compared to the reference, it can be "upregulated". This upregulation can be, for example, a comparison control mRNA level. Approximately 5%, 10%, 20%, 30%, 40%, 50%, 60%, and 70% of the total. %, approximately 80%, approximately 90%, approximately 100%, approximately 200%, approximately 300%, approximately 500%, approximately 1.0 It could increase by 00%, approximately 5,000%, or more. Alternatively, mRNA is It can be “downregulated” in response to the administration of certain compounds or other drugs, that is, It can be expressed at a lower level. Downregulated mRNA can be used, for example, as a control mRNA level. Bell's approximately 99%, approximately 95%, approximately 90%, approximately 80%, approximately 70%, approximately 60%, approximately 50%, approximately 4 It may exist at levels of 0%, approximately 30%, approximately 20%, approximately 10%, approximately 1%, or even lower.

[0136] Similarly, the levels of polypeptide or protein biomarkers from patient samples are related to the drug. When treated with a substance, the levels may increase compared to an untreated control. This increase is compared to the control protein. Quality levels: approximately 5%, 10%, 20%, 30%, 40%, 50%, 60% Approximately 70%, approximately 80%, approximately 90%, approximately 100%, approximately 200%, approximately 300%, approximately 500%, It could be approximately 1,000%, approximately 5,000%, or even more. Alternatively, protein Iomarker levels may decrease in response to the administration of certain compounds or other drugs. This decrease is, for example, about 99% of the comparative control level of a polypeptide or protein. Approximately 95%, approximately 90%, approximately 80%, approximately 70%, approximately 60%, approximately 50%, approximately 40%, approximately 30%, It may exist at levels of approximately 20%, 10%, 1%, or even lower.

[0137] In addition, the level of CTCs in patient samples is associated with the administration of certain compounds or other drugs. In response, it may decrease. This decrease is, for example, about 99% of the CTC control level. 95%, approximately 90%, approximately 80%, approximately 70%, approximately 60%, approximately 50%, approximately 40%, approximately 30%, approximately It may exist at levels of 20%, approximately 10%, approximately 1%, or even lower.

[0138] The DNA sequence of the TCR, or TCR clonality, is also used to compare with untreated controls. It may increase when treated with [a specific method]. Somatic TCR gene rearrangements involve diverse clones (polyc (Ronal) expansion, or monoclonal T cell population with a single TCR rearrangement pattern This can result in a nucleus expansion. This increase in a particular clone is compared to a control TCR clone. Sex, approximately 5%, approximately 10%, approximately 20%, approximately 30%, approximately 40%, approximately 50%, approximately 60%, approximately 70% %, approximately 80%, approximately 90%, approximately 100%, approximately 200%, approximately 300%, approximately 500%, approximately 1.0 It could be 00%, approximately 5,000%, or even higher.

[0139] "Deciding," "measuring," "evaluating," The terms "assessing" and "assaying" are used in this context. When used in a specification, it generally refers to any form of measurement, and whether or not an element is present. This includes making decisions. These terms include quantitative and / or qualitative decisions. To evaluate something can be relative or absolute. "To evaluate its existence" is to evaluate its existence. To determine the quantity of something, and to determine whether it exists or does not exist. It may include the following.

[0140] The terms "nucleic acid" and "polynucleotide" refer to nucleotides, for example, deoxyri A polymer of any length consisting of bonucleotides or ribonucleotides, or two Hybridizes with naturally occurring nucleic acids in a sequence-specific manner similar to that of naturally occurring nucleic acids. It is possible, for example, to be involved in Watson-Crick base pair interactions, produced by synthesis. The following terms are used interchangeably in this specification to describe compounds. (Polynucleotide sequence context) When used herein, "bases" (or "base The term "nucleotides" (or "nucleo") is used to refer to nucleotides. "nucleotide" (i.e., a monomer subunit of a polynucleotide) It is synonymous with "to". The terms "nucleoside" and "nucleotide" are known purines and This includes not only the pyrimidine base but also the moiety containing other modified heterocyclic bases. This is intended. Such modifications include methylated purines or pyrimidines, acylated purines. or containing pyrimidines, alkylated ribose or other heterocycles. In addition, "Nucreos The terms "deoxyribose" and "nucleotide" refer only to the conventional ribose and deoxyribose sugars. Modified nucleosides or nucleotides also include parts containing other sugars. This includes modifications to the fraction, for example, one or more of the hydroxyl groups being halogen atoms or They are either replaced with aliphatic groups or functionalized with ethers or amines. "Analog" can mean an imitation, a derivative, having a similar structure, or another similarity. As a term, it refers to molecules that possess structural characteristics recognized in the literature, for example, non-natural molecules. Polynucleotides incorporating creotides, 2'-modified nucleosides, and other nucleos Tide mimetic compounds, peptide nucleic acids, oligomeric nucleoside phosphonates, and protecting groups or ligatures. It includes any polynucleotide to which substituents such as binding portions have been added.

[0141] The term "complementary" refers to the specific characteristics between polynucleotides based on their sequences. This refers to heterogeneous bonding. As used herein, it refers to a first polynucleotide and a second polynucleotide. Nucleotides undergo hybridization under stringent conditions. If they bind to each other in (i), for example, in a hybridization assay... They are complementary when they produce a signal at a predetermined or detectable level. The polynucleotide portion consists of those that follow the conventional base pairing rules (for example, A is T (or U) and If they are in opposition (G is in opposition to C), they are complementary to each other, but mismatch, insertion or Small regions of the deleted sequence (e.g., less than approximately 3 bases) may exist.

[0142] In the context of two nucleic acid sequences, "sequence identity" or "identity" refers to the specified comparison. Residues in two sequences that are identical when aligned for maximum match across the window This refers to additions, deletions, and substitutions.

[0143] In the context of polynucleotides, there is a "substantial identity" or "homology" of various grammatical forms. The term "polynucleotide" generally refers to a polynucleotide that, compared to a reference sequence, exhibits the desired identity, for example. For example, at least 60% identity, at least 70% identity, at least 80% identity The sequence must have sex, at least 90% identity, and at least 95% identity. This means that the nucleotide sequences are substantially identical. Another indicator that the two molecules are... The question is whether they hybridize with each other under trigger conditions.

[0144] The terms "isolated" and "purified" refer to substances (mRNA, DNA, or other materials). Proteins, etc., constitute a substantial portion of the sample containing them, that is, typically The substance is larger than the portion of the substance found in its natural or unisolated state. This refers to isolating the substance. Typically, a substantial portion of the sample is isolated, for example, more than 1% of the sample, or about 2%. Over %, approximately over 5%, approximately over 10%, approximately over 20%, approximately over 50%, or more, usually up to approximately It contains 90% to 100%. For example, a sample of isolated mRNA typically contains at least It may contain approximately 1% total mRNA. Techniques for purifying polynucleotides are in the field of this technology. This is well known, for example, gel electrophoresis, ion exchange chromatography, affinity This includes chromatography, flow sorting, and density-based sedimentation.

[0145] As used herein, the term “combined” refers to direct or indirect combination. To indicate. In the context of chemical structure, "bound" (or "bound (b)"). "(connected)" means to connect two parts directly or indirectly (e.g., For example, it can refer to the presence of a chemical bond (through a linking group or any other intervening part of the molecule). Covalent bonds include covalent bonds, ionic bonds, coordination complexes, hydrogen bonds, and van der Waals interactions. Alternatively, it may be hydrophobic stacking, or it may exhibit the characteristics of multiple types of chemical bonding. In certain cases, "joined" can refer to embodiments where the joining is direct and embodiments where the joining is indirect. This includes embodiments that are such as

[0146] When used herein, the term "sample" typically refers to one or more of the target components. This relates to substances or mixtures of substances in fluid form, which are not necessarily contained in the substance.

[0147] When used herein, "biological sample" includes samples derived from biological tissue or bodily fluids. , obtained from biological subjects, obtained in vivo or by sight, reached or harvested This refers to collected samples. Biological samples may also contain precancerous or cancerous cells or tissues. This includes samples from areas of biological interest. Such samples include organs and tissues isolated from mammals. This may include, but is not limited to, tissues and cells. An example of a biological sample is a cell lysate. Cell cultures, cell lines, tissues, oral tissues, gastrointestinal tissues, organs, organelles, biological fluids, blood samples This includes, but is not limited to, urine samples, skin samples, etc. Preferred biological samples include whole blood, Partially purified blood, PBMCs, and bone marrow core biopsy, bone marrow aspirate, isolated bone marrow mononuclear cells, circulating This includes, but is not limited to, tissue biopsies containing ring tumor cells.

[0148] When used herein, the term "circulating tumor cells (CTCs)" refers to tumor cells in the bone marrow. This refers to multiple myeloma cells that have detached from cells and are detected in peripheral blood. Several embodiments Therefore, CTC may serve as a biomarker for response and prognosis. Other embodiments Therefore, CTC mutations in MM could serve as a potential biomarker.

[0149] When used herein, the term "analyte" refers to the known or unknown components of a sample. To point.

[0150] When used herein, the term “captured substance” means that the drug is from a homogeneous mixture. Sufficient to bind to RNA or protein and enable its enrichment. This refers to drugs that bind to mRNA or proteins through interactions.

[0151] The term "probe," as used herein, refers to a specific target mRNA biomass. This refers to a capture substance that targets the ker sequence. Therefore, each probe in the probe set is Each has its own target mRNA biomarker. The probe / target mRNA double strand is The lobe is formed by hybridizing it to its target mRNA biomarker. It has that structure.

[0152] The terms "nucleic acid probe" or "oligonucleotide probe" usually refer to hydrogen bonds. Through complementary base pairing by forming a bond, mRNA bio is provided herein. This refers to nucleic acids that can bind to target nucleic acids of complementary sequences, such as markers. When used, the probe is a natural base (e.g., A, G, C, or T) or a modified base ( It may contain 7-deazaguanosine, inosine, etc. In addition, the bases in the probe are Unless it interferes with hybridization, bonds other than phosphodiester bonds They can be linked. The probe depends on the stringency of the hybridization conditions. It is understood by those skilled in the art that the probe sequence can bind to a target sequence that lacks complete complementarity with the probe sequence. It will be understood. The probe is preferably a tag, for example, a chromophore, a luminescent phore, or a dye source. Directly labeled, or indirectly labeled with biotin to which the streptavidin complex can later bind. It can be labeled. By assaying for the presence or absence of the probe, the target mRN of interest can be identified. It can detect the presence or absence of biomarker A.

[0153] The term "stringent assay conditions" refers to the desired level of performance in an assay. A sufficiently complementary nucleic acid binding pair to provide specificity, e.g., probe and target mRNA. While suitable for producing binding pairs, not sufficiently complementary to provide the desired specificity. This refers to conditions that are generally incompatible for the formation of bond pairs between bond members. The term "gentle assay conditions" generally refers to hybridization conditions and wash conditions. This refers to a combination with another item.

[0154] A "label" or "detectable portion" of a nucleic acid, when linked to the nucleic acid, for example, By optical means, photochemical means, biochemical means, immunochemical means, or chemical means, This refers to compositions that make nucleic acids detectable. Exemplary labels include radioisotopes, magnetic beads, and metals. Contains beads, colloidal particles, fluorescent dyes, enzymes, biotin, digoxigenin, haptens, etc. However, it is not limited to these. "Labeled nucleic acid or oligonucleotide probes" are Generally, the presence of nucleic acids or probes can detect the presence of labels bound to nucleic acids or probes. To enable detection by releasing, either through a linker or a chemical bond Covalent bonds, or ionic bonds, van der Waals forces, electrostatic attraction, hydrophobic interactions, if The label is attached via a non-covalent bond through one of the hydrogen bonds.

[0155] The terms "polymerase chain reaction" or "PCR" are used herein. Generally, as described in U.S. Patent No. 4,683,195, for example, a small amount of nucleic acid, This refers to a procedure in which RNA and / or DNA are amplified. Generally, oligonucleotide ply Array information from or beyond the ends of the region of interest must be available so that the mers can be designed. These primers will be identical or similar in sequence to the strand opposite the template to be amplified. The 5' terminal nucleotides of the two primers can match the ends of the amplified material. PCR can be used to amplify specific RNA sequences, specific DNA sequences from whole genomic DNA, cDNA transcribed from whole cell RNA, bacteriophage sequences, or plasmid sequences, etc. For an overview, see Mullis et al., Cold Spring Harbor Symp. Quant. Biol. 1 PCR Technology (Stockton P ress, NY, Erlich, ed., 1989).

[0156] The term "number of cycles" or "C T " as used herein in the context of the PCR method refers to the number of PCR cycles at which the fluorescence level exceeds a predetermined set threshold level. C T measurements can be used, for example, to estimate the mRNA level of the original sample. C T measurements are often used in terms of the "dC T " or "difference in C T " score, where the C of one nucleic acid is subtracted from the C T of another nucleic acid.

[0157] As used herein, the terms "compound" and "therapeutic compound" are used interchangeably and include compound 1, compound 2, compound 3, or mixtures of their enantiomers, enantiomeric mixtures, tautomers, isotopologs or pharmaceutically acceptable salts. ​​

[0158] As used herein, "tautomer" refers to isomers of a compound that are in equilibrium with each other. This refers to the isomer form. The concentration of isomer forms depends on the environment in which the compound is found, for example, the chemical composition. Depending on whether the substance is a solid or in an organic solution or aqueous solution They can differ. For example, in aqueous solution, pyrazole can exhibit the following isomer forms. These are called tautomers of each other: [ka]

[0159] As used herein, unless otherwise indicated, the term “pharmaceutically acceptable salt” means Not limited to, but including N,N'-dibenzylethylenediamine, chloroprocaine, choline, Ammonia, diethanolamine and other hydroxyalkylamines, ethylenediamine N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chloro Robenzyl-2-pyrrolidine-1'-ylmethyl-benzimidazole, diethylamine and other alkylamines, piperazines and tris(hydroxymethyl)aminomethane, etc. Amine salts of, but not limited to, alkali metal salts such as lithium, potassium, and sodium , but not limited to, alkaline earth metal salts such as barium, calcium and magnesium, Transition metal salts such as zinc, and, not limited to, sodium hydrogen phosphate It includes other metal salts such as phosphate and disodium phosphate, and, but is not limited to, hydrochloride and Salts of mineral acids such as sulfates, and not limited to acetates, lactates, malates, and tartaric acid. Salt, citrate, ascorbate, succinate, butyrate, valerate, fumarate and Contains salts of organic acids such as organic sulfonates.

[0160] Unless otherwise stated, the compound is a substitute tautomer, positional isomer, and / or stereoisomer. If isomers are possible, all alternative isomers are included within the scope of the claimed subject matter. It is intended to include. For example, a compound having one of two tautomer forms If possible, both tautomers are intended to be included herein.

[0161] Therefore, the compounds provided herein may be enantiomerically pure, or It may be a stereoisomer or a mixture of diastereomers. When used herein, separately Unless otherwise specified, the term "stereoisomerically pure" refers to one stereoisomer of a compound. This means a composition that contains and substantially does not contain other stereoisomers of that compound. For example, one A stereoisomerically pure composition of a compound having a chiral center is the opposite enantio of the compound. It will likely contain virtually no mer. The stereoisomers of compounds with two chiral centers are pure. A sophisticated composition would contain virtually no other diastereomers of the compound. Typical, A stereoisomerically pure compound is one of its stereoisomers that makes up more than 80% by weight, and The other stereoisomers of the compound are less than about 20% by weight, more preferably one of the stereoisomers of the compound The stereoisomer is present in an amount of more than 90% by weight, and the other stereoisomers of the compound are present in an amount of less than 10% by weight. More preferably, the compound contains more than 95% by weight of one stereoisomer, and the compound Less than about 5% by weight of other stereoisomers of the compound, and most preferably one stereoisomer of the compound. It contains more than 97% by weight of isomers and less than 3% by weight of other stereoisomers of the compound. When used herein, an isomerically pure compound is one stereoisomer of that compound. More than approximately 80% by weight of one stereoisomer of the compound, more preferably more than approximately 90% by weight of one stereoisomer of the compound. More preferably, one stereoisomer of the compound is present in an amount of more than 95% by weight, and most preferably Or, it contains more than 97% by weight of one stereoisomer of the compound. Unless otherwise specified, the term "stereoisomerically enriched" refers to one of the characteristics of a compound. The stereoisomer is present in an amount of more than 60% by weight, preferably more than 70% by weight, of the compound. This means a composition containing more than approximately 80% by weight of one stereoisomer. As used herein, Unless otherwise specified, the term "enantiomerically pure" refers to a compound having one chiral center. It means a stereoisomerically pure composition of the compound. Similarly, "stereoisomerically enriched" The term refers to a stereoisomerically enriched composition of a compound having one chiral center. Taste. When used herein, stereoisomers or diastereomer mixtures are chemical compounds. This refers to a composition containing two or more stereoisomers of a substance. It is a typical mixture of stereoisomers of a compound. It contains approximately 50% by weight of one stereoisomer of the compound, and the other stereoisomer of the compound. It contains approximately 50% by weight, or more than 50% by weight of one stereoisomer of that compound, and The compound contains less than approximately 50% by weight of other stereoisomers, or one stereoisomer of the compound. It contains more than approximately 45% by weight of the compound and less than approximately 55% by weight of other stereoisomers of the compound, The compound contains more than 40% by weight of one stereoisomer and the other stereoisomer of the compound. It contains less than approximately 60% by weight, or more than approximately 35% by weight of one stereoisomer of that compound, The compound contains less than approximately 65% ​​by weight of other stereoisomers.

[0162] It should be understood that the compounds provided herein may contain chiral centers. The chiral center can be either (R) or (S) in configuration, or both It may be a mixture. The chiral centers of the compounds provided herein are epimerized in vivo. It should be understood that this may occur. Therefore, a person skilled in the art will know about the compound in (R) form. For compounds that undergo epimerization in vivo, administration is equivalent to administration of the (S) form compound. They will recognize that these are the cases.

[0163] Optically active (+) and (-), (R) and (S), or (D) and (L) isomers This can be prepared using a chiral synthon or chiral reagent, or a chiral steady-state phase. It can be partitioned using conventional techniques such as chromatography.

[0164] In the description herein, if there is any discrepancy between the chemical name and the chemical structure, the structure Construction takes priority.

[0165] It should also be noted that compounds can contain unnatural proportions of atomic isotopes in one or more atoms. For example, a compound is, for example, tritium ( 3 H), Iodine-125 ( 125 I) Sulfur 35( 35 S), or carbon-14 ( 14 Can it be radiolabeled with radioactive isotopes such as C? , or deuterium ( 2 H), carbon-13 ( 13 C), or nitrogen 15 ( 15 N) etc. It can be enriched physiologically. When used herein, "isotopol" An isotope enriched isotope It is a compound that has been enriched with isotopes. The term "isotope-enriched" refers to the natural isotopic composition of its atoms. This refers to atoms that have an isotopic composition different from that of the original atom. "Isotope-enriched" also means that the atoms Compounds containing at least one atom having an isotopic composition different from that of nature. The term "isotopic composition" can refer to each isotope present for a given atom. It refers to the amount of a substance. Radiolabeled and isotope-enriched compounds are used as therapeutic agents, for example, for cancer and Inflammatory agents, research reagents, such as binding assay reagents, and diagnostic agents, such as Inviol. It is useful as a contrast agent. All isotopic variations of the compounds described herein are radioactive. Whether or not it is a gender, it is included within the scope of the embodiments provided herein. This is intended. In some embodiments, isotopologs of compounds are provided, for example, Isotopologs are compounds rich in deuterium, carbon-13, or nitrogen-15. In the embodiments, the isotopologs provided herein are deuterium-rich compounds. In some embodiments, the isotopes provided herein are deuterium-rich compounds, and Hydrogenation occurs at the chiral center. In some embodiments, the hydrogenation is provided herein. Compound 1 is an isotopolog of the compound, and deuteration occurs at the chiral center. In this application, the isotopolog of compound 2 is provided herein, and deuteration is It occurs at the chiral center. In some embodiments, the compound 3 provided herein is It is an isotopolog, and deuteration occurs at the chiral center.

[0166] If there is a discrepancy between the structure shown and the name given to that structure, the structure shown Please note that priorities will be assigned. In addition, the stereochemistry of the structure or part of the structure. However, unless indicated in bold or dashed, for example, the structure or part of the structure is not entirely clear. It is interpreted as encompassing all stereoisomers.

[0167] Where used herein, the term “second activator” means a biologically active agent. This refers to additional treatments. The second activator is hematopoietic growth factor, cytokines, anticancer drugs, anti- Biomaterials, COX-2 inhibitors, immunomodulators, immunosuppressants, corticosteroids, cancer antigens This could be a therapeutic antibody that specifically binds, or a pharmacologically active variant or derivative thereof. It is understood that this is the case.

[0168] The term "supportive care therapeutic agent" refers to Compound 1, Compound 2, or Compound 3, or its Enantiomer or enantiomer, tautomer, isotopolog or pharmaceutically acceptable This refers to any substance used to treat, prevent, or manage adverse effects from treatment with a mixture of salts. The term "supportive care therapy" primarily refers to maintaining the patient's physical strength and / or comfort. It is understood to refer to any therapeutic agent directed toward a particular condition. Exemplary supportive care therapies are... Pain management, intravenous fluid administration, and electrolysis such as isotonic saline, glucose saline, or balanced crystalloid solution. This includes, but is not limited to, therapies for resolving and supporting the condition.

