CN115770288A - Use of mitoxantrone liposomes, bortezomib and dexamethasone for treating multiple myeloma - Google Patents

Abstract

The invention relates to application of mitoxantrone liposome, bortezomib and dexamethasone in preparing a medicine for treating multiple myeloma, a medicine combination product containing the mitoxantrone liposome, the bortezomib and dexamethasone for treating the multiple myeloma, and a method for treating the multiple myeloma by using the mitoxantrone liposome, the bortezomib and the dexamethasone. The multiple myeloma is preferably relapsed/refractory multiple myeloma. The mitoxantrone liposome is preferably mitoxantrone hydrochloride liposome.

Description

Liposome mitoxantrone, bortezomib and dexamethasone in the treatment of multiple myeloma use

technical field

The invention relates to the field of anti-tumor, in particular to the use of mitoxantrone liposome, bortezomib and dexamethasone in the preparation of medicines for treating relapsed/refractory multiple myeloma (MM).

Background technique

Multiple myeloma (MM) is a malignant disease of abnormal proliferation of monoclonal plasma cells, which occurs in the elderly, with a median age of onset of 66 years (Robert A Kyle, et al. Review of 1027 patients with newlydiagnosed multiple myeloma. Mayo Clin Proc. 2003 Jan; 78(1):21-33), the incidence rate is slightly higher in males. As a global disease, MM is the second most malignant tumor of the blood system in terms of epidemiology, with the highest incidence in Australia, North America, and Western Europe. In my country, the incidence rate of MM is 1-2/100,000. In 2016, there were 16,500 new cases and 10,400 deaths. , Global Burden of Multiple Myeloma: A Systematic Analysis for the Global Burden of Disease Study 2016. JAMA Oncol. 2018 Sep 1; 4(9):1221-1227). The continuous emergence of new drugs has changed the treatment mode and prognosis of MM, and the median OS is about 6 years (S Vincent Rajkumar. Multiple myeloma: 2020update on diagnosis, risk-stratification and management. Am J Hematol. 2020May; 95(5):548 -567). However, MM still has the characteristics of repeated recurrence and drug resistance, and is incurable, and relapse/refractory is still a difficult problem.

In the treatment of MM, whether it is anthracyclines combined with vincristine and dexamethasone (VAD program) in the traditional treatment era, or anthracyclines combined with bortezomib and dexamethasone (PAD program) in the new drug era, Anthracyclines are an important part of MM treatment. The use of anthracyclines has declined as newer drugs have become available. Mayo guidelines 2020 recommend anthracycline-containing multi-drug combination regimens for patients with aggressive relapses such as plasma cell leukemia and extramedullary lesions (S VincentRajkumar. Multiple myeloma: 2020 update on diagnosis, risk-stratification and management. Am J Hematol. 2020 May; 95(5):548-567). In the 2020 Chinese guidelines for the diagnosis and treatment of MM, regimens containing anthracyclines such as PAD and TAD (thalidomide + doxorubicin + dexamethasone) are still recommended as first-line, and cytotoxic drugs are also recommended for recurrent MM with extramedullary lesions ("Guidelines for the diagnosis and treatment of multiple myeloma in China (revised in 2020)" [J]. Chinese Medical Information Herald, 2020, 35(11): 12-12). Bortezomib + doxorubicin liposome + dexamethasone (PAD regimen), bortezomib + dexamethasone (PD regimen) in the treatment of relapsed/refractory MM is still a category 1 recommendation in the 2021 version of the NCCN Guidelines (NCCNC Clinical Practice Guidelines in Oncology (NCCN Guidelines). multiple myeloma. Version 3. 2021). A multi-center clinical trial included 64 patients with relapsed/refractory multiple myeloma, all of whom received PAD regimen (bortezomib+doxorubicin/doxorubicin liposome+dexamethasone), 43 patients The curative effect of the treatment achieved at least PR (67%), including CR (9%) and VGPR (16%); during the treatment of PAD regimen, the most common grade 1-2 adverse events were anemia (42%), neutrophils Decreased cell count (30%), decreased platelet count (27%), peripheral neuropathy (27%), nausea (14%), diarrhea (11%), and unexplained fever (11%); most common grade 3 Adverse events were decreased platelet count (23%), decreased neutrophil count (20%), anemia (11%), peripheral neuropathy (10%), and pneumonia (9%); grade 4 adverse events included decreased platelet count (25%), decreased neutrophil count (16%), and anemia (2%), acute heart failure (2%), and pneumonia (3%), and no patient had grade 4 peripheral neuropathy (A Palumbo, et al ., Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma. Ann Oncol. 2008 Jun; 19(6):1160-5). In another ENDEAVOR study, for 252 patients with relapsed/refractory MM who had previously used bortezomib, the objective response rate (ORR) of the PD regimen was 60.3%, and the median progression-free survival (PFS) was 8.1 months ; For 177 patients with relapsed/refractory MM who had previously used lenalidomide, the ORR of the PD regimen was 59.3%, and the median PFS was 7.3 months (P Moreau, et al., Impact of prior treatment on patients with relapsed multiple myeloma treated with carfifilzomib and dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR study, Leukemia. 2017Jan; 31(1):115-122).

Adverse reactions of anthracyclines mainly include cardiotoxicity, bone marrow toxicity, and gastrointestinal reactions. After doxorubicin, anthracyclines such as epirubicin and doxorubicin liposome appeared one after another, with improved safety but no difference in curative effect. A randomized controlled phase 3 clinical study of 646 patients with relapsed/refractory MM compared the efficacy of doxorubicin liposome combined with bortezomib and bortezomib monotherapy (Robert Z Orlowski, et al., Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007 Sep 1; 25(25):3892-901). The results of the study showed that the median PFS of doxorubicin liposome combined with bortezomib was 9 months, and the rate of remission ≥ VGPR accounted for 27%, which was significantly better than that of bortezomib alone, suggesting that the combination of the two drugs has a synergistic effect . Based on this study, liposomal doxorubicin was approved by the FDA in 2007 in combination with bortezomib for the treatment of relapsed/refractory MM. The combination of 3-4 drugs based on two drugs is also effective for relapsed/refractory MM (A Palumbo, et al., Bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma. Ann Oncol. 2008 Jun; 19(6):1160- 5; Stefania Ciolli, et al., The addition of liposomal doxorubicin tobortezomib, thalidomide and dexamethasone significantly improves clinical outcome of advanced multiple myeloma. Br J Haematol. 2008 Jun; 141(6):814-9; Massimo et al. Thalidomide, dexamethasone, Doxil and Velcade(ThaDD-V) followed by consolidation/maintenance therapy in patients with relapsed–refractory multiple myeloma. Ann Hematol. 2011 Dec; 90(12):1449-56; JR Berenson, et al., A phase 2 study of pegylated liposomal doxorubicin, bortezomib, dexamethasone and lenalidomide for patients with relapsed/refractory multiple myeloma, Leukemia. 2012 Jul; 26(7):1675-80), including for previous treatment with anthracyclines and bortezomib of patients.

