Compositions and methods for treating blood cancer

Abstract

Described herein are compositions and methods for treating, ameliorating, or inhibiting the progress of blood cancer in a cell or a subject. In some embodiments, the compositions and methods comprise one or more retinoid X receptor (RXR) modulators and one or more immunomodulatory agents. In some embodiments, the blood cancer is multiple myeloma (MM). In some embodiments, the subject has diabetes, dyslipidemia, or a combination thereof.

Description

[0001]COMPOSITIONS AND METHODS FOR TREATING BLOOD CANCER CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No.63 / 528,737 filed on July 25, 2023, which is incorporated by reference herein in its entirety. FEDERALLY SPONSORED RESEARCH This invention was made with government support under grant number 5R21-CA234701 awarded by the National Cancer Institute. The government has certain rights in the invention. REFERENCE TO SEQUENCE LISTING This application was filed with a Sequence Listing XML in ST.26 XML format accordance with 37 C.F.R. § 1.831 and PCT Rule 13ter. The Sequence Listing XML file submitted in the USPTO Patent Center, “028193-0036-WO01_sequence_listing_xml_8-JUL-2024.xml,” was created on July 8, 2024, contains 23 sequences, has a file size of 24.0 Kbytes (24,576 bytes), and is incorporated by reference in its entirety into the specification. BACKGROUND Multiple myeloma (MM) is a clonal plasma cell malignancy. It is the second most common hematologic malignancy in the United States. Although current anti-myeloma agents, such as immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies, have significantly improved the outcomes of MM patients, MM remains to be an incurable disease with high rates of drug resistance and relapse. There are unmet needs for the development of novel anti- myeloma agents and for understanding the mechanisms of MM’s drug resistance. Peroxisome proliferator-activator receptors (PPARs) belong to the nuclear hormone receptor superfamily of ligand activated transcription factors. PPARs are involved in the regulation of gene expression in response to nutritional and physiological stimuli. Moreover, PPARs form heterodimers with the retinoid X receptor (RXR) to regulate glucose and lipid metabolism. Activated ligand-bound PPARs then undergoes a conformational change. Thereafter, it subsequently binds to peroxisome proliferator response elements (PPREs), thereby leading to transcriptional regulation. During this process, additional co-activators or repressors are recruited to create a complex to fine-tune the expression of large gene arrays. Dysfunctional regulation of the expression in these genes is implicated in the development of a range of human diseases, including atherosclerosis, cancer, diabetes, and obesity. MM occurs largely in the elderly. The elderly commonly have a high incidence of comorbidities, including diabetes and dyslipidemia. PPAR agonists, such as fibrates and thiazolidinediones, are classes of Food and Drug Administration (FDA)-approved agents used for treating diabetes and dyslipidemia. Previous research has demonstrated that administration of PPAR agonists downregulated the expression of cereblon (CRBN) by facilitating the binding of PPAR to the CRBN promoter region and repressing CRBN transcription. CRBN is a direct target of immunomodulatory agents. Administration of PPAR agonists, such as fenofibrate, GW501516, and troglitazone, resulted in decreased CRBN at the mRNA and protein levels. Furthermore, administration of PPAR agonists resulted in the attenuation of the anti-myeloma activity of lenalidomide in vitro and in vivo. These findings led us to explore novel agents that can target the PPAR pathway and enhance CRBN expression, while retaining the beneficial effects of PPAR agonists on glucose and lipid metabolism. RXRs are key molecules in the PPAR signaling pathway. RXRs (RXRĮ, ȕ, and Ȗ) are master coordinators of cell growth, metabolism, and development. Among the three subtypes, malfunctioning RXRĮ, due to post-translational modification by phosphorylation, is associated with hepatic carcinogenesis. The phosphorylated form of RXRĮ (p-RXRĮ) lost its transactivation activity and interfered with the function of the remaining normal RXRĮ in a dominant-negative manner, thereby promoting the grow of hepatoma cells. Although RXRs exist in three isoforms, they do not confer different functions in various RXR-PPAR complexes. RXRs heterodimerize with many different nuclear receptors, including Retinoic Acid receptor (RAR), vitamin D receptor (VDR), PPAR, liver X receptor (LXR), and Nurr77. The RXR / PPAR complex plays an important role in retinoic acid metabolism, with documented clinical applications in inflammatory disease and certain cancers. RXR / PPARȖ heterodimers reportedly regulate the transcription of genes involved in insulin action, adipocyte differentiation, lipid metabolism, and inflammation. Hence, there has been considerable interest in utilizing the combination of ligands for PPAR and RXR for the prevention and treatment of various types of cancer. However, the significance of the interactions of RXR / PPAR in MM remains unclear. Hence, there is a strong need to critically evaluate the specific role of these complexes in MM pathobiology and their responses to current therapeutic strategies. RXR agonists exert their effects through RXR homodimers or through permissive heterodimers. LG100754, a novel RXR dimer modulator, is an agonist of RXR / PPARĮ and RXR / PPARȖ heterodimers. Although LG100754 activates the RXR / PPAR heterodimer, it does not activate TR / RXR, VDR / RXR, or LXR / RXR. At low concentrations, LG100754 acts as a weak agonist of RXR / PPARȖ. However, it strongly enhances signaling through the heterodimer in response to PPARȖ ligands, including the drug, rosiglitazone. LG100754 activates endogenous RXR / PPARȖ heterodimer-mediated pathways through inducing adipocyte differentiation of 3T3- L1 cells. Moreover, LG100754 blocks TNFĮ-mediated inhibition of insulin receptor (IR) phosphorylation in mature adipocytes. Through this mechanism, LG100754 prevents hyperglycemia in murine diabetes models, thereby reducing insulin resistance. Although the various roles of LG100754 have been identified in different metabolic physiological processes, such as glucose regulation, its function in cancer remains unknown. Bexarotene is an FDA- approved RXR-specific agonist used in the treatment of cutaneous T cell lymphoma (CTCL). Bexarotene stimulates the formation of RXR and PPARȖ heterodimers. The RXR agonist, AGN194204, acted through RXR-PPAR heterodimer and potentiated the anti-tumor effects of PPAR agonists on breast cancer cell lines. LG101506 is the most potent among the selective RXR-PPAR heterodimer activators. Binding to RXR results in selective activation of RXR: PPARĮ, RXR: PPARȖ, and RXR: PPAR į heterodimers. LG101506 lowers blood glucose levels in genetically predisposed type II diabetic mice. The effects of these RXR modulators on anti- myeloma activity either alone or in combination with immunomodulatory agents are unknown. What is needed are combination therapies for treating blood cancers such as myeloma. SUMMARY One embodiment described herein is a pharmaceutical composition for treating, ameliorating, or inhibiting the progress of blood cancer in a cell or a subject, the pharmaceutical composition comprising one or more retinoid X receptor (RXR) modulators and one or more immunomodulatory agents. In one aspect, the RXR modulator comprises LG100754, bexarotene, AGN194204 (IRX4204), LG101506, AGN195393, LGN100849, PA451, PA452, UVI 3003, AGN195183 (IRX5183), CD 3254, LG100268, retinoid acid, SR11237, or combinations thereof. In another aspect, the RXR modulator is an RXR agonist. In another aspect, the RXR modulator promotes RXR homodimerization. In another aspect, the RXR modulator promotes RXR heterodimerization with one or more peroxisome proliferator-activator receptors (PPARs). In another aspect, the immunomodulatory agent comprises lenalidomide, thalidomide, pomalidomide, iberdomide, mezigdomide, or combinations thereof. In another aspect, the pharmaceutical composition comprises LG100754 or AGN194204 (IRX4204), and lenalidomide. In another aspect, the pharmaceutical composition comprises a mass ratio of the RXR modulator to the immunomodulatory agent of about 1:10 to about 10:1. In another aspect, the pharmaceutical composition further comprises one or more peroxisome proliferator-activator receptor (PPAR) antagonists. In another aspect, the pharmaceutical composition further comprises one or more pharmaceutically acceptable buffers, salts, carriers, or diluents. Another embodiment described herein is a kit comprising: a pharmaceutical composition described herein; and optionally, one or more of packaging, a label, or instructions for use. Another embodiment described herein is the use of a pharmaceutical composition of described herein as a medicament for treating, ameliorating, or inhibiting the progress of blood cancer in a cell or a subject. Another embodiment described herein is a method of treating, ameliorating, or inhibiting the progress of blood cancer in a cell or a subject, the method comprising administering to the cell of the subject a therapeutically effective amount of a pharmaceutical composition comprising one or more retinoid X receptor (RXR) modulators and one or more immunomodulatory agents. In one aspect, the RXR modulator comprises LG100754, bexarotene, AGN194204 (IRX4204), LG101506, AGN195393, LGN100849, PA451, PA452, UVI 3003, AGN195183 (IRX5183), CD 3254, LG100268, retinoid acid, SR11237, or combinations thereof. In another aspect, the immunomodulatory agent comprises lenalidomide, thalidomide, pomalidomide, iberdomide, mezigdomide, or combinations thereof. In another aspect, the pharmaceutical composition comprises LG100754 or AGN194204 (IRX4204), and lenalidomide. In another aspect, the blood cancer is a leukemia or a lymphoma. In another aspect, the blood cancer is multiple myeloma (MM). In another aspect, the subject is receiving cellular therapy with chimeric antigen receptor (CAR) T cells. In another aspect, the subject has a precancerous condition comprising smoldering multiple myeloma (SMM), monoclonal gammopathy of undetermined significance (MGUS), or a combination thereof. In another aspect, the subject has diabetes, dyslipidemia, or a combination thereof. In another aspect, the method promotes T cell activation and reduces T cell exhaustion. In another aspect, the method enhances chimeric antigen receptor (CAR) T-cell therapy. In another aspect, the method reduces blood glucose and lipid levels. In another aspect, the method increases cereblon (CRBN) expression levels. In another aspect, the therapeutically effective amount of the pharmaceutical composition is from about 2 mg / kg to about 250 mg / kg. Another embodiment described herein is a pharmaceutical composition for use in a method of treating, ameliorating, or inhibiting the progress of blood cancer in a cell or a subject, the pharmaceutical composition comprising one or more retinoid X receptor (RXR) modulators and one or more immunomodulatory agents. DESCRIPTION OF THE DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee. FIG.1A–T show synergistic suppression of MM cell proliferation using lenalidomide and RXR agonists. FIG. 1A–D show MM1.R were treated with various combinations of different concentrations of RXR agonist and lenalidomide for 48 h, and combination index (CI) values were identified using CompuSyn software 1.0 (ComboSyn, Inc (Paramus, NJ, USA)). Fa-CI plots were generated using non-constant ration combination data for each of the drug combinations. Each circles presents one drug combinations. FIG. 1E–T show Lenalidomide (10 μM), LG100754 (8 μM), bexarotene (4 μM), AGN194204 (4 μM), and LG101506 (4 μM) were used in MM1.R for 48 h; cell apoptosis was measured using Annexin V / PI staining assay. FIG. 2A–H show MM1.R and U266 cells were treated with LG100754, Bexarotene, AGN194204, and LG101506 for 48h at indicated concentration and cell viability was measured by MTS assay. FIG.3A–T show synergistic suppression of MM cell proliferation using lenalidomide and LG100754. FIG. 3A–D show U266 were treated with multiple concentrations for 48 h, and combination index (CI) value identified using CompuSyn software. FIG.3E–T show U266 were treated with the above concentrations of Lenalidomide and RXR agonists for 48 h, cell apoptosis was measured using Annexin V / PI staining assay. FIG. 4A–T show increased CRBN expression is associated with synergistic effect of lenalidomide and RXR agonists. FIG.4A–H show U266 and MM1.R were treated with indicated concentrations of RXR agonists for 48 h. Protein lysate was subjected to Western blot with indicated antibodies. FIG. 4I–J show representative images of CRBN in MM cells treated with DMSO or 8 μM LG100754, 4 μM bexarotene, 4 μM AGN194204, and 4 μM LG101506 for 48 h. FIG.4K–R show U266 and MM1.R were treated with 10 μM lenalidomide and RXR agonists at concentrations indicated in FIG. 4A–H for 48 h. CRBN, caspase 3, and caspase 9 expression was measured by Western blot. FIG.4S–T show MM1.R and U266 cells were transduced with CRBN-specific CRISP / cas9 knockout vector for 24 h. Cells were then treated with lenalidomide alone, LG100754 alone, or in combination for additional 48 h with or without transduction of CRBN overexpressing plasmid. Cell viability was measured by MTT assay. Results are presented as mean ± SD from at least three separate experiments. NS: not statistically significant; *: p < 0.05; **: p < 0.01. FIG. 5A–E show LG100754 regulates CRBN transcription activity via promotion of heterodimer formation between PPAR and CRBN. FIG. 5A shows JASPAR databases predict binding sites of PPAR to CRBN promoter region. FIG.5B shows sgRNA sequence used to knock out CRBN in MM1.R and U266. FIG.5C–D show MM1.R and U266 cells