Tasquinimod or a pharmaceutically acceptable salt thereof for use in combination therapy

Abstract

A combination comprising tasquinimod or a pharmaceutically acceptable salt thereof and at least one additional compound selected from a proteasome inhibitor, an immunomodulatory imide, and an antibody for use in the treatment of multiple myeloma. A kit for treating multiple myeloma in an individual comprising tasquinimod and a package insert containing instructions for using tasquinimod in combination with at least one additional compound selected from a proteasome inhibitor, an immunomodulatory imide, and an antibody. Tasquinimod for use in the treatment of multiple myeloma in combination with another compound selected from a proteasome inhibitor, an immunomodulatory imide, and an antibody.

Description

Technical Field

[0001] The present invention relates to the compound 4-hydroxy-5-methoxy-N,1-dimethyl-2-oxo-N-[4-(trifluoromethyl)phenyl]-1,2-dihydroquinoline-3-carboxamide (tasquinimod) or a pharmaceutically acceptable salt thereof, and combinations with one or more other compounds. More particularly, the present invention relates to such combinations wherein such one or more other compounds are selected from proteasome inhibitors, immunomodulatory imides, and antibodies. The present invention further relates to tasquinimod for use in combination with one or more other compounds in the treatment of cancer, such as multiple myeloma.

Background Art

[0002] Tasquinimod and methods for its preparation are described in International Application No. PCT / SE99 / 00676 published as WO 99 / 55678, and International Application No. PCT / SE99 / 01270 published as WO 00 / 03991, which applications also disclose the usefulness of tasquinimod and several other quinoline carboxamides for the treatment of diseases resulting from autoimmunity, such as multiple sclerosis, insulin-dependent diabetes, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease and psoriasis, as well as diseases in which pathological inflammation plays a major role, such as asthma, atherosclerosis, stroke and Alzheimer's disease.

[0003] Methods for preparing tasquinimod are also described in International Application No. PCT / SE2003 / 000780 published as WO 03 / 106424, and International Application No. PCT / EP2011 / 061490 published as WO 2012 / 004338. A deuterated form of tasquinimod is described in International Application No. PCT / EP2012 / 061798 published as WO 2012 / 175541.

[0004] The use of various quinoline carboxamides for the treatment of cancer, and more particularly solid cancers such as prostate cancer and breast cancer, is disclosed in International Application No. PCT / SE00 / 02055 published as WO 01 / 30758. These compounds have been found to promote tumorigenesis, affect inhibitory and pro-angiogenic cells in the tumor microenvironment, bind to and inhibit the interaction of an immunomodulatory protein (S100A9) involved in the establishment of the pre-metastatic niche.

[0005] International Application No. PCT / EP2015 / 075769 published as WO 2016 / 078921 discloses tasquinimod for use in the treatment of leukemia, including acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia and chronic myeloid leukemia. International Application No. PCT / EP2015 / 071391 published as WO 2016 / 042112 discloses tasquinimod for use in the treatment of multiple myeloma. International Application No. PCT / EP2016 / 053288 published as WO 2016 / 146329 discloses tasquinimod for use in combination with PD-1 and / or PD-L1 inhibitors in the treatment of cancer, particularly bladder cancer.

[0006] The general term "cancer" encompasses a number of malignant diseases, which can be classified in two ways: the type of tissue (histotype) in which the cancer occurs and the primary site or the part of the body where the cancer first developed. The international standard for the classification of tissue structure and nomenclature is the International Classification of Diseases for Oncology. From a histological perspective, cancers can be broadly classified into six categories: carcinomas, sarcomas, myelomas, leukemias, lymphomas and so-called mixed types.

[0007] Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow. Normally, plasma cells produce antibodies and play a key role in the immune function. In MM, abnormal collections of plasma cells accumulate in the bone marrow and interfere with the production of normal blood cells. The symptoms of MM are skeletal (bone) pain and fractures, anemia, infections, and other complications, such as multiple neuropathy and kidney failure. MM is the second most common hematological malignancy, and its exact cause remains unknown.

[0008] Multiple myeloma remains a refractory and debilitating disease, and multiple myeloma patients ultimately relapse. The remission duration of relapsed multiple myeloma decreases with each regimen. Therefore, the treatment of multiple myeloma poses special therapeutic challenges. In recent years, new treatments have greatly improved the prognosis and survival of multiple myeloma patients, but disease progression is still commonly seen after achieving complete remission.

[0009] Multiple myeloma can be treated using drugs that can be administered orally or directly into the bloodstream. These systemic therapies can reach cancer cells anywhere in the body. Examples of systemic drugs for treating multiple myeloma are corticosteroids such as dexamethasone and prednisone, which are an important part of the treatment of multiple myeloma. Multiple myeloma can also be treated by using immunomodulatory drugs such as thalidomide, lenalidomide, and pomalidomide. Multiple myeloma is also treated with various proteasome inhibitors and antibodies targeting CD38 and BCMA.

[0010] MM can also be treated using chemotherapy, and then autologous stem cell transplantation (SCT) can optionally be performed. In SCT, stem cells are removed from the patient, frozen, and stored. Usually, the patient first undergoes high-dose chemotherapy that destroys both healthy cells and myeloma cells in the bone marrow that cause the disease, and then the removed stem cells are returned to the patient to produce new healthy blood cells in the bone marrow. Patients who have undergone SCT usually have to receive maintenance therapy, for example using thalidomide or lenalidomide, for up to two years. SCT cannot cure MM and can only extend survival. Furthermore, SCT can cause serious complications, especially vulnerability to infections.

[0011] MM can also be treated with chemotherapy alone, especially in patients with a higher risk of complications, especially those derived from SCT. In that case, chemotherapeutic drugs are often used in combination with other drugs to reduce the side effects of chemotherapy, such as corticosteroids. Finally, MM may be treated by radiotherapy.

[0012] If multiple myeloma does not respond to initial treatment, or if recurrence occurs immediately after the completion of initial treatment, multiple myeloma is considered refractory or resistant to treatment. In such cases, restarting the same treatment alone is generally not effective, additional drugs can be added to the treatment regimen, or different combinations of drugs can be used as second-line therapy. In the case of further recurrence, a third-line treatment may be required following this second-line treatment, etc.

[0013] Currently, MM is not considered curable. According to data from the National Cancer Institute of the National Institutes of Health in the United States in 2010, less than 45% of US patients survived more than five years after being diagnosed with MM. It is clear that new treatment options for MM are still urgently needed.

[0014] Proteasome inhibitors (PIs) are compounds that block the action of the proteasome, a cellular complex that degrades proteins, particularly those involved in cell division. There are several known classes of PIs, such as peptide boronic acids or their pharmaceutically acceptable salts (boronates), peptide aldehydes, peptide vinyl sulfones, peptide epoxyketones, and β-lactone inhibitors. The first known PI used in therapy was bortezomib ([(1R)-3-methyl-1-[[(2S)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]-boronic acid). Bortezomib acts as a reversible boronic acid inhibitor of the chymotrypsin-like activity of the proteasome. Later-generation PIs include carfilzomib ((2S)-4-methyl-N-[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxirane-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]-4-phenylbutanoyl]amino]pentanamide) and oprozomib (N-[(2S)-3-methoxy-1-[[(2S)-3-methoxy-1-[[(2S)-1-[(2R)-2-methyloxirane-2-yl]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]-2-methyl-1,3-thiazole-5-carboxamide), both of which are irreversible epoxyketone proteasome inhibitors, as well as ixazomib ([(1R)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]boronic acid) and delanzomib ([(1R)-1-[[(2S,3R)-3-hydroxy-2-[(6-phenylpyridine-2-carbonyl)amino]-butanoyl]amino]-3-methylbutyl]boronic acid), which are reversible boronic acid proteasome inhibitors like bortezomib.

[0015] Bortezomib is currently marketed under the registered name Velcade® and is sold as a powder for intravenous or subcutaneous injection.

[0016] Ixazomib is marketed as Ninlaro® under an oral prescription and is generally used in combination with Revlimid® (lenalidomide) and dexamethasone for the treatment of patients with multiple myeloma who have received at least one prior treatment (i.e., second-line treatment).

[0017] Carfilzomib is marketed as Kyprolis® under an injectable prescription and has been used in the setting of relapsed and / or refractory MM, either as a single agent with or without dexamethasone or in combination with lenalidomide.

[0018] Another PI is marizomib ((1R,4R,5S)-4-(2-chloroethyl)-1-[(S)-[(1S)-cyclohex-2-en-1-yl]-hydroxymethyl]-5-methyl-6-oxa-2-azabicyclo[3.2.0]heptane-3,7-dione), a β-lactone, and preclinical trials are currently underway in blood cancers such as multiple myeloma, Waldenström macroglobulinemia, Burkitt lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, mantle cell lymphoma, as well as solid tumors such as colon cancer, pancreatic cancer, prostate cancer, melanoma, glioma, squamous cell carcinoma, non-small cell lung cancer, and renal cancer.

[0019] Immunomodulatory drugs have also been developed for use in treatment. For example, thalidomide (2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione) and its two analogs, lenalidomide (3-(4-amino-1-oxoisoindoline-2-yl)piperidine-2,6-dione) and pomalidomide (4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione), are well-known immunomodulatory drugs that have been approved for the treatment of multiple myeloma.

