CN115770288A - Use of mitoxantrone liposomes, bortezomib and dexamethasone for treating multiple myeloma - Google Patents
Use of mitoxantrone liposomes, bortezomib and dexamethasone for treating multiple myeloma Download PDFInfo
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- CN115770288A CN115770288A CN202211089751.6A CN202211089751A CN115770288A CN 115770288 A CN115770288 A CN 115770288A CN 202211089751 A CN202211089751 A CN 202211089751A CN 115770288 A CN115770288 A CN 115770288A
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- mitoxantrone
- bortezomib
- dexamethasone
- multiple myeloma
- liposome
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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
Technical Field
The invention relates to the field of anti-tumor, in particular to application of mitoxantrone liposome, bortezomib and dexamethasone in preparing a medicament for treating relapsed/refractory Multiple Myeloma (MM).
Background
Multiple Myeloma (MM) is a malignant disease of abnormal proliferation of monoclonal plasma cells, which occurs well in the elderly, with a median age of 66 years (Robert A Kyle, et al, review of 1027 tissues with a new differentiated multiple myelomas. Mayo Clin Proc. 2003 Jan; 78 (1): 21-33), and with a slightly higher incidence in men. MM is the second largest malignancy of the blood system as a global disease from an epidemiological perspective, with highest incidence in australia, north america, and western europe. In China, the incidence of MM is 1-2/10 ten thousand, 1.65 million new cases in 2016, 1.04 million cases of death, and the number of cases of morbidity/mortality is ranked second around the world (Andrew J Cowan, et al, global Burden of Multiple Myeloma: A Systematic Analysis for the Global Burden of Disease Study 2016. MA Oncol. 2018 JASep 1; 4 (9): 1221-1227). The advent of new drugs, which altered the therapeutic modality and prognosis of MM with a median OS of about 6 years (S Vincent Rajkumar. Multiple myelomas: 2020 update on diagnosis, risk-modification and management. Am J Hematol. 2020 May; 95 (5): 548-567). However, MM still has the characteristics of repeated relapse and drug resistance, and cannot be cured, and relapse/difficult treatment still remains a problem.
In the treatment of MM, anthracyclines are an important component of MM therapy, whether they are the traditional therapy time anthracyclines in combination with vincristine, dexamethasone (VAD regimen), or the new drug time anthracyclines in combination with bortezomib, dexamethasone (PAD regimen). With the advent of new drugs, the use of anthracyclines has decreased. Mei ao guidelines 2020 recommend anthracycline-containing multi-drug combination regimens for patients with aggressive relapses of plasma cell leukemia, extramedullary lesions, and the like (S Vincent Rajkumar. Multiple myelomas: 2020 update on diagnosis, risk-targeting and management. Am J Hematol. 2020 May; 95 (5): 548-567). 2020 plan containing anthracene rings such as PAD and TAD (thalidomide + adriamycin + dexamethasone) in China MM medical guidelines are still recommended in the first line, and combined plan containing cytotoxic drugs is also recommended for relapsed MM with extramedullary lesions (Chinese multiple myeloma medical guidelines revised 2020 [ J ], chinese medical information guide, 2020, 35 (11): 12-12). Bortezomib + doxorubicin liposomes + dexamethasone (PAD regimen), bortezomib + dexamethasone (PD regimen) for treatment of relapsed/refractory MM, still under NCCN guideline class 1 recommendations version 2021 (NCCN Clinical practices Guidelines) multiple myeloelma. Version 3.2021. 64 relapsed/refractory multiple myeloma patients were enrolled in a multicenter clinical trial and received PAD regimen (bortezomib + doxorubicin/doxorubicin liposomes + dexamethasone) with 43 patients who achieved at least PR (67%), including CR (9%) and VGPR (16%); during PAD regimen treatment, the most common grade 1-2 adverse events were anemia (42%), decreased neutrophil count (30%), decreased platelet count (27%), peripheral neuropathy (27%), nausea (14%), diarrhea (11%), and unexplained fever (11%); the 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%), with no patients presenting with grade 4 peripheral neuropathy (A Palombo, et al, bortezomib, doxorubicin and dexamethone in advanced multiple myotoma. Ann Oncol. 2008 Jun; 19 (6): 1160-5). In another endeakor study, the Objective Remission Rate (ORR) of the PD regimen was 60.3% and median progression-free survival (PFS) was 8.1 months for 252 relapsed/refractory MM patients who had previously used bortezomib; for 177 relapsed/refractory MM patients who had previously been treated with lenalidomide, the PD regimen had an ORR of 59.3% and a median PFS of 7.3 months (P Moreau, et al, impact of prior treatment on tissues with replayed multiple myobacteria derived from a tissue with a nonfififizomib and a demethanisone vs. bortezomib and a demethanisone in the phase 3 ENDEAVOR study, leukamia 2017 Jan; 31 (1): 115-122).