were transduced with CRBN specific CRISP / cas9 knock out plasmid for 24h and then treated with lenalidomide or LG100754 alone or in combination for additional 48 h. Cell viability was measured by MTT assay. Results are presented as mean ± SD from at least three separate experiments. *: p < 0.05; **: p < 0.01. FIG.5E shows protein lysate was subjected to western blot with indicated antibodies. FIG. 6A–J show LG100754 attenuates the binding effect of PPARĮ and PPARȖ on the CRBN promoter area. FIG.6A shows U266 and MM1.R were transfected with CRBN / PGL3 firefly luciferase reported vector construct, then co-treated with PPAR agonist with LG100754 for 48 h, and luciferase bio-luminate activity was measured. FIG.6B–J shows bar graphs illustrating qRT- PCR data using immunoprecipitated DNA obtained from ChIP with anti-CRBN or anti-IgG (negative control) antibodies; error bars represent SD. Results are presented as mean ± SD from at least three separate experiments. NS: not statistically significant; *: p < 0.05; **: p < 0.01. FIG. 7A–F show bexarotene attenuates the binding effect of PPARȖ on the CRBN promoter area. U266 and MM1.R were transfected with CRBN / PGL3 firefly luciferase reported vector construct. Transfected cells were then co-treated with PPAR agonist (troglitazone) and / or RXR agonist Bexarotene for 48 h, and luciferase activity was measured. Results are presented as mean ± SD from at least three separate experiments. *: p < 0.05; **: p < 0.01; NS: not statistically significant. FIG. 8A–F show bar graphs illustrating qRT-PCR data using immunoprecipitated DNA obtained from ChiP with anti-CRBN or anti-IgG (negative control) antibodies, error bars represent SD. *: p < 0.05; **: p < 0.01; NS: not statistically significant. FIG. 9A–C show LG100754 changes the methylation pattern of CpG island in CRBN promoter region. FIG.9A shows the productions from the methylation-specific PCR run on 2% agarose gels. FIG. 9B shows U266 and MM1.R were treated with 8 μM LG100754, 4 μM Bexarotene, 4 μM AGN194204, and 4 μM LG101506 for 48 h. Protein lysate was subjected to Western blot with indicated antibodies. FIG. 9C shows co-IP assay between PPAR with EZH2 was conducted with the indicated antibody in U266 and MM1.R. FIG. 10A shows CpG island prediction using MethPrimer software, “a” represent the methylated regions. FIG.10B shows predicted sequences of the CRBN design using MethPrimer. Methylated nucleotides are indicated with “+”, unmethylated nucleotides with “:”, and other nucleotides with Top sequence is SEQ ID NO: 22; Bottom sequence is SEQ ID NO: 23. FIG.11A–D show co-IP assay between RXR with EZH2 was conducted with the indicated antibody in U266 and MM1.R. FIG. 12A–T show treatment with RXR agonists resulted in increased T cell activity and decreased checkpoint markers. FIG. 12A–H show Jurkat T cell was treated using multiple concentrations (1 μM, 2 μM, and 4 μM) of LG100754 in 24 h and 48 h. CD69, IFN-Ȗ, Granzyme B, and T cell checkpoints, such as TIM3, CTLA-4, TIGIT, LAG3, and PD-1. Cells were measured using flow cytometry. FIG.12I–K show primary human T cells were isolated from the bone marrow of three myeloma patients (P1, P2, P3), then treated with 2 μM LG100754 for 24 h. CD69, IFN- Ȗ, and Granzyme B were measured using flow cytometry. FIG. 12L–S show CRBN knockout reversed the effect of LG100754 on Jurkat T cell. Jurkat T cell was treated with 2 μM LG100754 for 24 h in CRBN-KO and wild-type cells. CD69, IFN-Ȗ, Granzyme B, and T cell checkpoints (such as TIM3, CTLA-4, TIGIT, LAG3, and PD-1) were measured using flow cytometry. FIG.12T shows the protein lysates acquired from CRBN knockout Jurkat T cells were analyzed by Western blotting using indicated antibodies. *: p < 0.05; **: p < 0.01; ***: p < 0.001; ****: p < 0.0001. FIG. 13A–G show LG100754 attenuates tumor growth and prolongs survival of mice injected with lenalidomide-resistant human MM cells. FIG.13A shows representative images of SCID mice with subcutaneous MM tumor. FIG.13B shows body weight was measured every 3 days and presented as means ± SD. FIG.13C shows LG100754 enhanced lenalidomide-induced attenuations of tumor growth in severe combined immunodeficient mice. FIG.13D shows overall survival was evaluated using Kaplan–Meier curve and long-rank analysis from the first day of tumor cell injection until death or occurrence of an event. FIG. 13E shows tumors treated as above were analyzed by immunoblotting with indicated antibodies. FIG.13F–G show LG100754 reduced the blood glucose level and decrease lipid accumulation. FIG.13F shows approximately 5 mg / kg LG100754 was injected intraperitoneally into mice. Blood glucose level was measured using glucose meter at indicated timepoint. FIG.13G shows approximately 5 mg / kg LG100754 was injected intraperitoneally into mice. Total blood lipid was measured using lipid quantification kit. *: p < 0.05; **: p < 0.01. FIG. 14 shows a proposed model for the effects of RXR modulator LG100754 on MM. LG100754 improves heterodimerization RXR with PPAR and regulates the CRBN transcription activity. Additionally, LG100754 induces demethylation of the CRBN promoter region. LG100754 has additional T-cell protective effects. FIG.15A–B show RXR agonists enhanced BCMA CAR T cell cytotoxicity against MM cells in vitro. FIG.15A shows AGN194204 + CAR T cells; FIG 15B shows LG100754 + CAR T cells. DETAILED DESCRIPTION Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For example, any nomenclatures used in connection with, and techniques of biochemistry, molecular biology, immunology, microbiology, genetics, cell and tissue culture, and protein and nucleic acid chemistry described herein are well known and commonly used in the art. In case of conflict, the present disclosure, including definitions, will control. Exemplary methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the embodiments and aspects described herein. As used herein, the terms “amino acid,” “nucleotide,” “polynucleotide,” “vector,” “polypeptide,” and “protein” have their common meanings as would be understood by a biochemist of ordinary skill in the art. Standard single letter nucleotides (A, C, G, T, U) and standard single letter amino acids (A, C, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, or Y) are used herein. As used herein, terms such as “include,” “including,” “contain,” “containing,” “having,” and the like mean “comprising.” The present disclosure also contemplates other embodiments “comprising,” “consisting essentially of,” and “consisting of” the embodiments or elements presented herein, whether explicitly set forth or not. As used herein, “comprising,” is an “open- ended” term that does not exclude additional, unrecited elements or method steps. As used herein, “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristics of the claimed invention. As used herein, “consisting of” excludes any element, step, or ingredient not specified in the claim. As used herein, the term “a,” “an,” “the” and similar terms used in the context of the disclosure (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context. In addition, “a,” “an,” or “the” means “one or more” unless otherwise specified. As used herein, the term “or” can be conjunctive or disjunctive. As used herein, the term “and / or” refers to both the conjunctive and disjunctive. As used herein, the term “substantially” means to a great or significant extent, but not completely. As used herein, the term “about” or “approximately” as applied to one or more values of interest, refers to a value that is similar to a stated reference value, or within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, such as the limitations of the measurement system. In one aspect, the term “about” refers to any values, including both integers and fractional components that are within a variation of up to ± 10% of the value modified by the term “about.” Alternatively, “about” can mean within 3 or more standard deviations, per the practice in the art. Alternatively, such as with respect to biological systems or processes, the term “about” can mean within an order of magnitude, in some embodiments within 5-fold, and in some embodiments within 2-fold, of a value. As used herein, the symbol means “about” or “approximately.” All ranges disclosed herein include both end points as discrete values as well as all integers and fractions specified within the range. For example, a range of 0.1–2.0 includes 0.1, 0.2, 0.3, 0.4. . . 2.0. If the end points are modified by the term “about,” the range specified is expanded by a variation of up to ±10% of any value within the range or within 3 or more standard deviations, including the end points, or as described above in the definition of “about.” As used herein, the terms “room temperature,” “RT,” or “ambient temperature” refer to the typical temperature in an indoor laboratory setting. In one aspect, the laboratory setting is climate controlled to maintain the temperature at a substantially uniform temperature or with a specific range of temperatures. In one aspect, “room temperature” refers a temperature of about 15–30 °C, including all integers and endpoints within the specified range. In another aspect, “room temperature” refers a temperature of about 15–30 °C; about 20–30 °C; about 22–30 °C; about 25–30 °C; about 27–30 °C; about 15–22 °C; about 15–25 °C; about 15–27 °C; about 20–22 °C; about 20–25 °C; about 20–27 °C; about 22–25 °C; about 22–27 °C; about 25–27 °C; about 15 °C ± 10%; about 20 °C ± 10%; about 22 °C ± 10%; about 25 °C ± 10%; about 27 °C ± 10%; ~20 °C, ~22 °C, ~25 °C, or ~27 °C, at standard atmospheric pressure. As used herein, the terms “active ingredient” or “active pharmaceutical ingredient” refer to a pharmaceutical agent, active ingredient, compound, or substance, compositions, or mixtures thereof, that provide a pharmacological, often beneficial, effect. As used herein, the terms “control,” or “reference” are used herein interchangeably. A “reference” or “control” level may be a predetermined value or range, which is employed as a baseline or benchmark against which to assess a measured result. “Control” also refers to control experiments or control cells. As used herein, the term “dose” denotes any form of an active ingredient formulation or composition, including cells, that contains an amount sufficient to initiate or produce a therapeutic effect with at least one or more administrations. “Formulation” and “composition” are used interchangeably herein. As used herein, the term “prophylaxis” refers to preventing or reducing the progression of a disorder, either to a statistically significant degree or to a degree detectable by a person of ordinary skill in the art. The disclosed compounds (i.e., therapeutic agents) may be incorporated into pharmaceutical compositions suitable for administration to a cell or a subject (such as a patient, which may be a human or non-human). The disclosed compounds may also be provided as formulations. Such pharmaceutical compositions can be administered in dosages and by techniques well known to those skilled in the medical and pharmaceutical arts taking into consideration such factors as the age, sex, weight, and condition of the particular subject, and the route of administration. As used herein, the terms “effective amount” or “therapeutically effective amount,” refer to a substantially non-toxic, but sufficient amount of an action, agent, composition, or cell(s) being administered to a subject that will prevent, treat, or ameliorate to some extent one or more of the symptoms of the disease or condition being experienced or that the subject is susceptible to contracting. The result can be the reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. An effective amount may be based on factors individual to each subject, including, but not limited to, the subject’s age, size, type or extent of disease, stage of the disease, route of administration, the type or extent of supplemental therapy used, ongoing disease process, and type of treatment desired. In some embodiments, “effective amount” may also refer to a dosage of the compounds or compositions effective for eliciting a desired effect. This term as used herein may also refer to an amount effective at bringing about a desired in vivo effect in an animal, mammal, or human. For example, a therapeutically effective amount of a compound disclosed herein may be about 0.1 mg / kg to about 1000 mg / kg, about 5 mg / kg to about 950 mg / kg, about 10 mg / kg to about 900 mg / kg, about 15 mg / kg to about 850 mg / kg, about 20 mg / kg to about 800 mg / kg, about 25 mg / kg to about 750 mg / kg, about 30 mg / kg to about 700 mg / kg, about 35 mg / kg to about 650 mg / kg, about 40 mg / kg to about 600 mg / kg, about 45 mg / kg to about 550 mg / kg, about 50 mg / kg to about 500 mg / kg, about 55 mg / kg to about 450 mg / kg, about 60 mg / kg to about 400 mg / kg, about 65 mg / kg to about 350 mg / kg, about 70 mg / kg to about 300 mg / kg, about 75 mg / kg to about 250 mg / kg, about 80 mg / kg to about 200 mg / kg, about 85 mg / kg to about 150 mg / kg, and about 90 mg / kg to about 100 mg / kg. While a compound described herein may be administered alone in the methods described herein, it may also be presented as one or more pharmaceutical compositions (e.g., formulations). A compound described herein may be formulated with one or more pharmaceutically acceptable carriers, salts, adjuvants, excipients, diluents, fillers, buffers, stabilizers, preservatives, lubricants, or other materials well known to those skilled in the art, and optionally other therapeutic or prophylactic agents. As used herein, the term “subject” refers to an animal. Typically, the subject is a mammal. A subject also refers to primates (e.g., humans, male or female; infant, adolescent, or adult), non- human primates, rats, mice, rabbits, pigs, cows, sheep, goats, horses, dogs, cats, fish, birds, and the like. In one embodiment, the