[0020] Thalidomide is used as a first-line treatment in multiple myeloma, for example, in combination with dexamethasone, and is further used, for example, in the treatment of graft-versus-host disease and aphthous stomatitis in children.

[0021] Lenalidomide is marketed as an oral pharmaceutical under various trade names, such as Revlimid®. Lenalidomide is used in combination with dexamethasone for patients with multiple myeloma who have received at least one prior therapy, and is also used as a single maintenance therapy for patients with multiple myeloma after autologous stem cell transplantation. Moreover, the use of lenalidomide in the treatment of mantle cell lymphoma (MCL) in patients whose disease has relapsed or progressed after two prior therapies has been approved, one of the two prior therapies being a prior therapy including bortezomib. Lenalidomide is being clinically tested as a treatment for Hodgkin lymphoma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, and solid tumor cancers, such as pancreatic cancer.

[0022] Pomalidomide is a biologically available oral derivative of thalidomide, and its use in the treatment of relapsed and refractory multiple myeloma has been approved and has been used in combination with bortezomib and dexamethasone.

[0023] Treatment agents for multiple myeloma include antibodies, particularly monoclonal antibodies, such as the monoclonal CD38 antibody daratumumab, which has been used in patients newly diagnosed with multiple myeloma who are not eligible for autologous stem cell transplantation. Daratumumab has been used in combination with bortezomib, melphalan, and prednisone. Daratumumab has also been used in combination with lenalidomide and dexamethasone or bortezomib and dexamethasone as a second-line treatment for multiple myeloma, and in combination with pomalidomide and dexamethasone as a third-line treatment. Daratumumab has been used as monotherapy in patients who have received at least three prior medications, including proteasome inhibitors and immunomodulatory imides, for the treatment of multiple myeloma, or who have not responded to proteasome inhibitors and immunomodulatory imides.

[0024] Another antibody approved for the treatment of multiple myeloma is the immunostimulatory monoclonal antibody elotuzumab, which targets SLAMF7 (CD319) and is used in combination with lenalidomide and dexamethasone as a second-line treatment.

[0025] Multiple myeloma is not a curable disease and is a disease that will ultimately but inevitably become refractory to ongoing treatment. So, in the best scenario, new treatment options may be found to fight disease progression. Clearly, another treatment is urgently needed to provide new options for disease control. SUMMARY OF THE INVENTION

[0026] The present invention is based on the surprising positive, and in some cases exactly synergistic, effect obtained in the treatment of multiple myeloma by the combination use of tasquinimod with at least one other compound selected from (i) proteasome inhibitors, (ii) immunomodulatory imides, and (iii) antibodies.

[0027] Accordingly, a first aspect is a combination comprising tasquinimod or a pharmaceutically acceptable salt thereof and at least one other compound selected from (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody.

[0028] Another aspect is the combination as defined above herein for use in a treatment.

[0029] Further disclosed herein is a combination comprising tasquinimod or a pharmaceutically acceptable salt thereof and at least one other compound selected from (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody for use in the treatment of cancer, such as blood cancer, particularly multiple myeloma.

[0030] Further disclosed herein is a pharmaceutical composition comprising tasquinimod or a pharmaceutically acceptable salt thereof and at least one other compound selected from (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody.

[0031] Further disclosed herein is a kit for the treatment of cancer, particularly blood cancer such as multiple myeloma, comprising tasquinimod and a package insert containing instructions for using tasquinimod in combination with at least one other compound selected from (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody.

[0032] In some embodiments, the kit further comprises one or more of the other compounds selected from (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody.

[0033] Another aspect is thalidomide or a pharmaceutically acceptable salt thereof for use in the treatment of cancer, such as a blood cancer such as multiple myeloma, wherein the treatment further comprises administration of at least one other compound selected from (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody, thalidomide or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the treatment comprises administration of 0.001 mg to 0.2 mg of thalidomide or the corresponding amount of its pharmaceutically acceptable salt per kg of body weight per day to an individual, in combination with, simultaneously with, or sequentially with the administration of at least one other compound.

[0035] Preferably, the administration of thalidomide or its pharmaceutically acceptable salt is oral administration, but can also be, for example, rectal administration, or parenteral administration, for example, parenteral administration by injection such as subcutaneous, intramuscular or intravenous injection. The mode of administration of at least one other compound depends on the particular other compound selected and can be enteral administration, for example oral administration, or parenteral administration, for example injection, for example parenteral administration by subcutaneous, intramuscular or intravenous injection.

[0036] In some embodiments, the treatment further comprises radiation therapy.

[0037] In some embodiments, the treatment further comprises stem cell transplantation, for example autologous stem cell transplantation.

[0038] The use of thalidomide or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating blood cancers such as multiple myeloma in combination with at least one other compound selected from (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody is further disclosed herein.

[0039] The use of tasquinimod or a pharmaceutically acceptable salt thereof, and at least one other compound selected from (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody, in the manufacture of a medicament for the treatment of blood cancers such as multiple myeloma is further disclosed herein.

[0040] The use in the manufacture of a medicament for the use of a compound selected from (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody, in combination with tasquinimod or a pharmaceutically acceptable salt thereof, for the treatment of blood cancers such as multiple myeloma is further disclosed herein.

[0041] A method of treating cancer, particularly blood cancer, such as multiple myeloma, the method comprising administering to an individual in need of such treatment tasquinimod or a pharmaceutically acceptable salt thereof in combination with at least one other compound selected from (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody is further disclosed herein.

[0042] In some embodiments, the at least one other compound is selected from (i) a proteasome inhibitor and (ii) an immunomodulatory imide. In some embodiments, the at least one other compound is selected from (i) a proteasome inhibitor and (iii) an antibody.

[0043] In some other embodiments, the at least one other compound is a proteasome inhibitor. For example, the proteasome inhibitor can be a peptide boronic acid or a pharmaceutically acceptable salt thereof, such as bortezomib, ixazomib, or delanzomib; a peptide epoxyketone, such as carfilzomib or oprozomib; or a β-lactone, such as marizomib. In some embodiments, the proteasome inhibitor is a peptide boronic acid or a peptide epoxyketone. In some embodiments, the proteasome inhibitor is a peptide boronic acid, such as bortezomib.

[0044] For example, the immunomodulatory imide can be selected from thalidomide, lenalidomide, and pomalidomide.

[0045] For example, the antibody can be a CD38 antibody, such as daratumumab or isatuximab, or an immunoreactive antibody targeting SLAMF7 (CD319), such as elotuzumab.

[0046] In some embodiments, the combination also includes a corticosteroid, such as dexamethasone or prednisone.

Brief Description of the Drawings

[0047]

Figure 1

Figure 2

Figure 3

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Figure 6

Figure 7

Mode for Carrying Out the Invention

[0048] Unless otherwise defined or clearly indicated by the context, all scientific and technical terms and abbreviations used in this specification have the same meaning as commonly understood by those skilled in the technical field to which this disclosure belongs. However, definitions of some of the terms used in this specification are set forth below in this specification.

[0049] It should be noted that there are several synonyms referring to the disease "multiple myeloma", including Kahler's disease, myeloma, myelomatosis, plasmacytosis, and plasmacytic myeloma. In the present invention, all of these terms are considered interchangeable with the term "multiple myeloma".

[0050] "Optional" or "optionally" means that the subsequently described event or situation may occur but does not have to occur, and the description includes both the case where the event or situation occurs and the case where it does not occur.

[0051] "Pharmaceutically acceptable" means useful in preparing pharmaceutical compositions that are generally safe, non-toxic, and not otherwise undesirable biologically or otherwise, and includes those acceptable for veterinary use and for use as human pharmaceuticals.

[0052] Examples of pharmaceutically acceptable salts include salts with (as counterions) alkali metal ions such as Li + , Na + or K + , or salts with alkaline earth metal ions such as Mg 2+ or Ca 2+ , or salts with any other pharmaceutically acceptable metal ions such as Zn 2+ or Al 3+ ; or pharmaceutically acceptable salts formed with organic bases such as diethanolamine, ethanolamine, N-methylglucamine, triethanolamine or tromethamine.

[0053] References to "tasquinimod" in this specification should be construed as references to the free base or its pharmaceutically acceptable salts or solvates, unless otherwise specified or apparent from the context.

[0054] As used herein, the term "proteasome inhibitor" (which may also be referred to as "PI") refers to a compound that blocks the action of the proteasome, a cellular complex that degrades proteins such as, for example, the p53 protein.

[0055] As used herein, the term "immunomodulatory imide" (which may also be referred to as an immunomodulatory imide drug or IMiD) refers to a compound having at least one imide functional moiety that can modify an immune response or the function of the immune system (such as by stimulating antibody formation or inhibiting leukocyte activity), and in particular, this term refers to compounds that are structural and functional analogs of thalidomide and have immunomodulatory properties, such as lenalidomide or pomalidomide. The imide functional moiety is a functional group containing two carbonyl groups bonded to the same nitrogen atom, i.e., a functional group that can be represented by the following structural formula.