[0169] The term "biological therapy" refers to the administration of biological therapeutic agents such as umbilical cord blood, stem cells, and growth factors. It refers to giving.

[0170] The terms "co-administration" and "in combination" refer to one or more therapeutic agents (e.g., as specified herein). The compound provided, and another anti-multiple myeloma agent, anticancer agent, or supportive care agent, simultaneously This includes administering the drugs simultaneously or sequentially without specific time restrictions. In this state, the drug may be present simultaneously in cells or the patient's body, or it may have a biological effect or It exerts therapeutic effects simultaneously. In one embodiment, the therapeutic agent is present in the same composition or unit dosage form. In another embodiment, the therapeutic agent is present in another composition or unit dosage form.

[0171] As used herein, "immunely binding" and "immunely recognizing" are used. The terms "specifically bind" and "specifically recognize" are used in the context of antibodies. It is a similar term and refers to a molecule that binds to an antigen / epitope. Because it is understood by the vendor. It specifically binds to the target structure or its subunits. The antibody does not cross-react with biomolecules outside the target structural family. In some embodiments, The antibody or antibody fragment is 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, or 10 -11 Higher than M, 10 -8 M~10 -11 M, 10 -9 M~10 -10 M, or 10 -10 M~10 -11 It binds to the antigen selected by M's specific affinity. For example, antigen Molecules that specifically bind to (e.g., antibodies) are used, for example, in immunoassays or in this technology. If determined by other assays known in the field, generally, other peptides with lower affinity It can bind to a molecule or polypeptide. In certain embodiments, a molecule that specifically binds to an antigen. It does not cross-react with other proteins.

[0172] Where used herein, the term “detectable label” means the detection of a protein or This refers to the addition of a specific tag to an antibody to aid in isolation / purification. Examples of labeling types include: Irradiative isotopes, fluorophores (e.g., fluorescein isothiocyanate (FITC)) ), phycoerythrin (PE), chemiluminescence, enzyme reporters, and elemental particles (e.g., Includes, but is not limited to, gold particles. Detection may be direct or indirect. Light Scientific methods include microscopy (both confocal and non-confocal), imaging methods, and non-imaging methods. Electrochemical methods include voltammetry and current measurement. Radio frequency methods are multipolar. Includes resonance spectroscopy.

[0173] The terms "about" or "approximately" refer to a specific value determined by those skilled in the art. This refers to tolerance, which partially depends on how the value is measured or determined. In certain embodiments, the terms “about” or “approximately” are used in 1, 2, 3, or 4 It means within the standard deviation. In certain embodiments, it means "about" or "approximately". The term refers to 50%, 20%, 15%, 10%, 9%, 8%, and 7% of a given value or range. This means it is within 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05%. do.

[0174] The practices of the embodiments provided herein are, unless otherwise indicated, within the scope of the art of those skilled in the art. It will employ conventional techniques from the fields of molecular biology, microbiology, and immunology. The techniques for preparing eels are thoroughly explained in the literature. A particularly suitable example of a text for reference is: Includes: Sambrook et al., Molecular Cloning: A Laboratory Bible(2nd ed. 1989), Glover, e d., DNA Cloning , Volumes I and II (1985), Ga it, ed., Oligonucleotide synthesis (1984), H Ames & Higgins, eds., Nucleic Index Hybridi zation (1984), Hames & Higgins, eds. Transc Translation and Translation (1984), Freshney, e d., Animal Cell Culture:Immobilized Cells and Enzymes (IRL Press, 1986) Immunochemi cal Methods in Cell and Molecular Biolog y (Academic Press, London), Scopes, Protein Purification: Principles and Practice (Spr inger Verlag, NY, 2d ed.1987), and Weir & B. Lackwell, eds., Handbook of Experimental I mmunology Volumes I-IV (1986).

[0175] 5.2 Biomarkers and their use The method provided herein involves, in part, the detection of certain biomarkers during compound therapy. A detectable increase or decrease is treated with a prescribed therapy, e.g., as described in Section 5.7 below. Compound 1, Compound 2, or Compound 3, or their enantiomers, enantiomers Compounds such as mixtures, tautomers, isotopologs, or pharmaceutically acceptable salts. The answer is the finding that it is observed in subjects with MM, and these biomer The discovery that Carr's level can be used to predict the subject's response to treatment Based on. In some embodiments, the levels of the biomarkers are compound 1, compound 2, and Alternatively, the response to compound 3 can be predicted. In some embodiments, the compound , as described herein. In certain embodiments, the compound is compound 1, Compound 2, or Compound 3. In one embodiment, the compound is Compound 1. Another embodiment In one embodiment, the compound is compound 2. In yet another embodiment, the compound is compound 3. be.

[0176] According to one embodiment, the present invention treats, prevents, and / or manages the diseases provided herein. This relates to compound 1, compound 2, or compound 3 for use in a method of processing.

[0177] As described in the examples in Section 6 and shown in the figures, certain proteins, molecules The levels of mRNA or cell composition are cured by compound 1, compound 2, or compound 3. These biomarkers change in response to treatment. 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 (s FLC), p21, p27, pRb1, IL-2, TNFα, IFNγ, tumor-infiltrating lymph TILs (T-cell globules), T-cell antigen receptor (TCR) clonal, and circulating tumor cells (CTCs) Includes. In addition, the examples and figures show that the expression of a particular protein is controlled by compound 1, compound 2, and or changes after treatment with compound 3, and / or compounds to predict the response to treatment. 1. To select patients who are likely to respond to treatment with compound 2 or compound 3. This demonstrates that these biomarkers can be useful as biomarkers. These biomarkers are CRB Contains N. Therefore, in some embodiments, the biomarkers provided herein This includes CRBN, IKZF1, IKZF3, ZFP91, c-Myc, IRF4, and Kaspar. Caspase-1, caspase-3, caspase-7, PARP, survivin, Bcl-2-like tampa Calcium 11 (BIM), serum free light chain (sFLC), p21, p27, pRb1, IL-2 TNFα, IFNγ, tumor-infiltrating lymphocytes (TILs), T cell antigen receptor (TCR) Selected from the group consisting of circulating tumor cells (CTCs). Provided herein Each biomarker exists in various isoforms, phosphorylated forms, cleaved forms, and modified forms. This includes the cleavage form and their splicing variants. For example, caspase-3 is a cleavage form. It contains caspase-3, and caspase-1 contains caspase-1 in a cleaved form, Ze-7 includes caspase-7 in its cleavage form, PARP includes cleavage-type PARP, and pRb1 It contains phosphorylated pRb1. Therefore, in some embodiments, these biomer Kerr isoforms, phosphorylated forms, cleaved forms, modified forms, and / or splices Guvariant levels increase or decrease in response to compound therapy, and therefore, bio These isoforms of the marker, phosphorylated forms, cleaved forms, modified forms, and / or Splicing variants can be used to predict patient responses.

[0178] IKAROS Family Zinc Finger 1 (IKZF1, also known as Ikaros) (and IKAROS family zinc finger 3 (IKZF3, Aiolos) IKZ (also known as IKZ) is a hematopoietic-specific transcription factor involved in regulating lymphocyte development. Expression of F1 and IKZF3 is restricted in the fetal and adult hemolymphocyte neogenesis systems, It functions as a regulator of Pacyl differentiation. Gene expression regulation is performed by Ikaros homodimer, I Involved in karos / Aiolos heterodimers and Aiolos homodimers. Human Multiple isoforms of Ikaros and Aiolos are found in normal B cells and leukemia B cells. They are found in both. Non-DNA-binding isoforms are mainly found in the cytoplasm, and It is thought to function as a dominant-negative factor. Several dominant-negative factors Overexpression of the iv isoform is associated with B-cell malignancies such as acute lymphoblastic leukemia (ALL). It is related to tumors.

[0179] Caspase-1, -3, and -7 are members of the caspase family. Caspase-3 cleaves and activates caspase-7, as well as caspase-6 and caspase-9. Caspase 7 cleavage occurs in response to cell death stimuli and induces apoptosis. Caspase-3 itself is processed by caspase-8, -9, and -10. Effector Caspases, specifically caspases-3, -6, and -7, are spases that transfer intracellular proteins to their host proteins. It breaks down substances qualitatively and induces cell apoptosis. Caspase-3 is involved in apoptosis. After a Gunar signaling event occurs, until it is cleaved by an initiator caspase, it is essentially It is not actively active. Similarly, Pro-caspase-1 is an active caspase during cleavage. Converted to 1, caspase-1 is also involved in several forms of apoptosis. In addition Poly(ADP-ribose) polymerase (PARP) is cleaved by caspases. It is possible that PARP is cleaved by caspase-3 during apoptosis. It is known that PARP plays a role in various important cell processes such as differentiation, proliferation, and tumor transformation. PARP is a family of proteins involved in regulating the process. A regulates molecular events involved in cellular recovery from injury. Caspase activation is involved in survival. It can be inhibited by, thereby preventing apoptosis. It is involved in promoting apoptosis. Another protein that does this is Bcl-2-like protein 11 (BIM). Apoptosis is Furthermore, it can be promoted by serum free light chains (sFLCs). Therefore, several implementations In this state, cleavage-type caspase-1 (c-caspase-1), cleavage-type caspase-3 (c-caspase-1) Spase-3), cleavage-type caspase-7 (c-caspase-7), cleavage-type PARP, mackerel Ivin, BIM, and serum free light chain (sFLC) are biomarkers indicating apoptosis. That is the case.

[0180] In certain embodiments of the various methods provided herein, the biomarker is, for example, Protein-protein interactions (for example, a specific CRBN substrate or its downstream effector) -) or through various cellular pathways (e.g., signal transduction pathways), cerebro It is a protein that is directly or indirectly affected by CRBN. In this case, the biomarker is CRBN-related protein (CAP). Several implementations Morphologically, biomarkers are proteins that are directly or indirectly affected by CRBN. It is a high-quality mRNA. In other embodiments, the biomarker is directly transmitted by CRBN. This is the cDNA of the protein that is indirectly affected. At least two of the protein CRBNs Two isoforms exist, with lengths of 442 amino acids and 441 amino acids, respectively.

[0181] As described in the examples, treatment with compounds 1-3 is Aiolos, Ikaros, The levels of ZFP91, c-Myc, and IRF4 are reduced (for example, Figure 4). Therefore, detecting the level of CRBN-related proteins is a way to monitor effectiveness. And, predicting the response, identifying subjects with cancer who are likely to respond, Treating the condition, which is likely a response to therapeutic compounds, is likely to be multiple myeloma. To identify the target population and to treat the target population with multiple myeloma using therapeutic compounds. It can be helpful in determining or adjusting the dosage of medication. Therefore, several In this embodiment, the biomarker is a CRBN-related protein, and the therapeutic compound is a compound It is substance 1. In other embodiments, the biomarker is a CRBN-related protein, and the treatment The compound used is compound 2. In other embodiments, in some embodiments, bio The marker is a CRBN-related protein, and the therapeutic compound is compound 3. In this embodiment, the biomarkers are Aiolos, Ikaros, ZFP91, and c-My A CRBN-related protein selected from the group consisting of c and IRF4. In certain embodiments, the biomarkers are Aiolos, Ikaros, ZFP91, c - A CRBN-related protein selected from the group consisting of Myc and IRF4, and therapeutic The compound used is compound 1. In certain specific embodiments, the biomarker is Aio Selected from the group consisting of los, Ikaros, ZFP91, c-Myc, and IRF4. It is a CRBN-related protein, and the therapeutic compound is compound 2. In terms of application methods, the biomarkers used were Aiolos, Ikaros, ZFP91, and c-Myc A CRBN-related protein selected from the group consisting of , and IRF4, and a therapeutic compound This is compound 3.

[0182] In some embodiments, the biomarker is an IKZF1 or IKZF3. It is a zinc finger transcription factor that is a member of the AROS family. In certain embodiments, The iomarker is IKZF1, and the therapeutic compound is compound 1. Another specific embodiment So, the biomarker is IKZF1, and the therapeutic compound is compound 2. In this embodiment, the biomarker is IKZF1, and the therapeutic compound is compound 3. In a specific embodiment, the biomarker is IKZF3, and the therapeutic compound is compound 1. In another specific embodiment, the biomarker is IKZF3, and the therapeutic compound is compound 2. In another specific embodiment, the biomarker is IKZF3, and the therapeutic compound This is compound 3. In a particular embodiment, the biomarker is ZFP91, and it is used for therapeutic purposes. The compound is compound 1. In another specific embodiment, the biomarker is I ZFP91. In another specific embodiment, the therapeutic compound is compound 2. 91 is the therapeutic compound, and compound 3 is the therapeutic compound. In yet another specific embodiment, bioma The carat is c-Myc, and the therapeutic compound is compound 1. In another specific embodiment, The biomarker is c-Myc, and the therapeutic compound is compound 2. Another specific implementation In this state, the biomarker is c-Myc, and the therapeutic compound is compound 3. In this embodiment, the biomarker is IRF4, and the therapeutic compound is compound 1. In a particular embodiment, the biomarker is IRF4 and the therapeutic compound is compound 2. In another specific embodiment, the biomarker is IRF4, and the therapeutic compound is compound 3. In other embodiments, the biomarkers are IKZF1, IKZF3, and ZFP91. c-Myc, or IRF4 coupling partner, its downstream effects, or to it Therefore, it is a factor in the cellular pathways that are affected.

[0183] As described in the examples, caspase-1, caspase-3, caspase-7, PA Proteins in apoptotic pathways such as RP, survivin, BIM, and sFLC The level changes with therapeutic compounds 1-3. For example, treatment with compounds 1-3 results in multiple C-caspase-3, C-caspase-1, C-caspase-7 in myeloma cells, cleavage It can increase the levels of type PARP, BIM, and sFLC, thereby inducing apoptosis. Treatment with compounds 1-3 can also reduce the levels of Survivin, thereby reducing the Apot - Indicates apoptosis. Detecting apoptosis is a way to monitor effectiveness and response. To predict, to identify subjects with cancer who are likely to respond, and to treat cancer Therefore, the subjects with multiple myeloma, whose response is likely to be to therapeutic compounds, are particularly targeted. To determine the dosage of therapeutic compounds for treating subjects with multiple myeloma. It can be useful in determining or adjusting. Therefore, in some embodiments Therefore, the biomarker has a function in the apoptotic pathway. In a particular embodiment Therefore, the biomarker has a function in the apoptotic pathway, and the therapeutic compound is compound 1 In certain embodiments, the biomarker has a function in the apoptotic pathway. The therapeutic compound is compound 2. In a particular embodiment, the biomarker is Apot. Compound 3 is the therapeutic compound that functions in the systolic pathway.

[0184] In certain embodiments, the biomarker functions in the apoptotic pathway and is cleavage type Caspase 1 (c-caspase 1), cleavage-type caspase 3 (c-caspase 3), cleavage-type Caspase 7 (c-caspase 7), cleavage-type PARP, Survivin, BIM BCL-2 It is selected from the group consisting of similar protein 11 (BIM) and serum free light chains. In some embodiments, the biomarker has a function in the apoptotic pathway. Cleavage caspase 1 (c-caspase 1), cleavage caspase 3 (c-caspase 3), Cleavage caspase 7 (c-caspase 7), cleavage PARP, Survivin, BIM BC Selected from the group consisting of L-2-like protein 11 (BIM) and serum free light chains, for therapeutic use The compound is compound 1. In some embodiments, the biomarker is used in the apoptotic process. It has a function in the pathway, and includes cleavage caspase 1 (c-caspase 1) and cleavage caspase 3. (c-caspase 3), cleavage-type caspase 7 (c-caspase 7), cleavage-type PARP, sa It consists of bivin, BIM BCL-2-like protein 11 (BIM), and serum free light chains. Selected from the group, the therapeutic compound is compound 2. In some embodiments, a biomer Kerr plays a role in the apoptotic pathway and is a cleavage-type caspase 1 (C-caspase 1). ), cleavage caspase 3 (c-caspase 3), cleavage caspase 7 (c-caspase 7 ), cleavage-type PARP, survivalin, BIM BCL-2-like protein 11 (BIM), and A group consisting of serum free light chains was selected, and the therapeutic compound is compound 3. Specific implementation In this state, the level of caspase-3, including cleavage-type caspase-3, is a biomarker. The therapeutic compound is compound 1. In some embodiments, it includes cleavage caspase-3. The caspase-3 level is a biomarker, and the therapeutic compound is compound 2. In several embodiments, the level of caspase-3 containing cleavage-type caspase-3 is biomer The therapeutic compound is compound 3. In some embodiments, a cleavage-type caspar is used. The level of caspase-1, including ze-1, is a biomarker, and the therapeutic compound is compound 1 In some embodiments, the level of caspase-1 including cleavage caspase-1 is a biomarker, and the therapeutic compound is compound 2. In some embodiments, The level of caspase-1, including fragmented caspase-1, is a biomarker and therapeutic compound The substance is compound 3. In some embodiments, the caspase contains cleavage-type caspase-7. Level -7 is a biomarker, and the therapeutic compound is compound 1. Several implementations Morphologically, the level of caspase-7, including cleavage-type caspase-7, is a biomarker. The therapeutic compound is compound 1. In some embodiments, it contains cleavage caspase-7. The caspase-7 level is a biomarker, and the therapeutic compound is compound 2. In some embodiments, the level of caspase-7, including cleavage-type caspase-7, is biomass The maker is compound 3, and the therapeutic compound is compound 3. In some embodiments, cleavage-type PAR The level of P-containing PARP is a biomarker, and the therapeutic compound is compound 1. In some embodiments, the level of PARP, including cleaved PARP, is a biomarker. The therapeutic compound is compound 2. In some embodiments, PA containing cleavage-type PARP is used. The RP level is a biomarker, and the therapeutic compound is compound 3. Several implementations Morphologically, the Survivin level is a biomarker, and the therapeutic compound is compound 1. In some embodiments, the level of survivin is a biomarker and a therapeutic compound. This is compound 2. In some embodiments, the survival level is a biomarker. The therapeutic compound is compound 3. In some embodiments, the BIM level is bio The marker and therapeutic compound is compound 1. In some embodiments, BIM Bell is the biomarker, and compound 2 is the therapeutic compound. In some embodiments, The BIM level is a biomarker, and the therapeutic compound is compound 3. In addition, blood Changes in the levels of clean free light chains (sFLCs) and cytotoxic tubules (CTCs) are observed along with therapeutic compounds 1-3. For example, treatment with compounds 1-3 can detect sFLC in the blood or serum / plasma. The amount can be reduced. Therefore, in some embodiments, sFLC is a biomarker. The therapeutic compound is compound 1. In some embodiments, sFLC is a biomarker. —and the therapeutic compound is compound 2. In some embodiments, sFLC is bio Compound 3 is the marker and the therapeutic compound. Similarly, treatment with compounds 1-3 is terminal. The amount of CTCs detected in peripheral blood can be reduced. Therefore, in some embodiments, The level of CTCs in peripheral blood is a biomarker, and the therapeutic compound is compound 1. In several embodiments, the level of CTCs in peripheral blood is a biomarker, and therapeutic compounds This is compound 2. In some embodiments, the level of CTCs in peripheral blood is a biomarker. —and the therapeutic compound is compound 3. Treatment with compounds 1-3 is also used for multiple myeloma. It can reduce the amount of soluble BCMA (sBCMA) detected in the serum of patients. In some embodiments, the level of sBCMA is a biomarker and is used for therapeutic purposes. The compound is compound 1. In some embodiments, the level of sBCMA is a biomarker. The therapeutic compound is compound 2. In some embodiments, the level of sBCMA This is a biomarker, and the therapeutic compound is compound 3.

[0185] Terminal deoxynucleotidyltransferase dUTP nick end labeling (T UNEL) is involved in the 3'-hydroxylase in double-strand DNA breaks generated during apoptosis. This is a method for detecting DNA fragmentation by labeling the DNA ends. This is a commonly known method in the field of technology (Darzynkiewicz et al., Me Thods, 2008, 44(3):250-254). Therefore, several implementation forms In this context, the biomarker is the detection of apoptosis by TUNEL, and the therapeutic compound This is compound 1. In some embodiments, the biomarker is apo by TUNEL. The detection of ptosis is compound 2 as the therapeutic compound. In some embodiments, The omarker is the detection of apoptosis by TUNEL, and the therapeutic compound is compound 3. be.