The adverse reactions of the anthracyclines mainly comprise cardiotoxicity, bone marrow toxicity, gastrointestinal reactions and the like. After doxorubicin, anthracyclines such as epidoxorubicin, doxorubicin liposome and the like appear in succession, so that the safety is improved, but the curative effect is not different. A Randomized controlled phase 3 clinical study was included in 646 patients with relapsed/refractory MM who compared the efficacy of doxorubicin liposomes in combination with bortezomib for monotherapy (Robert Z Orlowski, et al, randomized phase III study of pegylated lipofectin plus bortezomib complexed with bortezomib alone in a patient from a patient or a reaction multiple molecule, combination therapy approach time to progression, J Clin Oncol, 2007 Sep 1; 25 (25): 3892-901). Research results show that the median PFS of the adriamycin liposome combined with bortezomib is 9 months, the release rate is more than or equal to 27% of VGPR, the two drugs are all obviously superior to the single bortezomib drug, and the combination of the two drugs has a synergistic effect. Based on this study, doxorubicin liposomes were FDA approved in 2007 for relapsed/refractory MM treatment in combination with bortezomib. The combination of 3-4 drugs based on two drugs also has a certain therapeutic effect on relapsed/refractory MM (a Palumbo, et al, bortezomib, doxorubicin and dexamethasone in advanced multiple myeloma. Ann oncol. 2008 Jun; 1160-5, stefania ciri, et al, the addition of lipoplastic doxobicin to Bortezomib, clinical and Dexamethylketone design improvements, 14 (6), 814-9, massimo Offidani, et al, clinical, dexamethylketone, doxil and Velcade (ThaDD-V) foley association/maintanacet in palatine with modified specimen, 9-9, massimo specimen, et al, ampholytic, curative, dexamethylketone, doxil and Velcro (ThaDD-V), 9-56, no. 11, german and Western specimen with modified specimen, 9-56, no. 11, 28, application of beta, 7, 80, application of drugs including branched or branched peptides, 2, 80, for patients.
Mitoxantrone (Mitoxantrone) is an anthracycline drug that has been used to date in over 30 countries worldwide. At the end of the seventies of the twentieth century, the U.S. began a clinical study relating to mitoxantrone, and a series of clinical trials showed that mitoxantrone, whether administered alone or in combination with other drugs, has therapeutic effects on hematological tumors such as acute leukemia, lymphoma, and various solid tumors such as breast cancer. The adverse reactions are mainly manifested by bone marrow suppression, gastrointestinal reactions and cardiotoxicity. Mitoxantrone is mainly used for treating acute myeloid leukemia clinically.
Liposomes are a novel drug-loaded form. Studies have shown that it can alter the in vivo distribution of encapsulated drugs, allowing the drug to accumulate primarily in tumor tissue, thereby increasing the therapeutic index of the drug, reducing the therapeutic dose of the drug, and reducing drug toxicity. These characteristics make the application of liposome drug-loaded drugs in the research of antitumor drugs highly appreciated. There are researchers working on mitoxantrone liposome formulations. For example, chinese patent application 200610102339.8, filed on 29.12.2006, and PCT application WO2008/080367A1, filed on 29.12.2007, disclose mitoxantrone liposomes, the disclosures of which are incorporated herein by reference in their entirety. Researches show that compared with a mitoxantrone common preparation, the liposome preparation has lower toxicity (particularly cardiotoxicity), has the characteristic of passively targeting tumor tissues and improves the antitumor activity.
The mitoxantrone hydrochloride liposome injection single-drug phase I has completed the exploration of dose ramp and PK/PD studies in subjects with advanced solid tumors and lymphoma. According to the test result, the mitoxantrone hydrochloride liposome injection is 6-30 mg/m 2 Is safely tolerated within the dosage range and shows a certain therapeutic effect. Critical phase ii of mitoxantrone hydrochloride liposomal single drug administration was performed in relapsed/refractory Peripheral T Cell Lymphoma (PTCL) patients and completed into cohorts (n =108, administered at a dose of 20 mg/m) 2 ) The ORR, evaluated by the Independent Review Committee (IRC) and confirmed by efficacy, is currently 40.7%.
In view of the better single drug efficacy of mitoxantrone liposomes in relapsed/refractory PTCL patients, further investigations of mitoxantrone liposome combinations were carried out in relapsed/refractory MM patients. Preliminary clinical study results show that the regimen of mitoxantrone liposome in combination with bortezomib and dexamethasone is safe and tolerant, improves the Objective Remission Rate (ORR) of relapsed/refractory MM patients, prolongs the duration of remission (DoR), and improves PFS and OS, thereby improving the quality of life of patients and benefiting MM patients.