Chemical formula

[0056] "Therapeutically effective amount" means an amount of a therapeutically active ingredient, such as tasquinimod or a pharmaceutically acceptable salt thereof, that, when administered in combination with another compound defined herein, is sufficient to effect such treatment of a medical condition (such as MM) in a subject. A "therapeutically effective amount" will vary depending, for example, on the age and relative health of the subject being treated, the progression of the disease, the route and form of administration, and the particular combination of tasquinimod with the other compound selected.

[0057] As used herein, the term "treatment" or "treating" refers to a method of obtaining a beneficial or desired result, including clinical results. Beneficial or desired clinical results can include, but are not limited to, the reduction or improvement of one or more symptoms of a disease being treated (e.g., MM), whether detectable or not, a reduction in the extent of the disease, stabilization of the disease state (i.e., not worsening), prevention of disease spread, delay or slowing of disease progression, improvement or remission of the medical condition, and remission (partial or complete). This term can also mean extending survival as compared to survival expected without treatment.

[0058] Common symptoms of MM are bone pain due to lytic bone disease, weakness and fatigue due to anemia, weight loss, confusion, excessive thirst, constipation due to hypercalcemia, kidney impairment, and infections due to non-functional immunoglobulins. More rare symptoms include the accumulation of plasma cells into purple patches visible under the skin, so-called extramedullary plasmacytomas.

[0059] The term "relapsed multiple myeloma" (or "relapsed MM") refers to the worsening of the symptoms of multiple myeloma in an individual after a remission period that led to a previous improvement in symptoms, e.g., after a period of treatment of the individual.

[0060] The term "refractory multiple myeloma" refers to a state in which multiple myeloma does not respond to a given treatment, i.e., a state in which a new treatment modality or a new drug combination may be required.

[0061] As used herein, the term "CD38 antibody" (also referred to as anti-CD38 antibody) refers to an antibody that targets CD38 (cluster of differentiation 38), which is present on the surface of various immune cells (leukocytes), including CD4+, CD8+, B lymphocytes, and natural killer cells.

[0062] The term "SLAMF7 (CD319) antibody" (or anti-SLAMF7 antibody) refers to an antibody that targets the plasma cell surface antigen SLAMF7 (also known as SLAMF7, 19A, CD319, CRACC, CS1, or SLAM family member 7).

[0063] As used herein, the term "individual" (or "subject", which may be used interchangeably herein) broadly refers to mammals and can include humans or any mammalian animal, such as primates, domestic animals, pets, or laboratory animals. Preferably, the individual is a human.

[0064] Individuals who can be appropriately treated according to the present invention can be individuals suffering from MM, or individuals at risk (increased) of developing MM, or individuals who no longer respond to a given treatment. There are some other conditions in which patients suffer from an increased risk of developing MM. Such conditions are monoclonal gammopathy of undetermined significance (MGUS) and solitary plasmacytoma. In fact, these conditions can even be in the early form of MM. Thus, in some embodiments, the term MM also encompasses conditions selected from monoclonal gammopathy of undetermined significance (MGUS) and solitary plasmacytoma.

[0065] In some other embodiments, MM is smoldering multiple myeloma (SMM), an early precursor of MM that can be diagnosed by measuring certain proteins present in the blood and urine of a patient. Thus, SMM is generally diagnosed in humans who meet the following criteria: (1) serum monoclonal (M) protein ≥ 3 g / dL and / or 10 - 60% bone marrow clonal plasma cells; and (2) absence of lytic lesions, anemia, hypercalcemia, and renal insufficiency (end - organ damage) that can be attributed to a plasma cell proliferative disorder and absence of biomarkers associated with end - organ damage in almost inevitable progression (≥ 60% clonal plasma cells in the marrow; free light chain ratio of involved / uninvolved > 100; or more than one focal bone lesion on magnetic resonance imaging).

[0066] SMM is distinguished from multiple myeloma (MM) based on the absence of end - organ damage and from monoclonal gammopathy of undetermined significance (MGUS) based on the size of the M protein and the percentage of plasma cells (%) in the bone marrow.

[0067] Tasquinimod has the following structural formula. [Chemical Formula]

[0068] As described above in this specification, tasquinimod, its pharmaceutically acceptable salts, its deuterated forms, its crystalline salts, and pharmaceutical compositions containing tasquinimod or its salts; methods for preparing tasquinimod, its salts, deuterated forms, and pharmaceutical compositions containing tasquinimod and tasquinimod salts are described in WO 99 / 55678, WO 00 / 03991, WO 03 / 106424, WO 2012 / 004338, and WO 2012 / 175541 (references above), and those documents are incorporated herein by reference in their entirety.

[0069] In some embodiments, any reference to tasquinimod includes its deuterated forms. As described above in this specification, the deuterated forms of tasquinimod are described in WO 2012 / 175541. Thus, in some embodiments, tasquinimod has at least 70%, more preferably at least 90% deuterium enrichment at the amide - N - methyl. In some other embodiments, tasquinimod is non - deuterated and has a deuterium content corresponding to the natural abundance of deuterium.

[0070] Any proteasome inhibitor (PI) is contemplated to be useful in the present invention. For example, the PI can be a peptide boronic acid or its pharmaceutically acceptable salt (peptide boronate), such as bortezomib, ixazomib, or delanzomib; a peptide epoxyketone, such as carfilzomib or oprozomib; or a β - lactone, such as marizomib. The names, types, and structural formulas of some proteasome inhibitors contemplated to be useful herein are shown in Table 1.

[0071] [Table 1]

[0072] In some embodiments, the PI is selected from peptide boronic acids and peptide epoxyketones. In some embodiments, the PI is selected from peptide boronic acids and β-lactones. In some embodiments, the PI is selected from peptide epoxyketones and β-lactones. In some embodiments, the PI is a peptide boronic acid. In some embodiments, the PI is a peptide epoxyketone. In some embodiments, the PI is a β-lactone.

[0073] In some embodiments, the peptide boronic acid is selected from bortezomib, ixazomib, and delanzomib, for example selected from bortezomib and ixazomib. In some embodiments, the peptide boronic acid is bortezomib. In some embodiments, the peptide boronic acid is ixazomib. In some embodiments, the peptide boronic acid is delanzomib.

[0074] In some embodiments, the peptide epoxyketone is selected from carfilzomib and oprozomib. In some embodiments, the peptide epoxyketone is carfilzomib. In some embodiments, the peptide epoxyketone is oprozomib. In some embodiments, the β-lactone is marizomib. The immunomodulatory imide for use in combination with tasquinimod is preferably selected from thalidomide, lenalidomide, and pomalidomide. Their structural formulas are illustrated in Table 2.

[0075] [Table 2]

[0076] In some embodiments, the IMiD is selected from thalidomide and lenalidomide. In some embodiments, the IMiD is selected from thalidomide and pomalidomide. In some embodiments, the IMiD is selected from lenalidomide and pomalidomide. In some embodiments, the IMiD is lenalidomide. In some embodiments, the IMiD is pomalidomide. In some embodiments, the IMiD is thalidomide.

[0077] As used herein, an "antibody" can be a natural or normal antibody in which two heavy chains are linked to each other by disulfide bonds, and each heavy chain is linked to a light chain by a disulfide bond. There are two types of light chains, lambda (λ) and kappa (κ). There are five main heavy chain classes (or isotypes) that determine the functional activity of the antibody molecule, namely IgA, IgD, IgE, IgG, and IgM, and the heavy chains are named α, δ, ε, γ, and μ, respectively. The γ and α classes are further divided into subclasses based on relatively small differences in CH sequences and functions. For example, humans express the following subclasses: IgG1, IgG2A, IgG2B, IgG3, IgG4, IgA1, and IgA2. Each chain contains different sequence domains. The light chain contains two domains or regions, a variable domain (VL) and a constant domain (CL). The heavy chain contains four domains, one variable domain (VH) and three constant domains (CH1, CH2, and CH3, collectively called CH). The variable region of the light chain (VL) and the variable region of the heavy chain (VH) both determine the binding recognition and specificity for the antigen. The constant region domains of the light chain (CL) and the heavy chain (CH) confer important biological properties such as antibody chain association, secretion, transplacental mobility, complement binding, and binding to Fc receptors (FcR). The Fv fragment is the N-terminal part of the Fab fragment of an immunoglobulin and consists of the variable parts of one light chain and one heavy chain. The specificity of an antibody resides in the structural complementarity between the antibody binding site and the antigen determinant. The antibody binding site is mainly composed of residues from the hypervariable regions or complementarity-determining regions (CDRs). Occasionally, residues from non-hypervariable regions or framework regions (FRs) affect the overall domain structure and thus the binding site. The complementarity-determining region or CDR refers to the amino acid sequence that together defines the binding affinity and specificity of the natural Fv region of the native immunoglobulin binding site. The light and heavy chains of an immunoglobulin have three CDRs named CDR1-L, CDR2-L, CDR3-L, and three CDRs named CDR1-H, CDR2-H, and CDR3-H, respectively. Thus, a normal antibody antigen binding site contains six CDRs, a set of CDRs from each of the V regions of the heavy and light chains.