Mitoxantrone is an anthracycline drug that has been used in more than 30 countries around the world. At the end of the 1970s, the United States began clinical research on mitoxantrone. A series of clinical trials showed that mitoxantrone, whether used as a single drug or in combination with other drugs, is effective for hematological tumors such as acute leukemia, lymphatic Tumors and a variety of solid tumors such as breast cancer have therapeutic effects. Its adverse reactions are mainly bone marrow suppression, gastrointestinal reactions and cardiotoxicity. Mitoxantrone is mainly used clinically for the treatment of acute myeloid leukemia.

Liposome is a new form of drug loading. Studies have shown that it can change the distribution of the encapsulated drug in the body, so that the drug is mainly accumulated in the tumor tissue, thereby improving the therapeutic index of the drug, reducing the therapeutic dose of the drug and reducing the toxicity of the drug. These characteristics make the application of liposome-loaded drugs in the research of anti-tumor drugs attract much attention. Some researchers have conducted research on mitoxantrone liposome formulations. For example, Chinese patent application 200610102339.8 filed on December 29, 2006 and PCT application WO2008/080367A1 filed on December 29, 2007 disclose a mitoxantrone liposome, the disclosure of which is hereby incorporated by reference in its entirety . Studies have shown that compared with common mitoxantrone preparations, liposome preparations have lower toxicity (especially cardiotoxicity), and have the characteristics of passively targeting tumor tissues, improving anti-tumor activity.

Mitoxantrone hydrochloride liposome injection single drug Phase I has completed dose escalation exploration and PK/PD research in subjects with advanced solid tumors and lymphoma subjects. According to the test results, mitoxantrone hydrochloride liposome injection is safe and tolerated in the dose range of 6-30mg/ ^m2 , and shows a certain curative effect. The pivotal phase II of mitoxantrone hydrochloride liposome monotherapy was carried out in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) and the enrollment has been completed (n=108 cases, dosage 20mg/m ² ) , the current ORR assessed by an independent review committee (IRC) and confirmed by efficacy is 40.7%.

In view of the better single-drug efficacy of mitoxantrone liposomes in patients with relapsed/refractory PTCL, the combination of mitoxantrone liposomes was further explored in patients with relapsed/refractory MM. Preliminary clinical study results show that the regimen of mitoxantrone liposome combined with bortezomib and dexamethasone is safe and tolerable, improves the objective response rate (ORR) and prolongs the duration of response (DoR) in patients with relapsed/refractory MM. ), improved PFS and OS, thereby improving the quality of life of patients and benefiting MM patients.

Relapse/refractory MM is still a difficult problem for clinicians. In the era of new drugs, as traditional drugs for the treatment of MM, anthracyclines are still one of the important components of drug combination. Mitoxantrone liposome is an anthracycline (quinone) drug with high efficiency and low toxicity, and its combination with bortezomib and dexamethasone is expected to become a treatment option for relapsed/refractory MM, especially for aggressive relapsed patients. patient.

Contents of the invention

The invention relates to the application of mitoxantrone liposome, bortezomib and dexamethasone in the preparation of medicine for treating multiple myeloma.

The present invention also relates to the use of the mitoxantrone liposome in the preparation of medicines for improving the curative effect of bortezomib and dexamethasone in treating multiple myeloma.

The invention also relates to the use of bortezomib and dexamethasone in the preparation of medicines for improving the curative effect of mitoxantrone liposomes in treating multiple myeloma.

The present invention also provides a method for treating multiple myeloma, which comprises administering effective therapeutic doses of mitoxantrone liposome, bortezomib and dexamethasone to multiple myeloma patients.

The present invention also provides a method for improving the curative effect of bortezomib and dexamethasone in treating multiple myeloma. Therapeutically effective doses of liposomal mitoxantrone.

The present invention also provides a method for improving the curative effect of mitoxantrone liposomes in the treatment of multiple myeloma, said method comprising administering mitoxantrone liposomes to patients with multiple myeloma on the basis of further combined administration Bortezomib and dexamethasone at therapeutically effective doses.

The present invention also provides a drug combination product for treating multiple myeloma, the drug combination product comprising mitoxantrone liposome, bortezomib and dexamethasone.

The present invention also provides a medicine for improving the curative effect of bortezomib and dexamethasone in treating multiple myeloma, and the medicine comprises mitoxantrone liposome.

The present invention also provides a medicine for improving the curative effect of mitoxantrone liposome in treating multiple myeloma, the medicine comprises bortezomib and dexamethasone.

Detailed ways

Unless otherwise specified, the terms used in the present invention have the following definitions:

"Relapse" was defined as a minimal response (MR) or better from prior therapy followed by disease progression.

"Refractory" was defined as failure to achieve MR with any first-line treatment.

"Mitoxantrone" includes mitoxantrone and pharmaceutically acceptable salts thereof, and the pharmaceutically acceptable salt of mitoxantrone is preferably mitoxantrone hydrochloride. The mitoxantrone liposomes are preferably mitoxantrone hydrochloride liposomes.

"Administering in any order" means that mitoxantrone liposomes, bortezomib and dexamethasone are prepared separately and administered in a clinically acceptable manner, and there is no mandatory requirement for the order of administration; Mixing does not occur in vitro.

The invention provides the application of mitoxantrone liposome, bortezomib and dexamethasone in the preparation of medicine for treating multiple myeloma.

The present invention also provides the use of the mitoxantrone liposome in the preparation of medicines for improving the curative effect of bortezomib and dexamethasone in treating multiple myeloma.