subject is a primate. In one embodiment, the subject is a human. The methods and compositions disclosed herein can be used on a sample either in vitro (for example, on isolated cells or tissues) or in vivo in a subject (i.e., a living organism, such as a human patient). In some embodiments, the subject comprises a human who is undergoing treatment using a composition and / or method as prescribed herein. As used herein, a subject is “in need of treatment” if such subject would benefit biologically, medically, or in quality of life from such treatment. A subject in need of treatment does not necessarily present symptoms, particular in the case of preventative or prophylaxis treatments. As used herein, the terms “inhibit,” “inhibition,” or “inhibiting” refer to the reduction or suppression of a given biological process, condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. As used herein, “treatment” or “treating” refers to prophylaxis of, preventing, suppressing, repressing, reversing, alleviating, ameliorating, or inhibiting the progress of biological process including a disorder or disease, or completely eliminating a disease. A treatment may be either performed in an acute or chronic way. The term “treatment” also refers to reducing the severity of a disease or symptoms associated with such disease prior to affliction with the disease. “Repressing” or “ameliorating” a disease, disorder, or the symptoms thereof involves administering a cell, composition, or compound described herein to a subject after clinical appearance of such disease, disorder, or its symptoms. “Prophylaxis of” or “preventing” a disease, disorder, or the symptoms thereof involves administering a cell, composition, or compound described herein to a subject prior to onset of the disease, disorder, or the symptoms thereof. “Suppressing” a disease or disorder involves administering a cell, composition, or compound described herein to a subject after induction of the disease or disorder thereof but before its clinical appearance or symptoms thereof have manifested. “Administration” or “administering,” as used herein, refers to providing, contacting, and / or delivery of an action, agent, composition, or cell(s) by any appropriate route to achieve a desired effect. In some embodiments, the term “administering” may also refer to the placement of a compound or a composition as disclosed herein into a subject by a method or route that results in at least partial localization of the compound or composition at a desired site in the subject. Administration may include, but is not limited to, oral, sublingual, parenteral (e.g., intravenous, intracardiac, infusion (e.g., cardiac catheter infusion), subcutaneous, intracutaneous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional or intracranial injection), enteral, transdermal, topical, buccal, rectal, vaginal, nasal, ophthalmic, via inhalation, and implants. Via the parenteral route, the compound or composition may be in the form of solutions or suspensions for infusion or injection, or as lyophilized powders. Via the enteral route, the compound or composition may be in the form of capsules, gel capsules, tablets, sugar-coated tablets, syrups, suspensions, solutions, powders, granules, emulsions, or microspheres, nanospheres, lipid vesicles, or polymer vesicles allowing for controlled release. Via the topical route, the compound or composition may be in the form of an aerosol, spray, powder, lotion, cream, paste, gel, ointment, oil, suspensions, solutions, or emulsions. It will be appreciated that appropriate dosages of the active compounds and compositions comprising the active compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments described herein. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and / or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient. The amount of compound or composition and the route of administration will ultimately be at the discretion of a trained physician, although generally, the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects. The actual dosage can also depend on the determined experimental effectiveness of the specific compound or composition that is administered. For example, the dosage may be determined based on in vitro responsiveness of relevant cultured cells, or in vivo responses observed in appropriate animal models or human studies. Administration in vivo can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician. In some embodiments, a subject may be administered a single dose of the disclosed compounds or compositions. In other embodiments, a subject may be administered a plurality of doses over a period of time. For example, in various embodiments, a compound or composition as described herein may be administered to a subject once a day (SID / QD), twice a day (BID), three times a day (TID), four times a day (QID), or more, so as to administer a therapeutically effective amount to the subject, where the therapeutically effective amount is any one or more of the doses described herein. In some embodiments, a compound or composition as described herein is administered to a subject 1–3 times per day, 1–7 times per week, 1–9 times per month, 1–12 times per year, or more. In other embodiments, a compound or composition as described herein is administered for about 1–10 days, 10–20 days, 20–30 days, 30–40 days, 40–50 days, 50–60 days, 60–70 days, 70–80 days, 80–90 days, 90–100 days, 1–6 months, 6–12 months, 1– 5 years, or more. In various embodiments, a compound or composition as described herein is administered at about 0.001–0.01, 0.01–0.1, 0.1–0.5, 0.5–5, 5–10, 10–20, 20–50, 50–100, 100– 200, 200–300, 300–400, 400–500, 500–600, 600–700, 700–800, 800–900, 900–1000 mg / kg, or a combination thereof. In general, a suitable dose of the active compound may be in the range of about 100 g to about 250 mg per kilogram body weight of the subject per day. As used herein, “RXR modulator” means a compound that binds to one or more retinoid X receptors (RXRs) and modulates (i.e., increases or decreases the transcriptional activity and / or alters the biological properties of the given receptor dimer) an RXR homodimer (i.e., RXR:RXR) and / or an RXR in the context of a heterodimer. RXR refers to RXRĮ, RXRȕ, RXRȖ, and combinations thereof. In some embodiments described herein, the RXR modulator may be an RXR agonist, RXR partial agonist, and / or RXR antagonist. In some embodiments, the RXR modulator may be an agonist or partial agonist to one RXR and an antagonist to another RXR. In some embodiments, the RXR modulator may promote RXR homodimerization. In other embodiments, the RXR modulator may promote RXR heterodimerization with one or more peroxisome proliferator-activator receptors (PPARs), or one or more other receptors including, but not limited to, thyroid receptors (TRs), vitamin D receptors (VDRs), retinoic acid receptors (RARs), or liver X receptors (LXRs). PPAR refers to PPARĮ, PPARȕ, PPARȖ1, PPARȖ2, and combinations thereof. In the context of RXR heterodimer formation, the particular effect of an RXR modulator as an agonist, partial agonist, and / or antagonist will depend upon the cellular context as well as the heterodimer partner in which the modulator compounds acts. In certain non-limiting exemplary embodiments described herein, an RXR modulator may comprise LG100754 (IUPAC: (2E,4E,6Z)-3-methyl-7-(5,5,8,8-tetramethyl-3-propoxy-6,7- dihydronaphthalen-2-yl)octa-2,4,6-trienoic acid); bexarotene (IUPAC: 4-[1-(3,5,5,8,8- pentamethyl-6,7-dihydronaphthalen-2-yl)ethenyl]benzoic acid); AGN194204 (IRX4204) (IUPAC: (2E,4E)-3-methyl-5-[(1S,2S)-2-methyl-2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2- yl)cyclopropyl]penta-2,4-dienoic acid); LG101506 (IUPAC: 7-[3,5-ditert-butyl-2-(2,2- difluoroethoxy)phenyl]-3-methylocta-2,4,6-trienoic acid); AGN195393 (IUPAC: (2E,4E,6Z)-7-[2- hexoxy-3,5-di(propan-2-yl)phenyl]-3-methylocta-2,4,6-trienoic acid); LGN100849; PA451 (IUPAC: 2-[methyl-(5,5,8,8-tetramethyl-3-pentoxy-6, 7-dihydronaphthalen-2-yl)amino]pyrimidine- 5-carboxylic acid); PA452 (IUPAC: 2-[(3-hexoxy-5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)- methylamino]pyrimidine-5-carboxylic acid); UVI 3003 (IUPAC: (E)-3-[4-hydroxy-3-(5,5,8,8- tetramethyl-3-pentoxy-6,7-dihydronaphthalen-2-yl)phenyl]prop-2-enoic acid); AGN195183 (IRX5183) (IUPAC: 4-[(4-chloro-3-hydroxy-5,5,8,8-tetramethyl-6,7-dihydronaphthalene-2- carbonyl)amino]-2,6-difluorobenzoic acid); CD 3254 (IUPAC: (E)-3-[4-hydroxy-3-(3,5,5,8,8- pentamethyl-6,7-dihydronaphthalen-2-yl)phenyl]prop-2-enoic acid); LG100268 (IUPAC: 6-[1- (3,5,5,8,8-pentamethyl-6,7-dihydronaphthalen-2-yl)cyclopropyl]pyridine-3-carboxylic acid); retinoid acid (IUPAC: (2E,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethylcyclohexen-1-yl)nona- 2,4,6,8-tetraenoic acid); SR11237 (IUPAC: 4-[2-(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-yl)- 1,3-dioxolan-2-yl]benzoic acid); or combinations thereof. As used herein, “immunomodulatory agent” or “immunomodulatory drug” means a compound that modulates (i.e., stimulates or suppresses) the immune system and immune responses. In some embodiments described herein, the immunomodulatory agent may be an immunomodulatory imide drug (“IMiD”) that contains an imide group. These IMiDs may also be referred to as “cereblon modulators.” In certain non-limiting exemplary embodiments described herein, an immunomodulatory agent may comprise lenalidomide (IUPAC: 3-(7-amino-3-oxo-1H- isoindol-2-yl)piperidine-2,6-dione); thalidomide (IUPAC: 2-(2,6-dioxopiperidin-3-yl)isoindole-1,3- dione); pomalidomide (IUPAC: 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione); iberdomide (IUPAC: (3S)-3-[7-[[4-(morpholin-4-ylmethyl)phenyl]methoxy]-3-oxo-1H-isoindol-2- yl]piperidine-2,6-dione); mezigdomide (IUPAC: 4-[4-[[4-[[2-[(3S)-2,6-dioxopiperidin-3-yl]-1-oxo- 3H-isoindol-4-yl]oxymethyl]phenyl]methyl]piperazin-1-yl]-3-fluorobenzonitrile); or combinations thereof. As used herein, “blood cancer” or “hematological cancer” means a cancer that begins in blood-forming tissue, including bone marrow and certain immune cells. Examples of blood cancer include lymphoma, leukemia, and multiple myeloma (MM). Lymphoma is a cancer of lymphocytes which usually begins in a lymph node but can originate from the stomach, intestines, skin, or any other organ. The two main types of lymphoma are Hodgkin's lymphoma and non-Hodgkin's lymphoma. Multiple myeloma is cancer of the bone marrow caused by the uncontrolled growth of effector B cells (also called plasma cells) that normally make antibodies (e.g., immunoglobulins) to fight infections. In multiple myeloma, effector B cells multiply uncontrollably, generating too much of a single type of immunoglobulin or portion of immunoglobulin (light chain). The levels of other immunoglobulins drop, leaving a patient vulnerable to infection. The cancerous plasma cells collect in the bones and bone marrow and can form tumors that destroy the bone tissue, causing the bones to become fragile and prone to fracture. In some embodiments described herein, the blood cancer may be a leukemia or a lymphoma. In certain non-limiting exemplary embodiments described herein, the blood cancer is multiple myeloma (MM). As used herein, “precancerous condition” or “premalignant condition” refers to a condition associated with an increased risk of cancer, which, if left untreated, can lead to cancer. A precancerous condition can also refer to non-invasive cancer that has not yet progressed into an aggressive, invasive stage. In some embodiments described herein, a subject may have a precancerous condition comprising smoldering multiple myeloma (SMM), monoclonal gammopathy of undetermined significance (MGUS), or a combination thereof. As used herein, “CAR T cell therapy” means the therapeutic use of T cells engineered with CARs to treat cancer. “Chimeric antigen receptor” or “CAR” refers to an engineered chimeric immunoreceptor, chimeric T cell receptor, or artificial T cell receptor protein that gives T cells the new ability to target a specific cancer antigen. The engineered receptors are chimeric in that they combine both antigen-binding and T cell-activating functions into a single receptor. The structure of CAR constructs may be modulated based on the intended target antigen and the specific T cell type comprising the CAR. The standard approach to CAR T cell therapy is to harvest T cells from patients, genetically modify them, and then infuse the resulting CAR T cells into patients to attack the cancer. CAR T cells can be derived either autologously from T cells in a patient's own blood or allogeneically from those of a donor. After the modified CAR T cells are infused into a patient, they act as a “living drug” against cancer cells. Described herein are exemplary compositions and methods comprising the use of RXR modulators (e.g., LG100754) in combination with immunomodulatory agents to treat blood cancers. The disclosed approach is useful in patients who also have diabetes and / or dyslipidemia. Retinoid X receptor (RXR) heterodimerizes with the PPAR nuclear hormone receptor and regulates its downstream events. The effects of RXR agonists (e.g., LG100754, bexarotene, AGN194204, and LG101506) combined with lenalidomide’s anti-myeloma activity were investigated for T cell function, and glucose and lipid levels in vivo. Genetic overexpression and CRISPR / Cas9 knockout experiments were conducted in multiple myeloma (MM) cell lines and Jurkat T cell lines to determine the roles of CRBN in RXR-agonist mediated effects. A xenograft mouse model of MM was established to determine the combination effect of LG100754 and lenalidomide. The combination of RXR agonists and lenalidomide demonstrated synergistic activity in increasing CRBN expression and killing myeloma cells. Mechanistically, the RXR agonists reduced the binding of PPARs to the CRBN promoter, thereby relieving the repressor effect of PPARs on CRBN transcription. RXR