Relapse/refractory to MM remains a problem faced by clinicians. In the new drug age, anthracyclines are still one of the important components of combined drugs as a traditional drug for MM treatment. Mitoxantrone liposomes are highly effective and low toxic anthracycline (quinone) drugs, and the combination of mitoxantrone liposomes with bortezomib and dexamethasone is expected to be the treatment option for relapsing/refractory MM, especially for patients with invasive relapse.
Disclosure of Invention
The invention relates to application of mitoxantrone liposome, bortezomib and dexamethasone in preparation of a medicine for treating multiple myeloma.
The invention also relates to application of the mitoxantrone liposome in preparing a medicament for improving the curative effect of bortezomib and dexamethasone on treating multiple myeloma.
The invention also relates to application of bortezomib and dexamethasone in preparing a medicine for improving the curative effect of mitoxantrone liposome on treating multiple myeloma.
The invention also provides a method of treating multiple myeloma comprising administering to a multiple myeloma patient a therapeutically effective amount of mitoxantrone liposomes, bortezomib and dexamethasone.
The invention also provides a method for improving the efficacy of bortezomib and dexamethasone in the treatment of multiple myeloma, comprising the further co-administration of a therapeutically effective amount of mitoxantrone liposomes based on the administration of bortezomib and dexamethasone to a patient with multiple myeloma.
The invention also provides a method of improving the efficacy of mitoxantrone liposomes for the treatment of multiple myeloma, said method comprising administering to a patient with multiple myeloma a therapeutically effective amount of bortezomib in combination with dexamethasone.
The invention also provides a pharmaceutical combination for treating multiple myeloma, comprising mitoxantrone liposomes, bortezomib and dexamethasone.
The invention also provides a medicament for improving the efficacy of bortezomib and dexamethasone in the treatment of multiple myeloma, comprising mitoxantrone liposomes.
The invention also provides a medicament for improving the curative effect of mitoxantrone liposome on treatment of multiple myeloma, wherein the medicament comprises bortezomib and dexamethasone.
Detailed Description
Unless otherwise specified, the terms used in the present invention have the following definitions:
"relapse" is defined as the previous treatment achieving Minimal Remission (MR) and above, followed by disease progression.
"refractory" is defined as the first line application of any treatment that does not reach the MR.
"mitoxantrone" includes mitoxantrone and its pharmaceutically acceptable salts, preferably mitoxantrone hydrochloride. The mitoxantrone liposome is preferably mitoxantrone hydrochloride liposome.
The term "administration in any order" means that the mitoxantrone liposome, bortezomib and dexamethasone are separately prepared and administered separately in a clinically acceptable manner, and the order of administration is not mandatory; the drugs were not mixed in vitro.
The invention provides application of mitoxantrone liposome, bortezomib and dexamethasone in preparation of a medicine for treating multiple myeloma.
The invention also provides application of the mitoxantrone liposome in preparing a medicament for improving the curative effect of bortezomib and dexamethasone on treating multiple myeloma.
The invention also provides application of bortezomib and dexamethasone in preparing a medicine for improving the curative effect of mitoxantrone liposome on treating multiple myeloma.
Further, the invention provides application of mitoxantrone hydrochloride liposome, bortezomib and dexamethasone in preparing a medicine for treating multiple myeloma.
Further, the invention provides application of the mitoxantrone hydrochloride liposome in preparing a medicine for improving the curative effect of bortezomib and dexamethasone on treating multiple myeloma.
Further, the invention provides application of bortezomib and dexamethasone in preparing a medicine for improving the curative effect of mitoxantrone hydrochloride liposome on treating multiple myeloma.
In the above use, the multiple myeloma is preferably relapsed/refractory multiple myeloma.
The present invention provides a method of treating multiple myeloma comprising administering to a multiple myeloma patient a therapeutically effective amount of mitoxantrone liposomes, bortezomib and dexamethasone.
The invention also provides a method for improving the efficacy of bortezomib and dexamethasone in the treatment of multiple myeloma, comprising the further co-administration of a therapeutically effective amount of mitoxantrone liposomes based on the administration of bortezomib and dexamethasone to a patient with multiple myeloma.
The invention also provides a method of improving the efficacy of mitoxantrone liposomes for the treatment of multiple myeloma, said method comprising administering to a patient with multiple myeloma a therapeutically effective amount of bortezomib in combination with dexamethasone.
In the above method, the multiple myeloma is preferably relapsed/refractory multiple myeloma.