The present invention also provides the use of bortezomib and dexamethasone in preparing a medicine for improving the curative effect of mitoxantrone liposome in treating multiple myeloma.

Further, the present invention provides the use of mitoxantrone hydrochloride liposome, bortezomib and dexamethasone in the preparation of a drug for treating multiple myeloma.

Further, the present invention provides the use of mitoxantrone hydrochloride liposome in the preparation of a drug for improving the curative effect of bortezomib and dexamethasone in treating multiple myeloma.

Further, the present invention provides the use of bortezomib and dexamethasone in the preparation of a drug for improving the curative effect of mitoxantrone hydrochloride liposomes in treating multiple myeloma.

In the above use, the multiple myeloma is preferably relapsed/refractory multiple myeloma.

The invention provides a method for treating multiple myeloma, which comprises administering effective doses of mitoxantrone liposome, bortezomib and dexamethasone to patients with multiple myeloma.

The present invention also provides a method for improving the curative effect of bortezomib and dexamethasone in treating multiple myeloma. Therapeutically effective doses of liposomal mitoxantrone.

The present invention also provides a method for improving the curative effect of mitoxantrone liposomes in the treatment of multiple myeloma, said method comprising administering mitoxantrone liposomes to patients with multiple myeloma on the basis of further combined administration Bortezomib and dexamethasone at therapeutically effective doses.

In the above method, the multiple myeloma is preferably relapsed/refractory multiple myeloma.

In the above method, the administration of mitoxantrone liposome and bortezomib is preferably administered by injection; dexamethasone is preferably administered orally. Preferably, based on mitoxantrone, the effective therapeutic dose of the mitoxantrone liposome is 12-30 mg/m ² , more preferably 12-20 mg/m ² . Specific examples: 12 mg/m ² , 16 mg/m ² , 20 mg/m ² . Preferably, the mitoxantrone liposome is administered intravenously. Preferably, for each intravenous administration, the infusion administration time of the liposome preparation is 30 minutes to 120 minutes, preferably 60 minutes to 120 minutes, more preferably 90±15 minutes. Preferably, the administration method of bortezomib is injection administration, and the dosage is 1.3 mg/m ² . Preferably, the administration method of dexamethasone is oral administration, and the dosage is 20 mg/day. Preferably, the administration cycle of treatment is 4 weeks or 3 weeks, more preferably 4 weeks; in each administration cycle, mitoxantrone liposomes are administered once, bortezomib is administered 4 times, dexamethasone Methasone was administered 8 times. Preferably, multiple myeloma patients are administered effective therapeutic doses of mitoxantrone liposomes, bortezomib and dexamethasone in any order on the first day of each administration cycle, and on the fourth, eighth and Bortezomib was continued on day 11, and dexamethasone was continued on days 2, 4, 5, 8, 9, 11, and 12.

Further, the present invention provides a method for treating multiple myeloma, said method comprising administering effective therapeutic doses of mitoxantrone hydrochloride liposomes, bortezomib and dexamethasone to patients with multiple myeloma.

Further, the present invention provides a method for improving the curative effect of bortezomib and dexamethasone in the treatment of multiple myeloma, said method comprising on the basis of administering bortezomib and dexamethasone to patients with multiple myeloma, further A therapeutically effective dose of mitoxantrone hydrochloride liposomes is administered in combination.

Further, the present invention provides a method for improving the curative effect of mitoxantrone hydrochloride liposomes in treating multiple myeloma, said method comprising administering mitoxantrone hydrochloride liposomes to multiple myeloma patients on the basis of , further administering therapeutically effective doses of bortezomib and dexamethasone in combination.

In the above method, the multiple myeloma is preferably relapsed/refractory multiple myeloma.

In the above method, the administration of mitoxantrone hydrochloride liposome and bortezomib is preferably administered by injection; the administration of dexamethasone is preferably administered orally. Preferably, based on mitoxantrone, the effective therapeutic dose of the mitoxantrone hydrochloride liposome is 12-30 mg/m ² , more preferably 12-20 mg/m ² . Specific examples: 12 mg/m ² , 16 mg/m ² , 20 mg/m ² . Preferably, the mitoxantrone hydrochloride liposome is administered intravenously. Preferably, for each intravenous administration, the infusion administration time of the liposome preparation is 30 minutes to 120 minutes, preferably 60 minutes to 120 minutes, more preferably 90±15 minutes. Preferably, the administration method of bortezomib is injection administration, and the dosage is 1.3 mg/m ² . Preferably, the administration method of dexamethasone is oral administration, and the dose is 20 mg/day. Preferably, the treatment administration cycle is 4 weeks or 3 weeks, more preferably 4 weeks; in each administration cycle, mitoxantrone hydrochloride liposomes are administered once, bortezomib is administered 4 times, and Cemethasone was administered 8 times. Preferably, on the first day of each administration cycle, the multiple myeloma patients are administered effective therapeutic doses of mitoxantrone hydrochloride liposomes, bortezomib and dexamethasone in any order, and on the fourth and eighth days. Bortezomib was continued on days 1 and 11, and dexamethasone was continued on days 2, 4, 5, 8, 9, 11, and 12.

The present invention also provides a drug combination product for treating multiple myeloma, the drug combination product comprising mitoxantrone liposome, bortezomib and dexamethasone. Preferably, the liposomes of mitoxantrone, bortezomib and dexamethasone can be present in the same preparation, or can be separately prepared in the form of combined packaging. When the above three drugs are prepared separately, the dosage forms may be the same or different. The dosage form can be any clinically acceptable dosage form, such as injection dosage form, oral dosage form and the like. The injection dosage form includes liquid injection, powder for injection, tablet for injection, etc.; the oral dosage form includes tablet, capsule, oral liquid preparation, etc. Preferably, when the mitoxantrone liposome is a liquid injection, based on mitoxantrone, the active ingredient contains 0.5-5 mg/ml, preferably 1-2 mg/ml, more preferably 1 mg/ml; when bortezol When rice is powder for injection, the specification is 3.5mg/bottle, and it is prepared into a 2.5mg/ml solution when used; when dexamethasone is tablet, the specification is 0.75mg/tablet.

The drug combination product may further contain other second-line and above drugs for the treatment of multiple myeloma. Second-line and above drugs in the treatment of multiple myeloma.