agonists downregulated the exhaustion markers and increased the activation markers of Jurkat T cells and primary human T cells. Co- administration of LG100754 and lenalidomide showed enhanced anti-tumor activity in vivo. LG100754 retained its glucose- and lipid-lowering effects. RXR agonists demonstrate potential utility in enhancing drug sensitivity and T-cell function in the treatment of blood cancers such as myeloma. In some embodiments described herein, the pharmaceutical compositions and methods of the present disclosure can further comprise other therapeutically active compounds which are usually applied in the treatment of blood cancer. The above-described combinations include combinations of a disclosed compound not only with one other active compound but also with two or more other active compounds. Likewise, disclosed compounds can be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which disclosed compounds are useful (e.g., blood cancer). Such other drugs can be administered, by a route and in an amount commonly used therefor, contemporaneously, or sequentially with a compound of the present disclosure. When a compound of the present disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to a disclosed compound is preferred. Accordingly, the pharmaceutical compositions include those that also contain one or more other active ingredients, in addition to the compounds of the present disclosure. A compound described herein and at least one additional therapeutic agent can be administered simultaneously, in the same or in separate compositions, or sequentially. For sequential administration, a compound or composition described herein can be administered first, and the additional agent can be administered subsequently, or the order of administration can be reversed. When formulating the pharmaceutical compositions described herein, a clinician may utilize preferred dosages as warranted by the condition of the subject being treated. For example, in one embodiment, a compound or composition described herein may be administered at a dosing schedule described herein, e.g., once every one, two, three, four, five, or six weeks. Also, in general, a compound or composition described herein does not have to be administered to a subject in the same pharmaceutical composition as another compound or composition, and may, because of different physical and chemical characteristics, have to be administered by different routes. For example, in one embodiment, one or more RXR modulators and one or more immunomodulatory agents as described herein may be administered to a subject using two different pharmaceutical compositions and / or administration routes for each component. In other embodiments, the one or more RXR modulators and one or more immunomodulatory agents may be administered to a subject in the same pharmaceutical composition. The determination of the mode of administration and the advisability of administration, where possible, in the same pharmaceutical composition, is well within the knowledge of the skilled clinician. The initial administration can be made according to established protocols known in the art, and then, based on the observed effects, the dosage, modes of administration, and times of administration can be modified by the skilled clinician. One embodiment described herein is a pharmaceutical composition for treating, ameliorating, or inhibiting the progress of blood cancer in a cell or a subject, the pharmaceutical composition comprising one or more retinoid X receptor (RXR) modulators and one or more immunomodulatory agents. In one aspect, the RXR modulator comprises LG100754, bexarotene, AGN194204 (IRX4204), LG101506, AGN195393, LGN100849, PA451, PA452, UVI 3003, AGN195183 (IRX5183), CD 3254, LG100268, retinoid acid, SR11237, or combinations thereof. In another aspect, the RXR modulator is an RXR agonist. In another aspect, the RXR modulator promotes RXR homodimerization. In another aspect, the RXR modulator promotes RXR heterodimerization with one or more peroxisome proliferator-activator receptors (PPARs). In another aspect, the immunomodulatory agent comprises lenalidomide, thalidomide, pomalidomide, iberdomide, mezigdomide, or combinations thereof. In another aspect, the pharmaceutical composition comprises LG100754 or AGN194204 (IRX4204), and lenalidomide. In another aspect, the pharmaceutical composition comprises a mass ratio of the RXR modulator to the immunomodulatory agent of about 1:10 to about 10:1. In another aspect, the pharmaceutical composition further comprises one or more peroxisome proliferator-activator receptor (PPAR) antagonists. In another aspect, the pharmaceutical composition further comprises one or more pharmaceutically acceptable buffers, salts, carriers, or diluents. Another embodiment described herein is a kit comprising: a pharmaceutical composition described herein; and optionally, one or more of packaging, a label, or instructions for use. Another embodiment described herein is the use of a pharmaceutical composition of described herein as a medicament for treating, ameliorating, or inhibiting the progress of blood cancer in a cell or a subject. Another embodiment described herein is a method of treating, ameliorating, or inhibiting the progress of blood cancer in a cell or a subject, the method comprising administering to the cell of the subject a therapeutically effective amount of a pharmaceutical composition comprising one or more retinoid X receptor (RXR) modulators and one or more immunomodulatory agents. In one aspect, the RXR modulator comprises LG100754, bexarotene, AGN194204 (IRX4204), LG101506, AGN195393, LGN100849, PA451, PA452, UVI 3003, AGN195183 (IRX5183), CD 3254, LG100268, retinoid acid, SR11237, or combinations thereof. In another aspect, the immunomodulatory agent comprises lenalidomide, thalidomide, pomalidomide, iberdomide, mezigdomide, or combinations thereof. In another aspect, the pharmaceutical composition comprises LG100754 or AGN194204 (IRX4204), and lenalidomide. In another aspect, the blood cancer is a leukemia or a lymphoma. In another aspect, the blood cancer is multiple myeloma (MM). In another aspect, the subject is receiving cellular therapy with chimeric antigen receptor (CAR) T cells. In another aspect, the subject has a precancerous condition comprising smoldering multiple myeloma (SMM), monoclonal gammopathy of undetermined significance (MGUS), or a combination thereof. In another aspect, the subject has diabetes, dyslipidemia, or a combination thereof. In another aspect, the method promotes T cell activation and reduces T cell exhaustion. In another aspect, the method enhances chimeric antigen receptor (CAR) T-cell therapy. In another aspect, the method reduces blood glucose and lipid levels. In another aspect, the method increases cereblon (CRBN) expression levels. In another aspect, the therapeutically effective amount of the pharmaceutical composition is from about 2 mg / kg to about 250 mg / kg. Another embodiment described herein is a pharmaceutical composition for use in a method of treating, ameliorating, or inhibiting the progress of blood cancer in a cell or a subject, the pharmaceutical composition comprising one or more retinoid X receptor (RXR) modulators and one or more immunomodulatory agents. The disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non-human). The pharmaceutical compositions may include a “therapeutically effective amount” or a “prophylactically effective amount” of the agent. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the disclosure (e.g., a compound of formula (I)) are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount. The pharmaceutical compositions may include pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier,” as used herein, means a non-toxic, inert solid, semi- solid or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. Thus, the compounds and their physiologically acceptable salts and solvates may be formulated for administration by, for example, solid dosing, eyedrop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration. Techniques and formulations may generally be found in “Remington’s Pharmaceutical Sciences”, (Meade Publishing Co., Easton, Pa.). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage. The route by which the disclosed compounds are administered, and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis). Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions. Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. The amount of diluent(s) in a systemic or topical composition is typically about 50 to about 90%. Suitable lubricants include silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10%. Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50%. Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmelose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10%. Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0.1%. Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%. Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s) in a systemic or topical composition is typically about 0.001 to about 1%. Suitable antioxidants include butylated hydroxyanisole (“BHA”), butylated hydroxytoluene (“BHT”), and vitamin E. The amount of antioxidant(s) in a systemic or topical composition is typically about 0.1 to about 5%. Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5%. Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5%. Suitable solvents include water, isotonic saline, ethyl oleate, glycerine, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100%. Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic or topical composition is typically about 1 to about 8%. Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the C.T.F.A. Cosmetic Ingredient Handbook, 1992, pp.587-592; Remington’s Pharmaceutical Sciences, 15th Ed.1975, pp.335–337; and McCutcheon’s Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236–239. The amount of surfactant(s) in the systemic or topical composition is typically about 0.1% to about 5%. Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% of active [e.g., compound of formula (I)] and 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically include 0.1% to 10% of actives and 90% to 99.9% of a carrier including a diluent and a solvent. Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5%, and more particularly from about 25% to about 50% of actives. The oral dosage compositions include about 50% to about 95% of carriers, and more particularly, from about 50% to about 75%. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmelose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof. Capsules (including implants, time release and sustained release formulations) typically include an active compound [e.g., a compound of formula (I)], and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type. The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this invention. Solid compositions may be coated by conventional methods, typically with pH or time- dependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT coatings (available from Rohm & Haas G.M.B.H. of Darmstadt, Germany), waxes and shellac. Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non- effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners. Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants. The disclosed compounds can be topically administered. Topical compositions that can be applied locally to the skin may be in any form including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. Topical compositions include: a disclosed compound (e.g., a compound of formula (I)), and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components. The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the medicament. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nded., (1976). A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols. The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional. Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95%. Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically about 0% to about 95%. Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95%. Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95%. The amount of thickener(s) in a topical composition is typically about 0% to about 95%. Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically- modified Montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95%. The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1%. Suitable pH adjusting additives include HCl or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition. It will be apparent to one of ordinary skill in the relevant art that suitable modifications and adaptations to the compositions, formulations, methods, processes, and applications described herein can be made without departing from the scope of any embodiments or aspects thereof. The compositions and methods provided are exemplary and are not intended to limit the scope of any of the specified embodiments. All of the various embodiments, aspects, and options disclosed herein can be combined in any variations or iterations. The scope of the compositions, formulations, methods, and processes described herein include all actual or potential combinations of embodiments, aspects, options, examples, and preferences herein described. The exemplary compositions and formulations described herein may omit any component, substitute any component disclosed herein, or include any component disclosed elsewhere herein. The ratios of the mass of any component of any of the compositions or formulations disclosed herein to the mass of any other component in the formulation or to the total mass of the other components in the formulation are hereby disclosed as if they were expressly disclosed. Should the meaning of any terms in any of the patents or publications incorporated by reference conflict with the meaning of the terms used in this disclosure, the meanings of the terms or phrases in this disclosure are controlling. Furthermore, the foregoing discussion discloses and describes merely exemplary embodiments. All patents and publications cited herein are incorporated by reference herein for the specific teachings thereof. Various embodiments and aspects of the inventions described herein are summarized by the following clauses: Clause 1. A pharmaceutical composition for treating, ameliorating, or inhibiting the progress of blood cancer in a cell or a subject, the pharmaceutical composition comprising one or more retinoid X receptor (RXR) modulators and one or more immunomodulatory agents. Clause 2. The pharmaceutical composition of clause 1, wherein the RXR modulator comprises LG100754, bexarotene, AGN194204 (IRX4204), LG101506, AGN195393, LGN100849, PA451, PA452, UVI 3003, AGN195183 (IRX5183), CD 3254, LG100268, retinoid acid, SR11237, or combinations thereof. Clause 3. The pharmaceutical composition of clause 1 or 2, wherein the RXR modulator is an RXR agonist. Clause 4. The pharmaceutical composition of any one of clauses 1–3, wherein the RXR modulator promotes RXR homodimerization. Clause 5. The pharmaceutical composition of any one of clauses 1–4, wherein the RXR modulator promotes RXR heterodimerization with one or more peroxisome proliferator- activator receptors (PPARs). Clause 6. The pharmaceutical composition of any one of clauses 1–5, wherein the immunomodulatory agent comprises lenalidomide, thalidomide, pomalidomide, iberdomide, mezigdomide, or combinations thereof. Clause 7. The pharmaceutical composition of any one of clauses 1–6, wherein the pharmaceutical composition comprises LG100754 or AGN194204 (IRX4204), and lenalidomide. Clause 8. The pharmaceutical composition of any one of clauses 1–7, wherein the pharmaceutical composition comprises a mass ratio of the RXR modulator to the immunomodulatory agent of about 1:10 to about 10:1. Clause 9. The pharmaceutical composition of any one of clauses 1–8, further comprising one or more peroxisome proliferator-activator receptor (PPAR) antagonists. Clause 10. The pharmaceutical composition of any one of clauses 1–9, further comprising one or more pharmaceutically acceptable buffers, salts, carriers, or diluents. Clause 11. A kit comprising: the pharmaceutical composition of any one of clauses 1–10; and optionally, one or more of packaging, a label, or instructions for use. Clause 12. Use of the pharmaceutical composition of any one of clauses 1–10 as a medicament for treating, ameliorating, or inhibiting the progress of blood cancer in a cell or a subject. Clause 13. A method of treating, ameliorating, or inhibiting the progress of blood cancer in a cell or a subject, the method comprising administering to the cell of the subject a therapeutically effective amount of a pharmaceutical composition comprising one or more retinoid X receptor (RXR) modulators and one or more immunomodulatory agents. Clause 14. The method of any of clause 13, wherein the RXR modulator comprises LG100754, bexarotene, AGN194204 (IRX4204), LG101506, AGN195393, LGN100849, PA451, PA452, UVI 3003, AGN195183 (IRX5183), CD 3254, LG100268, retinoid acid, SR11237, or combinations thereof. Clause 15. The method of clause 13 or 14, wherein the immunomodulatory agent comprises lenalidomide, thalidomide, pomalidomide, iberdomide, mezigdomide, or combinations thereof. Clause 16. The method of any one of clauses 13–15, wherein the pharmaceutical composition comprises LG100754 or AGN194204 (IRX4204), and lenalidomide. Clause 17. The method of any one of clauses 13–16, wherein the blood cancer is a leukemia or a lymphoma. Clause 18. The method of any one of clauses 13–17, wherein the blood cancer is multiple myeloma (MM). Clause 19. The method of any one of clauses 13–18, wherein the subject is receiving cellular therapy with chimeric antigen receptor (CAR) T cells. Clause 20. The method of any one of clauses 13–19, wherein the subject has a precancerous condition comprising smoldering multiple myeloma (SMM), monoclonal gammopathy of undetermined significance (MGUS), or a combination thereof. Clause 21. The method of any one of clauses 13–20, wherein the subject has diabetes, dyslipidemia, or a combination thereof. Clause 22. The method of any one of clauses 13–21, wherein the method promotes T cell activation and reduces T cell exhaustion. Clause 23. The method of any one of clauses 13–22, wherein the method enhances chimeric antigen receptor (CAR) T-cell therapy. Clause 24. The method of any one of clauses 13–23, wherein the method reduces blood glucose and lipid levels. Clause 25. The method of any one of clauses 13–24, wherein the method increases cereblon (CRBN) expression levels. Clause 26. The method of any one of clauses 13–25, wherein the therapeutically effective amount of the pharmaceutical composition is from about 2 mg / kg to about 250 mg / kg. Clause 27. A pharmaceutical composition for use in a method of treating, ameliorating, or inhibiting the progress of blood cancer in a cell or a subject, the pharmaceutical composition comprising one or more retinoid X receptor (RXR) modulators and one or more immunomodulatory agents. EXAMPLES Example 1 Cell Lines MM1.R, RPMI8226, NCIH929, and U266 MM cell lines were used in this study. These cell lines were purchased from ATCC and authenticated periodically using short tandem repeat profiling. All cell lines were cultured at 37 °C under 5% CO2in Roswell Park Memorial Institute (RPMI) 1640 medium supplemented with 2 mM GlutaMAX and 10% fetal calf serum (Mediatech). Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) / CRISPR-Associated Protein 9 (Cas9) Genomic Editing CRBN-knockout using CRISPR / Cas9 technique was performed. Briefly, single guide RNAs (gRNAs) targeting the human CRBN gene, 5ƍ-CAGGACGCTGCGCACAACAT-3ƍ (SEQ ID NO: 1) and 5ƍ-CGCACCATACTGACTTCTTG-3ƍ (SEQ ID NO: 2), were obtained from Integrated DNA Technologies. The gRNA fragment was amplified via polymerase chain reaction (PCR) prior to use for transfection, as described previously. Cells were transfected with a ribonucleoprotein (RNP) complex using RNAiMAX kit (Cat# 13778150; Thermo Fisher Scientific). Two pairs of primers were used to verify the successful knockout of CRBN; pair 1, forward: 5ƍ- TCCTTTGCGGGTAAACAGAC-3ƍ (SEQ ID NO: 3) and reverse: 5ƍ-GGTTGGAATCCTGACTCTGC-3ƍ; (SEQ ID NO: 4) pair 2, forward: 5ƍ-TGGCACAATCTCAGCTCACT-3ƍ (SEQ ID NO: 5) and reverse: 5ƍ- ACCACTGCAATTACCCATGA-3ƍ (SEQ ID NO: 6). T7E1 digestion followed by electrophoresis at 100 V for 1.5–2 h in 3% (w / v) agarose gels was used to detect and visualize the CRBN knockout results. CRBN Firefly Luciferase Reporter System To generate a firefly luciferase reporter plasmid driven by the CRBN promoter, human CRBN promoter was subcloned into a pGL3-basic vector containing the firefly luciferase gene (Promega, GenBank accession number U47295). CRBN promoter sequences, 2000 bp upstream of CRBN start site, were obtained from the NCBI database. Potential PPAR binding sites in the CRBN promoter region were identified using the JASPAR database (jaspar.genereg.net). The PPARĮ binding site was identified as: 5ƍ-TTGAGCTCTTCCCTACTC-3ƍ (SEQ ID NO: 7), PPARȕ / į binding site: 5ƍ-GCGATCTTCAACCTCA-3ƍ (SEQ ID NO: 8), and PPARȖ binding site: 5ƍ- TCCCCTGTCACCTTC-3ƍ (SEQ ID NO: 9). The CRBN promoter regions containing various PPAR binding site were PCR-amplified with primers as follows: for CRBN promoter with PPARĮ binding site, forward: 5ƍ-AGATAAGGGGCTGAGCTTCC-3ƍ (SEQ ID NO: 10) and reverse: 5ƍ- ATGTTTGACTCATTTGGTTGAAGA-3ƍ (SEQ ID NO: 11); for CRBN promoter with PPARȕ / į binding site, forward: 5ƍ-AACTATAAATAAGCCAAGGTTTTTCTC-3ƍ (SEQ ID NO: 12) and reverse: 5ƍ- TCTTTTGGCCTCATTATTCAAA-3ƍ (SEQ ID NO: 13) and for CRBN promoter with a PPARȖ binding site, forward: 5ƍ-CCAACTTAAAGGCGAACCAC-3ƍ (SEQ ID NO: 14) and reverse: 5ƍ- GGAACTCTTGATGTAGCTTTAATGG-3ƍ (SEQ ID NO: 15). The pGL3-basic firefly luciferase reporter vector was used as the negative control. Methylation Specific PCR (MSP) The genomic DNA from cultured cells was extracted and subjected to MS-PCR analysis as described. Briefly, U266 and MM1.R cells were treated with DMSO control, 8 ^M LG100754 ((2E,4E,6Z)-3-methyl-7-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-propoxy-2-naphthalenyl)-2,4,6- octatrienoic acid), 4 ^M Bexarotere (4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2- naphthalenyl)vinyl)benzoic acid), 4 ^M AGN194204 ((2E,4E)-3-methyl-5-[2-methyl-2-(5,5,8,8- tetramethyl-5,6,7,8-tetrahydro-2-naphthalenyl)cyclopropyl]-2,4-pentadienoic acid) or 4 ^M LG101506 ((2E,4E,6Z)-7-(3,5-di-tert-butyl-2-(2,2-difluoroethoxy)phenyl)-3-methylocta-2,4,6- trienoic acid) for 48 h and cells were harvested and DNA isolated using the Tissue / Cell genomic DNA isolation kit with the Wizard DNA clean-up kit (Promega, USA). DNA was then treated with bisulfite according to the manufacturer’s instructions (EZ DNA Methylation Kit, Zymo Research, Irvine, California, USA), and amplified by PCR with two pairs of specific primers that recognize the methylated (M) and the unmethylated (U) CpG sites in CRBN promoter. Primers were designed using Meth Primer program (www.urogene.org / methprimer). The primer pair for the methylated form (129bp) was: Forward: 5-GAATAAAGTGAGGGTTTTGTAGC-3ƍ (SEQ ID NO: 16); Reverse: 5ƍ-ACCTAAAAATAATAACCTAAACGAA-3ƍ (SEQ ID NO: 17). The primer pair for the unmethylated form (131bp) was: Forward: 5ƍ-TGGAATAAAGTGAGGGTTTTGTAGT-3ƍ (SEQ ID NO: 18); Reverse: 5ƍ-ACCTAAAAATAATAACCTAAACAAA-3ƍ (SEQ ID NO: 19). The PCR amplification conditions were: 95°C for 5 min; 40 cycles of 95 °C for 45 sec, 60 °C for 45 sec, 72 °C for 45 sec, and finally 10 mins at 72 °C. The PCR products were visualized in Gene Genius (Syngene, UK) by ethidium bromide staining in 2% agarose gels. Lentiviral Gene Transduction For lentiviral production, HEK293 cells were transfected with triple plasmids: lentiviral vector plasmid, packing plasmids PMD2.G, and psPAX2 (Addgene, plasmid#12259 and 12260). Forty-eight hours later the cell supernatant was collected and concentrated using Lenti-X Concentrator (Takara Bio) per manufacturer’s instruction. For lentiviral gene transduction, cells were seeded on a six well plate (Corning) and transduced with lentivirus with polybrene (8 ^g / mL). Cells were treated with puromycin (Sigma) for 7 days to select transduced cells. Co-immunoprecipitation Co-immunoprecipitation (co-IP) was performed according to the manufacturer’s instructions (Pierce Co-Immunoprecipitation Kit, Thermo Scientific, #26149). Antibodies against PPARĮ (Abcam, #ab227074), PPARȖ (Proteintech, 16643-I-AP), and PPARį (#74076, Cell signaling Technology) were used. Reagents and Antibodies PPARĮ antibody was obtained from Santa Cruz Biotechnology (Cat# SC-398394). PPARȕ / į (NBP2-22468) and PPARȖ (NBP2-22106) antibodies were obtained from Novus Biologicals, LLC (Littleton, CO). IKZF1 antibody was purchased from Santa Cruz Biotechnology, Inc. (Dallas, TX, USA). IKZF3 antibody was purchased from Novus. CRBN antibody was obtained from Sigma-Aldrich (St. Louis, MO). Caspase 3 antibody, EZH2 antibody (#4905S) and H3K27me3 antibody (#9733T) were purchased from Cell Signaling Technology. Thiazolyl Blue Tetrazolium Bromide (MTT) Cell Proliferation Assay MM cells were plated in triplicates in a 96-well plate (5 × 104 cells / well at a final volume of 100 ^L) and treated with various concentrations of lenalidomide and / or RXR agonists for indicated durations. To measure cell proliferation, 20 ^L of the combined MTS / PMS solution (5 mg / mL MTT) was added to each well and incubated for 3–4 h at 37 °C in a 5% CO2 incubator. Absorbance at 490 nm was measured using an enzyme-linked immunosorbent assay plate reader (VERSAmax, Molecular Devices, San Jose, CA). Western Blot Analysis MM cells were harvested, washed with phosphate-buffered saline (PBS) and resuspended in a lysis buffer containing 50 mM Tris-HCl (pH 7.4), 150 mM NaCl, 1 mM EDTA, 1% Triton X- 100, 1% sodium deoxycholate, and 0.1% sodium dodecyl sulfate (SDS). Cells were lysed via brief sonication and then spined down to remove the cell debris. Total protein in the cell lysates was quantified using a Dc protein estimation kit (Bio-Rad) with bovine serum albumin (BSA) as a standard. Cell lysates were loaded and run on SDS-polyacrylamide gel electrophoresis. The proteins were transferred onto a nitrocellulose membrane. The membrane was blocked with 5% BSA in Tris-buffered saline containing 0.05% Tween 20 (TBST) and incubated with primary antibodies against PPARĮ (ab227074; Abcam), PPARȕ / į (A5656; ABclonal), PPARȖ (16643-1- AP; Thermo Fisher), IKZF1 (NBP1-98314; Novus Biologicals), and IKZF3 (NBP2-46048; Novus Biologicals) in TBST containing 5% BSA overnight at 4 °C with gentle rocking. The membrane was then probed with an HRP-conjugated secondary antibody and developed using a Pierce ECL substrate. Flow Cytometry for the Measurement of T Cell Activation and Exhaustion Jurkat T cells and primary patient T cells were characterized for markers of activation and exhaustion using flow cytometry. Cells were washed with PBS and centrifuged at 500 × g for 5 min. Supernatant was discarded and cells were stained with 100 ^l FACs buffer contained antibody for 15 mins at 4 °C. Cells were washed with 500 ^L PBS and Intracellular staining for the IFN-Ȗ and Granzyme was performed using eBioscience Foxp3 Transcription Factor Staining Buffer Set (Invitrogen, cat# 00-5523-00) according to the manufacturer’s instructions. Briefly, 500 ^L of fixation buffer was used to incubate the samples overnight at 4 °C and 1 mL of permeabilization buffer was added to the samples. Samples were washed, resuspended in 100 ^l permeabilization buffer contained 2 ^L antibody, and incubated at 4 °C for 30 min. Samples were washed again, fixed with 0.5% paraformaldehyde (PFA, Gibco) and ready for analysis by the flow cytometry. The following antibodies were used for cell surface or intracellular