Pharmaceutical composition for treating multiple myeloma and application thereof

Abstract

The invention relates to application of retinol compounds and carfilzomib in preparation of drugs for treating multiple myeloma, and belongs to the technical field of antitumor drugs. Aiming at the problem of drug resistance in treatment of multiple myeloma, the invention provides a technical scheme of drug combination. The retinol compound is preferably synthetic retinol WYC-209, the retinol compound can enhance the sensitivity of carfilzomib for treating multiple myeloma, and the action mechanism is that WYC-209 aggravates endoplasmic reticulum stress of multiple myeloma cells and destroys an endoplasmic reticulum structure. The combined treatment scheme can inhibit proliferation of multiple myeloma cells, induce cell apoptosis, reduce tumor load, inhibit bone marrow infiltration of tumor cells and improve the long-term survival rate of mice. The invention further provides a pharmaceutical composition containing WYC-209 and carfilzomib, the mass ratio of WYC-209 to carfilzomib is (0.01-3000): 1, and the pharmaceutical composition can be prepared into a solution or suspension and is suitable for treating first-diagnosis high-risk multiple myeloma or recurrent / refractory multiple myeloma.

Description

Technical Field

[0001] This invention relates to the field of antitumor drugs, specifically to a pharmaceutical composition for treating multiple myeloma and its application. Background Technology

[0002] Multiple myeloma (MM) is a blood-borne malignant tumor originating from plasma cells, primarily affecting the bone marrow, and is the second most common hematologic malignancy. The disease is characterized by the clonal proliferation of abnormal plasma cells in the bone marrow, the production of monoclonal immunoglobulins (M proteins), and associated organ dysfunction. Despite significant advances in the treatment of multiple myeloma in recent years, it remains a difficult-to-cure malignancy, and almost all patients eventually face disease relapse and drug resistance.

[0003] Proteasome inhibitors, as a crucial class of drugs for the treatment of multiple myeloma, have become the cornerstone of modern MM treatment regimens. Carfilzomib, as a second-generation irreversible proteasome inhibitor, has higher selectivity and lower neurotoxicity compared to the first-generation proteasome inhibitor bortezomib, and has been widely used in the treatment of relapsed / refractory multiple myeloma. However, clinical practice shows that not all patients benefit from carfilzomib treatment; some patients have poor sensitivity to carfilzomib, leading to poor treatment outcomes.

[0004] To improve the treatment outcomes of multiple myeloma, researchers are constantly exploring new treatment strategies and drug combinations. Chinese patent application CN120899916A discloses the application of SMARCC1 in the preparation of drugs for treating carfilzomib-resistant multiple myeloma. This study found a direct correlation between SMARCC1 and carfilzomib resistance in multiple myeloma. Chinese patent application WO2025162246A1 discloses the use of purisat mesylate and its analogues in combination for the prevention and treatment of multiple myeloma, showing that three- or four-drug combinations significantly enhance synergistic antitumor activity. Furthermore, Chinese patent application CN118717766A discloses the application of venetoclax in the preparation of drugs for treating IgD-type multiple myeloma, providing a new treatment option for a specific subtype of multiple myeloma. Chinese patent application CN112023022A reveals that carfilzomib can reverse tumor resistance induced by various chemotherapeutic drugs (such as cisplatin, cytarabine, irinotecan, etc.) by inhibiting proteasome activity and preventing the clearance of damaged proteins, thus achieving broad-spectrum resistance reversal. However, it only focuses on the combination of carfilzomib with traditional chemotherapeutic drugs and does not involve its synergistic application with targeted signaling regulatory molecules (such as retinol compounds), nor does it reveal its direct improvement effect on insufficient sensitivity to carfilzomib in the specific disease of multiple myeloma. Chinese patent application EP2005954A2 discloses the use of synthetic retinol (such as TM-411) in combination with various chemotherapeutic drugs for the treatment of various tumors, including multiple myeloma. However, it does not explore the combination mechanism of retinol with proteasome inhibitors (especially carfilzomib) and does not involve the synergistic regulation of the endoplasmic reticulum stress pathway. Chinese patent application WO94 / 20093 systematically describes a method for treating various solid tumors and hematological malignancies by inducing tumor cell apoptosis with RXR-specific retinol receptor agonists. However, its application method is monotherapy, without involving combination with any proteasome inhibitors, and it does not explore whether retinol compounds can enhance the killing efficiency of proteasome inhibitors by regulating endoplasmic reticulum homeostasis.