The present invention also provides a pharmaceutical composition for treating multiple myeloma, said pharmaceutical composition comprising mitoxantrone liposome, bortezomib and dexamethasone, said treatment includes treating multiple myeloma patients Use therapeutically effective liposomes of mitoxantrone, and administer bortezomib and dexamethasone at any time before, during, and after administration of liposomes with mitoxantrone. Preferably, based on mitoxantrone, the effective therapeutic dose of the mitoxantrone liposome refers to 12-30 mg/m ² , more preferably 12-20 mg/m ² . Specific examples: 12 mg/m ² , 16 mg/m ² , 20 mg/m ² . Preferably, the mitoxantrone liposome is administered intravenously. Preferably, for each intravenous administration, the infusion administration time of the liposome preparation is 30 minutes to 120 minutes, preferably 60 minutes to 120 minutes, more preferably 90±15 minutes. Preferably, the administration method of bortezomib is injection administration, and the dosage is 1.3 mg/m ² . Preferably, the administration method of dexamethasone is oral administration, and the dosage is 20 mg/day. Preferably, the administration cycle of treatment is 4 weeks or 3 weeks, more preferably 4 weeks; in each administration cycle, mitoxantrone liposomes are administered once, bortezomib is administered 4 times, dexamethasone Methasone was administered 8 times. Preferably, multiple myeloma patients are administered effective therapeutic doses of mitoxantrone liposomes, bortezomib and dexamethasone in any order on the first day of each administration cycle, and on the fourth, eighth and third days. Bortezomib was continued on day 11, and dexamethasone was continued on days 2, 4, 5, 8, 9, 11, and 12.

The present invention also provides a medicine for improving the curative effect of bortezomib and dexamethasone in the treatment of multiple myeloma, said medicine contains mitoxantrone liposome, and said mitoxantrone liposome Administer at any time before, during or after the administration of rice and dexamethasone. Preferably, based on mitoxantrone, the effective therapeutic dose of the mitoxantrone liposome is 12-30 mg/m ² , more preferably 12-20 mg/m ² . Specific examples: 12 mg/m ² , 16 mg/m ² , 20 mg/m ² . Preferably, the mitoxantrone liposome is administered intravenously. Preferably, for each intravenous administration, the infusion administration time of the liposome preparation is 30 minutes to 120 minutes, preferably 60 minutes to 120 minutes, more preferably 90±15 minutes. Preferably, the administration method of bortezomib is injection administration, and the dosage is 1.3 mg/m ² . Preferably, the administration method of dexamethasone is oral administration, and the dosage is 20 mg/day. Preferably, the administration cycle of treatment is 4 weeks or 3 weeks, more preferably 4 weeks; in each administration cycle, mitoxantrone liposomes are administered once, bortezomib is administered 4 times, dexamethasone Methasone was administered 8 times. Preferably, multiple myeloma patients are administered effective therapeutic doses of mitoxantrone liposomes, bortezomib and dexamethasone in any order on the first day of each administration cycle, and on the fourth, eighth and Bortezomib was continued on day 11, and dexamethasone was continued on days 2, 4, 5, 8, 9, 11, and 12.

The present invention also provides a medicine for improving the curative effect of mitoxantrone liposome in treating multiple myeloma, said medicine contains bortezomib and dexamethasone, and said bortezomib and dexamethasone are in the mitoxantrone Administration of anthraquinone liposome at any time before, during and after administration. Preferably, based on mitoxantrone, the effective therapeutic dose of the mitoxantrone liposome is 12-30 mg/m ² , more preferably 12-20 mg/m ² . Specific examples: 12 mg/m ² , 16 mg/m ² , 20 mg/m ² . Preferably, the mitoxantrone liposome is administered intravenously. Preferably, for each intravenous administration, the infusion administration time of the liposome preparation is 30 minutes to 120 minutes, preferably 60 minutes to 120 minutes, more preferably 90±15 minutes. Preferably, the administration method of bortezomib is injection administration, and the dosage is 1.3 mg/m ² . Preferably, the administration method of dexamethasone is oral administration, and the dosage is 20 mg/day. Preferably, the administration cycle of treatment is 4 weeks or 3 weeks, more preferably 4 weeks; in each administration cycle, mitoxantrone liposomes are administered once, bortezomib is administered 4 times, dexamethasone Methasone was administered 8 times. Preferably, multiple myeloma patients are administered effective therapeutic doses of mitoxantrone liposomes, bortezomib and dexamethasone in any order on the first day of each administration cycle, and on the fourth, eighth and Bortezomib was continued on day 11, and dexamethasone was continued on days 2, 4, 5, 8, 9, 11, and 12.

Further, the present invention provides a drug combination product for treating multiple myeloma, the drug combination product comprises mitoxantrone hydrochloride liposome, bortezomib and dexamethasone.

Preferably, the liposomes of mitoxantrone hydrochloride, bortezomib and dexamethasone can be present in the same preparation, or can be separately prepared in the form of combined packaging. When the above three drugs are prepared separately, the dosage forms may be the same or different. The dosage form can be any clinically acceptable dosage form, such as injection dosage form, oral dosage form and the like. The injection dosage form includes liquid injection, powder for injection, tablet for injection, etc.; the oral dosage form includes tablet, capsule, oral liquid preparation, etc. Preferably, when the mitoxantrone hydrochloride liposome is a liquid injection, the mitoxantrone contains 0.5-5 mg/ml active ingredient, preferably 1-2 mg/ml, more preferably 1 mg/ml; when boron When tezomib is powder for injection, the specification is 3.5mg/bottle, and it is prepared into a 2.5mg/ml solution when used; when dexamethasone is tablet, the specification is 0.75mg/tablet.

The drug combination product may further contain other second-line and above drugs for the treatment of multiple myeloma. Second-line and above drugs in the treatment of multiple myeloma.