[0186] Apoptosis also involves annexin V and 7-AAD, or annexin V and iodide It can be measured by lopidium (PI). Annexin V (or Annexin A5) A calcium-dependent intracellular protein that binds to phosphatidylserine (PS) It is a member of the nexin family. PS is normally found in healthy cells, affecting the plasma membrane. Although found only on intracellular leaflets, membrane asymmetry is lost during early apoptosis. Next, PS moves to the external leaflet. Then, the fluorescent dye-labeled annexin V is applied to the Apot. It can be used to specifically target and identify cis cells. Annexin V binding is simple In Germany, it is not possible to distinguish between apoptotic cells and necrotic cells. To help distinguish between them, 7-amino-actinomycin D (7-AAD) or P Solution I can be used. Early apoptotic cells are excluded from 7-AAD and PI. Late-stage apoptotic cells and necrotic cells have these colors that bind to the nucleus where they bind to DNA. The sample will be positively stained upon passage of the element. Therefore, in some embodiments, The omarker is the detection of apoptosis by annexin V / 7-AAD, and the therapeutic compound This is compound 1. In some embodiments, the biomarker is annexin V / 7-AA D is used to detect apoptosis, and the therapeutic compound is compound 2. Several implementations In this scenario, the biomarker is the detection of apoptosis by annexin V / 7-AAD. The therapeutic compound is compound 3. In other embodiments, the biomarker is annexin V / This is a method for detecting apoptosis using PI, and the therapeutic compound is compound 1. Further implementation Morphologically, the biomarker is the detection of apoptosis by annexin V / PI, and treatment The therapeutic compound is compound 2. In some embodiments, the biomarker is annexin. This method involves the detection of apoptosis using V / PI, and the therapeutic compound is compound 3.

[0187] In some embodiments, detecting the modulation of the immune response is used to monitor effectiveness. To predict the response, to identify cancer patients who are likely to respond. , treating cancer, patients with multiple myeloma who are likely to respond to therapeutic compounds Identifying elephants and administering therapeutic compounds to treat subjects with multiple myeloma. It can be helpful in determining or adjusting quantities. For example, in the following sections. The example in 6 describes enhanced T in a co-culture model using therapeutic compounds 1-3. Cell-mediated tumor cell lysis (Example 11), activation of effector T cells (Example 12), The activation and proliferation of T cells (Example 16) are described. Therefore, several implementations In this state, T cell activation may be a biomarker for treatment with compound 1. In that embodiment, T cell activation could be a biomarker for treatment with compound 2. In some embodiments, T cell activation is used as a biomarker for treatment with compound 3. —That's possible.

[0188] In some specific embodiments, T cell activation is used for therapeutic purposes with therapeutic compounds. It can be an omarker, and the biomarker is interleukin-2 (IL-2), tumor necrosis. Factor alpha (TNFα), interferon gamma (IFNγ), and T cell receptor ( Selected from the group consisting of TCRs (clonal properties). For example, in some embodiments, bi The omarker is the clonal T cell receptor (TCR) after treatment with compounds 1-3. In some specific embodiments, TCR clonality can be a biomarker, and therapeutic compounds The substance is compound 1. In some specific embodiments, TCR clonality is a biomarker. —and the therapeutic compound is compound 2. In some specific embodiments, TCR Loan properties can be a biomarker, and compound 3 is the therapeutic compound.

[0189] Furthermore, cytokine release is central to many aspects of T cell function. For example, IL-2 is a potent T cell growth factor essential for the long-term growth of activated T cells. Yes. The secretion of other cytokines such as TNFα and IFNγ is involved in killing tumor cells. It can promote the function of effector T cells. Therefore, detecting cytokines is It can indicate T cell activation. In some embodiments, the biomarker is T cell activation It has a function in sexualization, its biomarker is IL-2, and the therapeutic compound is compound 1. Yes. In some embodiments, the biomarker has a function in T cell activation, The iomarker is IL-2, and the therapeutic compound is compound 2. In some embodiments... The biomarker has a function in T cell activation, and the biomarker is IL-2. In other embodiments, the therapeutic compound is compound 3. In other embodiments, the biomarker is T cell activation. It has a function in [location], its biomarker is TNFα, and the therapeutic compound is compound 1. In some embodiments, the biomarker has a function in T cell activation, and bio The marker is TNFα, and the therapeutic compound is compound 2. In some embodiments, The biomarker has a function in T cell activation, and the biomarker is TNFα. The therapeutic compound is compound 3. In yet another embodiment, the biomarker is T cell activity It has a function in chemical processes, its biomarker is IFNγ, and the therapeutic compound is compound 1. In some embodiments, the biomarker has a function in T cell activation, and The omarker is IFNγ, and the therapeutic compound is compound 2. In some embodiments, The biomarker has a function in T cell activation, and the biomarker is IFNγ. The therapeutic compound is compound 3.

[0190] Circulating tumor cells (CTCs) indicate a prognosis for multiple myeloma, and associated mutations are found in peripheral blood. Characterizing CTCs, including specific ones, can indicate disease burden and predict treatment response. (Mishima et al.,Cell Rep.,2017,19(1):218 -224, Lohr et al.,Sci Transl Med.,2016,;8 (363):363ra147). Therefore, in some embodiments, C in peripheral blood TC can be a biomarker, and the therapeutic compound is compound 1, compound 2, or compound 3. Yes. In some specific embodiments, CTCs in peripheral blood can be a biomarker and cure The therapeutic compound is compound 1. In some specific embodiments, CTCs in peripheral blood are Compound 2 is a potential omarker and therapeutic compound. In some specific embodiments, CTCs in peripheral blood can be a biomarker, and compound 3 is the therapeutic compound. Morphologically, the mutation profile of CTCs is that of treatment with compound 1, compound 2, or compound 3. It may be a biomarker for predicting the response to. In some specific embodiments Therefore, the mutation profile of CTCs can be a biomarker, and the therapeutic compound is compound 1. In some specific embodiments, the mutation profile of CTCs is a biomarker. The therapeutic compound is compound 2. In some specific embodiments, the mutation of CTCs is promoted The file may be a biomarker, and the therapeutic compound is compound 3.

[0191] Inhibiting the progression of the cell cycle in cancer cells is an effective way to prevent cancer progression. It may be a step. As described in Example 6, compound 2 is G in multiple myeloma cells. It can induce cell cycle arrest and apoptosis. It can detect members of the cell cycle pathway. This involves monitoring effectiveness, predicting response, and identifying cancers that are likely to respond. Identifying subjects that have [certain characteristics], treating cancer, and the response to therapeutic compounds. To identify subjects with a high probability of having multiple myeloma, and subjects with multiple myeloma It is helpful in determining or adjusting the dosage of medication for treating with therapeutic compounds. This is possible. Therefore, in some embodiments, the biomarker is located in the cell cycle pathway. It has a function in the cell cycle pathway. In certain specific embodiments, the biomarker is in the cell cycle pathway. The therapeutic compound is compound 1, which has the function of [unclear]. In other specific embodiments, biomer Kerr plays a role in the cell cycle pathway, and the therapeutic compound is compound 2. Furthermore, other compounds In terms of application, biomarkers have a function in the cell cycle pathway, and therapeutic compounds are compounds The answer is 3.

[0192] In a particular embodiment, the biomarker has a function in the cell cycle pathway, Clin-dependent kinase inhibitor 1 (p21), cyclin-dependent kinase inhibitor 1B ( The group is selected from p27) and retinoblastoma protein (pRb1). In that embodiment, the biomarker is cyclin-dependent kinase inhibitor 1 (p21). , cyclin-dependent kinase inhibitor 1B (p27), and retinoblastoma protein (p A therapeutic compound is selected from the group consisting of Rb1), and the therapeutic compound is compound 1. In other embodiments, The biomarker is cyclin-dependent kinase inhibitor 1 (p21), cyclin-dependent A group consisting of kinase inhibitor 1B (p27) and retinoblastoma protein (pRb1). A therapeutic compound is selected from the above, and compound 2 is the therapeutic compound. In yet another embodiment, the biomarker - is cyclin-dependent kinase inhibitor 1 (p21), cyclin-dependent kinase inhibitor Selected from the group consisting of factor 1B (p27) and retinoblastoma protein (pRb1) The therapeutic compound is compound 3. In a particular embodiment, the biomarker is p21. In other embodiments, the therapeutic compound is compound 1. In other embodiments, the biomarker is p21. The therapeutic compound is compound 2. In yet another embodiment, the biomarker is p21. The therapeutic compound is compound 3. In a particular embodiment, the biomarker is p27 The therapeutic compound is compound 1. In other embodiments, the biomarker is p27. In one embodiment, the therapeutic compound is compound 2. In yet another embodiment, the biomarker is p2 The therapeutic compound is compound 3. In certain embodiments, the biomarker is pR b1 is the therapeutic compound, and compound 1 is the therapeutic compound. In other embodiments, the biomarker is pR b1 is the therapeutic compound, and compound 2 is the therapeutic compound. In yet another embodiment, a biomarker pRb1 is the active ingredient, and the therapeutic compound is compound 3.

[0193] As described in the examples in Section 6, the therapeutic compound reduced the number of cells but did not detect them. Even if you have a possible level of CRBN, lenalidomide and pomalidomide, etc. It inhibits the proliferation of multiple myeloma cells that have acquired resistance to cereblon modulators. It is possible (Example 8). Therefore, in some embodiments, a reduced level of CRBN It is a biomarker for diagnosing a subject that is likely to respond to a therapeutic compound. The therapeutic compound is compound 1. In other embodiments, the reduced level of CRBN is It is a biomarker for diagnosing a subject that is likely to respond to therapeutic compounds, and The therapeutic compound is compound 2. In yet another embodiment, the reduced level of CRBN is , a biomarker for diagnosing a subject that is likely to respond to a therapeutic compound, The therapeutic compound is compound 3. In some embodiments of the method for predicting response, the method detects a biomarker in the sample. This includes, where possible, diagnosing the subject as likely to respond to a therapeutic compound. In some specific embodiments, MM is relapsed, refractory, or resistant to conventional therapies. It is sexual. In one embodiment, MM is lenalidomide-resistant MM. In another embodiment, MM is pomalidomide-resistant MM.

[0194] Biomarkers are also used to develop therapeutic compounds for treating subjects with multiple myeloma. It may be useful in determining or adjusting the dosage of a drug. For example, IK after treatment with a therapeutic compound. Detecting increases in biomarkers such as ZF1 indicates that the subject may require more frequent or prolonged administration. It can be shown that treatment for the specified period is necessary. Therefore, in some embodiments So, biomarkers are used to develop therapeutic compounds for treating subjects with multiple myeloma. This is for determining or adjusting the dosage, and is derived from the group consisting of IKZF1 and IKZF3. Selected. In a particular embodiment, the biomarker consists of IKZF1 and IKZF3. A therapeutic compound is selected from the group, and compound 1 is used. In another specific embodiment, biomass The maker is selected from the group consisting of IKZF1 and IKZF3, and the therapeutic compound is compound 2 In yet another specific embodiment, the biomarkers are IKZF1 and IKZF3 A therapeutic compound is selected from the group consisting of the following, and compound 3 is selected. In a particular embodiment, The iomarker is IKZF1, and the therapeutic compound is compound 1. In a particular embodiment So, the biomarker is IKZF1, and the therapeutic compound is compound 2. In this embodiment, the biomarker is IKZF1, and the therapeutic compound is compound 3. In some embodiments, the biomarker is IKZF3, and the therapeutic compound is compound 1. In other embodiments, the biomarker is IKZF3 and the therapeutic compound is compound 2. In yet another embodiment, the biomarker is IKZF3, and the therapeutic compound is... This is compound 3.

[0195] In some embodiments, the measured biomarkers include one biomarker. In some embodiments, the measured biomarker is one or more biomarkers Includes. In a particular embodiment, the measured biomarkers are two biomarkers. Includes. In some embodiments, the measured biomarker is two or more biomarkers. —Includes. In other embodiments, the measured biomarkers include three biomarkers. In some embodiments, the measured biomarkers are three or more biomarkers. Includes. In a particular embodiment, the measured biomarkers are four biomarkers. Includes. In some embodiments, the measured biomarkers include four or more biomarkers. Includes Car. In some embodiments, the measured biomarkers are five biomarkers. Includes car. In some embodiments, the measured biomarkers are five or more biomarkers. Includes a marker. In other embodiments, the measured biomarker is one of six biomarkers. -Includes. In some embodiments, the measured biomarkers include six or more biomarkers. Includes markers. In yet another embodiment, the measured biomarkers include seven biomarkers. Includes markers. In some embodiments, the biomarkers being measured are seven or more biomarkers. Includes omarkers. In a particular embodiment, the measured biomarkers are eight biomarkers. Includes omarkers. In some embodiments, the measured biomarkers include eight or more. Includes biomarkers. In other embodiments, the measured biomarkers are nine biomarkers. Includes markers. In some embodiments, the measured biomarkers include nine or more markers. It includes biomarkers. In another embodiment, the measured biomarkers include 10 or more bacteria Includes Iomarker

[0196] Furthermore, the biomarkers provided herein include, for example, Aiolos, Ikar os, CRBN, ZFP91, c-MYC, IRF4, c-caspase 1, c-casper Ze-3, c-caspase 7, cleavage-type PARP, Survivalbin, BIM, sFLC, p21, p27, pRB1, soluble BCMA, CTC, TIL, IL-2, IFNγ, TNFα, Alternatively, TCR clonality may be a predictor or prognostic factor for the compounds provided herein. A method for treating or managing cancer, used as a child. In a particular embodiment, Provided herein are one or more biomarkers provided herein, for example , Aiolos, Ikaros, CRBN, ZFP91, c-MYC, IRF4, c-ka Spase 1, c-caspase-3, c-caspase 7, cleavage-type PARP, survivalin, B IM, sFLC, p21, p27, pRB1, soluble BCMA, CTC, TIL, IL- 2. Levels of IFNγ, TNFα, or TCR clonality as predictive or prognostic factors. To be used as a compound for screening multiple multiple myeloma patients for treatment, This is a method for identification. In some embodiments, what is provided herein is a method for identification. Iomarkers (e.g., Aiolos, Ikaros, CRBN, ZFP91, c-MY) C, IRF4, c-caspase 1, c-caspase-3, c-caspase 7, cleavage type PA RP, survivin, BIM, sFLC, p21, p27, pRB1, soluble BCMA, C Predicts levels of TC, TIL, IL-2, IFNγ, TNFα, or TCR clonality. As a factor or prognostic factor, it can be used to enhance the effectiveness of the therapy with the compounds provided herein. This is a method for selecting patients with a high response rate. In a particular embodiment, therapeutic The compound is compound 1, compound 2, or compound 3. In one embodiment, the therapeutic compound In another embodiment, the compound is compound 1. In yet another embodiment, the compound is compound 2. The therapeutic compound is compound 3.

[0197] In one embodiment, the herein provides a cancer that is likely to respond to a therapeutic compound. A method for identifying an object that possesses, (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Determining the level of biomarkers in the sample, (d) If the level of the biomarker in the sample differs from the reference level of the biomarker, This includes diagnosing the subject as likely to respond to a therapeutic compound, and the therapeutic compound However, compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0198] In another embodiment, what is provided herein is likely to respond to therapeutic compounds, A method for identifying an object that possesses (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Determining the level of biomarkers in the sample, (d) If the level of the biomarker in the sample differs from the reference level of the biomarker, This includes diagnosing the subject as likely to respond to a therapeutic compound, and the therapeutic compound However, compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0199] In another embodiment, what is provided herein is likely to respond to therapeutic compounds, A method for identifying an object that possesses (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Determining the level of biomarkers in the sample, (d) If the level of the biomarker in the sample differs from the reference level of the biomarker, This includes diagnosing the subject as likely to respond to a therapeutic compound, and the therapeutic compound However, compound 3: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0200] In another aspect of the present invention, the subject is likely to respond to the therapeutic compound being administered to him. A method for identifying subjects with cancer, (a) Determine the level of biomarkers in the sample obtained from the subject, (b) If the level of the biomarker in the sample differs from the reference level of the biomarker, This includes diagnosing the subject as likely to respond to a therapeutic compound, and the therapeutic compound is Compound 1, Compound 2 or Compound 3, or their enantiomers, enantiomers This includes mixtures, tautomers, isotopologs, or pharmaceutically acceptable salts.

[0201] In another embodiment, what is provided herein is likely to respond to therapeutic compounds, A method for identifying an object that possesses (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Determining the level of biomarkers in the sample, (d) If the level of the biomarker in the sample differs from the reference level of the biomarker, This includes diagnosing the subject as likely to respond to a therapeutic compound, and the therapeutic compound However, compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0202] In another embodiment, what is provided herein is likely to respond to therapeutic compounds, A method for identifying an object that possesses (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Determining the level of biomarkers in the sample, (d) If the level of the biomarker in the sample differs from the reference level of the biomarker, This includes diagnosing the subject as likely to respond to a therapeutic compound, and the therapeutic compound However, compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0203] In another embodiment, what is provided herein is likely to respond to therapeutic compounds, A method for identifying an object that possesses (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Determining the level of biomarkers in the sample, (d) If the level of the biomarker in the sample differs from the reference level of the biomarker, This includes diagnosing the subject as likely to respond to a therapeutic compound, and the therapeutic compound However, compound 3: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0204] In another embodiment, what is provided herein is likely to respond to therapeutic compounds, A method for identifying an object that possesses (a) Administering therapeutic compounds to samples obtained from the subject, (c) Determining the level of biomarkers in the sample, (d) If the level of the biomarker in the sample differs from the reference level of the biomarker, This includes diagnosing the subject as likely to respond to a therapeutic compound, and the therapeutic compound is Compound 1, Compound 2 or Compound 3, or their enantiomers, enantiomers A mixture, tautomer, isotopolog, or pharmaceutically acceptable salt, by any means ru.

[0205] In another embodiment, if a subject is diagnosed as likely to respond to a therapeutic compound, The method provided in the specification further involves administering a therapeutically effective amount of the therapeutic compound to the target. It is included in.

[0206] Therefore, in some embodiments, what is provided herein is a method for treating cancer. It is a law, (a) Obtaining samples from subjects with cancer, (b) Determining the level of biomarkers in the sample, (c) When the level of the biomarker in the sample differs from the reference level of the biomarker. , to diagnose the subject as likely to respond to the therapeutic compound, (d) administering a therapeutically effective amount of the therapeutic compound to the subject, and the therapeutic compound However, compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0207] In some embodiments, what is provided herein is a method for treating cancer, (a) Obtaining samples from subjects with cancer, (b) Determining the level of biomarkers in the sample, (c) When the level of the biomarker in the sample differs from the reference level of the biomarker. , to diagnose the subject as likely to respond to the therapeutic compound, (d) administering a therapeutically effective amount of the therapeutic compound to the subject, and the therapeutic compound However, compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0208] In some embodiments, what is provided herein is a method for treating cancer, (a) Obtaining samples from subjects with cancer, (b) Determining the level of biomarkers in the sample, (c) When the level of the biomarker in the sample differs from the reference level of the biomarker. , to diagnose the subject as likely to respond to the therapeutic compound, (d) administering a therapeutically effective amount of the therapeutic compound to the subject, and the therapeutic compound However, compound 3: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0209] In some embodiments, what is provided herein is for use in methods of treating cancer. Compound 1, Compound 2, or Compound 3, or their enantiomers, enantiomers A mixture, tautomer, isotopolog, or pharmaceutically acceptable salt of - The way to treat it is, (a) Obtaining samples from subjects with cancer, (b) Determining the level of biomarkers in the sample, (c) When the level of the biomarker in the sample differs from the reference level of the biomarker. , to diagnose the subject as likely to respond to the therapeutic compound, (d) administering a therapeutically effective amount of the therapeutic compound to the subject, Compound 1, Compound 2, or Compound 3, or the same, for use in methods of treating cancer Enantiomers, mixtures of enantiomers, tautomers, isotopologs, or pharmaceuticals It is a generally acceptable salt.

[0210] In some embodiments of the various methods provided herein, the method involves the therapeutic compound The step of administering the substance is included, or further included. Other embodiments are provided herein. This is for selectively treating selected patients using the methods provided herein. It is a method.

[0211] One embodiment of the method provided herein involves administering compound 1, or its enantiomer, to a patient. - Enantiomer mixtures, tautomers, isotopologs, or pharmaceutically acceptable Multiple cases selected based on biomarkers described herein, including administering a salt. This includes treating patients with myeloma.

[0212] Another embodiment of the method provided herein involves administering compound 2, or its tautomers, to a patient. This includes administering isotopologs or pharmaceutically acceptable salts as described herein. A method of treating multiple myeloma patients selected based on the levels of the listed biomarkers. It also includes.

[0213] In yet another embodiment of the method provided herein, the patient is given compound 3, or its interaction This includes administering a mutant, isotopolog, or pharmaceutically acceptable salt. Treat multiple myeloma patients selected based on the levels of biomarkers described in the manual. This includes further methods.

[0214] In another embodiment of the method provided herein, the compounds provided herein, for example Compound 1, Compound 2 or Compound 3, or their enantiomers, enantiomers Administer the patient a mixture, tautomer, isotopolog, or pharmaceutically acceptable salt. In patients selected based on the levels of biomarkers described herein, including the following: This further includes methods for preventing multiple myeloma.

[0215] In yet another embodiment of the method provided herein, the compound provided herein, For example, compound 1, compound 2, or compound 3, or their enantiomers, enantio The patient is given a mixture of Mar, a tautomer, an isotopolog, or a pharmaceutically acceptable salt. Multiple myeloma based on the levels of the biomarkers described herein, including administering This includes further methods of management.