[0078] The "framework region" (FR) refers to the amino acid sequence sandwiched between CDRs, i.e., the portions of the immunoglobulin light and heavy chain variable regions that are relatively conserved between different immunoglobulins in a single species. The light and heavy chains of an immunoglobulin each have four FRs named FR1-L, FR2-L, FR3-L, FR4-L and four FRs named FR1-H, FR2-H, FR3-H, FR4-H, respectively.

[0079] As used herein, a "human framework region" is a framework region that is substantially identical (about 85% or more, particularly 90%, 95%, 97%, 99% or 100%) to the framework region of a native human antibody.

[0080] As used herein, the term "antibody" refers to conventional antibodies and their fragments, as well as single domain antibodies and their fragments, particularly the variable heavy chain of a single domain antibody, and chimeric, humanized, bispecific or multispecific antibodies.

[0081] As used herein, an antibody or immunoglobulin also includes a "single domain antibody", which is an antibody recently described in which the complementarity determining region is part of a single domain polypeptide. Examples of single domain antibodies include heavy chain antibodies, antibodies that are naturally lacking a light chain, single domain antibodies derived from conventional four-chain antibodies, and engineered single domain antibodies. Single domain antibodies can be derived from any species including, but not limited to, mouse, human, camel, llama, goat, rabbit and cow. A single domain antibody can be a natural single domain antibody called a heavy chain antibody that lacks a light chain. In particular, camelid species such as camel, dromedary, llama, alpaca and guanaco produce heavy chain antibodies that are naturally lacking a light chain. The heavy chain antibodies of camelid animals also lack the CH1 domain.

[0082] The variable heavy chains of these single-domain antibodies lacking light chains are known in the art as "VHH" or "nanobodies". Similar to normal VH domains, VHHs contain four FRs and three CDRs. Nanobodies have advantages over normal antibodies. They are approximately one-tenth the size of IgG molecules, and as a result, properly folded functional nanobodies can be produced with high yields by in vitro expression. Furthermore, nanobodies are very stable and resistant to the action of proteases. The properties and production of nanobodies are reviewed by Harmsen and De Haard HJ (Appl. Microbiol. Biotechnol. November 2007;77(1):13-22).

[0083] The antibodies of the present invention can be polyclonal antibodies or monoclonal antibodies. The above monoclonal antibodies can be humanized. As another example, the antibody can be a fragment selected from the group consisting of Fv, Fab, F(ab’)2, Fab’, dsFv, (dsFv)2, scFv, sc(Fv)2, diabody, and VHH.

[0084] As used herein, the term "monoclonal antibody" or "mAb" refers to an antibody molecule of a single amino acid composition that is made against a specific antigen but should not be construed as requiring production of the antibody by any particular method. Monoclonal antibodies can be produced by a single clone of B cells or hybridomas, but can also be recombinant antibodies, i.e., antibodies produced by protein engineering.

[0085] The term "chimeric antibody" in its broadest sense refers to an engineered antibody that contains one or more regions from one antibody and one or more regions from one or more other antibodies. In particular, a chimeric antibody contains the VH and VL domains of an antibody derived from a non-human animal together with the CH and CL domains of another antibody, particularly a human antibody. As the non-human animal, any animal such as a mouse, rat, hamster, rabbit, etc. can be used. A chimeric antibody can also represent a multispecific antibody having specificity for at least two different antigens. In an embodiment, the chimeric antibody has a variable domain of mouse origin and a constant domain of human origin.

[0086] The term "humanized antibody" originally refers to an antibody that is wholly or partially of non-human origin and is modified by replacing certain amino acids, particularly certain amino acids in the framework regions of the heavy and light chains, in order to avoid or minimize the immune response in humans. The constant domains of a humanized antibody are in most cases human CH and CL domains. In an embodiment, the humanized antibody has a constant domain of human origin.

[0087] An "antibody fragment" includes a portion of an intact antibody, particularly the antigen-binding region or variable region of an intact antibody. Examples of antibody fragments include Fv, Fab, F(ab’)2, Fab’, dsFv, (dsFv)2, scFv, sc(Fv)2, diabody, bispecific and multispecific antibodies formed from antibody fragments. An antibody fragment can also be a single domain antibody, such as a heavy chain antibody or VHH.

[0088] The term "Fab" represents an antibody fragment having a molecular weight of about 50,000 Da and antigen-binding activity, in which about the first half of the H chain on the N-terminal side and the entire L chain are bound together through a disulfide bond, obtained by treating IgG with the protease papain.

[0089] The term "F(ab’)2" refers to an antibody fragment having a molecular weight of about 100,000 Da and antigen-binding activity, which is slightly larger than Fab that is bound via a disulfide bond in the hinge region among the fragments obtained by treating IgG with pepsin, a protease.

[0090] The term "Fab’" refers to an antibody fragment having a molecular weight of about 50,000 Da and antigen-binding activity, which is obtained by cleaving the disulfide bond in the hinge region of F(ab’)2.

[0091] A single-chain Fv ("scFv") polypeptide is a covalently linked VH::VL heterodimer that is usually expressed by gene fusion, including genes encoding VH and VL that are linked by a peptide-encoding linker. The human scFv fragments of the present invention include, in particular, CDRs that are held in an appropriate conformation by using recombinant DNA techniques. Bivalent and multivalent antibody fragments can be spontaneously formed by the binding of monovalent scFv, or can be generated by coupling monovalent scFv with a peptide linker, such as bivalent sc(Fv)2. "dsFv" is a VH::VL heterodimer stabilized by a disulfide bond.

[0092] The term "(dsFv)2" represents two dsFv coupled by a peptide linker.

[0093] The term "bispecific antibody" or "BsAb" represents an antibody that combines the antigen-binding sites of two antibodies within a single molecule. Thus, BsAb can bind two different antigens simultaneously. Genetic engineering has been increasingly used to design, modify, and produce antibodies or antibody derivatives having a desired set of binding properties and effector functions, as described, for example, in EP 2 050 764 A1.

[0094] The term "multispecific antibody" represents an antibody that combines the antigen-binding sites of two or more antibodies within a single molecule.

[0095] The term "diabody" refers to a small antibody fragment having two antigen-binding sites, in which the heavy-chain variable domain (VH) is connected to the light-chain variable domain (VL) in the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains of the same chain, the domains are made to pair with the complementary domains of another chain, generating two antigen-binding sites.

[0096] Typically, antibodies are prepared according to conventional methods. Monoclonal antibodies can be produced using the method of Kohler and Milstein (Nature, 256:495, 1975). To prepare monoclonal antibodies useful in the present invention, a mouse or other suitable host animal is immunized at suitable intervals (e.g., twice a week, weekly, twice a month or monthly) with an appropriate antigen form. The final "boost" of the antigen can be administered to the animal within one week of sacrifice. It is often desirable to use an immunoadjuvant during immunization. Suitable immunoadjuvants include Freund's complete adjuvant, Freund's incomplete adjuvant, alum, Ribi adjuvant, Hunter's Titermax, saponin adjuvants such as QS21 or Quil A, or CpG-containing immunostimulatory oligonucleotides. Other suitable adjuvants are well known in the art. The animal can be immunized subcutaneously, intraperitoneally, intramuscularly, intravenously, intranasally or by other routes. A given animal can be immunized by multiple routes with multiple antigen forms.

[0097] The present invention provides, in some embodiments, compositions and methods that include humanized antibody forms. Methods of humanization include, but are not limited to, those described in U.S. Patent Nos. 4,816,567, 5,225,539, 5,585,089, 5,693,761, 5,693,762, and 5,859,205, which are incorporated herein by reference. The above-mentioned U.S. Patent Nos. 5,585,089 and 5,693,761, as well as WO 90 / 07861, also propose four possible criteria that can be used in designing humanized antibodies. The first proposal was to use a framework from a particular human immunoglobulin that is unusually homologous to the donor immunoglobulin to be humanized for the acceptor, or a consensus framework from many human antibodies. The second proposal was that when the amino acids in the framework of a human immunoglobulin are rare and the donor amino acids at that position are typical of the human sequence, the donor amino acids rather than the acceptor amino acids can be selected. The third proposal was that donor amino acids rather than acceptor amino acids can be selected at positions immediately adjacent to the three CDRs in the humanized immunoglobulin chain. The fourth proposal was to use donor amino acids present at framework positions where the amino acids are expected to have side chain atoms within 3A of the CDRs in the three-dimensional model of the antibody and to be able to interact with the CDRs. The above methods merely illustrate some of the methods that can be employed by those skilled in the art to produce humanized antibodies. Those skilled in the art are proficient in other methods of antibody humanization.

[0098] In one embodiment of a humanized antibody form, some, most or all of the amino acids outside the CDR regions are replaced with amino acids from human immunoglobulin molecules, while some, most or all of the amino acids within one or more CDR regions remain unchanged. Minor additions, deletions, insertions, substitutions or modifications of amino acids are acceptable as long as they do not inhibit the ability of the antibody to bind to a given antigen. Suitable human immunoglobulin molecules include IgGl, IgG2, IgG3, IgG4, IgA and IgM molecules. A "humanized" antibody retains the same antigen specificity as the original antibody. However, using some methods of humanization, the binding affinity and / or specificity of the antibody can be enhanced using the "directed evolution" method described by Wu et al., I. Mol. Biol. 294:151, 1999 (the content of which is incorporated herein by reference).