Further, the present invention provides a pharmaceutical composition for the treatment of multiple myeloma, the pharmaceutical composition comprising mitoxantrone hydrochloride liposomes, bortezomib and dexamethasone, the treatment includes the treatment of multiple myeloma Myeloma patients were treated with an effective therapeutic dose of mitoxantrone hydrochloride liposomes, and bortezomib and dexamethasone were administered at any time before, during and after the administration of mitoxantrone hydrochloride liposomes. Preferably, based on mitoxantrone, the effective therapeutic dose of the mitoxantrone hydrochloride liposome refers to 12-30 mg/m ² , more preferably 12-20 mg/m ² . Specific examples: 12 mg/m ² , 16 mg/m ² , 20 mg/m ² . Preferably, the mitoxantrone hydrochloride liposome is administered intravenously. Preferably, for each intravenous administration, the infusion administration time of the liposome preparation is 30 minutes to 120 minutes, preferably 60 minutes to 120 minutes, more preferably 90±15 minutes. Preferably, the administration method of bortezomib is injection administration, and the dosage is 1.3 mg/m ² . Preferably, the administration method of dexamethasone is oral administration, and the dosage is 20 mg/day. Preferably, the treatment administration cycle is 4 weeks or 3 weeks, more preferably 4 weeks; in each administration cycle, mitoxantrone hydrochloride liposomes are administered once, bortezomib is administered 4 times, and Cemethasone was administered 8 times. Preferably, multiple myeloma patients are administered effective therapeutic doses of mitoxantrone hydrochloride liposomes, bortezomib and dexamethasone in any order on the first day of each administration cycle, and on the fourth, eighth and Bortezomib was continued on day 11, and dexamethasone was continued on days 2, 4, 5, 8, 9, 11, and 12.

Further, the present invention provides a medicine for improving the curative effect of bortezomib and dexamethasone in treating multiple myeloma, the medicine contains mitoxantrone hydrochloride liposome, and the mitoxantrone hydrochloride lipid The body was administered at any time before, during and after the administration of bortezomib and dexamethasone. Preferably, based on mitoxantrone, the effective therapeutic dose of the mitoxantrone hydrochloride liposome is 12-30 mg/m ² , more preferably 12-20 mg/m ² . Specific examples: 12 mg/m ² , 16 mg/m ² , 20 mg/m ² . Preferably, the mitoxantrone hydrochloride liposome is administered intravenously. Preferably, for each intravenous administration, the infusion administration time of the liposome preparation is 30 minutes to 120 minutes, preferably 60 minutes to 120 minutes, more preferably 90±15 minutes. Preferably, the administration method of bortezomib is injection administration, and the dosage is 1.3 mg/m ² . Preferably, the administration method of dexamethasone is oral administration, and the dosage is 20 mg/day. Preferably, the treatment administration cycle is 4 weeks or 3 weeks, more preferably 4 weeks; in each administration cycle, mitoxantrone hydrochloride liposomes are administered once, bortezomib is administered 4 times, and Cemethasone was administered 8 times. Preferably, multiple myeloma patients are administered effective therapeutic doses of mitoxantrone hydrochloride liposomes, bortezomib and dexamethasone in any order on the first day of each administration cycle, and on the fourth and eighth days. Bortezomib was continued on days 1 and 11, and dexamethasone was continued on days 2, 4, 5, 8, 9, 11, and 12.

Further, the present invention provides a kind of medicine that is used for improving the curative effect of mitoxantrone hydrochloride liposome treatment multiple myeloma, and described medicine contains bortezomib and dexamethasone, and described bortezomib and dexamethasone Administer at any time before, during and after the administration of mitoxantrone hydrochloride liposomes. Preferably, based on mitoxantrone, the effective therapeutic dose of the mitoxantrone hydrochloride liposome is 12-30 mg/m ² , more preferably 12-20 mg/m ² . Specific examples: 12 mg/m ² , 16 mg/m ² , 20 mg/m ² . Preferably, the mitoxantrone hydrochloride liposome is administered intravenously. Preferably, for each intravenous administration, the infusion administration time of the liposome preparation is 30 minutes to 120 minutes, preferably 60 minutes to 120 minutes, more preferably 90±15 minutes. Preferably, the administration method of bortezomib is injection administration, and the dosage is 1.3 mg/m ² . Preferably, the administration method of dexamethasone is oral administration, and the dosage is 20 mg/day. Preferably, the treatment administration cycle is 4 weeks or 3 weeks, more preferably 4 weeks; in each administration cycle, mitoxantrone hydrochloride liposomes are administered once, bortezomib is administered 4 times, and Cemethasone was administered 8 times. Preferably, on the first day of each administration cycle, the multiple myeloma patients are administered effective therapeutic doses of mitoxantrone hydrochloride liposomes, bortezomib and dexamethasone in any order, and on the fourth and eighth days. Bortezomib was continued on days 1 and 11, and dexamethasone was continued on days 2, 4, 5, 8, 9, 11, and 12.

Among the above-mentioned pharmaceutical combination products, pharmaceutical compositions and medicines related to the treatment of multiple myeloma, the multiple myeloma is preferably relapsed/refractory multiple myeloma.

In the above-mentioned uses, methods, pharmaceutical combination products, pharmaceutical compositions and medicines, the mitoxantrone liposome can be a mitoxantrone ester prepared by a conventional method in the art or any method disclosed in the prior art The plastid can be, for example, mitoxantrone hydrochloride liposome prepared by the method disclosed in WO2008/080367 A1, the disclosure of which is hereby incorporated by reference in its entirety.

In some embodiments, the particle size of the mitoxantrone hydrochloride liposome is about 30-80 nm, which contains: 1) the active ingredient mitoxantrone, which can form with multivalent counterions in the liposome An insoluble precipitate, and 2) a phospholipid bilayer containing phospholipids with a phase transition temperature (Tm) higher than body temperature, thereby giving liposomes a phase transition temperature higher than body temperature. Wherein, the multivalent counter ion is, for example, an organic acid radical, for example, an acid radical selected from the following organic acids: citric acid, tartaric acid, fumaric acid, oxalic acid, malonic acid, succinic acid, malic acid, and maleic acid, etc., or Inorganic acid radicals, such as sulfate radicals, phosphate radicals, or ionized forms of amino acids such as cystine, preferably citrate radicals, sulfate radicals or phosphate radicals; the phospholipids whose Tm is higher than body temperature are phosphatidylcholine, hydrogenated soybean lecithin , hydrogenated egg yolk lecithin, dispalmitate lecithin or distearate lecithin, or any combination thereof.

In some embodiments, the particle diameter of the liposome is about 35-75 nm, preferably 40-70 nm, more preferably 40-60 nm, especially preferably 60 nm.