[0005] Retinols, as derivatives of vitamin A, play a crucial role in regulating cell differentiation, proliferation, and apoptosis. Studies have shown that retinols exert anti-tumor effects through multiple mechanisms, including inducing tumor cell differentiation, promoting apoptosis, and regulating the cell cycle. Endoplasmic reticulum (ER) stress is a cellular stress response that occurs when cells face abnormal protein folding or ER dysfunction; excessive ER stress can lead to apoptosis. Multiple myeloma cells, due to their high production of immunoglobulins, are highly dependent on ER function; therefore, the ER stress pathway is considered an important therapeutic target for multiple myeloma.

[0006] Despite the existence of various methods and drug combinations for treating multiple myeloma, significant limitations remain. First, carfilzomib monotherapy has limited efficacy, with some patients exhibiting poor sensitivity and failing to achieve the desired depth of treatment. Second, while existing combination therapies have improved treatment outcomes to some extent, they cannot completely address the issue of insufficient carfilzomib sensitivity in patients. Third, as treatment progresses, patients often develop drug resistance, leading to treatment failure and disease progression. Finally, overcoming drug resistance often requires increasing the carfilzomib dosage, which not only increases the financial burden on patients but may also lead to more severe toxic side effects, impacting their quality of life and treatment adherence. Therefore, there is an urgent need to develop new treatment strategies to significantly enhance the sensitivity of carfilzomib in treating multiple myeloma, thereby improving patient outcomes and prognosis. Summary of the Invention

[0007] In order to address the technical problems of poor sensitivity and unsatisfactory treatment response rate of carfilzomib in patients with multiple myeloma in the prior art, and to achieve the technical effect of significantly enhancing the sensitivity of carfilzomib to multiple myeloma treatment, this invention provides a pharmaceutical composition for treating multiple myeloma and its application.

[0008] This invention provides a pharmaceutical composition for treating multiple myeloma.

[0009] Furthermore, the pharmaceutical composition includes a proteasome inhibitor and a retinol compound.

[0010] Furthermore, the retinol compound is selected from one or more of the following: synthetic retinol WYC-209, retinoic acid, tazarotene, bexarotine, etretinoic acid, esostatin, and trachostatin A derivative.

[0011] Preferably, the retinol compound is a synthetic retinol, WYC-209.

[0012] Furthermore, the synthetic retinoid WYC-209 can enhance the sensitivity of carfilzomib in the treatment of multiple myeloma. Specifically, WYC-209 can exacerbate the stress response of the endoplasmic reticulum in multiple myeloma cells and destroy the endoplasmic reticulum structure.

[0013] Furthermore, the proteasome inhibitor is selected from one or more of carfilzomib, bortezomib, ixazomib, mafilzomib, opzomib, renazomib, and MLN9708.

[0014] Preferably, the proteasome inhibitor is carfilzomib.

[0015] Furthermore, the mass ratio of WYC-209 to carfilzomib in the pharmaceutical composition is (0.01-3000):1.

[0016] Preferably, the mass ratio of WYC-209 to carfilzomib is 0.1-10:1, more preferably 5:1.

[0017] Furthermore, the concentration of the synthetic retinoid WYC-209 is 0.01-3 μM, preferably 1 μM.

[0018] Furthermore, the concentration of the carfilzomib is 1-300 nM, preferably 10 nM.

[0019] Furthermore, the administration route of the pharmaceutical composition is selected from oral, nasal, non-gastrointestinal, intravenous, intradermal, subcutaneous, or local administration.

[0020] Optionally, the active ingredient of the pharmaceutical composition is placed in a solution or suspension.

[0021] Preferably, the solution or suspension further comprises one or more of the following: a sterile diluent, a liposome particle suspension, a saline solution, a non-volatile oil, an antibacterial agent, an antioxidant, a chelating agent, a buffer, and a tension-regulating substance.

[0022] Optionally, the pharmaceutical composition is used to prepare a drug for treating newly diagnosed high-risk multiple myeloma or relapsed / refractory multiple myeloma.