[0099] Fully human monoclonal antibodies can also be prepared by immunizing transgenic mice in which most of the human immunoglobulin heavy and light chain loci are present. See, for example, U.S. Pat. Nos. 5,591,669, 5,598,369, 5,545,806, 5,545,807, 6,150,584, and the references cited therein (the content of which is incorporated herein by reference). These animals have been genetically modified such that there are functional deficiencies in the production of endogenous (e.g., murine) antibodies. The animals are further modified to contain all or part of the human germline immunoglobulin gene loci, and immunization of these animals produces fully human antibodies against the antigen of interest. After immunizing these mice (e.g., XenoMouse (Abgenix), HuMAb mouse (Medarex / GenPharm)), monoclonal antibodies can be prepared according to standard hybridoma technology. These monoclonal antibodies have human immunoglobulin amino acid sequences and thus do not induce a human anti-mouse antibody (KAMA) response when administered to humans.

[0100] There are also in vitro methods for producing human antibodies. These include phage display technology (U.S. Pat. Nos. 5,565,332 and 5,573,905) and in vitro stimulation of human B cells (U.S. Pat. Nos. 5,229,275 and 5,567,610). The contents of these patents are incorporated herein by reference.

[0101] In some embodiments, the antibodies of the invention are modified to reduce or inhibit the ability of the antibody to mediate antibody-dependent cell cytotoxicity (ADCC) and / or complement-dependent cell cytotoxicity (CDC) functionality (i.e., "antibodies with reduced Fc-effector function"). In particular, the antibodies of the invention do not have an Fc portion or have an Fc portion that does not bind to FcγRI and C1q. In one embodiment, the Fc portion of the antibody does not bind to FcγRI, C1q, or FcγRIII. Antibodies having such functionality are generally known. There are naturally occurring antibodies of this type, such as antibodies having an IgG4 Fc region. There are also antibodies having an Fc portion that has been genetically or chemically modified to abolish antibody-dependent cell cytotoxicity (ADCC) and / or complement-dependent cell cytotoxicity (CDC) functionality.

[0102] In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a CD38 antibody, such as a monoclonal CD38 antibody, such as daratumumab or isatuximab. In some embodiments, the antibody is daratumumab or isatuximab. In some embodiments, the antibody is daratumumab. In some embodiments, the antibody is isatuximab.

[0103] In some other embodiments, the antibody is a (preferably monoclonal) SLAMF7 (CD319) antibody, such as a monoclonal immunostimulatory antibody directed against SLAMF7 (CD319), such as elotuzumab.

[0104] In some embodiments, the antibody is selected from daratumumab, isatuximab, and elotuzumab, for example from daratumumab and elotuzumab, or from isatuximab and elotuzumab.

[0105] The antibody can be administered by intravenous (IV) infusion, or by injection, for example subcutaneous injection. For example, subcutaneous injection of daratumumab is approved, and thus, in some embodiments, the antibody is administered by subcutaneous injection.

[0106] The combinations disclosed herein of tasquinimod or a pharmaceutically acceptable salt thereof with at least one other compound as defined herein are useful in the treatment for the treatment of cancer, particularly blood cancers such as multiple myeloma including relapsed and / or refractory multiple myeloma.

[0107] As used herein, "combination" means that tasquinimod and at least one other compound (hereinafter also referred to as "the other compound") can be administered simultaneously in exactly the same formulation or in separate formulations. The combination of tasquinimod and the other compound includes administering each compound separately, for example sequentially or at different times. In the case of administration at different times, the time elapsed between the administration of tasquinimod and the administration of the other compound is preferably short enough for the two compounds to exhibit therapeutic activity in the treated individual, and it is contemplated that the therapeutic activities overlap in time. In some embodiments, tasquinimod and the other compound are administered essentially simultaneously, for example simultaneously (concomitantly) or sequentially.

[0108] As shown herein, in some embodiments, the use of the combination of tasquinimod and another compound as defined herein can, very advantageously, result in a synergistic therapeutic effect, i.e., an effect that exceeds an additive effect.

[0109] Tasquinimod and another compound as defined herein can be used in a molar ratio of Tasquinimod to the other compound of about 1:100 to about 100:1, such as 1:50 to 50:1, or 1:20 to 20:1, such as 1:10 to 10:1, or 1:5 to 5:1, or 1:2 to 2:1, although it is contemplated that higher or lower ratios may apply depending on the particular other compound being used.

[0110] In some embodiments, the combination comprises Tasquinimod or a pharmaceutically acceptable salt thereof and, (i) a proteasome inhibitor such as bortezomib, ixazomib, delanzomib, carfilzomib, oprozomib, or marizomib, (ii) an immunomodulatory imide such as thalidomide, lenalidomide, or pomalidomide, and (iii) an antibody such as daratumumab, isatuximab, or elotuzumab, such as daratumumab or elotuzumab and one other compound selected therefrom.

[0111] In some embodiments, the combination comprises Tasquinimod or a pharmaceutically acceptable salt thereof and two other compounds selected from (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody.

[0112] In some embodiments, the combination comprises Tasquinimod or a pharmaceutically acceptable salt thereof and at least one other compound selected from (i) a proteasome inhibitor and (ii) an immunomodulatory imide and (iii) an antibody.

[0113] In some embodiments, the combination comprises Tasquinimod or a pharmaceutically acceptable salt thereof and (i) a proteasome inhibitor and (ii) an immunomodulatory imide.

[0114] In some embodiments, the combination comprises Tasquinimod or a pharmaceutically acceptable salt thereof and (i) a proteasome inhibitor and (ii) an antibody.

[0115] In some embodiments, the combination comprises tasquinimod or a pharmaceutically acceptable salt thereof and at least one other compound selected from (i) an immunomodulatory imide, (ii) a proteasome inhibitor, and (iii) an antibody.

[0116] In some embodiments, the combination further comprises a corticosteroid, such as prednisone or dexamethasone, particularly dexamethasone.

[0117] One aspect of the invention is a pharmaceutical composition comprising tasquinimod or a pharmaceutically acceptable salt thereof for use in the treatment of multiple myeloma, wherein the treatment also comprises administration of another compound selected from (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody as defined herein.

[0118] Also disclosed herein are pharmaceutical compositions comprising, as an active ingredient, a combination of tasquinimod or a pharmaceutically acceptable salt thereof and another compound selected from (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody as defined herein, together with a pharmaceutically acceptable excipient, such as a carrier. In embodiments of such compositions, the other compound is as specified above in this specification in relation to embodiments of the combinations defined herein.

[0119] The pharmaceutical composition may be suitable for enteral administration, such as rectal or oral administration, or parenteral administration to a mammal (particularly a human), and comprises a therapeutically effective amount of the active ingredient, optionally together with a pharmaceutically acceptable excipient, such as a pharmaceutically acceptable carrier. The therapeutically effective amount of the active ingredient is defined above in this specification and depends, for example, on the mammalian species, body weight, age, condition of the individual, pharmacokinetic data of the individual, and mode of administration.

[0120] In the case of enteral administration, for example oral administration, the active ingredient can be formulated in a wide variety of dosage forms. The pharmaceutically acceptable carrier can be either solid or liquid. Solid form preparations include powders, tablets, pills, lozenges, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more substances that can also act as a diluent, flavoring agent, solubilizing agent, lubricant, suspending agent, binder, preservative, tablet disintegrant, or encapsulating material. In powders, the carrier is generally a fine solid which is a mixture with the fine active ingredient. In tablets, the active ingredient is generally mixed in a suitable ratio with a carrier having the necessary binding capacity and compressed into the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like.

[0121] Other forms suitable for oral administration include preparations in liquid form, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations intended to be converted to a liquid form preparation immediately before use. Emulsions may be prepared as solutions, for example as aqueous propylene glycol solutions, or may contain an emulsifying agent, for example lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable coloring agents, flavoring agents, stabilizers, and thickening agents. Aqueous suspensions can be prepared by dispersing the fine active ingredient in water together with a viscous material, such as natural or synthetic rubber, resin, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and can contain, in addition to the active ingredient, coloring agents, flavoring agents, stabilizers, buffering agents, artificial and natural sweeteners, dispersing agents, thickening agents, solubilizing agents, and the like.

[0122] Exemplary compositions for rectal administration include, for example, suppositories which can contain suitable non-irritating excipients such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at room temperature but liquefy and / or dissolve in the rectal cavity to release the drug.