In the above method, the administration of mitoxantrone liposomes and bortezomib is preferably administered by injection; dexamethasone is preferably administered orally. Preferably, the therapeutically effective amount of mitoxantrone liposomes is 12 to 30mg/m, based on mitoxantrone 2 More preferably 12 to 20mg/m 2 . Specific examples thereof include: 12mg/m 2 ，16 mg/m 2 ，20mg/m 2 . Preferably, the mitoxantrone liposomes are administered intravenously. Preferably, the administration time of the liposome preparation by instillation is 30min to 120min, preferably 60min to 120min, and further preferably 90 +/-15 min for each intravenous administration. Preferably, the bortezomib is administered by injection at a dose of 1.3mg/m 2 . Preferably, dexamethasone is administered orally at a dose of 20 mg/day. Preferably, the administration period for the treatment is 4 weeks or 3 weeks, further preferably 4 weeks; in each administration cycle, mitoxantrone liposome was administered 1 time, bortezomib 4 times, and dexamethasone 8 times. Preferably, therapeutically effective amounts of mitoxantrone liposomes, bortezomib and dexamethasone are administered sequentially, in any order, to multiple myeloma patients on day 1 of each dosing cycle, with bortezomib continuing on days 4, 8 and 11, and on days 2, 4, 5, 8, b,Dexamethasone continued to be administered on days 9, 11, and 12.
Further, the present invention provides a method of treating multiple myeloma comprising administering to a patient with multiple myeloma a therapeutically effective amount of mitoxantrone hydrochloride liposomes, bortezomib and dexamethasone.
Further, the present invention provides a method for improving the efficacy of bortezomib and dexamethasone in the treatment of multiple myeloma, said method comprising administering a therapeutically effective amount of mitoxantrone hydrochloride liposomes in combination with further bortezomib and dexamethasone to a patient with multiple myeloma.
Further, the present invention provides a method for improving the efficacy of mitoxantrone hydrochloride liposomes for the treatment of multiple myeloma, said method comprising administering to a patient with multiple myeloma a therapeutically effective amount of bortezomib in combination with dexamethasone.
In the above method, the multiple myeloma is preferably relapsed/refractory multiple myeloma.
In the above method, the mitoxantrone hydrochloride liposome and bortezomib are administered preferably by injection; dexamethasone is preferably administered orally. Preferably, the mitoxantrone hydrochloride liposome has a therapeutically effective dose, calculated as mitoxantrone, of 12 to 30mg/m 2 More preferably 12 to 20mg/m 2 . Specific examples thereof include: 12mg/m 2 ，16 mg/m 2 ，20mg/m 2 . Preferably, the mitoxantrone hydrochloride liposome is administered intravenously. Preferably, the administration time of the liposome preparation by instillation is 30min to 120min, preferably 60min to 120min, and further preferably 90 +/-15 min for each intravenous administration. Preferably, the bortezomib is administered by injection at a dose of 1.3mg/m 2 . Preferably, dexamethasone is administered orally at a dose of 20 mg/day. Preferably, the administration period for the treatment is 4 weeks or 3 weeks, further preferably 4 weeks; in each administration cycle, mitoxantrone hydrochloride liposome was administered 1 time, bortezomib 4 times, and dexamethasone 8 times. Preferably, each administration weekMultiple myeloma patients were given therapeutically effective doses of mitoxantrone hydrochloride liposomes, bortezomib and dexamethasone, in any order, on day 1, with continued bortezomib administration on days 4, 8 and 11, and dexamethasone on days 2, 4, 5, 8, 9, 11 and 12.
The invention also provides a pharmaceutical combination for treating multiple myeloma, comprising mitoxantrone liposomes, bortezomib and dexamethasone. Preferably, the mitoxantrone liposome, bortezomib and dexamethasone can be present in the same formulation or separate formulations, in a combined package. When the above 3 drugs are separately prepared, 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 forms comprise liquid injection, powder for injection, tablets for injection and the like; the oral dosage forms include tablets, capsules, oral liquid preparations and the like. Preferably, when the mitoxantrone liposome is a liquid injection, the mitoxantrone liposome contains 0.5-5mg/ml of active ingredient, preferably 1-2mg/ml, and more preferably 1mg/ml of active ingredient; when the bortezomib is powder for injection, the specification is 3.5 mg/bottle, and a solution of 2.5mg/ml is prepared when the bortezomib is used; when dexamethasone is used as tablet, the specification is 0.75 mg/tablet.
The drug combination product can further comprise other second-line and above drugs for treating multiple myeloma, and the drugs refer to second-line and above drugs approved for treating multiple myeloma by drug administration in China or other countries (such as the United states, european Union, japan, korea and the like).