[0216] One embodiment of the method provided herein involves using an effective amount of the compound described herein, for example Compound 1, Compound 2 or Compound 3, or their enantiomers, enantiomers Mixtures, tautomers, isotopologs, or pharmaceutically acceptable salts for multiple myeloma Based on the level of the biomarker described herein, including administering to patients who have the condition. Patient's International Uniform Response Criterion ia for Multiple Myeloma(IURC)(Durie BG,e See t al., Leukemia, 2006, 20(9):1467-73. The specification further includes methods for inducing the therapeutic response evaluated by ). In another embodiment, this specification The book provides an effective amount of the compounds described herein, for example, compound 1, compound 2, etc. or compound 3, or its enantiomer, mixture of enantiomers, tautomer, A Administering isotopologs or pharmaceutically acceptable salts to patients with multiple myeloma. This includes, in patients, International Uniform Respond According to the Criteria for Multiple Myeloma (IURC) The results were determined to be a stringent complete response, a complete response, or a very good partial response. This is a method for achieving this. In another embodiment, what is provided herein is an effective amount of book The compounds described in the specification, for example, compound 1, compound 2, or compound 3, or their ena Nthiomers, mixtures of enantiomers, tautomers, isotopologs, or pharmaceutically Administration of an acceptable salt to patients with multiple myeloma, including overall survival in patients To achieve an increase in progression-free survival, event-free survival, progression-free survival, or disease-free survival. This is a method for doing so. In another embodiment, what is provided herein is an effective amount of The compounds described, for example, compound 1, compound 2, or compound 3, or their enantio Mers, mixtures of enantiomers, tautomers, isotopologs, or pharmaceutically acceptable compounds The treatment involves administering a salt to patients with multiple myeloma, which increases overall survival in the patient. This is a method for achieving addition. In another embodiment, what is provided herein is an effective amount The compounds described herein, for example, compound 1, compound 2 or compound 3, or the Enantiomers, mixtures of enantiomers, tautomers, isotopologs, or pharmaceuticals This includes administering a moderately tolerable salt to a patient with multiple myeloma, which results in no progression in the patient. This is a method for achieving an increase in poor survival time. In another embodiment, provided herein This involves an effective amount of the compound described herein, for example, compound 1, compound 2, or compound 3. Enantiomers thereof, mixtures of enantiomers, tautomers, isotopologs or administering a pharmaceutically acceptable salt to a patient with multiple myeloma, This is a method for achieving an increase in event-free survival in individuals. In another embodiment, the present invention Provided in the details are effective amounts of the compounds described herein, for example, Compound 1, Compound 2 or compound 3, or its enantiomer, mixture of enantiomers, tautomers, Administer an isotopolog or a pharmaceutically acceptable salt to patients with multiple myeloma. This is a method for achieving an increase in progression-free survival in patients, which includes the following: Another embodiment Therefore, what is provided herein is an effective amount of the compounds described herein, for example, Compound 1 Compound 2 or Compound 3, or their enantiomers, mixtures of enantiomers, Mutagens, isotopologs, or pharmaceutically acceptable salts in patients with multiple myeloma. This method involves administering a drug to achieve an increase in disease-free survival in patients.

[0217] Furthermore, this specification provides for multiple myeloma that has been previously treated, but is not limited to This treatment is for patients who are unresponsive to alternative therapy, as well as patients who have not been previously treated. This method further includes the use of methods to treat multiple myeloma. This is a method of treating patients who have undergone surgery, as well as those who have not. This specification provides for patients who have previously undergone transplant therapy, as well as those who have received This is a method of treating patients who have never experienced a relapse.

[0218] Some embodiments of the methods provided herein are for recurrent, refractory, or resistant conditions. The treatment of certain multiple myelomas is further included. The methods provided herein are for relapsed, refractory, or prevention of resistant multiple myeloma. The methods provided herein include relapsed, This includes the management of refractory or resistant multiple myeloma. Several such embodiments So, myeloma is a type of multiple myeloma that has relapsed primary, secondary, tertiary, quadruple, or quintuple times. In one embodiment, the method provided herein reduces minimal residual disease (MRD) and maintains To retain or eliminate. In one embodiment, the method provided herein involves a therapeutically effective amount The effects of administering the compounds described herein on monoclonal gamma globulins of unknown significance Multiple myeloma (MGUS), low-risk, intermediate-risk, and high-risk multiple myeloma, newly diagnosed Newly diagnosed multiple myeloma (low-risk, intermediate-risk, and high-risk multiple myeloma) Multiple myeloma (including), transplant-eligible and transplant-ineligible, smoldering (painless) multiple myeloma (Including low-risk, intermediate-risk, and high-risk smoldering multiple myeloma), active multiple myeloma Myeloma, solitary plasmacytoma, extramedullary plasmacytoma, plasma cell leukemia, multiple myeloma of the central nervous system Myeloma, light chain myeloma, non-secretory myeloma, immunoglobulin D myeloma, and immunoglobulin E myeloma. This includes treating, preventing, and managing various types of multiple myeloma, such as myeloma. In another embodiment, the method provided herein involves a therapeutically effective amount of the method described herein. Cyclin D translocation (e.g., t(411;14)(q13)) can be caused by administering a compound. ;q32);t(6;14)(p21;32);t(12;14)(p13;q32); Alternatively, t(6;20));MMSET translocation (e.g., t(4;14)(p16;q32)) );MAF translocation (for example, t(14;16)(q32;q32);t(20;22);t (16;22)(q11;q13); or t(14;20)(q32;q11)); or other chromosomal factors (e.g., deletion of 17p13 or chromosome 13; del(17 / 17) Multiple bone marrow lesions characterized by genetic abnormalities such as p), non-hyperdiploidy, and gain(1q)). This includes treating, preventing, or managing tumors. In one embodiment, the method is therapeutically effective A quantity of compound 1, or its enantiomer, a mixture of enantiomers, a tautomer, i This includes administering a sotopolog or a pharmaceutically acceptable salt. In another embodiment, The method involves administering a therapeutically effective amount of compound 2, or its tautomer, isotopolog, or The method includes administering a pharmaceutically acceptable salt. In another embodiment, the method is therapeutically effective A quantity of compound 3, or its tautomers, isotopologs, or pharmaceutically acceptable salts. This includes administering [the drug].

[0219] In one embodiment, high-risk multiple myeloma is characterized by relapses within 12 months of the first treatment. It is a myeloma. In yet another embodiment, high-risk multiple myeloma is caused by a genetic abnormality. For example, one or more del(17 / 17p and t(14;16)(q32;q32) It is a multiple myeloma characterized by multiple myeloma.

[0220] In some such embodiments, multiple myeloma is a newly diagnosed multiple myeloma that is eligible for transplantation. It is a primary myeloma. In another embodiment, multiple myeloma is a newly diagnosed transplant-ineligible patient. It is multiple myeloma. In another embodiment, multiple myeloma progresses rapidly following initial treatment. Characterized by a row (e.g., less than 12 months). In yet another embodiment, multiple myeloma is It is characterized by early progression (e.g., less than 12 months) following autologous stem cell transplantation. In another embodiment, Multiple myeloma is refractory to pomalidomide. Several such practices Morphologically, multiple myeloma is predicted to be refractory to pomalidomide (for example). (by molecular characterization). In another embodiment, multiple myeloma is treated with three or more therapies. The condition is relapsed or refractory, and proteasome inhibitors (e.g., bortezomib, calfenac) are used. Luzomib, ixazomib, oprozomib, or marizomib) and immunomodulatory compounds (e.g.) If exposed to thalidomide, lenalidomide, or pomalidomide, or if pro... It is doubly refractory to theasome inhibitors and immunomodulatory compounds. Furthermore, in other embodiments... For example, multiple myeloma is treated with CD38 monoclonal antibodies (CD38 mAb), for example. , daratumumab or isatuximab), proteasome inhibitors (e.g., bortezomib) , carfilzomib, ixazomib, or marizomib), and immunomodulatory compounds (e.g., For three or more prior treatments including thalidomide, lenalidomide, and pomalidomide The disease is relapsed or refractory, or is caused by proteasome inhibitors or immunomodulatory compounds. It is also doubly refractory to CD38 mAb. Furthermore, in other embodiments, multiple myelopathy The tumor is triple-refractory; for example, multiple myeloma, as described herein, is proteoplastic. Asome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, oprozomib) (e.g., bu or marizomib), immunomodulatory compounds (e.g., thalidomide, lenalidomide, and It is refractory to pomalidomide and one other active ingredient.

[0221] Certain embodiments of the methods provided herein are used for recurrent / refractory renal impairment. For patients with multiple myeloma, a therapeutically effective dose of compound 1, compound 2, or compound 3 or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, administering a pharmaceutically acceptable salt, including, for patients with renal impairment or symptoms thereof. Multiple myeloma, including relapsed / refractory multiple myeloma in patients, is treated, prevented, and / or further include methods of management.

[0222] Certain embodiments of the methods provided herein are for a frail patient with multiple myeloma. to the therapeutically effective amount of compound 1, compound 2, or compound 3, or their enantiomer , mixtures of enantiomers, tautomers, isotopologs, or pharmaceutically acceptable Salt administration is included in the treatment of relapsed or refractory multiple myeloma or other conditions in frail patients. This further includes methods for treating, preventing, and / or managing multiple myeloma, including the symptoms of the disease. In some such embodiments, frail patients are unsuitable for induction therapy, or Characterized by intolerance to xamethasone treatment. In some such embodiments, Weak patients are, for example, elderly people aged 65 or older.

[0223] In certain embodiments, the therapeutically or prophylactically effective amount of the compound is about about 0.01 to about 25mg / day, about 0.01~about 10mg / day, about 0.01~about 5mg / day, about 0.01~ Approx. 2mg / day, approx. 0.01 to approx. 1mg / day, approx. 0.01 to approx. 0.5mg / day, approx. 0.01 ~about 0.25mg / day, about 0.1 to about 25mg / day, about 0.1 to about 10mg / day, about 0. 1 to about 5 mg / day, about 0.1 to about 2 mg / day, about 0.1 to about 1 mg / day, about 0.1 to about 0 .5mg / day, about 0.1~about 0.25mg / day, about 0.5~about 25mg / day, about 0.5~ Approximately 10 mg / day, approximately 0.5 to 5 mg / day, approximately 0.5 to 2 mg / day, approximately 0.5 to 1 mg g / day, about 1 to about 25 mg / day, about 1 to about 10 mg / day, about 1 to about 5 mg / day, about 1 to about The dosage is 2.5 mg / day, or approximately 1 to approximately 2 mg / day. In one embodiment, compound 1, The therapeutically or prophylactically effective dose of compound 2 or compound 3 is approximately 0.1 mg / day to approximately 0.4 mg / day. It is g / day.

[0224] In certain embodiments, therapeutically or prophylactically effective amounts are about 0.1, about 0.2, and about 0 0.3, approximately 0.4, approximately 0.5, approximately 0.6, approximately 0.7, approximately 0.8, approximately 0.9, approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, approximately 10, approximately 15, approximately 20, or approximately 25 mg This is / day. In some such embodiments, the therapeutically or prophylactically effective amount is about 0 0.1, approximately 0.2, approximately 0.3, approximately 0.4, approximately 0.5, approximately 0.6, or approximately 0.7 mg / day ru.

[0225] In one embodiment, compound 1, compound 2 or the state described herein This refers to compound 3, its enantiomer, a mixture of enantiomers, a tautomer, or an iso The recommended daily dose range for topologs, or pharmaceutically acceptable salts, is approximately 0.1 mg. ~The dose is within the range of approximately 25 mg / day, preferably as a single once-daily dose, or per day It is administered in several divided doses. In other embodiments, the dosage is approximately 0.1 The dosage ranges from approximately 10 mg / day. Specific daily doses 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 / day Includes. More specific daily doses are 0.1, 0.2, 0.3, 0.4, or 0.5 Contains mg / day

[0226] In certain embodiments, the recommended starting dose is 0.1, 0.2, 0.3, 0.4, 0 It may be 0.5, 1, 2, 3, 4, 5, 10, 15, 20, or 25 mg / day. In terms of administration methods, the recommended starting dose is 0.1, 0.2, 0.3, 0.4, or 0.5 The dose may be mg / day. The dose may be gradually increased to 1, 2, 3, 4, or 5 mg / day.

[0227] In certain embodiments, the therapeutically or prophylactically effective dose is approximately 0.001 to approximately 5 mg / kg / day, about 0.001 to about 4 mg / kg / day, about 0.001 to about 3 mg / kg / day, about 0.001~about 2mg / kg / day, about 0.001~about 1mg / kg / day, about 0.001~ Approximately 0.05 mg / kg / day, approximately 0.001 to approximately 0.04 mg / kg / day, approximately 0.001 to Approximately 0.03 mg / kg / day, approximately 0.001 to approximately 0.02 mg / kg / day, approximately 0.001 to The recommended daily intake is approximately 0.01 mg / kg / day, and also approximately 0.001 to 0.005 mg / kg / day.

[0228] The administered dose may also be expressed in units other than mg / kg / day. For example, parenteral administration. The dosage for this purpose is mg / m². 2 It can be expressed as / day. A person skilled in the art can determine the height or weight of the subject. The dosage can be changed from either or both mg / kg / day to mg / m 2 How to convert to / day It will be easy to understand (www.fda.gov / cder / cancer / anima (See lframe.htm). For example, 1 mg / kg for a 65 kg person. The dosage of / day is 38 mg / m². 2 / Approximately equal to one day

[0229] In a particular embodiment, a patient treated with one of the methods provided herein is Compound 1, Compound 2, or Compound 3, or its enantiomer, provided herein. - Enantiomer mixtures, tautomers, isotopologs, or pharmaceutically acceptable Prior to the administration of the salt, the patient had not been treated with multiple myeloma therapy. In certain embodiments, the present Patients treated with one of the methods provided in the details shall be those who are treated with compound 1 provided herein. Compound 2 or Compound 3, or their enantiomers, mixtures of enantiomers, Before administering a mutant, isotopolog, or pharmaceutically acceptable salt, multiple myeloma therapy It is treated by law. In certain embodiments, one of the methods provided herein Patients treated with this therapy are developing drug resistance to anti-multiple myeloma therapy. In such an embodiment, the patient receives one, two, or three anti-multiple myeloma therapies. They have developed resistance to it, and the therapy involves CD38 monoclonal antibodies (CD38 mA b. For example, daratumumab or isatuximab), proteasome inhibitors (for example, vo Lutezomib, carfilzomib, ixazomib, or marizomib, and immunomodulatory compounds A substance (for example, thalidomide, lenalidomide, and pomalidomide) is selected.

[0230] The methods provided herein encompass treating patients regardless of their age. In some embodiments, the subjects are 18 years of age or older. In other embodiments, the subjects are 18 , 25, 35, 40, 45, 50, 55, 60, 65, or over 70 years old. Other implementations In one embodiment, the target group is under 65 years of age. In other embodiments, the target group is over 65 years of age. In this embodiment, the subjects are elderly patients with multiple myeloma, such as those aged 65 or older. In one embodiment, the subjects are elderly patients with multiple myeloma, such as those aged 75 or older. .

[0231] Depending on the disease being treated and the condition of the subject, Compound 1 or compound provided herein may be used. Substance 2, or its enantiomers, mixtures of enantiomers, tautomers, isotopolo G, or pharmaceutically acceptable salts, can be administered orally or parenterally (e.g., intramuscular, intraperitoneal, intravenous). CIV, intracisional injection or infusion, subcutaneous injection or implantation, inhalation, nasal, vaginal, rectal It may be administered via sublingual, or topical (e.g., transdermal or local) routes. Compound 1, Compound 2, or Compound 3, or their enantiomers, provided in the book. Mixtures of antiomers, tautomers, isotopologs, or pharmaceutically acceptable salts are, Appropriate, pharmaceutically acceptable excipients, carriers, adjuvants, and bifurcations for each route of administration. Suitable dosage units having a specific characteristic can be formulated alone or together.

[0232] In one embodiment, compound 1, compound 2, or compound 3 provided herein, or The enantiomer, mixture of enantiomers, tautomers, isotopologs, or The pharmaceutically acceptable salt is administered orally. In another embodiment, the chemicals provided herein Compound 1, Compound 2, or Compound 3, or their enantiomers, enantiomers - Mixtures, tautomers, isotopologs, or pharmaceutically acceptable salts of - may be administered parenterally. In yet another embodiment, compound 1, compound 2 or Compound 3, or its enantiomer, mixture of enantiomers, tautomers, Isotopologes or pharmaceutically acceptable salts are administered intravenously.

[0233] Compound 1, Compound 2, or Compound 3, or their enantiomers, provided herein - Enantiomer mixtures, tautomers, isotopologs, or pharmaceutically acceptable The salt may be administered as a single dose, such as a single bolus injection, or as an oral tablet or pill. Or, for example, over time, such as continuous infusion or divided bolus doses over time. The compounds described herein may be delivered if necessary, for example, to stabilize a patient's disease. Or until regression occurs, or until the patient experiences disease progression or unacceptable toxicity. It may be administered repeatedly until the disease stabilizes or is not stabilized by X-ray, CAT, PET, or Imaged using MRI scans and other commonly accepted evaluation modalities. This involves methods known in the art, such as patient symptom assessment, physical examination, and tumor visualization. It will be decided.

[0234] Compound 1, Compound 2, or Compound 3, or their enantiomers, provided herein - Enantiomer mixtures, tautomers, isotopologs, or pharmaceutically acceptable The salt can be administered once daily (QD), twice daily (BID), or three times daily (TI). D), and it can be divided into multiple daily doses such as four times daily (QID). In addition, administration This refers to continuous (i.e., daily or ever) days. (y day), intermittently, for example, in cycles (i.e., a few days, a few weeks, or a few days). (This may include a month-long break from medication.) Where used herein, the term “daily” means “daily.” Compound 1, Compound 2, or Compound 3, or their enantiomers, provided in the details. A mixture of nantiomers, tautomers, isotopologs, or pharmaceutically acceptable salts Which therapeutic compound is administered once or twice daily, for example, for a certain period of time? It is intended to have a taste. The term "sustained" is used in relation to Compound 1 provided herein. Compound 2 or Compound 3, or its enantiomer, mixture of enantiomers, tautomers Therapeutic compounds such as ferrites, isotopologs, or pharmaceutically acceptable salts are available at least This is intended to mean that it will be administered daily for an uninterrupted period of 7 to 52 weeks. The terms “intermittent” or “intermittently” as used herein mean regular or irregular. It is intended to mean stopping and starting at any regular interval. For example, Compound 1, Compound 2, or Compound 3, or their enantiomers, provided herein. , mixtures of enantiomers, tautomers, isotopologs, or pharmaceutically acceptable Intermittent salt administration involves administering the salt 1 to 6 days per week, or in cycles (e.g., 2 consecutive days). Daily administration for up to 8 weeks, followed by a break of up to 1 week with no administration, or The drug is administered every other day. The term "cycling" as used herein is defined herein. The provided compound 1, compound 2, or compound 3, or their enantiomers, enantiomers, and enantiomers are available. Omer mixtures, tautomers, isotopologs, or pharmaceutically acceptable salts, etc. The intention is that the therapeutic compound is administered daily or continuously with breaks in between. In some such embodiments, the administration is once a day for 2 to 6 days, and then Then, there is a 5-7 day rest period with no administration.

[0235] In some embodiments, the frequency of administration ranges from daily doses to monthly doses. In certain embodiments, administration is once daily, twice daily, three times daily, four times daily, or every other day. This can be twice a week, once a 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 so Enantiomers, mixtures of enantiomers, tautomers, isotopologs, or drugs A scientifically acceptable salt is administered once daily. In another embodiment, provided herein Compound 1, Compound 2, or Compound 3, or their enantiomers, or mixtures of enantiomers Compounds, tautomers, isotopologs, or pharmaceutically acceptable salts are administered twice daily. In yet another embodiment, compound 1, compound 2, or compound provided herein may be combined. Substance 3, or its enantiomers, mixtures of enantiomers, tautomers, isotopolo The salt, or a pharmaceutically acceptable salt, is administered three times a day. In yet another embodiment, Compound 1, Compound 2, or Compound 3, or their enantiomers, provided herein. , mixtures of enantiomers, tautomers, isotopologs, or pharmaceutically acceptable Salt is administered four times a day.

[0236] In one embodiment, a therapeutically effective amount of compound 1, compound 2, or compound 3 is administered during a resting period. It is administered in a treatment cycle that includes a subsequent administration period of up to 20 days. In one embodiment, therapeutically An effective dose of compound 1, compound 2, or compound 3 for a maximum administration period of 15 days, followed by a rest period. It is administered in a treatment cycle that includes the compound 1 and compound 2. In one embodiment, therapeutically effective amounts of compound 1 and compound 2 are administered. Alternatively, compound 3 may be administered in a treatment cycle that includes a maximum administration period of 10 days, followed by a rest period. In one embodiment, a therapeutically effective amount of compound 1, compound 2, or compound 3 is administered during the resting period. It is administered in a treatment cycle that includes an administration period of up to 7 days. In one embodiment, therapeutically An effective dose of compound 1, compound 2, or compound 3 is administered for a maximum duration of 5 days, followed by a rest period. It is administered in a treatment cycle. In one embodiment, therapeutically effective amounts of compound 1 and compound 2 are administered. Compound 3 is administered in a treatment cycle that includes a maximum of 4 days of administration followed by a rest period. In one embodiment, a therapeutically effective amount of compound 1, compound 2, or compound 3 is administered during the resting period. It is administered in treatment cycles that include a maximum administration period of 3 days.