[0123] The active ingredient may also be parenterally administered, for example by injection or infusion, for example intravenously, intraarterially, intraosseously, intramuscularly, intracerebrally, intraventricularly, intrasynovially, intrasternal, intramedullary, intralesionally, intracranially, intratumorally, intradermally and subcutaneously. Thus, for parenteral administration, the pharmaceutical composition can take the form of a sterile injectable or infusion preparation, for example as a sterile aqueous or oily suspension. This suspension can be formulated using suitable dispersing or wetting agents (e.g., Tween 80) and suspending agents according to techniques known in the art. The sterile injectable or infusion preparation can also be a sterile injectable or infusion solution or suspension in a non-toxic parenterally acceptable diluent or solvent. For example, the pharmaceutical composition can be a solution in 1,3-butanediol. Other examples of acceptable vehicles and solvents that can be employed in the compositions of the present invention include, but are not limited to, mannitol, water, Ringer's solution and isotonic saline. Additionally, sterile non-volatile oils are commonly employed as solvents or suspending media. For this purpose, any non-irritating non-volatile oil can be employed, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives, and pharmaceutically acceptable natural oils such as olive oil or castor oil are useful in the preparation of injectables, especially in their polyoxyethylated forms. These oily solutions or suspensions can also contain long-chain alcohol diluents or dispersing agents.

[0124] Solutions for parenteral use can contain suitable stabilizers and, if necessary, buffer substances. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, citric acid and its salts, and sodium EDTA. Parenteral solutions can also contain preservatives such as benzalkonium chloride, methyl - or propyl - paraben, and chlorobutanol.

[0125] For the selection and normal procedures of preparing suitable pharmaceutical dosage forms, see, for example, "Pharmaceutics - The Science of Dosage Form Design", M.B. Aulton, Churchill Livingstone, 2nd Edition, 2002 (ISBN 0443055173, 9780443055171). Information on suitable pharmaceutical excipients, such as carriers, and methods for preparing pharmaceutical dosage forms can also be found in Remington’s Pharmaceutical Sciences, a standard reference book in the field of pharmaceutical formulation, published by Mack Publishing Company.

[0126] The pharmaceutical composition can contain from about 1 wt% to about 95 wt% of the active ingredient with respect to the composition, the balance consisting of at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains at least 5%, at least 10%, at least 15% or at least 20% of the active ingredient. In some embodiments, the pharmaceutical composition contains at most 90%, at most 85%, or at most 80% of the active ingredient. For example, in some embodiments, the pharmaceutical composition contains from about 20% to about 90% of the active ingredient and at least one pharmaceutically acceptable excipient.

[0127] Generally, the active ingredients used in the combinations of the present invention are administered by any of the accepted modes of administration of agents for which a therapeutically effective amount serves a similar utility.

[0128] Some of the active ingredients contemplated for use in the combinations of the present invention are commercially available and are approved for use as pharmaceuticals. Thus, for example, bortezomib is marketed as Velcade®, ixazomib is marketed as Ninlaro®, carfilzomib is marketed as Kyprolis®, lenalidomide is marketed as Revlimid®, pomalidomide is marketed as Pomalyst®, daratumumab is marketed as Darzalex®, isatuximab is marketed as Sarclisa®, and elotuzumab is marketed as Empliciti®.

[0129] It is contemplated that such commercially available formulations may be useful in various aspects of the present invention, including uses, combinations, kits and methods. Similarly, the modes of administration and dosages known and specified for such formulations may be optionally adapted, taking into account the advantageous effects obtained by the combination with tasquinimod or a pharmaceutically acceptable salt thereof, to be useful in various aspects of the present invention.

[0130] Thus, as described above in this specification, combination therapies based on combinations of, in particular, proteasome inhibitors such as bortezomib and dexamethasone and immunomodulatory imides such as lenalidomide are already known. The treatment modalities used in these combination methods may also be applied when practicing the methods of the present invention, for example by suitably adapting the mode of administration and dosage, taking into account the advantageous synergistic effects that can be obtained, in particular the possibility of reducing the dosage. As is common when determining an appropriate treatment regimen, the appropriate dosage will usually have to be determined by the physician administering the treatment, taking into account factors such as the age, weight, condition, etc. of the patient being treated.

[0131] In some embodiments, the combination of the present invention includes administration of a proteasome inhibitor. For example, bortezomib is administered as a short-term intravenous infusion, based on foreign patients, for example, on the 1st, 4th, 8th, and 11th days of a 3-week cycle, for a maximum of 8 cycles in total. In some of these embodiments, the treatment further includes administering dexamethasone, for example, at a dose of about 20 mg once, for example, on the day of PI (for example, bortezomib) administration and the day following each PI administration.

[0132] For example, injection or rectal administration of the active ingredient may be contemplated if necessary, but oral administration is generally considered to be the most convenient.

[0133] For example, ixazomib, oprozomib, and delanzomib, which are proteasome inhibitors, can be administered orally, and thalidomide, lenalidomide, and pomalidomide, which are immunomodulatory imides, can also be administered orally. However, bortezomib, carfilzomib, and marizomib, which are proteasome inhibitors, as well as antibodies, are generally administered by injection or infusion. In some embodiments, another compound can be administered orally and is, for example, selected from ixazomib, oprozomib, delanzomib, thalidomide, lenalidomide, and pomalidomide.

[0134] In embodiments in which a corticosteroid is also administered, such corticosteroid can be, for example, dexamethasone or prednisone and can be administered, for example, orally as a tablet formulation.

[0135] In some embodiments, tasquinimod and another compound are administered as separate formulations. For example, tasquinimod is administered as an oral preparation and another compound is administered by injection. In such cases, the above description of suitable pharmaceutical preparations can be applied to such formulations independently. For example, in some embodiments, tasquinimod is administered orally to an individual, and simultaneously, sequentially, or separately, another compound is administered via injection or infusion.

[0136] In some embodiments, tasquinimod is orally administered to an individual, for example, as a capsule or tablet, before, after, or in between an injection or intravenous administration of another compound as defined herein.

[0137] In some embodiments, the administration of tasquinimod and the administration of one or more other compounds occur during the same 24-hour period, more preferably during the same 12-hour period, or the same 6-hour period, or the same 3-hour period, or the same 2-hour period, or the same 1-hour period, for example, one following directly after the other.

[0138] In some embodiments, the administration of tasquinimod occurs daily, but each administration of one or more other compounds may occur on a treatment schedule that is the same as or different from the treatment schedule of tasquinimod, for example, daily or weekly, or at any other suitable interval.

[0139] Generally, a daily dose of tasquinimod is contemplated from a minimum of 0.001 mg / kg body weight, or 0.002 mg / kg body weight, or 0.005 mg / kg body weight, or 0.01 mg / kg body weight, up to a maximum of 0.2 mg / kg body weight, or 0.1 mg / kg body weight, or 0.05 mg / kg body weight, or 0.02 mg / kg body weight.

[0140] In one embodiment, tasquinimod is administered in an amount of 0.05 - 0.15 mg / day, or 0.08 - 0.1 mg / day, for example, 0.1 mg / day (or the corresponding amount of a pharmaceutically acceptable salt of tasquinimod).

[0141] In one embodiment, tasquinimod is administered in an amount of 0.1 - 0.3 mg / day, or 0.15 - 0.25 mg / day, for example, 0.2 mg / day (or the corresponding amount of a pharmaceutically acceptable salt of tasquinimod).

[0142] In one embodiment, tasquinimod is administered in an amount of 0.1 to 1 mg / day, or 0.2 to 0.8 mg / day, such as 0.5 mg / day (or the corresponding amount of a pharmaceutically acceptable salt of tasquinimod).

[0143] In one embodiment, tasquinimod is administered in an amount of 0.2 to 1.5 mg / day, or 0.4 to 1.2 mg / day, such as 0.8 mg / day (or the corresponding amount of a pharmaceutically acceptable salt of tasquinimod).

[0144] In one embodiment, tasquinimod is administered in an amount of 0.5 to 2 mg / day, or 0.8 to 1.2 mg / day, such as 1 mg / day (or the corresponding amount of a pharmaceutically acceptable salt of tasquinimod).

[0145] In one embodiment, tasquinimod is administered in an amount of 0.8 to 3 mg / day, or 1 to 2.5 mg / day, such as 2 mg / day (or the corresponding amount of a pharmaceutically acceptable salt of tasquinimod).

[0146] In one embodiment, tasquinimod is administered in an amount of 1 to 6 mg / day, or 2 to 4 mg / day, such as 3 mg / day (or the corresponding amount of a pharmaceutically acceptable salt of tasquinimod).

[0147] In some embodiments, the dosage is gradually adjusted to reach an optimal result and can be so-called titrated. For example, dose titration can include starting with a low daily dose of the active ingredient as defined herein, such as 0.25 mg, and maintaining this dosage level for one or two weeks. If no significant side effects that could contraindicate an increase in dosage are encountered, the level can be increased, for example, to 0.5 mg / day for one or two weeks, and after that period, another increase can be contemplated to reach a daily dose such as 1 mg. In such a method, if any significant side effects occur after a gradual increase in dosage, the dosage can be reduced back to the previous level.

[0148] In some embodiments, when the combination includes PI, the PI is administered once a week, for example, at a dosage of 1 to 5 mg / week.

[0149] In some embodiments, when the combination includes IMiD, the IMiD is administered daily, for example, at a dosage of 10 to 40 mg / week.

[0150] In some embodiments, when the combination includes an antibody, the antibody is administered as an intravenous infusion of about 10 to 16 mg / kg body weight, for example, by weekly infusion for up to 2 months, then, for example, by infusion every 2 weeks for up to about 3 months, and then by infusion about once a month for the entire treatment period.