The invention also provides a pharmaceutical composition for treating multiple myeloma, wherein the pharmaceutical composition comprises mitoxantrone liposome, bortezomib and dexamethasone, and the treatment comprises the steps of using mitoxantrone liposome with effective treatment dose for patients with multiple myeloma and administering the mitoxantrone liposome and the dexamethasone before, in the middle of and after the mitoxantrone liposome is administrated. Preferably, the therapeutically effective amount of mitoxantrone liposomes, based on mitoxantrone, is12-30 mg/m of finger 2 More preferably 12 to 20mg/m 2 . Specific examples thereof include: 12mg/m 2 ，16 mg/m 2 ，20mg/m 2 . Preferably, the mitoxantrone liposomes are administered intravenously. Preferably, the administration time of the liposome preparation by instillation is 30min to 120min, preferably 60min to 120min, and further preferably 90 +/-15 min for each intravenous administration. Preferably, the bortezomib is administered by injection at a dose of 1.3mg/m 2 . Preferably, dexamethasone is administered orally at a dose of 20 mg/day. Preferably, the administration period for the treatment is 4 weeks or 3 weeks, further preferably 4 weeks; in each administration cycle, mitoxantrone liposome was administered 1 time, bortezomib 4 times, and dexamethasone 8 times. Preferably, therapeutically effective doses of mitoxantrone liposomes, bortezomib and dexamethasone are administered to multiple myeloma patients on day 1 of each dosing cycle, in any order, with bortezomib being administered on days 4, 8 and 11, and dexamethasone being administered on days 2, 4, 5, 8, 9, 11 and 12.
The invention also provides a medicament for improving the curative effect of bortezomib and dexamethasone on treatment of multiple myeloma, which comprises mitoxantrone liposome, wherein the mitoxantrone liposome is administered before, during and after bortezomib and dexamethasone. Preferably, the therapeutically effective amount of mitoxantrone liposomes is 12 to 30mg/m, based on mitoxantrone 2 More preferably 12 to 20mg/m 2 . Specific examples thereof include: 12mg/m 2 ，16 mg/m 2 ，20mg/m 2 . Preferably, the mitoxantrone liposomes are administered intravenously. Preferably, the administration time of the liposome preparation by instillation is 30min to 120min, preferably 60min to 120min, and further preferably 90 +/-15 min for each intravenous administration. Preferably, the bortezomib is administered by injection at a dose of 1.3mg/m 2 . Preferably, dexamethasone is administered orally at a dose of 20 mg/day. Preferably, the administration period for the treatment is 4 weeks or 3 weeks, further preferably 4 weeks; in each administration cycle, mitoxantrone liposome was administered 1 time, bortezomib was administeredDexamethasone was administered 4 times and 8 times. Preferably, therapeutically effective doses of mitoxantrone liposomes, bortezomib and dexamethasone are administered to multiple myeloma patients on day 1 of each dosing cycle, in any order, with bortezomib being administered sequentially on days 4, 8 and 11, and dexamethasone being administered sequentially on days 2, 4, 5, 8, 9, 11 and 12.
The invention also provides a medicament for improving the curative effect of mitoxantrone liposome on treatment of multiple myeloma, which comprises bortezomib and dexamethasone, wherein the bortezomib and the dexamethasone are administered at any time before, during and after the mitoxantrone liposome is administered. Preferably, the therapeutically effective amount of mitoxantrone liposome is 12 to 30mg/m, based on mitoxantrone 2 More preferably 12 to 20mg/m 2 . Specific examples thereof include: 12mg/m 2 ，16 mg/m 2 ，20mg/m 2 . Preferably, the mitoxantrone liposome is administered intravenously. Preferably, the administration time of the liposome preparation by instillation is 30min to 120min, preferably 60min to 120min, and further preferably 90 +/-15 min for each intravenous administration. Preferably, the bortezomib is administered by injection at a dose of 1.3mg/m 2 . Preferably, dexamethasone is administered orally at a dose of 20 mg/day. Preferably, the administration period for the treatment is 4 weeks or 3 weeks, further preferably 4 weeks; in each administration cycle, mitoxantrone liposome was administered 1 time, bortezomib 4 times, and dexamethasone 8 times. Preferably, therapeutically effective doses of mitoxantrone liposomes, bortezomib and dexamethasone are administered to multiple myeloma patients on day 1 of each dosing cycle, in any order, with bortezomib being administered sequentially on days 4, 8 and 11, and dexamethasone being administered sequentially on days 2, 4, 5, 8, 9, 11 and 12.
Further, the present invention provides a pharmaceutical combination for the treatment of multiple myeloma, said pharmaceutical combination comprising mitoxantrone hydrochloride liposomes, bortezomib and dexamethasone.
Preferably, the mitoxantrone hydrochloride liposome, bortezomib and dexamethasone can be present in the same preparation or can be separately prepared and present in a combined package. When the above 3 drugs are separately prepared, 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 forms comprise liquid injection, powder for injection, tablets for injection and the like; the oral dosage forms include tablets, capsules, oral liquid preparations and the like. Preferably, when the mitoxantrone hydrochloride liposome is a liquid injection, the mitoxantrone hydrochloride liposome contains 0.5-5mg/ml of active ingredient, preferably 1-2mg/ml, and more preferably 1mg/ml; when the bortezomib is powder for injection, the specification is 3.5 mg/bottle, and a solution of 2.5mg/ml is prepared when the bortezomib is used; when dexamethasone is used as tablet, the specification is 0.75 mg/tablet.