[0023] Furthermore, the pharmaceutical composition can include one or more of the following: inhibiting the proliferation of multiple myeloma cells, inducing apoptosis of multiple myeloma cells, reducing tumor burden, and inhibiting bone marrow infiltration of tumor cells, and can improve the long-term survival rate of mice.

[0024] Furthermore, the tumor burden is evaluated using M protein levels as an indicator.

[0025] The beneficial effects of this invention are as follows: 1. Synergistic Enhancement of Anti-Multiple Myeloma Effect: Compared with carfilzomib monotherapy in existing technologies, this invention uses retinol compound WYC-209 in combination with carfilzomib, which has a significant synergistic effect against multiple myeloma (MM): it significantly increases the apoptosis rate of MM cells induced by carfilzomib and enhances the inhibitory effect of carfilzomib on MM cell proliferation; it further reduces tumor burden (such as M protein level) and effectively inhibits bone marrow infiltration of tumor cells; in animal experiments, it can effectively improve the long-term survival rate of transplanted tumor mice, providing a reliable basis for improving clinical efficacy.

[0026] 2. The two drugs are clearly complementary, overcoming monotherapy resistance: The synergistic mechanism of this drug combination is clear and complementary: the proteasome inhibitor (carfilzomib) blocks abnormal protein degradation pathways, thereby inducing tumor cell apoptosis; the retinoid compound (WYC-209) regulates the expression of genes related to cell differentiation and apoptosis, enhancing the sensitivity of tumor cells to carfilzomib. This mechanism effectively overcomes the decline in efficacy caused by carfilzomib monotherapy due to resistance, without altering the original drug structure; enhanced sensitivity is achieved solely through the synergistic combination of active ingredients, without the risk of new toxic side effects.

[0027] 3. Improved prognosis and enhanced treatment benefits: This drug combination is expected to significantly improve the response rate and remission depth of carfilzomib in patients with multiple myeloma, further improve clinical efficacy, improve patient prognosis, and ultimately prolong patient survival and improve long-term survival rate. At the same time, its high efficacy and low toxicity characteristics can provide a more efficient and stable new treatment strategy for refractory cases of multiple myeloma, with good technological innovation and clinical applicability.

[0028] 4. Low toxicity, low cost, and strong practicality: On the one hand, the synthesis technology of WYC-209 is very mature, and the drug acquisition cost is low, which can effectively reduce the economic burden on patients; on the other hand, as a retinol compound (a derivative of vitamin A), WYC-209 has few toxic side effects. In summary, this forms a new drug combination for the treatment of multiple myeloma that is effective, low toxicity, and low cost. Attached Figure Description

[0029] Figure 1 Statistical analysis of the effects of WYC-209 and CFZ alone and in combination on the apoptosis of primary MM cells using the Annexin V-FITC / PI apoptosis detection kit combined with flow cytometry; Figure 2 To detect the apoptosis-inducing effects of WYC-209 and CFZ alone and in combination on MM cell line H929 using the Annexin V-FITC / PI apoptosis detection kit combined with flow cytometry; Figure 3 The inhibitory effects of WYC-209 and CFZ alone and in combination on the activity of MM cell lines H929 and ARP-1 cells; Figure 4 To detect the inhibition rate of H929 cell proliferation by the combined action of different concentrations of WYC-209 and CFZ using the CCK-8 assay, and to obtain the ZIP synergistic index of different concentration combinations of the two drugs using SynergyFinder software. Figure 4 The left figure shows the dose-response matrix of growth inhibition rate. Figure 4 The right figure illustrates the strength of the synergistic effect; Figure 5 To observe the ultrastructure of the endoplasmic reticulum in H929 cells after WYC-209 and CFZ were administered alone and in combination using transmission electron microscopy; Figure 6 shows the effects of WYC-209 and CFZ alone and in combination on tumor burden and bone marrow invasion ability of tumor cells in mice. The tumor burden indicator is plasma M protein. Figure 6-1 To assess tumor burden by detecting the concentration of human light chain immunoglobulin (M protein) secreted by MM cells in mouse plasma using enzyme-linked immunosorbent assay (ELISA); Figure 6-2 To detect and analyze the extent of MM cell infiltration into the bone marrow using flow cytometry; Figure 7 The effects of WYC-209 and CFZ alone and in combination on the survival of mice. Detailed Implementation

[0030] The synthetic retinoids WYC-209 and carfilzomib used in the following examples were purchased from MedChemExpress, Inc., USA, and dimethyl sulfoxide was purchased from Thermo Fisher Scientific, Inc., USA.