[0151] In some embodiments, when the combination includes an antibody, the antibody is administered by subcutaneous injection. For example, the combination includes daratumumab and is administered by subcutaneous injection.

[0152] In some embodiments, when the combination further includes a corticosteroid, such corticosteroid is administered daily at a daily dosage of 0.5 to 10 mg and can be administered, for example, orally.

[0153] Thus, generally, the active ingredient can be administered, for example, daily, for example, once to three times a day, or once to two times a day, for example, once a day. In some embodiments, the administration is carried out at a lower frequency, for example, every two days, once a week, etc., or according to an established treatment cycle, for example, over 3 to 6 weeks.

[0154] In some embodiments, tasquinimod and another compound (i.e., any one of compounds (i)-(iii) as defined herein) are administered according to various dosing schedules and modes of administration. For example, tasquinimod is administered daily and the other compound is administered at a lower frequency, for example, every other day, once a week, or every other week.

[0155] In some embodiments, tasquinimod is administered in combination with lenalidomide, which is also administered as an oral preparation, for example a capsule preparation, as an oral preparation, for example a capsule preparation.

[0156] In some embodiments, tasquinimod is administered in combination with pomalidomide, which is also administered as an oral preparation, for example a capsule preparation, as an oral preparation, for example a capsule preparation.

[0157] In some embodiments, tasquinimod is administered in combination with thalidomide, which is also administered as an oral preparation, for example a capsule preparation, as an oral preparation, for example a capsule preparation.

[0158] In some embodiments, tasquinimod is administered in combination with bortezomib, which is administered by intravenous injection, as an oral preparation, for example a capsule preparation.

[0159] In some embodiments, tasquinimod is administered in combination with bortezomib, which is administered by subcutaneous injection, as an oral preparation, for example a capsule preparation.

[0160] In some embodiments, tasquinimod is administered in combination with carfilzomib, which is administered by intravenous injection, as an oral preparation, for example a capsule preparation.

[0161] In some embodiments, tasquinimod is administered in combination with ixazomib, which is also administered as an oral preparation, for example a capsule preparation, as an oral preparation, for example a capsule preparation.

[0162] In some embodiments, tasquinimod is used in combination with one or more other therapeutically active compounds selected from compounds (i)-(iii) as defined herein.

[0163] For example, in some embodiments, tasquinimod is used in combination with a PI and an IMiD. For example, tasquinimod is used in combination with a PI selected from bortezomib, ixazomib, delanzomib, carfilzomib, oprozomib, and marizomib and an IMiD selected from thalidomide, lenalidomide, and pomalidomide.

[0164] In some embodiments, tasquinimod is used in combination with bortezomib and an IMiD selected from thalidomide, lenalidomide, and pomalidomide. In some embodiments, tasquinimod is used in combination with ixazomib and an IMiD selected from thalidomide, lenalidomide, and pomalidomide. In some embodiments, tasquinimod is used in combination with delanzomib and an IMiD selected from thalidomide, lenalidomide, and pomalidomide. In some embodiments, tasquinimod is used in combination with carfilzomib and an IMiD selected from thalidomide, lenalidomide, and pomalidomide. In some embodiments, tasquinimod is used in combination with oprozomib and an IMiD selected from thalidomide, lenalidomide, and pomalidomide. In some embodiments, tasquinimod is used in combination with marizomib and an IMiD selected from thalidomide, lenalidomide, and pomalidomide.

[0165] In some of the above embodiments, the IMiD is thalidomide. In some of the above embodiments, the IMiD is lenalidomide. In some of the above embodiments, the IMiD is pomalidomide.

[0166] In some of the above embodiments, the combination also includes an antibody defined herein, such as an antibody targeting CD38 or SLAMF7, such as an antibody selected from daratumumab, isatuximab, and elotuzumab.

[0167] In some embodiments, the combination further comprises administration of a corticosteroid. In some embodiments, the corticosteroid is dexamethasone. In some embodiments, the corticosteroid is prednisone.

[0168] The combinations described herein are useful in the treatment of, in particular, cancer, and more particularly hematological cancers such as multiple myeloma. The combination is considered to be particularly useful in the treatment of relapsed and / or refractory multiple myeloma. In some embodiments, the combination described herein is a combination for use in the treatment of relapsed multiple myeloma. In some embodiments, the combination described herein is a combination for use in the treatment of refractory multiple myeloma.

[0169] In some embodiments, the combination described herein is a combination for use as a first-line treatment for multiple myeloma, i.e., for use in the treatment of patients who have not received prior treatment for multiple myeloma.

[0170] In some embodiments, the combination described herein is a combination for use as a second-line treatment for multiple myeloma, i.e., for use in the treatment of relapsed patients who have previously received first-line treatment for multiple myeloma.

[0171] In some embodiments, the combination described herein is a combination for use as a third-line treatment for multiple myeloma, i.e., for use in the treatment of patients who have previously received second-line treatment for multiple myeloma.

[0172] It is contemplated that the combinations herein may also be provided for fourth-line treatment, fifth-line treatment, etc. of multiple myeloma.

[0173] In some embodiments, the combination is used for the treatment of smoldering multiple myeloma. In some embodiments, the combination is used for the treatment of monoclonal gammopathy of undetermined significance (MGUS). In some other embodiments, the combination is used for the treatment of solitary plasmacytoma.

[0174] Another aspect disclosed herein is a kit for the treatment of cancer, particularly blood cancer such as multiple myeloma, comprising a package insert containing instructions for using tasquinimod or a pharmaceutically acceptable salt thereof in combination with at least one other compound selected from (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody. In some embodiments, the kit further comprises instructions for using tasquinimod and the other compound in combination with an additional formulation comprising a corticosteroid such as dexamethasone or prednisone.

[0175] Particular embodiments of any such kit include features defined in relation to the particular combinations, uses, and pharmaceutical compositions described herein.

[0176] Another aspect disclosed herein is a method of treating cancer, particularly blood cancer such as multiple myeloma, comprising administering to an individual in need of such treatment tasquinimod or a pharmaceutically acceptable salt thereof in combination with at least one other compound selected from (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody. Particular embodiments of such methods include features defined in relation to the particular combinations, pharmaceutical combinations, uses, and kits described herein.

Example

[0177] The present invention is illustrated by the following non-limiting examples.

[0178] Example 1 Use of tasquinimod in combination with bortezomib Human NCI-H929 (H929) multiple myeloma cells were subcutaneously inoculated into NSG mice. Tumor-bearing mice were treated with vehicle (VC), tasquinimod (TQ), ad libitum at 30 mg / kg in drinking water starting when palpable tumors were present (i.e., on day 18 after tumor inoculation); bortezomib (VEL), 0.5 mg / kg, intravenous administration, every 4 days; dexamethasone (DEX), 10 mg / kg, intraperitoneal administration, 5-day treatment, no treatment for 2 days; or combinations (TQ + DEX) and (TQ + VEL). Statistics: two-way ANOVA; p-values VC vs TQ p = 0.0009, VC vs VEL p = 0.041, VC vs DEX p = 0.0081, DEX vs DEX + TQ ns, TQ vs TQ + VEL p = 0.0002, VEL vs VEL + TQ p = 0.0361. The results are shown in Figure 1. Both tasquinimod and bortezomib, when administered as single therapeutic agents in the H929 tumor model, reduced multiple myeloma tumor growth compared to control mice (Figure 1). When tasquinimod was combined with bortezomib, a synergistic improvement in efficacy was recorded.

[0179] Example 2 Use of tasquinimod in combination with lenalidomide The effect of combining tasquinimod with lenalidomide was investigated in the human MM1.S model of multiple myeloma. MM1.S cells were established from an IgA myeloma patient with typical characteristics of human myeloma cells (Greenstein et al., Exp Hematol. April 2003; 31(4):271-82). The MM1.S model was 5×10 6It was established by subcutaneously inoculating NSG mice with individual MM1.S cells. Tosedostat (TQ), 30 mg / kg / day in drinking water; lenalidomide (LEN), 5 mg / kg via forced oral administration, up to the endpoint, followed by 5-day treatment, 2-day treatment-free, or treatment with a combination of tosedostat and lenalidomide (TQ+LEN), starting when the tumor became measurable (14 days after tumor cell injection). The calipers were used to monitor the tumor size and calculate the tumor volume. Two-way ANOVA was used to evaluate the differences between groups; p-values: TQ vs TQ+LEN p = 0.0001, LEN vs LEN+TQ p = 0.0183. The results are shown in Figure 2.

[0180] Both tosedostat and lenalidomide, when administered as single therapeutic agents in the MM1.S tumor model, reduced multiple myeloma growth compared to control mice (Figure 2). When tosedostat was combined with lenalidomide, an improvement in the effect was recorded.

[0181] Example 3 Use of tosedostat in combination with lenalidomide Human NCI-H929 myeloma cells (5×10 6 ) were subcutaneously injected into NSG mice. On the 11th day after tumor cell injection, the mice were divided into 4 groups: vehicle (VC); tosedostat (TQ), 30 mg / kg ad libitum in drinking water; lenalidomide (LEN), 20 mg / kg, forced oral administration, 5-day treatment, 2-day treatment-free; or a combination of tosedostat and lenalidomide (TQ+LEN), (TQ, 30 mg / kg ad libitum in drinking water; LEN, 20 mg / kg, forced oral administration, 5-day treatment, 2-day treatment-free) for treatment. Tumor growth was evaluated. Figure 3 shows the results regarding tumor growth presented as mean ± SEM for each group (n = 5 mice per group).