stains: Granzyme-B (Cat#561998, BD Biosciences, San Jose, CA); Anti-IFN-Ȗ APC (Biolegend, San Diego, CA, Cat#502512); CD69 PE-Cy7(BD Biosciences, San Jose, CA, Cat#310911); CD223 (LAG-3) (Biolegend, San Diego, CA, Cat#369211); CD279 (PD-1) (Biolegend, San Diego, CA, Cat#329905); CD366 (Tim3) (Biolegend, San Diego, CA, Cat#345013); CD152 (CTLA-4) (Biolegend, San Diego, CA, Cat#369633); TIGIT (Biolegend, San Diego, CA. Cat#372717); CD3 (Cat#561806, BD Biosciences, San Jose, CA). Chromatin Immunoprecipitation (ChIP) Assay ChIP assays were performed by collecting MM cells, cross-linking them with 1% formaldehyde, and centrifuging to pellet the cells. The resulting pellets were sonicated, and the chromatin solution was precleared with 30 ^L of CHiP-Grade protein G magnetic beads (#9006; Cell Signaling Technology, Danvers, MA). The soluble fraction was collected, and the chromatin beads were incubated with positive control histone H3 rabbit (#4620; Cell Signaling), normal rabbit IgG (#2729; Cell Signaling), anti-PPARĮ (ab227074; Abcam), anti-PPARȖ (16643-1-AP; Proteintech Rosemont, IL), anti-FLAG M2 (F1804; Sigma; for PPARȕ / į with a FLAG tag) antibodies at 4 °C overnight. ChIP-enriched DNA was analyzed by quantitative PCR using the CRBN promoter primers as follows: forward: 5ƍ-TCCCCTGTCACCTTCAAAAC-3ƍ (SEQ ID NO: 20) and reverse: 5ƍ-TGCCTTGTGAGTCTGACACC-3ƍ (SEQ ID NO: 21). The enrichment of CRBN promoter regions was assessed relative to the input DNA, followed by normalization to the respective control IgG values. Percent input = 4% × 2(C[T] 4% input sample-C[T] IP sample). Confocal Microscopy Examination of CRBN in MM Cell Lines Confocal examination of CRBN was performed as described. Glass slides were first coated with 10 ^g / mL of fibronectin (catalog 341635; Sigma-Aldrich, St. Louis, MO). MM cells were then added and remained onto the slides for 1 h at 37 °C. The cells were subsequently fixed with 4% formaldehyde in PBS for 15 min at room temperature, blocked with cell culture medium containing 10% fetal bovine serum and incubated overnight at 4 °C with the CRBN antibody (PA598707; Thermo Fisher Scientific). The slides were then washed thrice with PBS,stained with Alexa Fluor 594 goat anti-rabbit antibody (R37117; Thermo Fisher Scientific) for 1 h, labeled with 4ƍ,6-diamidino-2-phenylindole dihydrochloride (DAPI; 4083; Cell Signaling) for 5 min, and mounted with the antifade mounting medium (Vector, H-1000). Images were acquired using a confocal laser-scanning microscope (Leica SP5 inverted confocal microscope). Sequential scanning of the different channels was performed at a resolution of 512 × 512 pixels. Brightness was optimized and applied to the entire image. In vivo Glucose and Lipid Measurements C57Bl / 6 mice were given LG100754 (5 mg / kg intraperitoneally). Blood samples were collected at the time-points indicated. Blood glucose level was measured by AimStrip Plus Blood Glucose Testing System. Total lipids were determined with quantitative enzymatic assays using the Lipid quantification kit STA-613(Cell Biolabs, INC, San Diego, CA, Cat#101420224). The procedures were performed in accordance with the protocols provided by the manufacturers. Myeloma Xenograft Mouse Model Immunodeficient (SCID) mice (male, 6-8 weeks old; OCI) were injected subcutaneously with 1 × 107MM1.R at the lower right flank. When tumors were palpable (approximately 21 days after injection), mice were randomly assigned into 4 groups (n = 7 in each group), receiving intraperitoneal injection with 10 mg / kg / day lenalidomide or combination with LG1007545 mg / kg three times a week. Tumors were measured with external calipers every 3 days, and tumor volume (in mm3) was calculated using the following standard formula: V = 0.5a × b2, where “a” and “b” are the long and short diameter of the tumor. Animal survival was monitored from the first day of tumor injection until death. Mice were sacrificed when the mice reached humane endpoints, such as their tumors reaching 1.5 cm in diameter or in the event of paralysis or major compromise in their quality of life, to prevent unexpected suffering. All studies involving vertebrate animal models were conducted under approved Duke University Institutional Animal Care and Use protocols. Statistical Analysis Statistical analyses were conducted in GraphPad Prism v9 (Dotmatics). Values represent the mean ± standard error of the mean, unless stated otherwise. Graphical displays were used to determine appropriate transformations, and in some cases, data were analyzed on a log scale to adhere to the assumptions of parametric tests. Comparisons of the mean expression across groups were performed using two-sample t-tests. Based on the distribution within groups, a t-test with equal or unequal variances was used. For all comparisons, an alpha level of 0.05 was used to denote significance. Example 2 Synergistic anti-myeloma Activity of Lenalidomide and RXR Agonists In Vitro The anti-myeloma activity of RXR agonists was examined alone and in combination with lenalidomide. MM cell viability and apoptosis were first examined. Four RXR agonists (LG100754, Bexarotene, AGN194204, and LG101506) were tested on U266 and MM1.R cell lines. The dose response curves were first determined individually and obtained the IC50 value for each of them (FIG. 2). A range of drug combination concentrations was then selected to evaluate the inhibition of growth with the drug combination of RXR agonist and lenalidomide (FIG. 1). The Compusyn software was used to predict the additive and synergistic effects arising from combinations of multiple drugs with independent mechanisms of action using the combination index theorem. RXR agonists (LG100754, Bexarotene, AGN194204, or LG101506) demonstrated single agent anti-myeloma activity with IC50 ranging from 4.5 ^M to 20 ^M (FIG. 2). After co-treatment with lenalidomide and RXR agonist, the survival of MM cells was significantly reduced in comparison with cells that were treated with lenalidomide or RXR agonist alone. Almost all combination index values were <1. In certain combinations, the combination index (CI) value is below 0.5, suggesting that the growth inhibition effect of lenalidomide and RXR agonists in particular cancer cells is synergistic (FIG. 1A–D and FIG. 3A–D). Based on the multiple dose combination strategies, LG100754 (8 ^M) with 10 ^M lenalidomide and Bexarotene, AGN194204, and LG101506 (4 ^M) with 8 ^M lenalidomide caused about a 50% decrease in cell viability. Moreover, MM cells exhibited a marked increase in apoptosis when the RXR agonists were combined with lenalidomide (FIG. 1E–T). In summary, cytotoxicity increased significantly when treated with combined lenalidomide and RXR agonists compared to lenalidomide or RXR agonists alone Subsection. Example 3 Increased CRBN Expression Correlates with IMiD and RXR Agonist Synergism CRBN is a direct target of immunomodulatory agents and plays an important role in IMiD mediated anti-myeloma activity. Thus, the effect of RXR agonists on the expression of CRBN in MM was determined. U266 and MM1.R cells were treated with increasing concentrations of RXR agonists and examined their CRBN expression after 48 hours. U266 and MM1.R showed appreciable dose response. There was a high induction of CRBN at 8 ^M of LG100754 and at 4 ^M of Bexarotene, AGN194204, and LG101506 (FIG. 4A–H). Consistent with the finding, immunofluorescence analysis showed that the expression of CRBN was significantly increased after treatment with RXR agonist at indicated concentrations (FIG.4I–J). IKZF1 and IKZF3 are transcription factors important in MM cell survival. CRBN induces ubiquitination and degradation of IKZF1 and IKZF3. RXR agonists induce CRBN upregulation and reduce IKZF1 and IKZF3 expression (FIG.4A–H). To further study the synergic effect of the combination of lenalidomide and RXR agonists, U266 and MM1.R cell lines were co-treated with lenalidomide and RXR agonists at indicated concentrations. CRBN expression was then measured (FIG.4K–R). In the presence of the RXR agonists, lenalidomide treatment further increased CRBN expression and dramatically promoted cleavage of caspase 3 and caspase 9, indicative of the induction of apoptosis (FIG.4K–R). These data showed that RXR agonists can increase CRBN expression alone and can also act synergistically with lenalidomide to further increase CRBN expression in MM. To confirm whether RXR agonists synergistically enhance the anti-myeloma activity of lenalidomide through altering CRBN expression, CRBN was genetically overexpressed in MM cell lines. The cells were then treated with lenalidomide in the presence or absence of LG100754. Compared with MM cells transduced with empty vector control, MM cells overexpressing CRBN showed increased sensitivity to lenalidomide. Additionally, CRBN overexpression enhanced lenalidomide’s anti-myeloma activity in the presence of LG100754 (FIG.4S–T). To further validate the role of CRBN in lenalidomide and RXR agonist mediated anti- myeloma effects, CRISPR / Cas9 technology was used to knock out the expression of CRBN in U266 and MM1.R cell lines. The deletion of CRBN was confirmed by Western blot (FIG.5A–E). Knockout of CRBN rendered MM cells resistant to treatment with lenalidomide, LG100754, and the combination of lenalidomide and LG100754. Transduction of CRBN overexpressing plasmid partially restored the apoptotic induction of lenalidomide and LG100754 (FIG.4S–T and FIG.5A– E). These data demonstrate the important role of CRBN in potentiating the synergistic anti- myeloma activity of LG100754 and lenalidomide. Example 4 RXR Agonists Attenuate the Binding Effect of PPARs on the CRBN Promoter Region in MM Cell Lines It was desirable to determine the molecular mechanism through which RXR agonists enhanced CRBN expression. A previous study demonstrated that PPARs negatively regulated CRBN transcription activity through binding to CRBN promoter region and repressing the CRBN transcription. PPARs heterodimerized with RXRs, translocated to nucleus, and bound to PPREs to regulate gene expression. It was thus hypothesized that RXR agonists could affect PPAR binding to the CRBN promoter region and reverse PPAR’s repressive effects on CRBN transcription. To test this hypothesis, the CRBN promoter was subcloned into the PGL3 firefly luciferase reporter vector and transfected the construct into U266 and MM1.R cells. The transduced MM cells were then treated with RXR agonists (LG100754 or Bexarotene) with or without PPAR agonists (PPARĮ agonist fenofibrate, PPARȖ agonist troglitazone, or PPARȕ / į agonist GW501516). As shown in FIG.6A–G, administration of LG100754 increased the PPARĮ and PPARȖ promoter activities but not the PPARȕ / į promoter activity. Furthermore, LG100754 reversed the inhibitory effects of fenofibrate and troglitazone on the activities of the CRBN promoter but had no effect on GW501516. These findings are consistent with the function of LG100754, which stabilizes the RXR: PPARĮ and RXR: PPARȖ heterodimers but not PPARȕ / į. For bexarotene, a similar phenotype was only observed for the PPARȖ promoter and for PPARȖ agonist troglitazone. (FIG.6A–G and FIG.7A–F). It was next determined whether RXR agonists affected the binding of PPARs to the CRBN promoter. Chromatin immunoprecipitation (CHiP) assay with qPCR was performed for LG100754-, bexarotene-, AGN194204-, and LG101506-treated MM cells. The binding of PPARs to the CRBN promoter was subsequently measured. LG100754 reduced the binding of PPARĮ and PPARȖ but not the binding of PPARȕ / į to the CRBN promoter. As expected, bexarotene only affected the binding of PPARȖ but not those of PPARĮ or PPARȕ / į to the CRBN promoter (FIG. 6H–J and FIG.8A–F). Example 5 RXR Agonists Facilitated DNA Demethylation in the CpG Islands Within the CRBN Promoter DNA methylation is one of the epigenetic events that plays important roles in transcriptional repression, genomic imprinting, and genomic stability. A previous study showed that PPAR agonists induced DNA methylation in the CpG islands of the CRBN promoter region. Here, to further analyze the mechanism underlying the enhanced effects of RXR agonists on CRBN transcription, methylation specific PCR (MSP) was used to evaluate the methylation or demethylation status of the CpG island in the CRBN promoter region. U266 and MM1.R cells were treated with LG100754, bexarotene, AGN194204, or LG101506. U266 and MM1.R cells are typically resistant to lenalidomide and had a lower level of CRBN expression (FIG. 4). Moreover, they are completely methylated in the CpG islands of the CRBN promoter region (FIG. 9A–B). Treatment with LG100754 and bexarotene resulted in significant demethylation of the CpG islands of the CRBN promoter region. AGN194204 and LG101506 are less effective in inducing DNA demethylation of the CpG islands (FIG.9A and FIG.10). Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase (HMT), induces trimethylation of histone H3 Lysine 27 (H3K27me3). It is important in the DNA methylation process. The effects of RXR agonists on EZH2 and H3k27me3 were determined. U266 and MM1.R were treated with 8 ^M of LG100754, 4 ^M of bexarotene, 4 ^M of AGN194204, or 4 ^M of LG101506 for 48 hours. The total protein was used for Western blotting. It was found that only LG100754 and bexarotene resulted in a decrease in the levels of EZH2 and H3K27me3 (FIG. 9B). These results are consistent with the MSP data. Co-IP, followed by Western blotting, was then performed to determine how the PPAR: RXR heterodimer interacted with EZH2. It was found that PPARĮ, PPARȕ / į, and PPARȖ form complexes with EZH2. Moreover, they interacted with EZH2 directly (FIG. 9C). On the other hand, direct protein interaction between RXR with EZH2 was not detected (FIG.11). These data suggest that RXR agonists affected the CRBN expression likely indirectly. The effect was probably through modulating the interaction and the binding between PPARs and the CRBN promoter, including the DNA methylation status. Example 6 LG100754 Improved Markers Of T-cell Activity and Suppressed T-cell Exhaustion Markers The tumor microenvironment (TME) is a key mediator of tumor development and progression. It also plays an important role in mediating the clinical response to therapy. T-cell activation and expansion in the TME are important for antitumor immunity. However, anergy, exhaustion, and active suppression can occur in T cells of MM patients. Because CRBN was important in T cell co-stimulation, the effects of RXR agonists on T cell activation and exhaustion were investigated. Jurkat T cells were treated with LG100754 at 1 ^M, 2 ^M, and 4 ^M for 24 and 48 hours. CD69, IFN-Ȗ, granzyme B, and T cell check points (TIM3, CTLA-4, TIGIT, LAG3, and PD-1) were assessed. Cells were then measured using flow cytometry (FIG.12A–H). These data suggest that LG100754 resulted in significant enhancement of the T cell activation markers (CD69, IFN-Ȗ, and granzyme B) and attenuated T cell exhaustion markers, such as TIM3, CTLA- 4, TIGIT, LAG3, and PD-1. To evaluate whether LG100754 had enhancing effects on primary T cells, primary human T cells were isolated from the bone marrow aspirate of patients with MM. The primary human T cells were then treated with 2 ^M of LG100754 for 24 hours (FIG. 12I–K). This was used to evaluate the effect of LG100754 on T cell’s function. Consistent with the data on Jurkat T cells, LG100754 resulted in an increase in T cell activation markers. The percentage of cells expressing CD69, IFN-Ȗ, and granzyme B was significantly higher with LG100754 treatment in all three primary T cell samples. To further verify that the effect of LG100754 was mediated by CRBN, a CRISPR / Cas9 assay to knockout CRBN in Jurkat T cells was performed (FIG.12D–T). CRBN knockout reversed the percentage expressing the above checkpoint marker in the presence of LG100754. These findings show that LG100754 induces T cell response by enhancing the efficiency of T cell activation and by protecting T cells from exhaustion in a CRBN-dependent mechanism. Example 7 LG100754 Enhanced Lenalidomide’s Anti-Myeloma Activity in a Preclinical Model of MM To examine the therapeutic implications of the findings in vivo, the efficacy of combined RXR agonist and lenalidomide was investigated in a preclinical model of lenalidomide-resistant human MM. A mouse xenograft model was established with MM1.R in SCID mice by implanting MM1.R cells subcutaneously in the flank of the mice. Once tumor was established and palpable, the following were administered to the mice: PBS control, LG100754 (5 mg / kg, IP, three times a week), lenalidomide (10 mg / kg / day), or a combination of both (FIG.13A). Body weight was then measured. Mice were sacrificed if humane endpoints were reached or at the end of the experiments when tumors were harvested. Notably, the combination of LG100754 and lenalidomide resulted in a more effective tumor control as compared with LG100754 treatment alone, lenalidomide alone, or vehicle-alone (FIG.13A–C). Importantly, the combination treatment resulted in a significant prolongation of survival of the mice without any appreciable toxicity when their total body weight was used as a proxy (FIG.13B, D). In addition, the level of CRBN in mouse tumors was increased in the LG100754 and lenalidomide combination-treated mice compared with those treated with lenalidomide alone, LG100754 alone, or PBS. Additionally, the expressions of cleaved caspase 3 and 9 were increased, while those of IKZF1 and IKZF3 were reduced in the LG100754 and lenalidomide combination group (FIG. 13E). These data demonstrated a synergistic anti-myeloma effect when combining RXR agonist with lenalidomide. A previous study showed that LG100754 led to a reduction in glucose levels and improvement in insulin resistance in vivo. To further characterize the effects of LG100754 on metabolic regulation, serum lipid analysis and fasting blood glucose testing was preformed at multiple timepoints after LG100754 treatment in animal models. C57Bl / 6 mice were given 5 mg / kg LG100754 intraperitoneally. After which, their blood glucose and lipid levels were measured at various time-points. These data suggest that LG100754 treatment resulted in the effective reduction of blood glucose and lipid levels. The effects were observed starting at around an hour after LG100754 treatment. The peak was reached at 6 hours, while the effect lasted for 24 hours (FIG.13F). CRBN is important in immunomodulatory agent-mediated anti-myeloma activity and there are data suggesting that the level of CRBN correlates with drug sensitivity or resistance to IMiD treatment. The CRBN expression is potentially a useful marker to gauge the efficacy of IMiDs. Previous research showed that PPAR agonists (fenofibrate, GW501516, and troglitazone) reduced the anti-myeloma effect of lenalidomide by downregulating the transcription activity of CRBN through DNA methylation and protein degradation. It was found that PPAR agonists affected the CRBN promoter CpG island methylation pattern and caused hypermethylation in the CRBN promoter region. Moreover, CRBN was rapidly degraded upon exposure to PPAR agonists. Although several mechanisms for this drug-drug interaction have been suggested, none has been proven. Notably, the PPAR pathway reduces blood glucose and lipid levels. However, it is unknown whether these metabolic effects can be maintained while enhancing their CRBN expression. In this study, the action of RXR heterodimer agonists (LG100754, bexarotene, AGN194204, and LG101506) was explored. It was found that they enhanced MM sensitivity to lenalidomide in vitro and in vivo in a xenograft myeloma mouse model. Data from the CHiP and firefly / Renilla reporter analysis demonstrated that RXR agonists resulted in the attenuation of the binding effect of PPAR on the CRBN promoter region. This provides the first direct evidence that RXR agonists can increase CRBN expression. Moreover, the MSP analysis demonstrated that LG100754 and bexarotene affected the CRBN promoter CpG island methylation patterns, thereby favoring demethylation. Furthermore, the dual role of LG100754 in T cell activation and exhaustion in Jurkat T cell lines and primary human T cells was idnetified, suggesting their T-cell protective and anti-exhaustion effects. These data demonstrated that the RXR agonist, LG100754, enhanced myeloma’s sensitivity to lenalidomide and reduced blood glucose and serum lipids in vivo. Thus, administration of LG100754 may be an effective strategy to overcome drug resistance in the chemotherapeutic treatment of MM, while providing additional benefits for patients with comorbidities, such as diabetes and / or dyslipidemia. These findings provide a strong justification for future clinical trial testing of the efficacy of RXR agonists in combination with IMiDs in patients with MM (FIG.14). This study was significant in several aspects. It provides the first evidence that RXR:PPAR heterodimer agonists are promising small molecule candidates that can upregulate CRBN expression and enhance the sensitivity of MM cells to IMiDs while maintaining glucose- and lipid- lowering beneficial effects. These properties are significantly better than the PPAR agonists. Previous studies showed that PPAR agonists reduced lenalidomide’s anti-myeloma activity. These dual functions of RXR agonists are particularly relevant in the treatment of patients with MM. MM is predominately a disease of the elderly, a population at risk of having comorbidities, such as diabetes and dyslipidemia. Furthermore, they are more likely to require co-treatment with glucose- or lipid-lowering agents and immunomodulatory agents. Importantly, the effects of RXR agonists in enhancing T cell activation while reducing T cell exhaustion provide additional benefits in the treatment of MM. Microenvironment and T cell immunity are crucial in maintaining treatment response and in keeping patients under remission. This study provides proof-of-concept evidence for further exploration and development of new RXR:PPAR heterodimer agonists. These RXR modulators are potentially useful in treating myeloma patients who also have dyslipidemia and / or type II diabetes. Several previous reports using isolated DNA or ligand-binding segments did not provide clear answers on how multiple domains acted synergistically to modulate the receptor properties of PPAR:RXR heterodimers. It has been shown that the balance of PPAR and RXR affects the heterodimerization of specific RXR / PPAR complex. Disproportion between the level of PPAR and the level of RXR resulted in less heterodimer formation capable of binding to the PPAR / RXR recognition site in the DNA. In addition, competition of PPARs for a limited amount of RXR to form functional heterodimer may also impact the transcription of target genes. The CHiP assay and CRBN promoter-luciferase reporter system demonstrated that RXR agonists reduced the binding of PPARs to the CRBN promoter and decreased the methylation status of the CpG islands of the CRBN promoter, thus reversing the repressor effects of PPARs on CRBN transcription. This observation was further supported by the results of the co-IP assay, which showed that PPARs, but not RXR, formed complexes with EZH2. These data support that RXR agonists act by affecting the binding and effect of PPARs on CRBN regulation. Interestingly, RXR agonists retained or enhanced the other functions of PPARs, such as regulation of glucose and lipid metabolism. Additional studies are needed in the future to determine the mechanisms resulting in these different effects of RXR agonists. CS018, a retinoid-like compound, was designed and synthesized based on the chemical structure of the RXR natural ligand. Interestingly, CS018 facilitates the formation of RXR homodimers and the heterodimers of RXR with PPARs but not FXR and LXR. Consistent with the data, CS018 induced the expression of PPARȖ target genes, CD36 and lipoprotein lipase (LPL) and significantly reduced animal blood glucose levels in vivo. Bexarotene is an FDA-approved RXR agonist. It has undergone trials in multiple myeloma patients (NCT01504490). This study tested the safety and efficacy of a new combination of drugs of PPARȖ agonists, such as CS7017 and bexarotene, on MM. Unfortunately, no conclusive benefits were found from the clinical trial. The combination strategy of Bexarotene with IMiDs was never explored. Acquired drug resistance to IMiDs remains to be a major therapeutic issue in myeloma treatment. However, RXR agonists may have significant clinical applicability on the drug resistance of MM. RXR and PPAR are ligand-activated transcription factors that form heterodimer with each other or with other members of the RXR family. The interaction occurs in the presence and absence of PPAR ligand. The RXR-PPAR heterodimers further recruit other cofactors before binding to PPRE at the promoter regions of PPAR-responsive genes and these coactivators or corepressors are tightly involved in the regulation of target gene transcriptional activity. T-cell death-associated gene 51(TDAG51) was previously identified as a novel corepressor of PPARȖ- mediated transcriptional regulation. Overexpression of TDAG51 reduced the differentiation of 3T3-L1 adipocyte cells. TDAG51 physically interacted with PPARȖ in a ligand-independent manner, blocked RXRĮ recruitment to the RXRĮ-PPARȖ heterodimer complex in adipogenesis, and negatively regulated the functions of PPARȖ by blocking. The finding of the effects of LG100754 on T cells is consistent with that of a previous study reporting that the LG100268, an RXR-PPARȖ heterodimer agonist, has favorably modulated the immune microenvironment in preclinical breast cancer models. Exposure to LG100268 increased cytotoxic activity of CD8 T cells in tumors of MMTV-Neu mice (a model of HER2-positive breast cancer). This enhanced immunity of LG100268 was due to the combined effects of decreased infiltration of myeloid-derived suppressor cells and CD206-expressing macrophages and increased ratio of CD8 / CD4 and CD25 T cells. LG100268 improved the response to immune checkpoint blockade in breast cancer. Taken together, these studies demonstrated that RXR:PPAR pathway plays important roles in immune regulation and in disease pathogenesis and that RXR agonists are novel agents with potential to modulate the functions of immune cells. This study demonstrates that RXR agonists significantly enhanced the sensitivity of the MM cells to lenalidomide in vitro and in vivo. RXR agonists upregulated CRBN transcription and attenuated the methylation status of the CRBN promoter. In addition, low concentrations of LG100754 protect T cells from exhaustion and improve anti-tumor activity. Combining RXR agonists with lenalidomide resulted in a more effective tumor control in the myeloma xenograft mouse model. This study provides new information regarding PPAR-RXR-CRBN interaction, which may be useful in guiding future studies and treatment. This study also provides novel targets for improving the efficacy of immunomodulatory agents for patients with MM, and it is particularly relevant to myeloma patients who have co-existing diabetes or dyslipidemia. Example 8 RXR Agonists Enhance B-cell Maturation Antigen (BCMA) CAR T-Cell Cytotoxicity Against MM Cells In Vitro RXR agonists were tested for the ability to enhance CAR T-cell function. Un-transduced control T cells (NT) or hBCMA CAR T-2 cells were cultured with NCI-H929 target cells in the presence or absence of AGN194204 (FIG. 15A) or LG100754 (FIG. 15B). Control T cells and hBCMA-CAR-T cells were co-cultured with NCI-H929 target cells for 48 hours at ET ratios of 4:1, 2:1, 1:1, and 0.5:1, and were treated with or without 2 μM or 4 μM of RXR agonist. Cytotoxic efficiency was normalized against the positive control. The RXR agonists enhanced BCMA CAR T cell’s killing of MM cells. Results are shown in FIG.15A–B.