[0031] The English abbreviations and their corresponding Chinese translations used in the following text are as follows:

[0032] Example 1 This embodiment provides a pharmaceutical composition for treating multiple myeloma, the pharmaceutical composition comprising two active ingredients: a retinoid compound and carfilzomib.

[0033] The retinol compound in this pharmaceutical composition is synthetic retinol WYC-209 (CAS No. 2131803-90-0, molecular formula C). 20 H 20 WYC-209 (N2O3S) is a novel synthetic retinol-like compound that enhances the sensitivity of carfilzomib in the treatment of multiple myeloma. Its mechanism of action involves WYC-209 exacerbating endoplasmic reticulum stress and disrupting the endoplasmic reticulum structure in multiple myeloma cells, thereby producing a synergistic therapeutic effect with carfilzomib.

[0034] The mass ratio of synthetic retinoid WYC-209 to carfilzomib in the pharmaceutical composition is (0.1-10):1, specifically 0.1:1, 0.5:1, 1:1, 2:1, 5:1, 8:1 or 10:1, preferably 5:1.

[0035] The concentration of the synthetic retinol WYC-209 is 0.01-3 μM, specifically 0.01 μM, 0.03 μM, 0.1 μM, 0.3 μM, 1 μM or 3 μM, preferably 1 μM.

[0036] The concentration of carfilzomib is 1-300 nM, specifically 1 nM, 3 nM, 10 nM, 30 nM, 100 nM or 300 nM, preferably 10 nM.

[0037] The active ingredient of this pharmaceutical composition is contained in a solution or suspension. The solution or suspension also contains one or more excipients selected from the following: a sterile diluent, a liposome suspension, a saline solution, a non-volatile oil, an antibacterial agent, an antioxidant, a chelating agent, a buffer, and a tonic agent. The sterile diluent may be water for injection or physiological saline; the liposome suspension helps improve the bioavailability of the drug; the antibacterial agent, such as benzyl alcohol or parabens, is used to prevent microbial contamination; the antioxidant, such as vitamin E or butylated hydroxyanisole, is used to prevent oxidative degradation of the active ingredient; the chelating agent, such as EDTA, is used to bind metal ions; the buffer, such as phosphate buffer, is used to maintain a suitable pH; and the tonic agent, such as sodium chloride or mannitol, is used to regulate osmotic pressure.

[0038] The drug composition can be administered orally, nasally, via non-gastrointestinal route, intravenously, intradermally, subcutaneously, or topically. For oral administration, it can be prepared as tablets, capsules, or oral solutions; for intravenous administration, it must be prepared as a sterile injection solution; for subcutaneous injection, it can be prepared as an injection suspension. The choice of different administration methods can be determined based on the severity of the patient's condition, treatment needs, and the clinician's judgment.

[0039] This drug composition, through the synergistic effect of WYC-209 and carfilzomib, effectively inhibits the proliferation of multiple myeloma cells and induces apoptosis, while simultaneously reducing tumor burden and inhibiting bone marrow infiltration of tumor cells, thus improving the long-term survival rate of mice. The tumor burden is evaluated using M protein levels; changes in M ​​protein levels can be used to assess treatment efficacy.

[0040] This pharmaceutical composition is particularly suitable for the formulation of drugs for the treatment of newly diagnosed high-risk multiple myeloma or relapsed / refractory multiple myeloma. For newly diagnosed high-risk multiple myeloma patients, this composition can provide potent treatment in the early stages of the disease; for relapsed / refractory multiple myeloma patients, this composition overcomes the drug resistance of tumor cells through a unique mechanism of action, providing a new treatment option for these refractory patients.

[0041] Example 2 This embodiment verifies the in vitro killing and activity-inhibiting effects of the pharmaceutical composition provided by the present invention on multiple myeloma cells. The specific operation steps are as follows: 1) MM cell line culture Human MM cell lines NCI-H929 (H929, American Center for Type Culture Collection) and ARP-1 (a gift from Professor Gu Chunyan of Nanjing University of Chinese Medicine) were cultured at 37°C and 5% CO2 in RPMI-1640 medium (purchased from Gibco, USA) containing 10% fetal bovine serum (purchased from Biological Industries, Israel) and 1% penicillin-streptomycin (purchased from Beyotime Biotechnology, China).