[0182] Statistics: Two-way ANOVA. VC vs TQ p = 0.0516; VC vs LEN p = 0.0345; VC vs TQ+LEN p < 0.0001; LEN vs LEN+TQ p < 0.0001; TQ vs TQ+LEN p < 0.0001.

[0183] Example 4 Use of tasquinimod in combination with daratumumab RPMI-8226 myeloma cells (5×10 6 ) were intravenously injected into the tail vein of NSG mice. Treatment with tasquinimod (TQ) at a discretionary 30 mg / kg in drinking water, treatment with daratumumab (Dara) (12 mg / kg, intraperitoneal administration, twice a week), treatment with vehicle only, or treatment with tasquinimod in combination with daratumumab (TQ+Dara) (TQ, discretionary 30 mg / kg in drinking water; Dara, 12 mg / kg, intraperitoneal administration, twice a week) was started on day 7 after tumor injection (n = 5 mice per group). The development of symptoms and the survival of the mice were evaluated. The results regarding asymptomatic mice (%) and surviving mice (%) are shown in Figures 4 and 5 respectively. The log-rank test was used for statistical analysis.

[0184] Statistics: Symptoms: VC vs TQ p = 0.0197; Dara vs Dara+TQ p = 0.0027; TQ vs TQ+Dara p = 0.0472; VC vs TQ+Dara p = 0.0018. Survival: VC vs TQ p = 0.0549; Dara vs Dara+TQ p = 0.0027; TQ vs TQ+Dara p = 0.0554; VC vs TQ+Dara p = 0.0027.

[0185] Example 5 Use of tasquinimod in combination with ixazomib Human NCI-H929 myeloma cells (4×10 6 ) were subcutaneously injected into NSG mice. The mice were assigned to one of 4 groups and treated with vehicle (VC); tasquinimod (TQ) at a discretionary 30 mg / kg in drinking water; ixazomib (IXA) at 5 mg / kg, forced oral administration, twice a week; or combination TQ+IXA (TQ, discretionary 30 mg / kg in drinking water; IXA, 5 mg / kg, forced oral administration, twice a week). Treatment with tasquinimod was started 8 hours after tumor cell injection. Treatment with ixazomib was started 13 days after tumor cell injection. Tumor growth was evaluated. The tumor growth presented as mean ± SEM for each group (n = 10 mice per group) is shown in Figure 6.

[0186] Statistics: two-way ANOVA. VC vs TQ p = 0.0178; VC vs IXA p = 0.2383; VC vs TQ+IXA p<0.0001; IXA vs IXA+TQ p<0.0001; TQ vs IXA+TQ p<0.0001.

[0187] Example 6 Use of tasquinimod in combination with lenalidomide Human NCI-H929 myeloma cells (3.5×10 6 ) were subcutaneously injected into NSG mice. The mice were assigned to one of four groups and treated with vehicle (UT), tasquinimod (TQ), 30 mg / kg ad libitum in drinking water, lenalidomide (LEN), 20 mg / kg, forced oral administration, 5 days / week, 5 days of lenalidomide treatment and 2 days without lenalidomide treatment, or combination LEN+TQ. Treatment with TQ was initiated 8 hours after tumor cell injection. Treatment with lenalidomide was initiated 14 days after tumor cell injection. Tumor growth was evaluated. Tumor growth presented as mean ± SEM for each group (n = 10 mice per group except for the lenalidomide group (n = 6 mice)) is shown in Figure 7.

[0188] Statistics: two-way ANOVA. UT vs TQ p<0.0001; UT vs LEN p = 0.0481; TQ vs TQ+LEN p<0.0001; LEN vs TQ+LEN p<0.0001; UT vs TQ+LEN p<0.0001. The claims at the time of filing are set forth below. [Claim 1] Use of tasquinimod or a pharmaceutically acceptable salt thereof, and (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody in combination for use in the treatment of multiple myeloma, comprising at least one other compound selected from . [Claim 2] The combination for use according to claim 1, wherein tasquinimod or a pharmaceutically acceptable salt thereof and at least one other compound are administered separately, sequentially or simultaneously. [Claim 3] (i) a proteasome inhibitor, and optionally, (ii) an immunomodulatory imide, and (iii) an antibody A combination for use according to claim 1 or 2, comprising a further compound selected from [Claim 4] (i) an immunomodulatory imide, and optionally, (ii) a proteasome inhibitor, and (iii) an antibody A combination for use according to claim 1 or 2, comprising a further compound selected from [Claim 5] (i) a proteasome inhibitor, and (ii) an immunomodulatory imide, and optionally, (iii) an antibody A combination for use according to any one of claims 1 to 4, comprising [Claim 6] A combination for use according to any one of claims 1 to 5, further comprising a corticosteroid. [Claim 7] The combination for use according to claim 6, wherein the corticosteroid is selected from dexamethasone and prednisone. [Claim 8] Thalidomide, and Thalidomide is (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody An instruction for use in combination with at least one further compound selected from A kit for treating multiple myeloma in an individual, comprising [Claim 9] (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody The kit according to claim 8, further comprising at least one further compound selected from [Claim 10] Thalidomide or a pharmaceutically acceptable salt thereof for use in the treatment of multiple myeloma, wherein the thalidomide or a pharmaceutically acceptable salt thereof is (i) a proteasome inhibitor, (ii) an immunomodulatory imide, and (iii) an antibody Thalidomide or a pharmaceutically acceptable salt thereof for use in combination with at least one compound selected from the group consisting of [Claim 11] Thalidomide or a pharmaceutically acceptable salt thereof is (i) a proteasome inhibitor, and optionally (ii) an immunomodulatory imide, and (iii) an antibody Thalidomide or a pharmaceutically acceptable salt thereof for use in combination with another compound selected from the group consisting of [Claim 12] Thalidomide or a pharmaceutically acceptable salt thereof is (i) an immunomodulatory imide, and optionally, (ii) a proteasome inhibitor, and (iii) an antibody Thalidomide or a pharmaceutically acceptable salt thereof for use in combination with another compound selected from the group consisting of [Claim 13] Thalidomide or a pharmaceutically acceptable salt thereof is (i) a proteasome inhibitor, and (ii) an immunomodulatory imide, and optionally, (iii) an antibody Thalidomide or a pharmaceutically acceptable salt thereof for use in combination with, for use according to any one of claims 10 to 12 [Claim 14] Thalidomide or a pharmaceutically acceptable salt thereof for use according to any one of claims 10 to 13, wherein the combination also includes administration of a corticosteroid. [Claim 15] (i) The proteasome inhibitor is selected from bortezomib, ixazomib, delanzomib, carfilzomib, oprozomib, and marizomib, (ii) The immunomodulatory imide is selected from thalidomide, lenalidomide, and pomalidomide, (iii) The antibody is selected from daratumumab, isatuximab, and elotuzumab, A combination for use according to any one of claims 1 to 7, or a kit according to claim 8 or 9, or tasquinimod or a pharmaceutically acceptable salt thereof for use according to any one of claims 10 to 14.

Claims

1. Tasquinimod or a pharmaceutically acceptable salt thereof, and (i) a proteasome inhibitor selected from the group consisting of bortezomib and ixazomib, (ii) an immunomodulatory imide which is lenalidomide, and (iii) an antibody which is daratumumab and at least one other compound selected from A pharmaceutical or pharmaceutical kit for the treatment of multiple myeloma.

2. The pharmaceutical or pharmaceutical kit according to claim 1, which is suitable for separate, sequential or simultaneous administration of tasquinimod or a pharmaceutically acceptable salt thereof and the at least one other compound.

3. The pharmaceutical or pharmaceutical kit according to claim 1 or 2, wherein the at least one other compound comprises the proteasome inhibitor defined in claim 1.

4. The pharmaceutical or pharmaceutical kit according to claim 3, wherein the proteasome inhibitor is bortezomib.

5. The pharmaceutical or pharmaceutical kit according to claim 4, wherein the proteasome inhibitor is ixazomib.

6. The pharmaceutical or pharmaceutical kit according to any one of claims 1 to 5, wherein the at least one other compound comprises lenalidomide.

7. The pharmaceutical or pharmaceutical kit according to any one of claims 1 to 6, wherein the at least one other compound comprises daratumumab.

8. The pharmaceutical or pharmaceutical kit according to any one of claims 1 to 7, further comprising a corticosteroid.

9. The pharmaceutical or pharmaceutical kit according to claim 8, wherein the corticosteroid is selected from dexamethasone and prednisone.

10. A pharmaceutical comprising tasquinimod or a pharmaceutically acceptable salt thereof for the treatment of multiple myeloma, wherein the treatment is (i) a proteasome inhibitor selected from the group consisting of bortezomib and ixazomib, (ii) an immunomodulatory imide which is lenalidomide, and (iii) an antibody which is daratumumab The pharmaceutical, which is a combination treatment with at least one other compound selected from.

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