Claims

CLAIMS What is claimed:

1. A pharmaceutical composition for treating, ameliorating, or inhibiting the progress of blood cancer in a cell or a subject, the pharmaceutical composition comprising one or more retinoid X receptor (RXR) modulators and one or more immunomodulatory agents.

2. The pharmaceutical composition of claim 1, wherein the RXR modulator comprises LG100754, bexarotene, AGN194204 (IRX4204), LG101506, AGN195393, LGN100849, PA451, PA452, UVI 3003, AGN195183 (IRX5183), CD 3254, LG100268, retinoid acid, SR11237, or combinations thereof.

3. The pharmaceutical composition of claim 1, wherein the RXR modulator is an RXR agonist.

4. The pharmaceutical composition of claim 1, wherein the RXR modulator promotes RXR homodimerization.

5. The pharmaceutical composition of claim 1, wherein the RXR modulator promotes RXR heterodimerization with one or more peroxisome proliferator-activator receptors (PPARs).

6. The pharmaceutical composition of claim 1, wherein the immunomodulatory agent comprises lenalidomide, thalidomide, pomalidomide, iberdomide, mezigdomide, or combinations thereof.

7. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises LG100754 or AGN194204 (IRX4204), and lenalidomide.

8. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises a mass ratio of the RXR modulator to the immunomodulatory agent of about 1:10 to about 10:

1.

9. The pharmaceutical composition of claim 1, further comprising one or more peroxisome proliferator-activator receptor (PPAR) antagonists.

10. The pharmaceutical composition of claim 1, further comprising one or more pharmaceutically acceptable buffers, salts, carriers, or diluents.

11. A kit comprising: the pharmaceutical composition of claim 1; and optionally, one or more of packaging, a label, or instructions for use.

12. Use of the pharmaceutical composition of claim 1 as a medicament for treating, ameliorating, or inhibiting the progress of blood cancer in a cell or a subject.

13. A method of treating, ameliorating, or inhibiting the progress of blood cancer in a cell or a subject, the method comprising administering to the cell of the subject a therapeutically effective amount of a pharmaceutical composition comprising one or more retinoid X receptor (RXR) modulators and one or more immunomodulatory agents.

14. The method of claim 13, wherein the RXR modulator comprises LG100754, bexarotene, AGN194204 (IRX4204), LG101506, AGN195393, LGN100849, PA451, PA452, UVI 3003, AGN195183 (IRX5183), CD 3254, LG100268, retinoid acid, SR11237, or combinations thereof.

15. The method of claim 13, wherein the immunomodulatory agent comprises lenalidomide, thalidomide, pomalidomide, iberdomide, mezigdomide, or combinations thereof.

16. The method of claim 13, wherein the pharmaceutical composition comprises LG100754 or AGN194204 (IRX4204), and lenalidomide.

17. The method of claim 13, wherein the blood cancer is a leukemia or a lymphoma.

18. The method of claim 13, wherein the blood cancer is multiple myeloma (MM).

19. The method of claim 13, wherein the subject is receiving cellular therapy with chimeric antigen receptor (CAR) T cells.

20. The method of claim 13, wherein the subject has a precancerous condition comprising smoldering multiple myeloma (SMM), monoclonal gammopathy of undetermined significance (MGUS), or a combination thereof.

21. The method of claim 13, wherein the subject has diabetes, dyslipidemia, or a combination thereof.

22. The method of claim 13, wherein the method promotes T cell activation and reduces T cell exhaustion.

23. The method of claim 13, wherein the method enhances chimeric antigen receptor (CAR) T-cell therapy.

24. The method of claim 13, wherein the method reduces blood glucose and lipid levels.

25. The method of claim 13, wherein the method increases cereblon (CRBN) expression levels.

26. The method of claim 13, wherein the therapeutically effective amount of the pharmaceutical composition is from about 2 mg / kg to about 250 mg / kg.

27. A pharmaceutical composition for use in a method of treating, ameliorating, or inhibiting the progress of blood cancer in a cell or a subject, the pharmaceutical composition comprising one or more retinoid X receptor (RXR) modulators and one or more immunomodulatory agents.

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