In some embodiments, the liposomes also contain cholesterol. In some embodiments, the phospholipid bilayer of the liposome may also contain other excipients, especially excipients that can further modify the surface characteristics of the liposome, such as lipids modified with hydrophilic polymers , which can be selected from, for example, polyethylene glycol-modified distearoylphosphatidylethanolamine (DSPE-PEG), polyethylene glycol-modified distearoylphosphatidylglycerol (DSPG-PEG), polyethylene glycol-modified Cholesterol (chol-PEG), povidone-modified distearoylphosphatidylethanolamine (DSPE-PVP), polyethylene glycol-modified distearoylphosphatidylglycerol (DSPG-PVP), polyethylene glycol-modified Cholesterol (chol-PVP) or its combination, preferably distearoylphosphatidylethanolamine modified with polyethylene glycol 2000.

In some embodiments, the phospholipid bilayer contains hydrogenated soybean lecithin (HSPC), cholesterol (Chol) and polyethylene glycol 2000 modified distearoylphosphatidylethanolamine ( DSPE-PEG2000), the particle size of the liposome is about 60nm, and the counter ion is sulfate ion. In some embodiments, the phospholipid bilayer contains HSPC, Chol and DSPE-PEG2000 in a mass ratio of 3:1:1, the particle size of the liposome is about 60 nm, and the counterion is sulfate ion , and the weight ratio of HSPC:Chol:DSPE-PEG2000:mitoxantrone in the liposome is 9.58:3.19:3.19:1. In some embodiments, the mitoxantrone liposomes are mitoxantrone hydrochloride liposomes (trade name: Doenda) approved by the National Pharmaceutical Standard H20220001.

The mitoxantrone liposomes can be prepared by conventional methods in the art, or by any method disclosed in the prior art, for example, by the method disclosed in WO2008/080367 A1, and the content disclosed in this patent is hereby It is incorporated by reference in its entirety. In some embodiments, the mitoxantrone liposomes are prepared as follows: HSPC, Chol and DSPE-PEG2000 are weighed according to a mass ratio of 3:1:1, dissolved in 95% ethanol to obtain a clear solution (i.e. ethanol solution of phospholipids). Mix the ethanol solution of phospholipids with 300 mM ammonium sulfate solution, shake and hydrate at 60-65° C. for 1 hour to obtain heterogeneous multilamellar liposomes. The liposomes are then reduced in size using a microfluidic device. The obtained sample was diluted 200 times with 0.9% NaCl solution, and then detected by NanoZS. The average particle size of the particles was about 60nm, and the main peaks were concentrated between 40nm and 60nm. Afterwards, the ammonium sulfate in the outer phase of the blank liposome was removed using an ultrafiltration device, and the outer phase was replaced with 290 mM sucrose and 10 mM glycine to form a transmembrane ammonium sulfate gradient. According to the lipid-drug ratio of 16:1, mitoxantrone hydrochloride solution (10 mg/mL) was added to the blank liposomes, and the drug was loaded at 60-65°C. After approximately 1 h of incubation, the encapsulation efficiency was demonstrated to be approximately 100% using gel exclusion chromatography. Wherein the weight ratio of HSPC:Chol:DSPE-PEG2000:mitoxantrone is 9.58:3.19:3.19:1, and the osmotic pressure of the sucrose glycine solution is close to the physiological value.

It should be understood that various technical details and parameters in the above exemplary preparation methods can be adjusted and determined within a reasonable range by those skilled in the art. For example, amino acid species that can be substituted for glycine in the outer phase of the transmembrane ammonium sulfate gradient include, but are not limited to, histidine, asparagine, glutamic acid, leucine, proline, alanine. For another example, the mass ratio of HSPC, Chol and DSPE-PEG2000 can be adjusted appropriately. Also for example, for the lipid-drug ratio parameters in the preparation of specific liposome pharmaceutical preparations, those skilled in the art can design, test and finally obtain a suitable lipid-drug ratio to maximize the drug loading while reducing drug leakage. For the mitoxantrone liposome preparation of the present application, the lipid-drug ratio that can be used is in a wide range, such as as low as 2:1 or as high as 30:1, 40:1 or 50:1, which is more suitable The lipid-drug ratio can be about (15-20):1, for example about 15:1, 16:1, 17:1, 18:1, 19:1 or 20:1.

Example

The following examples are intended to specifically illustrate the present invention, but should not be interpreted as limiting the scope of the present invention.

Example 1 Clinical study of mitoxantrone hydrochloride liposome combined with bortezomib and dexamethasone in the treatment of relapsed/refractory multiple myeloma

This study is an open, multi-center, multi-cohort phase I clinical study. 60 subjects with relapsed/refractory MM were randomly assigned to three dose groups (20 cases in each group) according to the ratio of 1:1:1. , were given different doses of mitoxantrone hydrochloride liposomes and fixed doses of bortezomib and dexamethasone. The purpose of this study is to explore the safety and effectiveness of mitoxantrone hydrochloride liposome combined with bortezomib and dexamethasone regimen, and to determine the optimal dosage of mitoxantrone hydrochloride liposome in the combined regimen.

1. Experimental design

1. Overall design

The study consisted of a screening period, a treatment period and a follow-up period.

The screening period is up to 28 days. During this period, the inclusion/exclusion criteria will be reviewed, and the subjects will provide information related to tumor diagnosis and treatment, and complete clinical assessment within the specified time window. Those who pass the screening will enter the treatment period. The first day of each cycle (D1) liposomal mitoxantrone hydrochloride (study drug), bortezomib on D1, D4, D8, D11, D1, D2, D4, D5, D8, D9, D11, D12 Apply dexamethasone. Every 4 weeks (28 days) is a treatment cycle, and 8 cycles of treatment are planned. For subjects who have completed 8 cycles of treatment, if there is a possibility of continuing to benefit and the treatment is tolerated, the investigator and the sponsor can negotiate to determine whether the treatment can be continued. During the treatment period, blood routine, blood biochemical and other laboratory tests, electrocardiogram, echocardiogram, physical examination, vital signs, ECOG score, etc. will be used to evaluate the safety of the subjects until 28 days after the last administration of the study drug, and according to the international According to the evaluation criteria of the Myeloma Working Group (IMWG), the efficacy evaluation was conducted every 2 cycles. Dose adjustments and dosing delays per protocol were allowed from the second treatment cycle onwards. Continue to follow up the survival status of the subjects at the end of the treatment: assess the disease status every 8 weeks (±7d) until the disease progresses/relapses; the subjects who have disease progression/relapse or start other anti-tumor treatments continue to follow up the survival status, A visit or telephone follow-up was performed every 8 weeks (±7d).