[0042] 2) The killing effect of WYC-209 combined with CFZ on primary MM cells Bone marrow fluid was collected from MM patients, and primary CD138+ MM cells were isolated using magnetic bead sorting. These cells were cultured in RPMI-1640 medium containing 10% fetal bovine serum and 1% penicillin-streptomycin at 37°C and 5% CO2. The primary MM cells were divided into four groups and treated for 48 h with DMSO, CFZ (10 nM), WYC-209 (1 μM), or WYC-209+CFZ (n=8). The apoptosis rate of primary MM cells induced by WYC-209 and CFZ alone and in combination was detected using the Annexin V-FITC / PI apoptosis detection kit (Beyotime Biotechnology, China) combined with flow cytometry. Statistical analysis was then performed. Table 1. Grouping Design of WYC-209 and CFZ as Monotherapy and in Combination Therapy

[0043] The results showed no significant difference between the WYC-209 group and the DMSO group, while significant differences were found between the CFZ group and the DMSO group, the CFZ+WYC-209 group and the DMSO group, the CFZ+WYC-209 group and the CFZ group, and the CFZ+WYC-209 group and the WYC-209 group. This indicates that the apoptosis rate induced by the combination of the two drugs was significantly higher than that induced by the single drug. Figure 1 ).

[0044] 3) The killing effect of WYC-209 combined with CFZ on MM cell lines MM cells (H929) were divided into four groups and treated with DMSO, CFZ (10 nM), WYC-209 (1 μM), or WYC-209+CFZ (n = 3) for 48 h, respectively. The groups are shown in Table 1.

[0045] The proportion of MM cells induced by WYC-209 and CFZ alone and in combination was detected by Annexin V-FITC / PI apoptosis detection kit combined with flow cytometry, and statistical analysis was performed.

[0046] The results are as follows Figure 2 As shown, there was no significant difference between the WYC-209 group and the DMSO group, while there were significant differences between the CFZ group and the DMSO group, the WYC-209+CFZ group and the DMSO group, the WYC-209+CFZ group and the CFZ group, and the WYC-209+CFZ group and the WYC-209 group. This indicates that the apoptosis rate induced by the combination of the two drugs was significantly higher than that induced by the single drug.

[0047] 4) Inhibitory effect of WYC-209 combined with CFZ on the activity of MM cell lines MM cells (H929 and ARP-1) were divided into four groups and treated with DMSO, CFZ (10 nM), WYC-209 (1 μM), or WYC-209+CFZ (n = 3) for 48 h, respectively. The groups are shown in Table 1.

[0048] After 48 h of treatment, cell viability was detected using the CCK-8 assay, and the results are as follows: Figure 3 As shown, there was no significant difference between the WYC-209 group and the DMSO group, while there were significant differences between the CFZ group and the DMSO group, the CFZ+WYC-209 group and the DMSO group, the CFZ+WYC-209 group and the CFZ group, and the CFZ+WYC-209 group and the WYC-209 group. This indicates that the combined effect of the two drugs on the inhibitory activity of MM cell proliferation is significantly stronger than that of the single drug. Figure 3 ).

[0049] 5) Verify that WYC-209 and CFZ exert a significant synergistic inhibitory effect on MM cells in vitro: The following groups were set up: a solvent control group, a WYC-209 monotherapy group (0-3000 nM), a CFZ monotherapy group (0-300 nM), and a combination therapy group with different concentrations of both drugs. The specific groupings are shown in Table 2.

[0050] Table 2 Grouping Design of Different Concentrations of WYC-209 and CFZ as Monotherapy and in Combination

[0051] After 48 h of treatment, cell viability was detected by the CCK-8 assay, and the synergistic killing effect of WYC-209 and CFZ on H929 cells was analyzed using SynergyFinder software.

[0052] Figure 4 The left figure shows the dose-response matrix of growth inhibition rate; Figure 4 The figure on the right shows the strength of the synergistic effect, which is calculated based on the Zero Interaction Potency (ZIP) model. When the ZIP synergistic effect score exceeds 10, it indicates that the synergistic effect is very significant.