The drug combination product can further comprise other second-line and above drugs for treating multiple myeloma, and the drugs refer to second-line and above drugs approved for treating multiple myeloma by drug administration in China or other countries (such as the United states, european Union, japan, korea and the like).
Further, the invention provides a pharmaceutical composition for treating multiple myeloma, wherein the pharmaceutical composition comprises mitoxantrone hydrochloride liposome, bortezomib and dexamethasone, and the treatment comprises the step of administering the mitoxantrone hydrochloride liposome with effective treatment dose to a patient with multiple myeloma and the step of administering the mitoxantrone hydrochloride liposome and the dexamethasone at any time before, during and after the mitoxantrone hydrochloride liposome is administered. Preferably, the effective therapeutic dose of mitoxantrone hydrochloride liposome is 12-30 mg/m based on mitoxantrone 2 More preferably 12 to 20mg/m 2 . Specific examples thereof include: 12mg/m 2 ，16 mg/m 2 ，20mg/m 2 . Preferably, the mitoxantrone hydrochloride liposome is administered intravenously. Preferably, the administration time of the liposome preparation by instillation is 30min to 120min, preferably 60min to 120min, and further preferably 90 +/-15 min for each intravenous administration. Preferably, the bortezomib is administered by injection at a dose of 1.3mg/m 2 . Preferably, dexamethasone is administered orally,the dosage was 20 mg/day. Preferably, the administration period for the treatment is 4 weeks or 3 weeks, further preferably 4 weeks; in each administration cycle, mitoxantrone hydrochloride liposome was administered 1 time, bortezomib 4 times, and dexamethasone 8 times. Preferably, therapeutically effective doses of mitoxantrone hydrochloride liposomes, bortezomib and dexamethasone are administered to multiple myeloma patients on day 1 of each dosing cycle, sequentially in any order, with bortezomib being administered on days 4, 8 and 11, and dexamethasone being administered on days 2, 4, 5, 8, 9, 11 and 12.
Further, the invention provides a medicament for improving the curative effect of bortezomib and dexamethasone on treatment of multiple myeloma, wherein the medicament contains mitoxantrone hydrochloride liposome, and the mitoxantrone hydrochloride liposome is administered before, during and after bortezomib and dexamethasone. Preferably, the mitoxantrone hydrochloride liposome has a therapeutically effective dose, calculated as mitoxantrone, of 12 to 30mg/m 2 More preferably 12 to 20mg/m 2 . Specific examples thereof include: 12mg/m 2 ，16 mg/m 2 ，20mg/m 2 . Preferably, the mitoxantrone hydrochloride liposome is administered intravenously. Preferably, the administration time of the liposome preparation by instillation is 30min to 120min, preferably 60min to 120min, and further preferably 90 +/-15 min for each intravenous administration. Preferably, the bortezomib is administered by injection at a dose of 1.3mg/m 2 . Preferably, dexamethasone is administered orally at a dose of 20 mg/day. Preferably, the administration period for the treatment is 4 weeks or 3 weeks, further preferably 4 weeks; in each administration cycle, mitoxantrone hydrochloride liposome was administered 1 time, bortezomib 4 times, and dexamethasone 8 times. Preferably, therapeutically effective doses of mitoxantrone hydrochloride liposomes, bortezomib and dexamethasone are administered to multiple myeloma patients on day 1 of each dosing cycle, in any order, with bortezomib being administered sequentially on days 4, 8 and 11, and dexamethasone being administered sequentially on days 2, 4, 5, 8, 9, 11 and 12.
Further, the invention provides a method for improving mitoxantrone hydrochlorideA medicament for the plastidic treatment of multiple myeloma, said medicament comprising bortezomib and dexamethasone administered at any time before, during or after the administration of mitoxantrone hydrochloride liposomes. Preferably, the mitoxantrone hydrochloride liposome has a therapeutically effective dose, calculated as mitoxantrone, of 12 to 30mg/m 2 More preferably 12 to 20mg/m 2 . Specific examples thereof include: 12mg/m 2 ，16 mg/m 2 ，20mg/m 2 . Preferably, the mitoxantrone hydrochloride liposome is administered intravenously. Preferably, the administration time of the liposome preparation by instillation is 30min to 120min, preferably 60min to 120min, and further preferably 90 +/-15 min for each intravenous administration. Preferably, the bortezomib is administered by injection at a dose of 1.3mg/m 2 . Preferably, dexamethasone is administered orally at a dose of 20 mg/day. Preferably, the administration period for the treatment is 4 weeks or 3 weeks, further preferably 4 weeks; in each administration cycle, mitoxantrone hydrochloride liposome was administered 1 time, bortezomib 4 times, and dexamethasone 8 times. Preferably, therapeutically effective doses of mitoxantrone hydrochloride liposomes, bortezomib and dexamethasone are administered to multiple myeloma patients on day 1 of each dosing cycle, in any order, with bortezomib being administered sequentially on days 4, 8 and 11, and dexamethasone being administered sequentially on days 2, 4, 5, 8, 9, 11 and 12.