2. Dosing regimen

Mitoxantrone hydrochloride liposome, injection (1.0 mg/ml), provided by CSPC Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd. (Guoyao Zhunzi H20220001), the dosages are 12mg/m ² and 16mg respectively /m ² , 20mg/m ² , intravenous infusion on the first day (D1) of each cycle;

Bortezomib, commercially available, with a dosage of 1.3 mg/m ² , subcutaneously injected on D1, D4, D8, and D11;

Dexamethasone is commercially available, and the dosage is 20 mg/d, orally on D1, D2, D4, D5, D8, D9, D11, and D12.

3. Provisions for continued medication

(1) Dosing criteria for the next cycle (CnD1)

1) Absolute neutrophil count (ANC) ≥ 1.5x10 ⁹ /L, platelet ≥ 75x10 ⁹ /L;

2) Non-hematological toxicity must return to ≤ grade 1 or baseline level (except hair loss, pigmentation, peripheral neuropathy);

3) If the administration is delayed due to the inability to meet the 1 or 2 administration criteria, in principle, it shall not exceed 14 days;

4) If the dosing criteria of 1 or 2 cannot be met, or the dosing is delayed for more than 14 days, if the investigator judges that the subject can still benefit, he may consider continuing to take the medicine after communicating with the sponsor.

(2) Dose adjustment

Dose adjustments were allowed during study treatment. The dose of mitoxantrone hydrochloride liposome is reduced by 4mg/m ² each time, the lowest can be reduced to 8mg/m ² ; the dose of bortezomib is reduced by 0.3mg/m ² each time, and the lowest can be reduced to 1.0mg/m ² . Once the dose is reduced, the subsequent treatment of the two drugs will be carried out according to the adjusted dose, or further reduced if necessary, and no increase in dose is allowed. The dosage of dexamethasone is allowed to be adjusted according to the actual clinical situation, and the minimum dosage is 10mg/time.

2. Test population:

(1) Inclusion criteria:

Patients who met all of the following criteria were eligible for this study:

1. The subject fully understands the study, participates voluntarily and signs the informed consent (ICF);

2. Age 18-75 years old, male or female;

3. Cytology or tissue biopsy meets the diagnostic criteria for multiple myeloma (according to IMWG criteria), and relapsed or refractory patients who have received at least one line of treatment;

4. At least one of the following evaluable indicators:

(1) Blood M protein level ≥ 10g/L

(2) 24-hour urinary M protein level ≥ 200mg

(3) The difference between affected and non-involved serum free light chains (dFLC) ≥ 100 mg/L;

5. ECOG score 0-2 points;

6. Laboratory inspections meet the following criteria:

(1) Absolute neutrophil count (ANC) ≥ 1.5x10 ⁹ /L (without receiving G-CSF treatment within 1 week before the examination);

(2) Platelet (PLT) ≥ 75x10 ⁹ /L (no platelet transfusion therapy within 1 week before the test);

(3) Total bilirubin ≤ 1.5 times the upper limit of normal (ULN);

(4) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times ULN;

(5) Creatinine clearance rate (Ccr) ≥ 30ml/min;

7. Female subjects must have a negative blood HCG test result before enrolling in this trial, and agree to take a recognized very effective contraceptive measure from signing the ICF to at least 7 months after the end of the last dose [for example: combined hormone ( Containing estrogen and progesterone) combined with ovulation suppression, progesterone contraception combined with ovulation suppression, intrauterine device, intrauterine hormone releasing system, bilateral tubal ligation, vasectomy, etc.]. Except those who have been menopausal (stopping menstruation for at least 1 year); except those who have undergone hysterectomy or bilateral oophorectomy;

8. Male subjects and their partners agree to take one of the contraceptive measures described in Article 8 from signing the ICF to at least 4 months after the end of the last dose.

(2) Exclusion criteria:

Those who meet any of the following exclusion criteria are not eligible for this study:

1. Subjects with amyloidosis or central nervous system invasion or undergoing dialysis treatment;

2. Expected survival time < 3 months;

3. Have a history of allergy to mitoxantrone or liposomal drugs; or have received anthracyclines in the past, and the total cumulative dose of anthracyclines is converted to doxorubicin ≥ 350mg/m ² (anthracyclines, etc. Effective dose conversion: 1mg doxorubicin=2mg epirubicin/pyrarubicin/daunorubicin=0.5mg demethoxydaunorubicin=0.45mg mitoxantrone; except for doxorubicin liposome );

4. Have a history of allergy to bortezomib (except for local injection reactions) or intolerance; or one of the following situations in the previous standard treatment of bortezomib-containing regimens: no therapeutic response (not reaching MR); 6 months after the end of the last medication Disease progression within a month;

5. Contraindications or intolerance to dexamethasone;

6. Received any clinical routine anti-myeloma drug therapy (3 weeks before the first administration of thalidomide, 2 weeks before the first administration of systemic glucocorticoids) or radiotherapy within 4 weeks before the first administration of the study drug; Or received investigational anti-myeloma drug treatment within 3 months before the first dose of the study drug;

7. Received autologous hematopoietic stem cell transplantation within 6 months before screening;

8. After allogeneic hematopoietic stem cell transplantation or allogeneic organ transplantation;

9. The toxicity of previous anti-tumor therapy has not recovered to ≤ grade 1 (except hair loss and pigmentation);

10. Persistent ≥ grade 2 peripheral neuropathy or grade 1 peripheral neuropathy with pain;

11. Impaired cardiac function or significant cardiac disease, including but not limited to:

(1) Myocardial infarction and viral myocarditis occurred within 6 months before screening;

(2) There are heart diseases that need to be treated during screening, such as unstable angina, chronic congestive heart failure (NYHA ≥ 2), arrhythmia, valvular disease, etc., or persistent cardiomyopathy;

(3) QTc interval > 480ms or suffering from long QTc syndrome at the time of screening;

(4) Cardiac ejection fraction is lower than 50% or lower than the lower limit of the inspection value range of the research center at the time of screening;