[0237] 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. The treatment cycle includes an administration period of up to 7 days, followed by a rest period. In one embodiment, A treatment cycle includes an administration period of up to 5 days, followed by a rest period. In one embodiment, the treatment cycle The treatment cycle includes an administration period of up to 4 days, followed by a rest period. In one embodiment, the treatment cycle includes a rest period. This includes a maximum administration period of 3 days during which the discontinuation period may be extended.

[0238] In one embodiment, the downtime is approximately 2 days to a maximum of approximately 11 days. The duration ranges from approximately 2 days to a maximum of approximately 10 days. In one embodiment, the downtime is approximately 2 days. In one embodiment, the downtime is approximately 3 days. In another embodiment, the downtime is approximately 4 days. In one embodiment, the downtime is approximately 5 days. In another embodiment, the downtime is approximately 6 days. In another embodiment, the rest period is approximately 7 days. In another embodiment, the rest period is , approximately 8 days. In another embodiment, the rest period is approximately 9 days. In another embodiment, The downtime is approximately 10 days. In another embodiment, the downtime is approximately 11 days.

[0239] In one embodiment, the treatment cycle is up to 15 days, with rest periods of approximately 2 to 10 days. This includes a treatment period of days. In one embodiment, the treatment cycle has a rest period of about 2 days to a maximum of about 10 days. This includes a maximum administration period of 10 days. In one embodiment, the treatment cycle is approximately 2 days This includes a maximum administration period of 7 days, followed by a maximum rest period of approximately 10 days. In one embodiment, the therapeutic cycle The administration period includes a maximum of 5 days, followed by a rest period of approximately 2 to 10 days. (One embodiment) The treatment cycle consists of a maximum of 3 days of administration followed by a break of approximately 10 to 15 days. This includes. In one embodiment, the treatment cycle is followed by a rest period of approximately 3 to 15 days. This includes a 3-day administration period.

[0240] In one embodiment, the treatment cycle includes a maximum administration period of 15 days, followed by a 7-day rest period. In one embodiment, the treatment cycle includes a maximum administration period of 10 days, followed by a 5-day rest period. In one embodiment, the treatment cycle includes a maximum administration period of 10 days, followed by a 4-day rest period. In one embodiment, the treatment cycle includes a maximum administration period of 10 days, followed by a 3-day rest period. In one embodiment, a treatment cycle includes a maximum administration period of 10 days, followed by a 2-day rest period. In one embodiment, the treatment cycle includes a maximum administration period of 7 days, followed by a 7-day rest period. In one embodiment, the treatment cycle includes a maximum administration period of 5 days, followed by a 5-day rest period. In one embodiment, the treatment cycle includes a maximum administration period of 3 days, followed by an 11-day rest period. In this embodiment, the treatment cycle includes a maximum administration period of 5 days followed by a 9-day rest period. In this embodiment, the treatment cycle includes a maximum administration period of 5 days, followed by a 2-day rest period. In this embodiment, the treatment cycle includes a maximum administration period of 3 days, followed by a 4-day rest period.

[0241] In one embodiment, the treatment cycle consists of a therapeutically effective amount on days 1-5 of a 28-day cycle. The treatment cycle includes administration of compound 1, compound 2, or compound 3. In another embodiment, the treatment cycle is: This includes administration of compound 1, compound 2, or compound 3 on days 1-10 of a 28-day cycle. In the embodiment, the treatment cycle is a 28-day cycle in which a therapeutically effective amount is administered on days 1 to 21. The treatment comprises administration of compound 1, compound 2, or compound 3. In another embodiment, the treatment cycle is 7 Administer a therapeutically effective amount of compound 1, compound 2, or compound 3 on days 1-5 of the daily cycle. This includes. In another embodiment, the treatment cycle is therapeutically effective on days 1 to 7 of a 7-day cycle. The treatment cycle comprises administering an amount of compound 1, compound 2, or compound 3. In one embodiment, the treatment cycle This involves a therapeutically effective amount of compound 1 on days 1-10 and 15-24 of the 28-day cycle. The treatment comprises administration of compound 2 or compound 3. In one embodiment, the treatment cycle is a 28-day cycle. A therapeutically effective amount of compound 1, compound 2, or compound 2 on days 1-3 and 15-18 of the treatment. The administration of substance 3 is included. In one embodiment, the treatment cycle is days 1 to 7 of a 28-day cycle and This includes administering a therapeutically effective amount of compound 1, compound 2, or compound 3 on days 15 to 21. In one embodiment, the treatment cycle is a 28-day cycle, with days 1-5 and 15-19 The method includes administering a therapeutically effective amount of compound 1, compound 2, or compound 3. In one embodiment, The treatment cycle involves administering therapeutically effective doses on days 1-3 and 15-17 of a 28-day cycle. The administration includes compound 1, compound 2, or compound 3.

[0242] In one embodiment, the treatment cycle consists of a therapeutically effective dose administered on days 1-14 of a 21-day cycle. The treatment cycle comprises administration of compound 1, compound 2, or compound 3. In another embodiment, the treatment cycle is Compound 1, Compound 2, or Compound 3 on days 1-4 and 8-11 of the 21-day cycle This includes the administration of [the substance]. In one embodiment, the treatment cycle is a 21-day cycle, with days 1-5 and 8- The administration of a therapeutically effective amount of compound 1, compound 2, or compound 3 on day 12 is also included. In terms of treatment methods, the treatment cycle consists of treatments performed on days 1-5 and 11-15 of a 21-day cycle. The above comprises administering an effective amount of compound 1, compound 2, or compound 3. In another embodiment, the treatment The cycle is a 21-day cycle, with treatment taking place on days 1-5, 8-12, and 15-19. The administration comprises an effective amount of compound 1, compound 2, or compound 3. In another embodiment, the therapeutic Ikuru has therapeutic effects on days 1-4, 8-11, and 15-18 of the 21-day cycle. The administration includes an effective amount of compound 1, compound 2, or compound 3. In another embodiment, the therapeutic site Kuru is therapeutically effective on days 1-4, 8-10, and 15-17 of the 21-day cycle. This comprises administering an amount of compound 1, compound 2, or compound 3. In another embodiment, the therapeutic cycle The drug contains a therapeutically effective amount of compound 1 on days 1-3 and 8-11 of the 21-day cycle. The treatment cycle includes administration of compound 2 or compound 3. In another embodiment, the treatment cycle is 21 days. A therapeutically effective amount of compound 1, compound 2, or compound 2 on days 1-3 and 11-13 of the treatment. This includes the administration of substance 3.

[0243] Any treatment cycle described herein must be at least 2, 3, 4, 5, 6, 7, 8 Or, the cycle may be repeated more than once. In certain cases, the treatment described herein The cycles are 1 to approximately 24 cycles, approximately 2 to approximately 16 cycles, or approximately 2 to approximately 4 cycles. Includes Cycle. In certain cases, the treatment cycle described herein is 1 to about 4 cycles. Includes cycles. In a particular embodiment, cycles 1-4 are all 28-day cycles. In some embodiments, a therapeutically effective amount of compound 1, compound 2, or compound 3 is 1 It is administered in 28-day cycles of ~13 (for example, for about a year). In certain cases, cycle Ring therapy is not limited to a certain number of cycles, and the therapy continues until the disease progresses. The cycles are: In certain cases, the duration of the administration period and / or the rest period described herein may be altered. This includes the act of making something happen.

[0244] In one embodiment, the treatment cycle involves administering compound 1, compound 2, or compound 3 once a day. The prescribed dosage is approximately 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0. 5mg / day, 0.6mg / day, 0.7mg / day, 0.8mg / day, 0.9mg / day, 1. This includes administering the drug at doses of 0 mg / day, 5.0 mg / day, or 10 mg / day. In terms of administration, the treatment cycle involves administering compound 1, compound 2, or compound 3 once a day. Approximately 0.1 mg / day, 0.2 mg / day, 0.3 mg / day, 0.4 mg / day, 0.5 mg Administer at a dosage of 0.6 mg / day, 0.7 mg / day, or 0.8 mg / day. This includes. In some such embodiments, the treatment cycle is 1 to 1 of a 28-day cycle. On day 0, administer compound 1, compound 2, or compound 3 in doses of approximately 0.1 mg, 0.2 mg, and 0.3 mg. This includes administering g, 0.4 mg, or 0.5 mg once daily. In such embodiments, the treatment cycle consists of days 1-10 and 15-2 of a 28-day cycle. On the fourth day, take compound 1, compound 2, or compound 3 in doses of approximately 0.1 mg, 0.2 mg, and 0.3 mg. This includes administering g, 0.4 mg, or 0.5 mg once daily. In such embodiments, the treatment cycle consists of days 1-10 and 15-2 of a 28-day cycle. On day 4, administer compound 1, compound 2, or compound 3 once daily at a dose of approximately 0.1 mg. This includes doing so. In other embodiments, the treatment cycle is a 28-day cycle, on days 1-3, Compound 1, Compound 2, or Compound 3 in approximately 0.1 mg, 0.2 mg, 0.3 mg, and 0.4 mg doses. This includes administering a dose of mg or 0.5 mg twice daily. In other embodiments, The treatment cycle consists of a 28-day cycle, with compound 1 and compound 2 administered on days 1-3 and 15-19. Alternatively, compound 3 in approximately 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg. This includes administering a dose of mg twice daily. In other embodiments, the treatment cycle is 28 On days 1-3 and 15-17 of the daily cycle, take compound 1, compound 2, or compound 3. The daily dose is approximately 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, or 0.5 mg. This includes administering the drug twice. In other embodiments, the treatment cycle consists of 1 to 3 28-day cycles. On day 1 and on days 15-17, administer approximately 0.2 mg of compound 1, compound 2, or compound 3. This involves administering the compound twice a day in a given amount. In one such embodiment, the compound cycles Days 1-3 (morning and evening), Day 14 (evening only), Day 15 and Day 16 (morning and evening) It is administered on the 17th day (morning only).

[0245] In some embodiments, the herein provides for recurrent, refractory, or conventional Patients with multiple myeloma that are resistant to therapy and are likely to respond to therapeutic compounds. A method for identifying elephants, (a) Obtaining a sample from the subject, (b) Determining the level of biomarkers in the sample, (c) When the level of the biomarker in the sample is lower than the reference level of the biomarker This includes diagnosing the subject as having a high probability of responding to the therapeutic compound, and developing the therapeutic compound. Compound 1: [ka] Compounds thereof, or their enantiomers, mixtures of enantiomers, tautomers, isopropyl alcohols The method involves a polog, or a pharmaceutically acceptable salt.

[0246] In another embodiment, provided herein are treatments for relapsed, refractory, or conventionally treated conditions. In contrast, we specifically target patients with resistant multiple myeloma who are highly likely to respond to therapeutic compounds. A method of determination, (a) Obtaining a sample from the subject, (b) Determining the level of biomarkers in the sample, (c) When the level of the biomarker in the sample is lower than the reference level of the biomarker This includes diagnosing the subject as having a high probability of responding to the therapeutic compound, and developing the therapeutic compound. Compound 2: [ka] The compound, or its tautomer, isotopolog, or pharmaceutically acceptable salt thereof That is the method.

[0247] In yet another embodiment, the herein provides for recurrent, refractory, or conventional Patients with multiple myeloma that are resistant to therapy and are likely to respond to therapeutic compounds. A method for identifying elephants, (a) Obtaining a sample from the subject, (b) Determining the level of biomarkers in the sample, (c) When the level of the biomarker in the sample is lower than the reference level of the biomarker This includes diagnosing the subject as having a high probability of responding to the therapeutic compound, and developing the therapeutic compound. Compound 3: [ka] The compound, or its tautomer, isotopolog, or pharmaceutically acceptable salt thereof That is the method.

[0248] In some embodiments, the herein provides for recurrent, refractory, or conventional Patients with multiple myeloma that are resistant to therapy and are likely to respond to therapeutic compounds. A method for identifying elephants, (a) Determine the level of biomarkers in the sample obtained from the subject, (c) When the level of the biomarker in the sample is lower than the reference level of the biomarker This includes diagnosing the subject as having a high probability of responding to the therapeutic compound, and developing the therapeutic compound. The compound is a compound of compound 1, compound 2, or compound 3, or a tautomer thereof, or an iso The method involves using a topolog or a pharmaceutically acceptable salt.

[0249] In another aspect, the herein provides a therapeutic compound for multiple myeloma A method for predicting the responsiveness of an object, (a) Obtaining a sample from the subject, (b) Determining the level of biomarkers in the sample, (c) When the level of the biomarker in the sample is lower than the reference level of the biomarker This includes diagnosing the subject as having a high probability of responding to the therapeutic compound, and developing the therapeutic compound. Compound 1: [ka] Compounds thereof, or their enantiomers, mixtures of enantiomers, tautomers, isopropyl alcohols The method involves a polog, or a pharmaceutically acceptable salt.

[0250] In another embodiment, the present invention provides a therapeutic compound for multiple myeloma. A method for predicting the responsiveness of an object having the following characteristics: (a) Obtaining a sample from the subject, (b) Determining the level of biomarkers in the sample, (c) When the level of the biomarker in the sample is lower than the reference level of the biomarker This includes diagnosing the subject as having a high probability of responding to the therapeutic compound, and developing the therapeutic compound. Compound 2: [ka] The compound, or its tautomer, isotopolog, or pharmaceutically acceptable salt thereof That is the method.

[0251] In yet another embodiment, the response of a subject with multiple myeloma to a therapeutic compound A method of prediction, (a) Obtaining a sample from the subject, (b) Determining the level of biomarkers in the sample, (c) When the level of the biomarker in the sample is lower than the reference level of the biomarker This includes diagnosing the subject as having a high probability of responding to the therapeutic compound, and developing the therapeutic compound. Compound 3: [ka] The compound, or its tautomer, isotopolog, or pharmaceutically acceptable salt thereof A method.

[0252] In another aspect, the herein provides a therapeutic compound for multiple myeloma A method for predicting the responsiveness of an object, (a) Determine the level of biomarkers in the sample obtained from the subject, (c) When the level of the biomarker in the sample is lower than the reference level of the biomarker This includes diagnosing the subject as having a high probability of responding to the therapeutic compound, and developing the therapeutic compound. The compound is a compound of compound 1, compound 2, or compound 3, or a tautomer thereof, or an iso The method involves using a topolog or a pharmaceutically acceptable salt.

[0253] The administration regimen is adjusted according to the level of the biomarkers and the patient's response or lack thereof. It is understood that this may be the case. For example, the patient may have neutropenia or the patient may not respond If not, the dosage may be adjusted. Therefore, in some embodiments, this specification What is provided is the dosage of medication for treating subjects with multiple myeloma with therapeutic compounds. A method of making or adjusting, (a) Administering a dosage of the therapeutic compound to the subject, (b) Obtaining one or more samples from the subject at different time points, (c) Determine the level of biomarkers in one or more samples, and thereby determine the dosage. This includes determining whether it is appropriate or whether adjustments are needed. The therapeutic compound is compound 1: [ka] Compounds thereof, or their enantiomers, mixtures of enantiomers, tautomers, isopropyl alcohols The method involves a polog, or a pharmaceutically acceptable salt.

[0254] In another embodiment, provided herein is a therapeutic application for subjects having multiple myeloma. A method for determining or adjusting the dosage of medication for treatment with a compound, (a) Administering a dosage of the therapeutic compound to the subject, (b) Obtaining one or more samples from the subject at different time points, (c) Determine the level of biomarkers in one or more samples, and thereby determine the dosage. This includes determining whether it is appropriate or requires adjustment, and the therapeutic compound The substance is compound 2: [ka] The compound, or its tautomer, isotopolog, or pharmaceutically acceptable salt thereof That is the method.

[0255] In yet another embodiment, the present invention provides a method for treating subjects having multiple myeloma. A method for determining or adjusting the dosage of a therapeutic compound for treatment, (a) Administering a dosage of the therapeutic compound to the subject, (b) Obtaining one or more samples from the subject at different time points, (c) Determine the level of biomarkers in one or more samples, and thereby determine the dosage. This includes determining whether it is appropriate or requires adjustment, and the therapeutic compound The substance is compound 3: [ka] The compound, or its tautomer, isotopolog, or pharmaceutically acceptable salt thereof That is the method.

[0256] In yet another embodiment, the present invention provides a method for treating subjects having multiple myeloma. A method for determining or adjusting the dosage of a therapeutic compound for treatment, wherein the compound is the target It is administered to them, (a) Determine the level of a biomarker in one or more samples obtained from the subject, and Therefore, this includes determining whether the dosage is appropriate or whether adjustments are needed. , the therapeutic compound is a compound of compound 1, compound 2, or compound 3, or a tautomer thereof The method involves a body, isotopolog, or pharmaceutically acceptable salt.

[0257] In some embodiments, different time points are used for reference samples obtained before treatment with the therapeutic compound. and one or more samples obtained from the subject at different times during treatment with the therapeutic compound, Obtain. In other embodiments, different time points are used for the reference sample obtained during treatment and the therapeutic compound. This may include one or more samples taken at a later time during treatment. In this case, the different time points are a reference sample taken before treatment and a sample taken after treatment. It may include.

[0258] Furthermore, the biomarkers provided herein (e.g., Aiolos, Ikar) os, CRBN, ZFP91, c-MYC, IRF4, c-caspase 1, c-casper Ze-3, c-caspase 7, cleavage-type PARP, Survivalbin, BIM, sFLC, p21, p27, pRB1, soluble BCMA, CTC, TIL, IL-2, IFNγ, TNFα, Using (or TCR clonality), the patient's response to the therapeutic compound, or treatment This is a method for predicting or monitoring the effectiveness of a compound. In a particular embodiment, The following are provided herein: Aiolos, Ikaros, CRBN, ZFP91, c- MYC, IRF4, c-caspase 1, c-caspase-3, c-caspase 7, cleavage type PARP, survivin, BIM, sFLC, p21, p27, pRB1, soluble BCMA Predictions of CTC, TIL, IL-2, IFNγ, TNFα, or TCR clonality Using factors or prognostic factors, the treatment of cancer (e.g., multiple myeloma) with therapeutic compounds is determined. This is a method for predicting the responsiveness of an object that possesses or is suspected of possessing. In the embodiments herein, the predictor or prognostic factor is a bioma Carrier (e.g., Aiolos, Ikaros, CRBN, ZFP91, c-MYC, I RF4, c-caspase 1, c-caspase-3, c-caspase 7, cleavage-type PARP, Survivin, BIM, sFLC, p21, p27, pRB1, soluble BCMA, CTC, Using TIL, IL-2, IFNγ, TNFα, or TCR clonal levels, The effectiveness of therapeutic compounds in treating cancer (e.g., multiple myeloma) in a target population is monitored. This is a method for performing a procedure. In a particular embodiment, the therapeutic compound is compound 1, compound It is substance 2 or compound 3. In one embodiment, the therapeutic compound is compound 1. In one embodiment, the compound is compound 2. In another embodiment, the therapeutic compound is compound The answer is 3.

[0259] Therefore, in some embodiments, what is provided herein is for therapeutic compounds a method for predicting the responsiveness of subjects who have cancer or are suspected of having cancer. , (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Determining the level of biomarkers in the sample, (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If it differs from Bell's, the subject should be diagnosed as likely to respond to the therapeutic compound, Contains, therapeutic compounds, Compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, drugs A scientifically acceptable salt or polymorph, or method.

[0260] In another embodiment, the foregoing provides for therapeutic compounds for subjects with cancer. or a method for predicting the responsiveness of a subject suspected of having cancer, (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Determining the level of biomarkers in the sample, (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If it differs from Bell's, the subject should be diagnosed as likely to respond to the therapeutic compound, Contains, therapeutic compound, compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0261] In yet another embodiment, what is provided herein is a therapeutic compound for cancer A method for predicting the responsiveness of a subject or a subject suspected of having cancer, (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Determining the level of biomarkers in the sample, (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If it differs from Bell's, the subject should be diagnosed as likely to respond to the therapeutic compound, Contains, therapeutic compounds, compound 3: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0262] In another embodiment, what is provided herein is a therapeutic compound administered to a subject This was a method for predicting the responsiveness of subjects who have cancer or are suspected of having cancer. hand, (a) Determine the level of biomarkers in the sample obtained from the subject, (b) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If different from Bell's findings, it includes diagnosing the subject as likely to respond to the therapeutic compound. The therapeutic compound is compound 1, compound 2, or compound 3, or a tautomer thereof. The method involves using an isotopolog or a pharmaceutically acceptable salt.

[0263] In yet another embodiment, what is provided herein is a therapeutic compound for cancer A method for predicting the responsiveness of a subject or a subject suspected of having cancer, (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Determining the level of biomarkers in the sample, (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If it differs from Bell's, the subject should be diagnosed as likely to respond to the therapeutic compound, Contains, therapeutic compounds, Compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, drugs A scientifically acceptable salt or polymorph, or method.

[0264] In yet another embodiment, what is provided herein is a therapeutic compound for cancer A method for predicting the responsiveness of a subject or a subject suspected of having cancer, (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Determining the level of biomarkers in the sample, (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If it differs from Bell's, the subject should be diagnosed as likely to respond to the therapeutic compound, Contains, therapeutic compound, compound 2: [ka] or its tautomers, isotopologs, pharmaceutically acceptable salts, or polymorphs, It is a method.