In the above pharmaceutical combination, pharmaceutical composition and medicament for use in relation to the treatment of multiple myeloma, preferably said multiple myeloma is relapsed/refractory multiple myeloma.
In the above uses, methods, pharmaceutical combination products, pharmaceutical compositions and medicaments, the mitoxantrone liposomes can be mitoxantrone liposomes prepared using any of the methods conventional in the art or disclosed in the prior art, for example, mitoxantrone hydrochloride liposomes prepared using the method disclosed in WO2008/080367A1, the disclosure of which is incorporated herein by reference in its entirety.
In some embodiments, the mitoxantrone hydrochloride liposome has a particle size of about 30 to 80 nm comprising: 1) Mitoxantrone, an active ingredient, which forms a poorly soluble precipitate with multivalent counter ions within the liposome, and 2) phospholipid bilayers comprising phospholipids with a phase transition temperature (Tm) above body temperature, thereby bringing the phase transition temperature of the liposome above body temperature. Wherein the multivalent counter ion is, for example, an organic acid radical, such as 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, or the like, or an inorganic acid radical such as a sulfate radical, a phosphate radical, or an ionized form of an amino acid such as cystine, preferably a citrate radical, a sulfate radical, or a phosphate radical; the phospholipid with Tm higher than body temperature is phosphatidyl choline, hydrogenated soybean lecithin, hydrogenated yolk lecithin, dipalmitin lecithin or distearoyl lecithin or any combination thereof.
In some embodiments, the liposome has a particle size of about 35 to 75nm, preferably 40 to 70nm, more preferably 40 to 60nm, and particularly preferably 60nm.
In some embodiments, the liposome further comprises cholesterol. In some embodiments, the liposome may also contain other excipients in the phospholipid bilayer, particularly excipients that may further modify the surface characteristics of the liposome, such as lipid materials modified with hydrophilic polymers, which may be selected from, for example, polyethylene glycol modified distearoyl phosphatidyl ethanolamine (DSPE-PEG), polyethylene glycol modified distearoyl phosphatidyl glycerol (DSPG-PEG), polyethylene glycol modified cholesterol (chol-PEG), povidone modified distearoyl phosphatidyl ethanolamine (DSPE-PVP), polyethylene glycol modified distearoyl phosphatidyl glycerol (DSPG-PVP), polyethylene glycol modified cholesterol (chol-PVP), or combinations thereof, preferably polyethylene glycol 2000 modified distearoyl phosphatidyl ethanolamine.
In some embodiments, the phospholipid bilayer contains hydrogenated soy lecithin (HSPC), cholesterol (Chol), and polyethylene glycol 2000 modified distearoyl phosphatidyl ethanolamine (DSPE-PEG 2000) in a mass ratio of 3. In some embodiments, the phospholipid bilayer contains HSPC, chol, and DSPE-PEG2000 in a mass ratio of 3: chol: DSPE-PEG2000: the weight ratio of mitoxantrone is 9.58. In some embodiments, the mitoxantrone liposome is mitoxantrone hydrochloride liposome of the national drug standard H20220001 (trade name: dondada).
The mitoxantrone liposomes can be prepared by methods conventional in the art, or by any of the methods disclosed in the prior art, for example, by the method disclosed in WO2008/080367A1, the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the mitoxantrone liposomes are prepared by: HSPC, chol and DSPE-PEG2000 were weighed according to a mass ratio of 3. Mixing the ethanol solution of phospholipid with 300mM ammonium sulfate solution, and shaking to hydrate lh at 60-65 ℃ to obtain the inhomogeneous multi-chamber liposome. The particle size of the liposomes is then reduced using a microfluidizer. The obtained sample was diluted 200 times with 0.9% NaCl solution and then examined by NanoZS, and the average particle size of the particles was about 60nm and the main peak was concentrated between 40 and 60nm. The blank liposome external phase was then removed of ammonium sulfate using an ultrafiltration device and the external phase was replaced with 290mM sucrose and 10mM glycine to form a transmembrane ammonium sulfate gradient. According to the ratio of lipid to drug of 16. After an incubation of about lh, the encapsulation efficiency was about 100% as demonstrated using gel exclusion chromatography. Wherein HSPC: chol: DSPE-PEG2000: mitoxantrone weight ratio 9.58.