[0053] 6) Verification showed that the combined use of WYC-209 and CFZ could exacerbate the degree of endoplasmic reticulum damage in MM cells: H929 cells were divided into three groups and treated with DMSO, CFZ (10 nM), and WYC-209 (1 μM) + CFZ (10 nM) for 48 h, respectively.

[0054] Table 3. Group design of experiments on the degree of endoplasmic reticulum damage caused by CFZ alone and in combination with WYC-209.

[0055] Cell samples were fixed with 2.5% glutaraldehyde for 30 minutes at room temperature, followed by washing three times with PBS and then fixing in 1% osmium tetroxide fixative for 3 hours. After dehydration with graded ethanol, the samples were embedded in EPON 812 resin and cured. After double staining with 2% uranium acetate and lead citrate, the endoplasmic reticulum structure in ultrathin sections was observed and photographed using a Hitachi HT7800 transmission electron microscope at an accelerating voltage of 80 kV.

[0056] The results are as follows Figure 5 As shown, compared to CFZ monotherapy, the combination of WYC-209 and CFZ exacerbated the damage to the endoplasmic reticulum in MM cells.

[0057] Example 3 This embodiment evaluates the in vivo efficacy of WYC-209 combined with CFZ in the treatment of MM. The group design and specific operation are as follows: Table 4. In vivo efficacy experimental design of CFZ monotherapy and combination therapy with WYC-209 in the treatment of MM

[0058] Five-week-old female NSG mice were provided by Gem Pharmatech Co., Ltd. (Nanjing, China) and housed in a strictly pathogen-free environment. To establish a xenograft tumor model, H929 cells (5 × 10⁻⁶) were used. 6Each mouse was injected via tail vein and continued to be fed. Starting from day 15 post-injection, the mice were given intraperitoneal injections every 2 days: CFZ (2 mg / kg) and / or WYC-209 (10 mg / kg) (n=6), for a total of 7 administrations.

[0059] During the administration period, the survival status of mice was monitored daily, and any mice exhibiting severe symptoms (including but not limited to loss of mobility, paralysis, or respiratory distress) were promptly euthanized. On day 30 post-cell injection, blood samples were collected from each mouse, and the concentration of human light chain immunoglobulin (M protein) secreted by MM cells in the mouse plasma was measured using enzyme-linked immunosorbent assay (ELISA) to assess tumor burden. Figure 6-1 ).

[0060] After each mouse was euthanized, bone marrow samples were collected from the femur, and the degree of MM cell infiltration into the bone marrow was then detected and analyzed by flow cytometry. Figure 6-2 The study endpoint was reached on day 50 after MM cell injection. Kaplan-Meier survival curves were analyzed and plotted for all mice. Figure 7 The survival rates of mice in each group were statistically analyzed. On day 50, the survival rates were as follows: DMSO group 0%, WYC-209 monotherapy group 0%, CFZ monotherapy group 33.33%, and WYC-209 + CFZ combination therapy group 66.67%. Compared to WYC-209 or CFZ monotherapy, the combination of the two drugs significantly reduced MM tumor burden, inhibited MM cell infiltration into the bone marrow, and effectively improved the long-term survival rate of mice.

[0061] Example 4 This embodiment provides a method for treating multiple myeloma using a combination of the retinol compound WYC-209 and carfilzomib. This method enhances the therapeutic sensitivity of carfilzomib to multiple myeloma through WYC-209, achieving effective treatment of multiple myeloma.

[0062] Specifically, the retinol compound selected is the synthetic retinol WYC-209. WYC-209 can significantly enhance the sensitivity of carfilzomib in the treatment of multiple myeloma, and the combination of the two produces a synergistic therapeutic effect.

[0063] The mechanism by which WYC-209 enhances the sensitivity of carfilzomib treatment is that WYC-209 exacerbates endoplasmic reticulum (ER) stress and disrupts ER structure in multiple myeloma cells. When WYC-209 is used in combination with carfilzomib, WYC-209 further intensifies ER stress by disrupting the ER structure of multiple myeloma cells, thereby enhancing the killing effect of carfilzomib on tumor cells. This mechanism allows the combined drug therapy to more effectively attack key organelle structures in multiple myeloma cells.