[0265] In yet another embodiment, what is provided herein is a therapeutic compound for cancer A method for predicting the responsiveness of a subject or a subject suspected of having cancer, (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Determining the level of biomarkers in the sample, (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If it differs from Bell's, the subject should be diagnosed as likely to respond to the therapeutic compound, Contains, therapeutic compounds, compound 3: [ka] or its tautomers, isotopologs, pharmaceutically acceptable salts, or polymorphs, It is a method.

[0266] In yet another embodiment, what is provided herein is a therapeutic compound for cancer A method for predicting the responsiveness of a subject or a subject suspected of having cancer, (a) Administering therapeutic compounds to samples obtained from the subject, (b) Determining the level of biomarkers in the sample, (c) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If different from Bell's findings, it includes diagnosing the subject as likely to respond to the therapeutic compound. The therapeutic compound is compound 1, compound 2, or compound 3, or a tautomer thereof. The isotopolog, pharmaceutically acceptable salt, or polymorph is available.

[0267] In some embodiments of the various methods provided herein, biomarkers in a sample The level is higher than the level of the biomarker obtained from the reference sample. Provided herein In other embodiments of the various methods, the level of a biomarker in the sample is compared to that of a reference sample. The levels are lower than those of the biomarkers obtained from other sources.

[0268] In yet another aspect, what is provided herein is a therapeutic compound for cancer in a target. A method for monitoring the effectiveness of treatment, (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Determining the level of biomarkers in the sample, (d) The level of the biomarker in the sample is compared to the level of the biomarker obtained from the reference sample. The comparison is with Bell, and changes in biomarker levels indicate that cancer is being treated in the subjects. To demonstrate the effectiveness of therapeutic compounds in doing so, to compare and include therapeutic compounds However, compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, drugs A scientifically acceptable salt or polymorph, or method.

[0269] In yet another aspect, what is provided herein is a therapeutic compound for cancer in a target. A method for monitoring the effectiveness of treatment, (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Determining the level of biomarkers in the sample, (d) The level of the biomarker in the sample is compared to the level of the biomarker obtained from the reference sample. The comparison is with Bell, and changes in biomarker levels indicate that cancer is being treated in the subjects. This includes demonstrating the effectiveness of therapeutic compounds in doing so, and making comparisons. The therapeutic compound is compound 2: [ka] or its tautomers, isotopologs, pharmaceutically acceptable salts, or polymorphs, It is a method.

[0270] In yet another aspect, what is provided herein is a therapeutic compound for cancer in a target. A method for monitoring the effectiveness of treatment, (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Determining the level of biomarkers in the sample, (d) The level of the biomarker in the sample is compared to the level of the biomarker obtained from the reference sample. The comparison is with Bell, and changes in biomarker levels indicate that cancer is being treated in the subjects. To demonstrate the effectiveness of therapeutic compounds in doing so, to compare and include therapeutic compounds However, compound 3: [ka] or its tautomers, isotopologs, pharmaceutically acceptable salts, or polymorphs, It is a method.

[0271] In yet another embodiment, the therapeutic compound being administered to the subject is provided herein. A method for monitoring the effectiveness of cancer treatment in subjects in, (a) Determine the level of biomarkers in the sample obtained from the subject, (b) The level of the biomarker in the sample is compared to the level of the biomarker obtained from the reference sample. The comparison is with Bell, and changes in biomarker levels indicate that cancer is being treated in the subjects. This includes demonstrating the effectiveness of therapeutic compounds in doing so, and making comparisons. The therapeutic compound is compound 1, compound 2, or compound 3, or a tautomer thereof, i Sotopologs are pharmaceutically acceptable salts or polymorphs, or methods.

[0272] In some embodiments, an increased level compared to a reference level indicates cancer in the subject. This demonstrates the efficacy of therapeutic compounds in treating [condition]. For example, compared to a reference, c-cash Pase-3, c-caspase-1, c-caspase-7, cleavage-type PARP, BIM, TUNE L, Annexin V / 7-AAD, Annexin V / PI, p21, p27, Free light chain, IL -2, increased TNFα, IFNγ, or TCR clonality indicates multiple myelitis in the subject. The efficacy of the therapeutic compound in treating tumors is demonstrated. In other embodiments, reference level The reduced level compared to the therapeutic compound in treating cancer in the target It demonstrates effectiveness. For example, Aiolos(IKZF3), Ikaros(I The decrease in KZF1, CTC, ZFP91, c-MYC, IRF4, and phospho-Rb1 is in contrast to This study demonstrates the efficacy of therapeutic compounds in treating multiple myeloma in elephants.

[0273] It is understood that the levels of biomarkers are relative to the reference level. Therefore In some embodiments, the reduced level compared to the reference level indicates cancer in the subject. This demonstrates the efficacy of therapeutic compounds in treating [condition]. For example, from patients with multiple myeloma. For reference, c-caspase-3, c-caspase-1, and c-caspa from healthy patients. Ze7, scission-type PARP, BIM, TUNEL, Annexin V / 7-AAD, Annexin V / PI, p21, p27, free light chain, IL-2, TNFα, IFNγ, or TCR cross The reduction in fluency is the effectiveness of therapeutic compounds in treating multiple myeloma in the target population. It indicates that. In other embodiments, the increased level compared to the reference level is in the subject This demonstrates the effectiveness of therapeutic compounds in treating [the disease]. For example, from patients with multiple myeloma For reference, Aiolos(IKZF3), Ikaros(IKZ Increases in F1, CTC, ZFP91, c-MYC, IRF4, and phospho-Rb1 are observed in the target group. This paper demonstrates the efficacy of therapeutic compounds in treating multiple myeloma.

[0274] As will be discussed elsewhere in this specification, this specification includes, but is not limited to, , and the associated risks associated with conventional therapies including surgery, chemotherapy, radiation therapy, biological therapy, and immunotherapy. A method for reducing, treating, and / or preventing harmful or undesirable effects. The compounds provided in the book, for example, compound 1, compound 2, or compound 3, or their enamel Nthiomers, mixtures of enantiomers, tautomers, isotopologs, or pharmaceutically Acceptable salts and other active ingredients are identified using the biomarkers described herein. It can be administered to patients before, during, or after the onset of adverse effects associated with conventional therapy. .

[0275] Compound 1, Compound 2, or Compound 3, or their enantiomers, provided herein - Enantiomer mixtures, tautomers, isotopologs, or pharmaceutically acceptable The salt is a useful therapeutic agent for the treatment and / or prevention of multiple myeloma as described herein. It can be combined with, or used in combination with.

[0276] In some embodiments of the various methods provided herein, the method involves administering a compound to a patient. 1. Compound 2 or Compound 3, or its enantiomer, a mixture of enantiomers, Tautomers, isotopologs, or pharmaceutically acceptable salts are used in one or more secondary active ingredients. This includes administering the agent, and optionally in combination with radiotherapy, blood transfusions, or surgery.

[0277] As used herein, the term “in combination” means two or more therapies (for example) This includes the use of one or more prophylactic and / or therapeutic agents. However, "combined" The use of the term "treatment" implies that a therapy (e.g., a preventive and / or therapeutic agent) treats a disease or disorder. The order in which the drugs are administered to patients is not restricted. A second therapy to the target (e.g., a prophylactic agent or Before administering the therapeutic agent (for example, 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours prior) Previous, 4 hours ago, 6 hours ago, 12 hours ago, 24 hours ago, 48 hours ago, 72 hours ago, 96 hours ago Previous, 1 week ago, 2 weeks ago, 3 weeks ago, 4 weeks ago, 5 weeks ago, 6 weeks ago, 8 weeks ago or 1 Two weeks prior, simultaneously with or after the administration of the second therapy (for example, 5 minutes later) 15 minutes later, 30 minutes later, 45 minutes later, 1 hour later, 2 hours later, 4 hours later, 6 hours later, 12 hours later Later, 24 hours later, 48 hours later, 72 hours later, 96 hours later, 1 week later, 2 weeks later, 3 weeks later , 4 weeks later, 5 weeks later, 6 weeks later, 8 weeks later or 12 weeks later) the first therapy (for example) , preventive or therapeutic agents such as compounds provided herein, for example, compound 1, compound 2 or compound 3, or its enantiomer, mixture of enantiomers, tautomers, An isotopolog (or a pharmaceutically acceptable salt) may be administered. Triple therapy is also possible. As intended herein, such as quadruple therapy. In one embodiment, the second therapy is dexamethasone. It's a zombie.

[0278] Compound 1, Compound 2, or Compound 3, or their enantiomers, the enantiomer Mixtures, tautomers, isotopologs, or pharmaceutically acceptable salts, and one or more The second active agent may be administered to the patient simultaneously or sequentially via the same or different route of administration. It is possible. The suitability of a particular route of administration used for a particular activator depends on the activator itself (for example). (It would depend on whether it can be administered orally without being broken down before entering the bloodstream.) cormorant.

[0279] Compound 1, Compound 2, or Compound 3, or their enantiomers, the enantiomer The route of administration of mixtures, tautomers, isotopologs, or pharmaceutically acceptable salts is: This is unrelated to the administration route of the two therapies. In one embodiment, compound 1, compound 2 or Compound 3, or its enantiomer, mixture of enantiomers, tautomer, isotopo The log, or a pharmaceutically acceptable salt, is administered orally. In another embodiment, compound 1 Compound 2 or Compound 3 is administered intravenously. Therefore, according to these embodiments For example, compound 1, compound 2 or compound 3, or their enantiomers, enantiomers Mixtures, tautomers, isotopologs, or pharmaceutically acceptable salts thereof may be administered orally. The first therapy is administered intravenously, and the second therapy is administered orally, parenterally, intraperitoneally, or intravenously. Intra-arterial administration, transdermal administration, sublingual administration, intramuscular administration, rectal administration, oral administration, intranasal administration, Administration by posome, inhalation, vaginal, intraocular, catheter or stent Can it be administered via local delivery, subcutaneous, intrafat, intra-articular, or intrathecal delivery? , or it may be administered in a sustained-release form. In one embodiment, compound 1, compound 2 or compound 3. Enantiomers thereof, mixtures of enantiomers, tautomers, isotopologs , or a pharmaceutically acceptable salt, and the second treatment is administered orally or by the same mode of administration. It is administered intravenously. In another embodiment, compound 1, compound 2 or compound 3, or The enantiomer, mixture of enantiomers, tautomers, isotopologs, or Pharmacologically acceptable salts are administered by a single mode of administration, for example, intravenously. However, the second drug (an anti-multiple myeloma agent) is administered by a different mode of administration, for example, orally. ru.

[0280] In one embodiment, the second activator is administered intravenously or subcutaneously in an amount of approximately 1 to 1000 mg, approximately 5 Take approximately 500mg, 10-350mg, or 50-200mg once daily. It is administered in two doses. The specific amount of the second active ingredient depends on the specific drug, treatment, and / or drug used. The type of multiple myeloma being managed, the severity and stage of the disease, and as specified herein The provided compound 1, compound 2, or compound 3, or their enantiomers, enanes A mixture of thiomers, tautomers, isotopologs, or pharmaceutically acceptable salts, and It will depend on the amount of any optional additional activator administered to the patients simultaneously.

[0281] One or more second active ingredients or agents are used in the methods and compositions provided herein. The second activator is a macromolecule. (For example, proteins), small molecules (for example, synthetic inorganic, organometallic, or organic molecules), Alternatively, it could be cell therapy (for example, CAR cells).

[0282] An example of a second activator that may be used in the methods and compositions described herein is melphalan. Vincristine, cyclophosphamide, etoposide, doxorubicin, bendamustine, Proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib, op) Rozomib or marizomib), histone deacetylase inhibitors (e.g., panobinostat) (e.g., ACY241), BET inhibitors (e.g., GSK525762A, OTX015, B) MS-986158, TEN-010, CPI-0610, INCB54329, BAY 1238097, FT-1101, C90010, ABBV-075, BI894999 , GS-5829, GSK1210151A(I-BET-151), CPI-203, RVX-208, XD46, MS436, PFI-1, RVX2135, ZEN3365 XD14, ARV-771, MZ-1, PLX5117, EP11313 and EP11 336), BCL2 inhibitors (e.g., venetoclax or navitoclax), MCL- 1. Inhibitors (e.g., AZD5991, AMG176, MIK665, S64315, also (S63845), corticosteroids (e.g., prednisone), dexamethasone; anti Body (for example, CS1 antibodies such as elotuzumab, CD3 antibodies such as daratumumab and isatuximab) 8 antibodies, or BCMA antibodies such as GSK2857916 or BI 836909 are also available. (or antibody conjugates), checkpoint inhibitors (as described herein), and This comprises one or more CAR cells (as described herein).

[0283] In one embodiment, the method and composition described herein includes compound 1 and compound 2. ku is compound 3, or its enantiomer, mixture of enantiomers, tautomer, i The second activator used with sotopolog or a pharmaceutically acceptable salt is dexa It's methamphetamine.

[0284] In some embodiments, dexamethasone is administered on days 1 and 8 of a 21-day cycle. It is administered in doses of mg. In some other embodiments, dexamethasone is administered over 21 days. It is administered in doses of 4 mg on days 1, 4, 8 and 11 of the cycle. In some embodiments, Dexamethasone is administered at a dose of 4 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered in 1, 4, 8, and 11 of a 28-day cycle. It is administered in doses of 4 mg on days 15 and 18. In some embodiments, dexamethasone is used. Zon is administered in doses of 4 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered in cycles 1, 10, 15, and 2 of cycle 1. It is administered at a dose of 4 mg on the second day. In some embodiments, dexamethasone is 28 It is administered in doses of 4 mg on days 1, 3, 15, and 17 of the daily cycle. In one embodiment, dexamethasone is administered at a dose of 4 mg on days 1, 3, 14, and 17 of cycle 1. It is administered in the following dose.

[0285] In some other embodiments, dexamethasone is administered on days 1 and 8 of a 21-day cycle. It is administered at a dose of 8 mg. In some other embodiments, dexamethasone is administered for 21 days. It is administered in doses of 8 mg on days 1, 4, 8, and 11 of the cycle. In some embodiments, Dexamethasone is administered at a dose of 8 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered in 1, 4, and 8 of a 28-day cycle. It is administered in doses of 8 mg on days 11, 15, and 18. In some embodiments, dexamethasone is used. Metasone is administered in doses of 8 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered in cycles 1, 10, 15, and It is administered at a dose of 8 mg on day 22. In some embodiments, dexamethasone is It is administered in doses of 8 mg on days 1, 3, 15, and 17 of a 28-day cycle. In such embodiments, dexamethasone is administered on days 1, 3, 14, and 17 of cycle 1. It is administered in doses of mg.

[0286] In some embodiments, dexamethasone is administered on days 1 and 8 of a 21-day cycle. It is administered in doses of 0 mg. In some other embodiments, dexamethasone is administered for 21 days. It is administered in doses of 10 mg on days 1, 4, 8, and 11 of Ikul. In some embodiments Dexamethasone is administered in doses of 10 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered in the 1st, 4th, and 8th cycles of a 28-day cycle. It is administered in doses of 10 mg on days 11, 15 and 18. In some embodiments, Xamethasone is administered at a dose of 10 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered in cycles 1, 10, and 1. It is administered in doses of 10 mg on days 5 and 22. In some embodiments, dexamethasone Zon is administered in doses of 10 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered in cycles 1, 3, 14, and 1 It is administered at a dose of 10 mg on the 7th day.

[0287] In some embodiments, dexamethasone is administered on days 1 and 8 of a 21-day cycle. It is administered in doses of 0 mg. In some other embodiments, dexamethasone is administered for 21 days. It is administered in doses of 20 mg on days 1, 4, 8, and 11 of Ikul. In some embodiments Dexamethasone is administered at a dose of 20 mg on days 1, 8, and 15 of a 28-day cycle. In some other embodiments, dexamethasone is administered in the 1st, 4th, and 8th cycles of a 28-day cycle. It is administered in doses of 20 mg on days 11, 15 and 18. In some embodiments, Xamethasone is administered at a dose of 20 mg on days 1, 8, 15, and 22 of a 28-day cycle. In one such embodiment, dexamethasone is administered in cycles 1, 10, and 1. It is administered in doses of 20 mg on days 5 and 22. In some embodiments, dexamethasone Zon is administered in doses of 20 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered in cycles 1, 3, 14, and 1 It is administered at a dose of 20 mg on the 7th day.

[0288] In some embodiments, dexamethasone is administered on days 1 and 8 of a 21-day cycle. It is administered in doses of 0 mg. In some other embodiments, dexamethasone is administered for 21 days. It is administered at a dose of 40 mg on days 1, 4, 8, and 11 of Ikul. In some embodiments Dexamethasone is administered at a dose of 40 mg on days 1, 8, and 15 of a 28-day cycle. In one such embodiment, dexamethasone is administered in cycles 1, 10, and 15 of cycle 1. And on day 22, a dose of 40 mg is administered. In some other embodiments, dexamethasone is used. Zon is administered in doses of 40 mg on days 1, 4, 8, 11, 15, and 18 of a 28-day cycle. In other such embodiments, dexamethasone is administered in a 28-day cycle, 1, 8, 1 It is administered in doses of 40 mg on days 5 and 22. In other such embodiments, dexamethoxazole is used. Metasone is administered at a dose of 40 mg on days 1, 3, 15, and 17 of a 28-day cycle. In one such embodiment, dexamethasone is administered in cycles 1, 3, 14, and It is administered at a dose of 40 mg on the 17th day.

[0289] In another embodiment, in the method and composition described herein, compound 1 and compound 2 are also or compound 3, or its enantiomer, mixture of enantiomers, tautomer, A The second activator used with isotopologs or pharmaceutically acceptable salts is bolus. It is tezomib. In yet another embodiment, the method and composition described herein, Compound 1, Compound 2, or Compound 3, or their enantiomers, or mixtures of enantiomers It is used in combination with compound, tautomer, isotopolog, or pharmaceutically acceptable salts. The second activator is daratumumab. In some such embodiments, the method is further The method further includes the administration of dexamethasone. In some embodiments, the method is described herein. Proteasome inhibitors, CD38 inhibitors as described herein and cortisols as described herein Along with the costeroid, Compound 1, Compound 2, or Compound 3, or their enantiomers , mixtures of enantiomers, tautomers, isotopologs, or pharmaceutically acceptable This includes the administration of salt.

[0290] In certain embodiments, Compound 1, Compound 2, or Compound 3 provided herein or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, pharmaceutically acceptable salts are administered in combination with checkpoint inhibitors. In one embodiment, a checkpoint inhibitor is used in relation to the method provided herein. Compound 1, its tautomers, isotopologs, or pharmaceutically acceptable salts. It is used in combination with the present invention. In another embodiment, two checkpoint inhibitors are used In relation to the methods provided in the details, Compound 1, or its tautomers, isotopologs, Alternatively, it is used in combination with a pharmaceutically acceptable salt. In yet another embodiment, 3 One or more checkpoint inhibitors, in relation to the method provided herein, Compound 1, Compound 2 or Compound 3, or their enantiomers, mixtures of enantiomers, or treadmills. Used in combination with isomers, isotopologs, or pharmaceutically acceptable salts thereof. .

[0291] As used herein, the term "immune checkpoint inhibitor" or "checkpoint inhibitor" is used. The term "checkpoint inhibitor" refers to the complete or partial removal of one or more checkpoint proteins. Molecules that reduce, inhibit, interfere with, or modulate them This refers to... Without being limited by any particular theory, checkpoint proteins are T cells. It regulates cytoplasmic activation or function. Numerous checkpoint proteins, e.g., CTLA -4 and its ligands CD80 and CD86, and ligands PD-Ll and PD-L2 PD-1, which has the characteristic (Pardoll, Nature Reviews), is known to have this characteristic. Cancer, 2012, 12, 252-264). These proteins respond to T cells. These immune checkpoint proteins are thought to be responsible for the co-stimulatory or inhibitory interactions of the answer. It is thought to regulate and maintain self-tolerance, as well as the duration and extent of physiological immune responses. Immune checkpoint inhibitors contain antibodies or are derived from antibodies.

[0292] In one embodiment, the checkpoint inhibitor is a CTLA-4 inhibitor. Therefore, CTLA-4 inhibitors are anti-CTLA-4 antibodies. An example of an anti-CTLA-4 antibody is: All of the above are incorporated herein by reference. U.S. Patent No. 5,811,097, Paragraph 5 , No. 811,097, No. 5,855,887, No. 6,051,227, No. 6, Nos. 207,157, 6,682,736, 6,984,720, and 7 This includes, but is not limited to, those described in patents 605 and 238. In one embodiment, The anti-CTLA-4 antibody is tremelimumab (also known as tisilimmab or CP-675,2 (Also known as 06). In another embodiment, the anti-CTLA-4 antibody is ipilimma It is ipilimumab (also known as MDX-010 or MDX-101). It is a fully human monoclonal IgG antibody that binds to CTLA-4. Ipilimumab is a Y It is sold under the product name ervoy (trademark).

[0293] In one embodiment, the checkpoint inhibitor is a PD-1 / PD-L1 inhibitor. Examples of Dl / PD-L1 inhibitors are all incorporated herein in their entirety. Permit No. 7,488,802, No. 7,943,743, No. 8,008,449, Same Patent Nos. 8,168,757, 8,217,149, and PCT Patent Application Publication No. W O2003042402, WO2008156712, WO2010089 411, WO2010036959, WO2011066342, W O2011159877, WO2011082400, and WO20111 This includes, but is not limited to, the items listed in item 61699.