12. HBsAg or HBcAb positive and HBV-DNA titer higher than the lower limit of the detection value of the research center, or HCV antibody positive and HCV-RNA titer higher than the lower limit of the detection value of the research center, or HIV antibody positive;

13. Obvious digestive system dysfunction, which may affect the intake, transport, and absorption of drugs (such as inability to swallow, total gastrectomy, intestinal obstruction, etc.);

14. Suffer from bacterial infection, fungal infection or viral infection requiring systemic treatment within 1 week before the administration of the study drug;

15. Those who have undergone major surgery within 6 weeks before the first drug administration, or plan to have major surgery during the study treatment;

16. Suffering from other malignant tumors in the past 5 years (except cured locally curable tumors, such as basal or squamous cell skin cancer or prostate cancer in situ, cervical cancer or breast cancer);

17. Suffering from other diseases judged by the investigators to be inappropriate to participate in this study, including but not limited to hypertension (systolic blood pressure ≥ 140mmHg and/or diastolic blood pressure ≥ 90mmHg measured multiple times), drug control not up to standard Diabetes (fasting blood sugar>7mmol/L or glycosylated hemoglobin≥7.0%), chronic obstructive pulmonary disease, pulmonary embolism, cerebral thrombosis or cerebral hemorrhage within 6 months;

18. Women who are pregnant or breastfeeding;

19. There are situations where other researchers judge that it is not suitable to participate in this study.

3. Research results

Efficacy evaluation

According to the IMWG standard for efficacy evaluation, it is divided into strict complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), stable disease (SD) and progressive disease (PD). .

Overall response rate (ORR) = (sCR+CR+VGPR+PR)/total number of evaluable cases*100%.

As of August 17, 2022, a total of 12 multiple myeloma subjects have been enrolled in this project. 5 subjects had at least one efficacy evaluation, of which, 1 subject was evaluated for PR (partial response), 3 subjects were evaluated for VGPR (very good partial response), and 1 subject was evaluated for sCR (strict response). Significant complete remission), ORR=100% (5/5).

The above results showed that the regimen of mitoxantrone hydrochloride liposome combined with bortezomib and dexamethasone significantly improved the ORR in patients with relapsed/refractory MM.

4. Typical cases

Case 1: After multiple myeloma was diagnosed, the effect of thalidomide was not good, and the TD (thalidomide + dexamethasone) program was evaluated as VGPR. After re-examination and evaluation of PD, he participated in a clinical trial and was given CPT/placebo + Thalidomide + dexamethasone was treated for 4 courses, and after the disease progression was evaluated, mitoxantrone liposome + bortezomib + dexamethasone was given for 2 courses, and the evaluation was sCR.

Case 2: After multiple myeloma was diagnosed, bortezomib + doxorubicin liposome + dexamethasone was given for 4 courses of treatment, and it was evaluated as CR, and then Isapride + doxorubicin liposome + dexamethasone was given for treatment 1 course of treatment, after assessment of disease progression, 2 courses of mitoxantrone liposome + bortezomib + dexamethasone were given, and the assessment was VGPR.

Case 3: After diagnosis of multiple myeloma, TBCD (thalidomide + bortezomib + cyclophosphamide + dexamethasone) program 1 course, BCD (bortezomib + cyclophosphamide + dexamethasone) program 3 After a course of treatment, it was evaluated as PR, and it was evaluated as disease recurrence after continuing to give 4 courses of BCD regimen, 2 courses of BD (bortezomib + dexamethasone) regimen, and 1 course of BRD (bortezomib + lenalidomide + dexamethasone) regimen , BRD regimen was given for 2 courses, and after the assessment of disease progression, mitoxantrone liposome + bortezomib + dexamethasone was given for 2 courses of treatment, and the assessment was VGPR.

Case 4: After multiple myeloma was diagnosed, VADT (vincristine + doxorubicin + dexamethasone + thalidomide) regimen was given for 8 courses, and it was evaluated as SD, and then dexamethasone + thalidomide was given for treatment After 2 courses of treatment, it was assessed as PD, and then participated in clinical trials, given CPT/placebo + thalidomide + dexamethasone regimen for 4 courses of treatment, and after evaluating disease progression, mitoxantrone liposome + bortezomib + dexamethasone was given Methasone treatment for 2 courses, assessed as VGPR.

Claims (10)

1. The purposes of mitoxantrone liposome, bortezomib and dexamethasone in the preparation of the medicine for treating multiple myeloma. 2. The use of mitoxantrone liposomes in the preparation of drugs for improving the curative effect of bortezomib and dexamethasone in treating multiple myeloma. 3. The use of bortezomib and dexamethasone in the preparation of drugs for improving the curative effect of mitoxantrone liposomes in treating multiple myeloma. 4. The use according to any one of claims 1-3, characterized in that the multiple myeloma is relapsed/refractory multiple myeloma. 5. The use according to any one of claims 1-3, wherein the mitoxantrone liposome is mitoxantrone hydrochloride liposome. 6. purposes as claimed in claim 5, the particle diameter of wherein said mitoxantrone hydrochloride liposome is 30～80 nm, and it contains: 1) active ingredient mitoxantrone, it and liposome poly 2) phospholipid bilayers containing phospholipids with a phase transition temperature (Tm) above body temperature selected from phosphatidylcholine, hydrogenated soybean lecithin, hydrogenated egg yolk lecithin , lecithin disistearate or lecithin distearate, or any combination thereof. 7. A drug combination product for treating multiple myeloma, said drug combination product comprising mitoxantrone liposome, bortezomib and dexamethasone. 8. The pharmaceutical combination product according to claim 7, wherein said multiple myeloma is relapsed/refractory multiple myeloma. 9. The pharmaceutical combination product according to claim 7 or 8, wherein the mitoxantrone liposome is mitoxantrone hydrochloride liposome. 10. The pharmaceutical combination product as claimed in claim 9, wherein the particle diameter of the mitoxantrone hydrochloride liposome is 30-80 nm, which contains: 1) active ingredient mitoxantrone, which is mixed with liposome 2) a phospholipid bilayer containing phospholipids with a phase transition temperature (Tm) above body temperature selected from the group consisting of phosphatidylcholine, hydrogenated soybean lecithin, hydrogenated egg yolk Lecithin, dispalmitate lecithin or distearate lecithin, or any combination thereof.