[0064] This combined treatment approach achieves multiple therapeutic effects, including inhibiting multiple myeloma cell proliferation, inducing multiple myeloma cell apoptosis, reducing tumor burden, and inhibiting tumor cell infiltration into the bone marrow, while effectively improving the long-term survival rate of mice. Through the synergistic effect of WYC-209 and carfilzomib, it works simultaneously from two dimensions: inhibiting cell proliferation and inducing apoptosis, effectively controlling the growth and spread of tumor cells, reducing the degree of tumor cell infiltration in the bone marrow, thereby achieving the therapeutic goals of controlling disease progression, prolonging patient survival, and improving long-term survival rates.

[0065] When evaluating treatment efficacy, tumor burden is assessed using M protein levels. M protein is a characteristic biomarker of multiple myeloma, and changes in its level directly reflect changes in tumor burden. By monitoring the degree of reduction in M ​​protein levels, the therapeutic effect of combined WYC-209 and carfilzomib in multiple myeloma can be objectively evaluated, providing a reliable biomarker for clinical treatment efficacy evaluation.

[0066] This treatment method can be formulated into various dosage forms, including oral, nasal, non-gastrointestinal, intravenous, intradermal, subcutaneous, or local dosage forms, to meet different clinical administration needs. The active ingredient of the pharmaceutical composition can be placed in a solution or suspension, which may also contain one or more excipients selected from sterile diluents, liposome suspensions, saline solutions, non-volatile oils, antibacterial agents, antioxidants, chelating agents, buffers, and tonic agents to ensure drug stability and bioavailability.

[0067] The above description is merely a preferred embodiment of this invention and is not intended to limit this invention. Various modifications and variations can be made to this invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this invention should be included within the protection scope of this invention.

Claims

1. A pharmaceutical composition for treating multiple myeloma (MM), characterized in that, The pharmaceutical composition includes retinoids and proteasome inhibitors.

2. The pharmaceutical composition according to claim 1, characterized in that, The retinol compounds are selected from one or more of the following: synthetic retinol WYC-209, retinoic acid, tazarotene, bexarotine, etratic acid, esostatin, and trachostatin A derivatives; the proteasome inhibitors are selected from one or more of the following: carfilzomib, bortezomib, ixazomib, mafilzomib, opzomib, renazomib, and MLN9708.

3. The pharmaceutical composition according to claim 1, characterized in that, The retinol compound is a synthetic retinol WYC-209, and the proteasome inhibitor is carfilzomib.

4. The pharmaceutical composition according to claim 3, characterized in that, The mass ratio of the synthetic retinoid WYC-209 to the carfilzomib is (0.01-3000):

1.

5. The pharmaceutical composition according to claim 4, characterized in that, The mass ratio of the synthetic retinol WYC-209 to the carfilzomib is 5:

1.

6. The pharmaceutical composition according to claim 5, characterized in that, The concentration of the synthetic retinol WYC-209 is 0.01-3 μM, preferably 1 μM; the concentration of the carfilzomib is 1-300 nM, preferably 10 nM.

7. The pharmaceutical composition according to any one of claims 1-6, characterized in that, The administration route of the pharmaceutical composition is selected from oral, nasal, non-gastrointestinal, intravenous, intradermal, subcutaneous, or local administration.

8. The pharmaceutical composition according to any one of claims 1-6, characterized in that: The active ingredient of the pharmaceutical composition is placed in a solution or suspension; the solution or suspension further comprises one or more of the following: a sterile diluent, a liposome particle suspension, a saline solution, a non-volatile oil, an antibacterial agent, an antioxidant, a chelating agent, a buffer, and a tension-regulating substance.

9. The pharmaceutical composition according to any one of claims 1-6, characterized in that: The pharmaceutical composition is used to prepare a drug for treating newly diagnosed high-risk multiple myeloma or relapsed / refractory multiple myeloma.

10. A method for preparing a pharmaceutical composition for treating multiple myeloma, characterized in that, Includes the following steps: The synthetic retinoid WYC-209 and carfilzomib were dissolved in water, anhydrous ethanol, or DMSO, respectively, and then mixed and pharmaceutically acceptable excipients were added to obtain the pharmaceutical composition.

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