[0294] In one embodiment, the checkpoint inhibitor is a PD-1 inhibitor. A PD-1 inhibitor is an anti-PD-1 antibody. In one embodiment, the anti-PD-1 antibody is BG B-A317, nivolumab (ONO-4538, BMS-936558, or MDX1 Also known as 106), or pembrolizumab (MK-3475, SCH9004) 75, also known as lambrolizumab. In one embodiment, anti-PD-1 The antibody is nivolumab. Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody. It is sold under the trade name Opdivo (trademark). In another embodiment, anti-P The D-1 antibody is pembrolizumab. Pembrolizumab is a humanized monoclonal I It is a gG4 antibody and is sold under the trade name Keytruda (trademark). In this embodiment, the anti-PD-1 antibody is the humanized antibody CT-011. It is administered alone. CT-011 was found to be effective in treating acute myeloid leukemia (AML) at the time of relapse. I was unable to provide an answer. In yet another embodiment, the anti-PD-1 antibody is a fusion protein The substance is AMP-224. In another embodiment, the PD-1 antibody is BGB-A31 7. BGB-A317 has been specifically manipulated to enhance its ability to bind to Fc gamma receptor I. Furthermore, it possesses a unique binding signature to PD-1 with high affinity and excellent target specificity. It is a monoclonal antibody containing char.

[0295] In one embodiment, the checkpoint inhibitor is a PD-L1 inhibitor. In one embodiment, a PD-L1 inhibitor is an anti-PD-L1 antibody. In another embodiment, an anti-PD-L1 antibody is used. This is BMS-936559 (also known as MDX-1105-01). In another embodiment, the PD-L1 inhibitor is atezolizumab (MPDL3280A, and T It is also known as ecentriq (registered trademark).

[0296] In one embodiment, the checkpoint inhibitor is a PD-L2 inhibitor. A PD-L2 inhibitor is an anti-PD-L2 antibody. In one embodiment, an anti-PD-L2 antibody This is rHIgM12B7A.

[0297] In one embodiment, the checkpoint inhibitor is a lymphocyte-activating gene 3 (LAG-3) It is an inhibitor. In one embodiment, the LAG-3 inhibitor is a soluble Ig fusion protein. It is IMP321 (Brignone et al., J.Immunol., 200 7,179,4202-4211). In another embodiment, the LAG-3 inhibitor is BMS- The number is 986016.

[0298] In one embodiment, the checkpoint inhibitor is a B7 inhibitor. In one embodiment, B 7. The inhibitor is a B7-H3 inhibitor or a B7-H4 inhibitor. In one embodiment, B7- The H3 inhibitor is the anti-B7-H3 antibody MGA271 (Loo et al., C (lin.Cancer Res.,2012,3834).

[0299] In one embodiment, the checkpoint inhibitor is TIM3 (T cell immunoglobulin May It is an inhibitor of the mucin domain (Fourcade et al., J.Exp.) .Med.,2010,207,2175-86,Sakuishi et al.,J .Exp.Med.,2010,207,2187-94).

[0300] In one embodiment, the checkpoint inhibitor is an OX40 (CD134) agonist. In one embodiment, the checkpoint inhibitor is an anti-OX40 antibody. In this embodiment, the anti-OX40 antibody is anti-OX-40. In another embodiment, the anti-OX40 antibody is M This is EDI6469.

[0301] In one embodiment, the checkpoint inhibitor is a GITR agonist. In this case, the checkpoint inhibitor is an anti-GITR antibody. In one embodiment, anti-GITR The antibody is TRX518.

[0302] In one embodiment, the checkpoint inhibitor is a CD137 agonist. In this embodiment, the checkpoint inhibitor is an anti-CD137 antibody. The 137 antibody is urelumab. In another embodiment, the anti-CD137 antibody is PF-05 The number is 082566.

[0303] In one embodiment, the checkpoint inhibitor is a CD40 agonist. In this case, the checkpoint inhibitor is an anti-CD40 antibody. In one embodiment, anti-CD40 The antibodies are CF-870 and CF-893.

[0304] In one embodiment, the checkpoint inhibitor is recombinant human interleukin-15(r It is hIL-15.

[0305] In one embodiment, the checkpoint inhibitor is an IDO inhibitor. The IDO inhibitor is INCB024360. In another embodiment, the IDO inhibitor is It is Ndoximod.

[0306] In certain embodiments, the combination therapy provided herein is as described herein. Among checkpoint inhibitors (including checkpoint inhibitors of the same or different classes) It includes two or more. Furthermore, the combination therapies described herein treat the diseases described herein. Appropriate for and as understood in the art, one or more second methods described herein It can be used in combination with an activator.

[0307] In a particular embodiment, compound 1, compound 2, or compound 3 are on their surfaces (for example) For example, one or more chimeric antigen receptors (CARs) are expressed on modified immune cells. It can be used in combination with the immune cells mentioned above. Generally, CAR is the first protein (for example) (For example, the extracellular domain, transmembrane domain, and intracellular signaling from antigen-binding proteins) It includes a signaling domain. In certain embodiments, the extracellular domain is a tumor-associated antigen (TA). A) When it binds to a target protein such as a tumor-specific antigen (TSA), the signal is, For example, to target and kill cells that express a target protein, immune cells are activated. It is generated via intracellular signaling domains that transform.

[0308] Extracellular domain: The extracellular domain of a CAR binds to the target antigen. Morphologically, the extracellular domain of the CAR is a receptor that binds to the antigen, or a part of the receptor. Includes. In certain embodiments, the extracellular domain includes an antibody or its antigen-binding moiety. It is either a mummified The nucleotide contains a single-stranded Fv(scFv) domain, or a single-stranded Fv(scFv) domain. The single-stranded Fv domain is, for example, formed by a flexible linker. H V connected to L May include, the V L and V H This is derived from the antibody that binds to the antigen.

[0309] In certain embodiments, the extracellular domain of the polypeptide described herein is recognized The antigens identified are tumor-associated antigens (TAAs) or tumor-specific antigens (TSAs). In certain embodiments, the tumor-associated antigen or tumor-specific antigen is Her2, prostate stem cell Antigen (PSCA), alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) Cancer antigen-125 (CA-125), CA19-9, calretinin, MUC-1, B-cell Cellular maturation antigen (BCMA), epithelial membrane protein (EMA), epithelial tumor antigen (ETA), tyrofoam Sinase, melanoma-24 related antigen (MAGE), CD19, CD22, CD27, C D30, CD34, CD45, CD70, CD99, CD117, EGFRvIII (upper Skin growth factor variant III), mesothelin, PAP (prostatic acid phosphatase), p Lostaine, TARP (T cell receptor gamma surrogate leading frame protein), T rp-p8, STEAPI (prostate 6-transmembrane antigen 1), chromogranin, site Keratin, desmin, glial fibrous acidic protein (GFAP), common cystic disease fluid sputum Protein (GCDFP-15), HMB-45 antigen, protein melan-A (T lymphocytes) Therefore, the recognized melanoma antigens (MART-I), myo-D1, muscle-specific actin ( MSA), neurofilaments, neuron-specific enolase (NSE), placental alkali Rephosphatase, synaptophysis, thyroglobulin, thyroid transcription factor-1, dimeric form The state of pyruvate kinase isoenzyme M2 (tumor M2-PK), abnormal rastan This includes, but is not limited to, a protein or an abnormal p53 protein. In this embodiment, the TAA or TSA recognized by the extracellular domain of the CAR is It is lentegrin αvβ3 (CD61), galactin, or Ral-B.

[0310] In certain embodiments, TAA or T are recognized by the extracellular domain of CAR. SA stands for cancer / testicular (CT) antigen, e.g., BAGE, CAGE, CTAGE, FATE , GAGE, HCA661, HOM-TES-85, MAGEA, MAGEB, MAGE C, NA88, NY-ES0-1, NY-SAR-35, OY-TES-1, SPANX These are BI, SPA17, SSX, SYCPI, or TPTE.

[0311] In certain other embodiments, TAA is recognized by the extracellular domain of CAR. TSA is a carbohydrate or ganglioside, for example, fuc-GMI, GM2 (tumor embryo). Child antigen-immunogenicity-1, OFA-I-1); GD2 (OFA-I-2), GM3, GD3 And so on.

[0312] In certain other embodiments, TAA is recognized by the extracellular domain of CAR. TSA is alpha-actinin-4, Bage-1, BCR-ABL, Bcr-Ab l Fusion protein, beta-catenin, CA 125, CA 15-3 (CA 27.2 9\BCAA), CA 195, CA 242, CA-50, CAM43, Casp-8 cdc27, cdk4, cdkn2a, CEA, coa-l, dek-can fusion tan Protein, EBNA, EF2, Epstein-Barr virus antigen, ETV6-AML1 fusion protein, HLA-A2, HLA-All, hsp70-2, KIAA0205, Mar t2, Mum-1, 2, and 3, neo-PAP, myosin class I, OS-9, pml -RARα fusion protein, PTPRK, K-ras, N-ras, triose phosphate Somerase, Gage 3,4,5,6,7, GnTV, Herv-K-mel, Lag e-1, NA-88, NY-Eso-1 / Lage-2, SP17, SSX-2, TRP 2-Int2, gp100(Pmel17), tyrosinase, TRP-1, TRP-2, MAGE-l, MAGE-3, RAGE, GAGE-l, GAGE-2, p15(58) , RAGE, SCP-1, Hom / Mel-40, PRAME, p53, HRas, HE R-2 / neu, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR, Hi Topapillomavirus (HPV) antigens E6 and E7, TSP-180, MAGE-4, M AGE-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-9 It is 0, TAAL6, TAG72, TLP, or TPS.

[0313] In various specific embodiments, the tumor-associated antigen or tumor-specific antigen is S. Anguil Described in le et al., Leukemia (2012), 26, 2186-2196. It is an AML-associated tumor antigen.

[0314] Other tumor-associated antigens and tumor-specific antigens are known to those skilled in the art.

[0315] Receptors, antibodies, and antibodies that bind to TSA and TAA, which are useful for constructing chimeric antigen receptors. scFv is known in the art, and the nucleotide sequence encoding it is also known in the art. It is known in the technical field.

[0316] In certain specific embodiments, the extracellular domain of the chimeric antigen receptor is recognized. The antigen is not generally considered to be TSA or TAA, but even if it is, tumor cells It is an antigen associated with or related to damage caused by a tumor. In the embodiment, for example, the antigen is, for example, a growth factor, cytokine, or intero Cytokines, for example, growth factors, cytokines, or those related to angiogenesis or angiogenesis. It is an interleukin. Such growth factors, cytokines, or interleukins Examples include vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), Platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), insulin-like growth factor ( It may contain IGF, or interleukin-8 (IL-8). The tumor may also localize to the tumor. A hypoxic environment can also be created. Therefore, in other specific embodiments, the antigen is in a hypoxic environment. Related factors, e.g., HIF-1α, HIF-1β, HIF-2α, HIF-2β, HIF It is -3α or HIF-3β. Tumors also cause localized damage to normal tissue. This molecule is known as a damage-related molecular pattern molecule (DAMP; also known as alarmin). This can cause the release of (which can be) in certain other specific embodiments. So, the antigen is DAMP, for example, heat shock protein, chromatin-related protein high Mobility group box 1 (HMGB1), S100A8 (MRP8, cargranulin A), S100A9 (MRP14, cargranulin B) is serum amyloid A (SAA). Or, deoxyribonucleic acid, adenosine triphosphate, uric acid, or heparin sulfate. ru.

[0317] In certain embodiments, the extracellular domain of the CAR is a linker, spacer, or A hinge polypeptide sequence, for example, a sequence from CD28 or a sequence from CTLA4 It is linked to the transmembrane domain of the polypeptide. The transmembrane domain is linked to any transmembrane It can be obtained from or derived from the transmembrane domain of a protein, and so It may include all or part of the transmembrane domain. In certain embodiments, the transmembrane domain may Examples include CD8, CD16, cytokine receptors, and interleukin receptors. Alternatively, it can be obtained from or derived from growth factor receptors, etc.

[0318] In a particular embodiment, the intracellular domain of CAR is expressed on the surface of T cells. The intracellular domain or motif of a protein that triggers cell activation and / or proliferation It is either a 'f' or contains one. Such a domain or motif is a CAR cell. In response to the binding of an antigen to an external substance, the primary antigen-binding signal necessary for the activation of T lymphocytes It can transmit signals. Typically, this domain or motif is used in ITAM (immune). It contains a receptor tyrosine system activating motif or is an ITAM. Suitable for CAR TAM-containing polypeptides include, for example, zeta CD3 chains (CD3ζ) or their ITAM-containing polypeptides. It includes a portion. In certain embodiments, the intracellular domain is the CD3ζ intracellular signaling pathway. This is the main component. In other specific embodiments, the intracellular domain is the lymphocyte receptor chain, TCR. / CD3 complex protein, Fe receptor subunit, or IL-2 receptor subunit It is from. In certain embodiments, CAR is additionally, for example, polyp The intracellular domain of the cydo includes one or more co-stimulatory domains or motifs. One or more co-stimulatory domains or motifs are co-stimulatory CD27 polypeptide sequences. Co-stimulatory CD28 polypeptide sequence, co-stimulatory OX40 (CD134) polypeptide sequence , a co-stimulatory 4-1BB(CD137) polypeptide sequence, or a co-stimulatory inducible T cell co Irritant (ICOS) polypeptide sequences, or other co-stimulatory domains or motifs, Or it could be one or more of any combination thereof, or include them. obtain.

[0319] CARs may also contain T cell survival motifs. T cell survival motifs are triggered by antigens. This could be any polypeptide sequence or motif that promotes post-aggressive T lymphocyte survival. In a particular embodiment, the T cell survival motif is CD3, CD28, IL-7 receptor Intracellular signaling domain (IL-7R), intracellular signaling domain of the IL-12 receptor Main, intracellular signaling domain of IL-15 receptor, intracellular signaling domain of IL-21 receptor The signaling domain of the transforming growth factor β (TGFβ) receptor, or intracellular signaling It is either a domain or originates from one.

[0320] Modified immune cells that express CAR include, for example, T lymphocytes (T cells, e.g., CD cells). 4+ T cells or CD8+ T cells), cytotoxic lymphocytes (CTLs), or natural It may be a killer (NK) cell. The T cells used in the compositions and methods provided herein The lymphocytes may be naive T lymphocytes or MHC-restricted T lymphocytes. Morphologically, T lymphocytes are tumor-infiltrating lymphocytes (TILs). In a particular embodiment, T lymphocytes are isolated from tumor biopsies, or T lymphocytes isolated from tumor biopsies. They are proliferated from pocytes. In certain other embodiments, T cells are derived from peripheral blood, umbilical cord blood, and It is either isolated from lymph fluid, or isolated from peripheral blood, umbilical cord blood, or lymph fluid. They are proliferated from modified T lymphocytes. They produce modified immune cells that express CAR. The immune cells used are obtained by conventional methods recognized in the art, such as blood collection, and Subsequent apheresis, and optionally antibody-mediated isolation or sorting of cells, They can be separated.

[0321] Modified immune cells are preferably self-sufficient for the individual to whom the modified immune cells are administered. It is hereditary. In certain other embodiments, modified immune cells are modified immune cells The cells are of the same species as the individual to which the drug is administered. These are T lymphocytes modified from allogeneic T lymphocytes or NK cells. When used to prepare [a certain substance], there is a possibility of graft-versus-host disease (GVHD) in the individual. It is preferable to select T lymphocytes or NK cells that will reduce the number of T lymphocytes or NK cells. For example, In certain embodiments, virus-specific T lymphocytes are used for the preparation of modified T lymphocytes. Selected. Such lymphocytes have a significantly reduced ability to bind to any recipient antigen. It is expected to possess natural capabilities and, therefore, to be activated by any recipient antigen. In certain embodiments, recipient-mediated rejection of allogeneic T lymphocytes occurs. This includes one or more immunosuppressants, such as cyclosporine, tacrolimus, sirolimus, and cyclosporine. This can be reduced by co-administration to the host, such as lophosphamide.

[0322] T lymphocytes, for example, unmodified T lymphocytes, or T lymphocytes expressing CD3 and CD28 Pacocytes, or polyps containing the CD3ζ signaling domain and the CD28 costimulatory domain. T lymphocytes containing ptide bind to antibodies against CD3 and CD28, such as beads. It can be proliferated using antibodies. For example, U.S. Patent No. 5,948,893, No. 6,5 No. 34,055, No. 6,352,694, No. 6,692,964, No. 6,88 See issues 7,466 and 6,905,681.

[0323] Modified immune cells, for example, modified T lymphocytes, are modified if desired. A "suicide gene" or "safety switch" that enables the death of virtually all immune cells. It may optionally include. For example, modified T lymphocytes may, in certain embodiments, be Ganshik HSV thymidine kinase, which causes the death of modified T lymphocytes upon contact with Robil. It may contain the gene (HSV-TK). In another embodiment, modified T lymphocytes are induced Sexual caspases, for example, inducible caspase 9 (icaspase 9), for example, caspase Human FK506-binding protein enables dimerization using Ze9 and specific small molecule drugs. Contains a fusion protein with the substance. Straathof et al., Blood 1 0 See 5(11):4247-4254(2005). In certain embodiments, Compound 1, Compound 2, or Compound 3 provided herein are of various types or st In patients with multiple myeloma, in combination with chimeric antigen receptor (CAR) T cells It is administered. In certain embodiments, CAR T cells in combination are B cell maturation antigens. (BCMA) is targeted, and in a more specific embodiment, CAR T cells bb2121 It is bb21217. In some embodiments, CAR T cells are JCARH1 It is 25.

[0324] In some embodiments of the various methods provided herein, a reference sample is used to treat a subject. The control sample is obtained from the subject before administering the compound, and is from the same source as the sample. In other embodiments of the various methods provided herein, the reference sample is cancer-free. The control sample was obtained from a healthy patient and originated from the same source as the sample.

[0325] In some embodiments of the various methods provided herein, the cancer is a blood-derived cancer. In certain embodiments, blood-derived cancers are metastatic. In some embodiments of the various methods, the cancer is multiple myeloma.

[0326] In some embodiments, the methods provided herein treat various types of cancer. This includes prevention or control. In some embodiments, provided herein The methods encompass treating or preventing various types of cancer. Several embodiments The methods provided herein are for various types of cancer and other cancers provided herein. It includes treating [unclear]. In one embodiment, the method provided herein has therapeutic effects A sufficient amount of compound 1, or its enantiomer, mixture of enantiomers, tautomers, Multiple myeloma can be treated by administering isotopologs or pharmaceutically acceptable salts. This includes treating, preventing, or managing. In one embodiment, as provided herein. The law requires a therapeutically effective amount of compound 2, or its tautomers, isotopologs, or drugs. Treating, preventing, or managing multiple myeloma by administering scientifically acceptable salts. This includes, in one embodiment, a therapeutically effective amount of Administer substance 3, its tautomers, isotopologs, or pharmaceutically acceptable salts. This includes treating, preventing, or managing multiple myeloma.

[0327] In certain embodiments, what is provided herein is for patients with renal impairment. A method for treating, preventing, or managing cancer. In certain embodiments, as described herein The benefits provided are due to, but are not limited to, disease, aging, or other patient factors. This method provides appropriate dose adjustments for patients with renal impairment who cannot take the medication.

[0328] In certain embodiments, the herein provides a therapeutically effective amount of compound 1, Compound 2, or Compound 3, or its enantiomer, mixture of enantiomers, or alternator. Isomers, isotopologs, or pharmaceutically acceptable salts are used in patients with recurrent renal impairment. For patients with refractory MM, administer alone or in combination with a second active agent. This includes relapsed / refractory MM in patients with renal impairment or symptoms thereof. A method for treating, preventing, or managing a disease. In some embodiments, the method is as described herein. Compounds provided, or their enantiomers, mixtures of enantiomers, tautomers In patients with renal impairment, an isotopolog or a pharmaceutically acceptable salt is used. Combined with a second activator in an effective dose to treat, prevent, or manage relapsed / refractory MM. The process also includes the step of administering the compound to the subject. In a particular embodiment, the compound is compound 1 In a particular embodiment, the compound is compound 2. In a particular embodiment, The compound is compound 3.

[0329] In some embodiments, the levels of biomarkers decrease with compound therapy. In some embodiments, the biomarkers are CRBN, IKZF1, IKZF3, and CTC. , soluble BCMA, survivin, serum free light chain, ZFP91, c-MYC, IRF4, p Selected from the group consisting of RB1, the biomarker levels were compared to those before treatment with the therapeutic compound. It decreases compared to the reference level.

[0330] In other embodiments, the levels of biomarkers increase with compound therapy. In this embodiment, the biomarkers are caspase 1, caspase-3, caspase 7, and P ARP, IFNγ, TNFα, IL2, p21, p27, BIM, and TCR clonality A group consisting of the following is selected, and the level of the biomarker is the reference level before treatment with the therapeutic compound. Compared to Bell, it increases.

[0331] In certain embodiments of the various methods provided herein, the biomarker is, for example, Protein-protein interactions (for example, a specific CRBN substrate or its downstream effector) CRBN It is a protein that is directly or indirectly affected by. In certain embodiments, bio The marker is CRBN-associated protein (CAP). In some embodiments, Omarkers are mRNAs of proteins that are directly or indirectly affected by CRBN. In other embodiments, the biomarker is directly or indirectly affected by CRBN. This is the cDNA of the protein being processed.

[0332] Therefore, in some embodiments, the therapeutic compound provided herein corresponds to A method for identifying subjects with cancer who are likely to respond, (a) Administering a therapeutic 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 C AP is about making decisions. (d) When the level of the biomarker in the sample differs from the reference level of the biomarker. This includes diagnosing the subject as likely to respond to therapeutic compounds, and the therapeutic compounds The substance is compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0333] In another embodiment, what is provided herein is likely to respond to therapeutic compounds. A method for identifying subjects who have cancer, (a) Administering a therapeutic 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 C AP is about making decisions. (d) When the level of the biomarker in the sample differs from the reference level of the biomarker. This includes diagnosing the subject as likely to respond to therapeutic compounds, and the therapeutic compounds The substance is compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0334] In yet another embodiment, what is provided herein is the possibility of responding to therapeutic compounds. A method for identifying subjects with a high risk of cancer, (a) Administering a therapeutic 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 C AP is about making decisions. (d) When the level of the biomarker in the sample differs from the reference level of the biomarker. This includes diagnosing the subject as likely to respond to therapeutic compounds, and the therapeutic compounds The substance is compound 3: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0335] In another embodiment, provided herein is a therapeutic compound administered to a subject. A method for identifying subjects with cancer who are likely to respond, (a) Determining the level of biomarkers in the sample obtained from the subject, The iomarker is determined to be CAP. (b) When the level of the biomarker in the sample differs from the reference level of the biomarker. , including diagnosing the subject as likely to respond to a therapeutic compound, and the therapeutic compound However, compound 1, compound 2 or compound 3, or their tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0336] In some embodiments, what is provided herein is the possibility of responding to therapeutic compounds. A method for identifying subjects with a high risk of cancer, (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Determining the level of a biomarker in the sample, wherein the biomarker is C AP is about making decisions. (d) When the level of the biomarker in the sample differs from the reference level of the biomarker. This includes diagnosing the subject as likely to respond to therapeutic compounds, and the therapeutic compounds The substance is compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0337] In some embodiments, what is provided herein is the possibility of responding to therapeutic compounds. A method for identifying subjects with a high risk of cancer, (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Determining the level of a biomarker in the sample, wherein the biomarker is C AP is about making decisions. (d) When the level of the biomarker in the sample differs from the reference level of the biomarker. This includes diagnosing the subject as likely to respond to therapeutic compounds, and the therapeutic compounds The substance is compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0338] In some embodiments, what is provided herein is the possibility of responding to therapeutic compounds. A method for identifying subjects with a high risk of cancer, (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Determining the level of a biomarker in the sample, wherein the biomarker is C AP is about making decisions. (d) When the level of the biomarker in the sample differs from the reference level of the biomarker. This includes diagnosing the subject as likely to respond to therapeutic compounds, and the therapeutic compounds The substance is compound 3: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0339] In some embodiments, what is provided herein is the possibility of responding to therapeutic compounds. A method for identifying subjects with a high risk of cancer, (a) Administering therapeutic compounds to samples obtained from the subject, (b) Determining the level of a biomarker in the sample, wherein the biomarker is C AP is about making decisions. (c) When the level of the biomarker in the sample differs from the reference level of the biomarker. , including diagnosing the subject as likely to respond to a therapeutic compound, and the therapeutic compound However, compound 1, compound 2 or compound 3, or their tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0340] In some embodiments, what is provided herein is a method for treating cancer, (a) Obtaining samples from subjects with cancer, (b) Determining the level of a biomarker in the sample, wherein the biomarker is C AP is about making decisions. (c) When the level of the biomarker in the sample differs from the reference level of the biomarker. , to diagnose the subject as likely to respond to the therapeutic compound, (d) administering a therapeutically effective amount of the therapeutic compound to the subject, and the therapeutic compound However, compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0341] In some embodiments, what is provided herein is a method for treating cancer, (a) Obtaining samples from subjects with cancer, (b) Determining the level of a biomarker in the sample, wherein the biomarker is C AP is about making decisions. (c) When the level of the biomarker in the sample differs from the reference level of the biomarker. , to diagnose the subject as likely to respond to the therapeutic compound, (d) administering a therapeutically effective amount of the therapeutic compound to the subject, and the therapeutic compound However, compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0342] In some embodiments, what is provided herein is a method for treating cancer, (a) Obtaining samples from subjects with cancer, (b) Determining the level of a biomarker in the sample, wherein the biomarker is C AP is about making decisions. (c) When the level of the biomarker in the sample differs from the reference level of the biomarker. , to diagnose the subject as likely to respond to the therapeutic compound, (d) administering a therapeutically effective amount of the therapeutic compound to the subject, and the therapeutic compound However, compound 3: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0343] In some embodiments, what is provided herein is for use in methods of treating cancer. Compound 1, Compound 2, or Compound 3 for the treatment of cancer is, (a) Obtaining samples from subjects with cancer, (b) Determining the level of a biomarker in the sample, wherein the biomarker is C AP is about making decisions. (c) When the level of the biomarker in the sample differs from the reference level of the biomarker. , to diagnose the subject as likely to respond to the therapeutic compound, (d) administering a therapeutically effective amount of the therapeutic compound to the subject, and the therapeutic compound However, compound 1, compound 2 or compound 3, or their tautomers, isotopologs, Or it is a pharmaceutically acceptable salt. Compound 1, Compound 2, or Compound 3 are for use in methods of treating cancer.

[0344] In some embodiments, what is provided herein is a therapeutic compound for cancer A method for predicting the responsiveness of a subject who has cancer or is suspected of having cancer, (a) Administering a therapeutic 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 C AP is about making decisions. (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If it differs from Bell's, the subject should be diagnosed as likely to respond to the therapeutic compound, Contains, therapeutic compounds, Compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0345] In some embodiments, what is provided herein is a therapeutic compound for cancer A method for predicting the responsiveness of a subject who has cancer or is suspected of having cancer, (a) Administering a therapeutic 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 C AP is about making decisions. (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If it differs from Bell's, the subject should be diagnosed as likely to respond to the therapeutic compound, Contains, therapeutic compound, compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0346] In some embodiments, what is provided herein is a therapeutic compound for cancer A method for predicting the responsiveness of a subject who has cancer or is suspected of having cancer, (a) Administering a therapeutic 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 C AP is about making decisions. (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If it differs from Bell's, the subject should be diagnosed as likely to respond to the therapeutic compound, Contains, therapeutic compounds, compound 3: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0347] In some embodiments, the therapeutically administered substance to a subject is provided herein. Predicting the response of subjects with cancer or suspected cancer to a compound. It is a method, (a) Determining the level of biomarkers in the sample obtained from the subject, The iomarker is determined to be CAP. (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If different from Bell's findings, it includes diagnosing the subject as likely to respond to the therapeutic compound. The therapeutic compound is compound 1, compound 3, or compound 3, or its tautomer, A The method involves using an isotopolog or a pharmaceutically acceptable salt.

[0348] In some embodiments, what is provided herein is a therapeutic compound for cancer A method for predicting the responsiveness of a subject who has cancer or is suspected of having cancer, (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Determining the level of a biomarker in the sample, wherein the biomarker is C AP is about making decisions. (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If it differs from Bell's, the subject should be diagnosed as likely to respond to the therapeutic compound, Contains, therapeutic compounds, Compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0349] In some embodiments, what is provided herein is a therapeutic compound for cancer A method for predicting the responsiveness of a subject who has cancer or is suspected of having cancer, (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Determining the level of a biomarker in the sample, wherein the biomarker is C AP is about making decisions. (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If it differs from Bell's, the subject should be diagnosed as likely to respond to the therapeutic compound, Contains, therapeutic compound, compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0350] In some embodiments, what is provided herein is a therapeutic compound for cancer A method for predicting the responsiveness of a subject who has cancer or is suspected of having cancer, (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Determining the level of a biomarker in the sample, wherein the biomarker is C AP is about making decisions. (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If it differs from Bell's, the subject should be diagnosed as likely to respond to the therapeutic compound, Contains, therapeutic compounds, compound 3: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0351] In some embodiments, the therapeutically administered substance to a subject is provided herein. Predicting the response of subjects with cancer or suspected cancer to a compound. It is a method, (a) Determining the level of biomarkers in the sample obtained from the subject, The iomarker is determined to be CAP. (d) The level of the biomarker in the sample is the same as the level of the biomarker obtained from the reference sample. If different from Bell's findings, it includes diagnosing the subject as likely to respond to the therapeutic compound. The therapeutic compound is compound 1, compound 2, or compound 3, or a tautomer thereof. The method involves using an isotopolog or a pharmaceutically acceptable salt.

[0352] In some embodiments, what is provided herein is a therapeutic compound in a target A method for monitoring the effectiveness of cancer treatment, (a) Administering a therapeutic 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 C AP is about making decisions. (d) The level of the biomarker in the sample is compared to the level of the biomarker obtained from the reference sample. The comparison is with Bell, and changes in biomarker levels indicate that cancer is being treated in the subjects. To demonstrate the effectiveness of therapeutic compounds in doing so, to compare and include therapeutic compounds However, compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0353] In some embodiments, what is provided herein is a therapeutic compound in a target A method for monitoring the effectiveness of cancer treatment, (a) Administering a therapeutic 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 C AP is about making decisions. (d) The level of the biomarker in the sample is compared to the level of the biomarker obtained from the reference sample. The comparison is with Bell, and changes in biomarker levels indicate that cancer is being treated in the subjects. To demonstrate the effectiveness of therapeutic compounds in doing so, to compare and include therapeutic compounds However, compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0354] In some embodiments, what is provided herein is a therapeutic compound in a target A method for monitoring the effectiveness of cancer treatment, (a) Administering a therapeutic 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 C AP is about making decisions. (d) The level of the biomarker in the sample is compared to the level of the biomarker obtained from the reference sample. The comparison is with Bell, and changes in biomarker levels indicate that cancer is being treated in the subjects. This includes demonstrating the effectiveness of therapeutic compounds in doing so, and making comparisons. The therapeutic compound is compound 3: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0355] In some embodiments, the therapeutically administered substance to a subject is provided herein. A method for monitoring the effectiveness of cancer treatment in a compound, (a) Determining the level of biomarkers in the sample obtained from the subject, The iomarker is determined to be CAP. (b) The level of the biomarker in the sample is compared to the level of the biomarker obtained from the reference sample. The comparison is with Bell, and changes in biomarker levels indicate that cancer is being treated in the subjects. To demonstrate the effectiveness of therapeutic compounds in doing so, to compare and include therapeutic compounds However, compound 1, compound 2 or compound 3, or their tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0356] In some embodiments, the biomarkers are IKZF1, IKZF3, ZFP91, A CAP selected from the group consisting of c-MYC and IRF4. Several embodiments So, biomarkers are Ikaros family members such as IKZF1 or IKZF3. It is a number. In certain embodiments, the biomarker is IKZF1. In this embodiment, the biomarker is IKZF3. In a specific embodiment, the biomarker The car is ZFP91. In some embodiments, the biomarker is IKZF1 and The IKZF3's coupling partners, their downstream effects, or those that affect them. It is a factor in the cellular pathway. For example, in some embodiments, the biomarker is A coupling partner for IKZF1 or IKZF3, its downstream effects, or a combination of these. It is a factor in the cellular pathway that is affected. In certain embodiments, the biomarker is I It is a downstream effector of IKZF1 such as RF4. In certain embodiments, biomarkers - is a downstream effect of IKZF3 such as IRF4. In certain embodiments, by Omarker is a downstream effect pedal of IKZF1, such as c-MYC. Specific Embodiments So, the biomarker is a downstream effect of IKZF3, such as c-MYC.

[0357] As shown in the examples, CRBN, IKZF1, IKZF3, CTC, soluble BCM A, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, pRB1, etc. The level of the Iomarker is referenced in response to treatment with compound 1, compound 2, or compound 3. It decreases in comparison. Therefore, in some embodiments, the biomarker is CRBN IKZF1, IKZF3, CTC, soluble BCMA, Survivin, serum free light chain, ZF A biomarker is selected from the group consisting of P91, c-MYC, IRF4, and pRB1. The level decreases in response to treatment with compound 1, compound 2, or compound 3. Therefore In some embodiments of the various methods provided herein, the biomarker is C RBN, IKZF1, IKZF3, CTC, soluble BCMA, TIL, survivin, serum Free light chain, ZFP91, c-MYC, IRF4, pRB1, or those affected by them It is a protein (or factor), and the level of the biomarker is lower than the reference level. stomach.

[0358] Therefore, in some embodiments, the therapeutic compound provided herein corresponds to A method for identifying subjects with cancer who are likely to respond, (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Levels of CRBN, IKZF1, IKZF3, CTC, SBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 To make a decision, (d) Levels of CRBN, IKZF1, IKZF3, CTC, SBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 CRBN, IKZF1, IKZF3, CTC, sBCMA, TIL, Saba in the reference sample Ivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 levels If the rate is also low, it includes diagnosing the subject as likely to respond to the therapeutic compound, The therapeutic compound is compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0359] In another embodiment, what is provided herein is likely to respond to therapeutic compounds. A method for identifying subjects who have cancer, (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Levels of CRBN, IKZF1, IKZF3, CTC, sBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 To make a decision, (d) Levels of CRBN, IKZF1, IKZF3, CTC, sBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 CRBN, IKZF1, IKZF3, CTC, sBCMA, TIL, Saba in the reference sample Ivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 levels If the rate is also low, it includes diagnosing the subject as likely to respond to the therapeutic compound, The therapeutic compound is compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0360] In yet another embodiment, what is provided herein is the possibility of responding to therapeutic compounds. A method for identifying subjects with a high risk of cancer, (a) Administering a therapeutic compound to the subject, (b) Obtaining a sample from the subject, (c) Levels of CRBN, IKZF1, IKZF3, CTC, sBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 To make a decision, (d) Levels of CRBN, IKZF1, IKZF3, CTC, sBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 CRBN, IKZF1, IKZF3, CTC, sBCMA, TIL, Saba in the reference sample Ivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 levels If the rate is also low, it includes diagnosing the subject as likely to respond to the therapeutic compound, The therapeutic compound is compound 3: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0361] In another embodiment, provided herein is a therapeutic compound administered to a subject. A method for identifying subjects with cancer who are likely to respond, (a) Levels of CRBN, IKZF1, IKZF3, CTC in the samples obtained from the subjects sBCMA, TIL, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, Alternatively, to determine pRB1, (b) Levels of CRBN, IKZF1, IKZF3, CTC, sBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 CRBN, IKZF1, IKZF3, CTC, sBCMA, TIL, Saba in the reference sample Ivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 levels If the rate is also low, it includes diagnosing the subject as likely to respond to the therapeutic compound, The therapeutic compound is compound 1, compound 2, or compound 3, or their tautomers, iso The method involves using a topolog or a pharmaceutically acceptable salt.

[0362] In some embodiments, what is provided herein is the possibility of responding to therapeutic compounds. A method for identifying subjects with a high risk of cancer, (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Levels of CRBN, IKZF1, IKZF3, CTC, sBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 To make a decision, (d) Levels of CRBN, IKZF1, IKZF3, CTC, sBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 CRBN, IKZF1, IKZF3, CTC, sBCMA, TIL, Saba in the reference sample Ivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 levels If the rate is also low, it includes diagnosing the subject as likely to respond to the therapeutic compound, The therapeutic compound is compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0363] In some embodiments, what is provided herein is the possibility of responding to therapeutic compounds. A method for identifying subjects with a high risk of cancer, (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Levels of CRBN, IKZF1, IKZF3, CTC, sBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 To make a decision, (d) Levels of CRBN, IKZF1, IKZF3, CTC, sBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 CRBN, IKZF1, IKZF3, CTC, sBCMA, TIL, Saba in the reference sample Ivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 levels If the rate is also low, it includes diagnosing the subject as likely to respond to the therapeutic compound, The therapeutic compound is compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0364] In some embodiments, what is provided herein is the possibility of responding to therapeutic compounds. A method for identifying subjects with a high risk of cancer, (a) Obtaining a sample from the subject, (b) Administering a therapeutic compound to the sample, (c) Levels of CRBN, IKZF1, IKZF3, CTC, sBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 To make a decision, (d) Levels of CRBN, IKZF1, IKZF3, CTC, sBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 CRBN, IKZF1, IKZF3, CTC, sBCMA, TIL, Saba in the reference sample Ivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 levels If the rate is also low, it includes diagnosing the subject as likely to respond to the therapeutic compound, The therapeutic compound is compound 3: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by means of be.

[0365] In some embodiments, what is provided herein is the possibility of responding to therapeutic compounds. A method for identifying subjects with a high risk of cancer, (a) Administering therapeutic compounds to samples obtained from the subject, (b) Levels of CRBN, IKZF1, IKZF3, CTC, sBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 To make a decision, (c) Levels of CRBN, IKZF1, IKZF3, CTC, sBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 CRBN, IKZF1, IKZF3, CTC, sBCMA, TIL, Saba in the reference sample Ivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 levels If the rate is also low, it includes diagnosing the subject as likely to respond to the therapeutic compound, The therapeutic compound is compound 1, compound 2, or compound 3, or their tautomers, iso The method involves using a topolog or a pharmaceutically acceptable salt.

[0366] In some embodiments, what is provided herein is a method for treating cancer, (a) Obtaining samples from subjects with cancer, (b) Levels of CRBN, IKZF1, IKZF3, CTC, sBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 To make a decision, (c) Levels of CRBN, IKZF1, IKZF3, CTC, sBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 CRBN, IKZF1, IKZF3, CTC, sBCMA, TIL, Saba in the reference sample Ivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 levels If the rate is also low, it is important to diagnose the subject as likely to respond to the therapeutic compound. (d) administering a therapeutically effective amount of the therapeutic compound to the subject, and the therapeutic compound However, compound 1: [ka] or its enantiomer, mixture of enantiomers, tautomers, isotopologs, Alternatively, it is a method involving a pharmaceutically acceptable salt.

[0367] In some embodiments, what is provided herein is a method for treating cancer, (a) Obtaining samples from subjects with cancer, (b) Levels of CRBN, IKZF1, IKZF3, CTC, sBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 To make a decision, (c) Levels of CRBN, IKZF1, IKZF3, CTC, sBCMA, TI in the sample L, Survivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 CRBN, IKZF1, IKZF3, CTC, sBCMA, TIL, Saba in the reference sample Ivin, serum free light chain, ZFP91, c-MYC, IRF4, or pRB1 levels If the rate is also low, it is important to diagnose the subject as likely to respond to the therapeutic compound. (d) administering a therapeutically effective amount of the therapeutic compound to the subject, and the therapeutic compound However, compound 2: [ka] or its tautomer, isotopolog, or pharmaceutically acceptable salt, by...

Claims

1. A method for determining the dosage of a therapeutic compound in a subject with multiple myeloma (MM) who is receiving treatment with a therapeutic compound, The method includes determining the level of a biomarker in two or more samples obtained at different times from a subject to which a certain dose of a therapeutic compound has been administered, and comparing the level of the biomarker to a reference level. A level of the biomarker equal to the reference level indicates that the dosage is appropriate, while a level of the biomarker higher than the reference level indicates that the dosage or frequency of administration needs to be increased. The therapeutic compound is compound 1: 【Chemistry 1】 or its enantiomer, mixture of enantiomers, tautomers, isotopologs, or pharmaceutically acceptable salts, The biomarker is selected from the group consisting of IKZF1, IKZF3, ZFP91, c-MYC, and IRF4, and The method wherein the sample is a blood sample or a bone marrow aspirate sample.

2. The method according to claim 1, wherein the biomarker is IKZF1.

3. The method according to claim 1, wherein the biomarker is IKZF3.

4. The method according to claim 1, wherein the biomarker is ZFP91.

5. The method according to claim 1, wherein the biomarker is c-MYC.

6. The method according to claim 1, wherein the biomarker is IRF4.

7. The method according to claim 1, wherein the reference level is the level of the biomarker in a sample obtained from the subject to which a therapeutically effective amount of the therapeutic compound has been administered.

8. The method according to claim 1, wherein the adjustment of the dosage includes increasing the dosage of the therapeutic compound.

9. The method according to claim 1, wherein the adjustment of the dosage includes increasing the frequency of administration of the therapeutic compound.

10. The method according to claim 1, wherein the MM is recurrent, refractory, or resistant to conventional therapies.

11. The level of the aforementioned biomarker is (a) Determining the protein level of the biomarker; (b) Determining the mRNA level of the biomarker; (c) Determining the cDNA level of the biomarker; or (d) RNA sequencing (RNA-seq) The method according to claim 1, measured by

12. The aforementioned enantiomers are as follows: 【Chemistry 2】 The method according to any one of claims 1 to 11.

13. The aforementioned enantiomers are as follows: 【Transformation 3】 The method according to any one of claims 1 to 11.

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