It should be understood that numerous technical details and parameters of the above-described exemplary preparation methods can be set forth and determined within the scope of those skilled in the art. For example, the amino acid species that are replaced by glycine in the outer phase used to form the transmembrane ammonium sulfate gradient include, but are not limited to, histidine, asparagine, glutamic acid, leucine, proline, alanine. As 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 a particular liposomal pharmaceutical formulation, one skilled in the art can design, test, and ultimately arrive at an appropriate lipid-drug ratio to maximize drug loading while minimizing drug leakage. For mitoxantrone liposomal formulations of the present application, lipid-drug ratios that can be used are wide ranging, e.g., as low as 2:1 or as high as 30: a more suitable lipid-drug ratio may be about (15-20): 1, e.g., about 15: 1. 16: 1. 17: 1. 18: 1. 19:1 or 20:1.
examples
The following examples are intended to illustrate the invention specifically and should not be construed as limiting the scope of the invention.
Example 1 clinical study of mitoxantrone hydrochloride liposomes in combination with bortezomib and dexamethasone for treatment of relapsed/refractory multiple myeloma
The study was an open, multicenter, multi-cohort phase I clinical study, enrolled in 60 relapsing/refractory MM subjects, randomized to three dose groups (20 per group) at a ratio of 1. The research aims to explore the safety and the effectiveness of the mitoxantrone hydrochloride liposome combined with bortezomib and dexamethasone and determine the optimal administration dosage of the mitoxantrone hydrochloride liposome in the combined administration scheme.
1. Design of experiments
1. Overall design
The study included a screening phase, a treatment phase and a follow-up phase.
The screening period is up to 28 days during which time subjects are reviewed for inclusion/exclusion criteria and provided with tumor diagnosis and treatment-related data and a complete clinical assessment within a defined time window. Screening eligible subjects will enter a treatment phase. Mitoxantrone hydrochloride liposomes (study drug) were applied on the first day of the cycle (D1), bortezomib was applied to D1, D4, D8, D11, and dexamethasone was applied to D1, D2, D4, D5, D8, D9, D11, D12. Every 4 weeks (28 days) is a treatment cycle, with 8 cycles of treatment planned. For subjects who have completed 8 cycles of treatment, if there is a continuing benefit potential and treatment is tolerated, the researcher and sponsor can negotiate together to determine whether treatment can continue. During treatment, subjects will be evaluated for safety using laboratory tests such as hematology and biochemistry, electrocardiogram, echocardiogram, physical examination, vital signs, ECOG scores, etc., up to 28 days after the last administration of study medication, and for efficacy once every 2 cycles according to the evaluation criteria of the International Myeloma Working Group (IMWG). From the beginning of the second treatment cycle, dose adjustments and administration delays are allowed according to the protocol. The subjects were followed up for survival after treatment was completed: disease status assessment every 8 weeks (± 7 d) until disease progression/relapse; subjects who developed disease progression/recurrence or started other anti-tumor therapy continued to follow-up for survival, with visits or phone calls every 8 weeks (+ -7 d).
2. Dosing regimens
Mitoxantrone hydrochloride liposome, injection (1.0 mg/ml), provided by Shiyao pharmaceutical industries, inc. (Shijiazha) of Shiyao group (national Standard H20220001), and the administration dose is 12mg/m 2 、16mg/m 2 、20mg/m 2 Intravenous drip on the first day of the cycle (D1);
bortezomib, commercially available, administered at a dose of 1.3mg/m 2 D1, D4, D8, D11 subcutaneous injections;
dexamethasone was purchased commercially and administered at 20mg/D, D1, D2, D4, D5, D8, D9, D11, D12 orally.
3. Provisions for continued medication
(1) Dosing criteria for the next cycle (CnD 1)
1) Absolute value (ANC) of neutrophil not less than 1.5x10 9 L, platelet is more than or equal to 75x10 9 /L；
2) Non-hematologic toxicity must be restored to grade 1 or baseline levels (except for hair loss, pigmentation, peripheral neuropathy);
3) If the administration is delayed due to failure to meet the 1 or 2 administration criteria, in principle, no more than 14 days;
4) If the 1 or 2 dosing criteria are not met, or if the dosing is delayed by >14 days, the investigator judges that the subject still benefits and can consider continuing the dosing after communicating with the sponsor.
(2) Dose adjustment
During study treatment, dose adjustments were allowed. The mitoxantrone hydrochloride liposome is reduced by 4mg/m each time 2 The minimum can be reduced to 8mg/m 2 (ii) a Each decrement of bortezomib is 0.3mg/m 2 The minimum can be reduced to 1.0mg/m 2 . Once reduced, subsequent treatments of both drugs will be performed at the adjusted dose, or further reduced if necessary, without allowing the dose to be increased. Dexamethasone was allowed to dose according to clinical practice with a minimum dose of 10 mg/dose.
2. The test population is as follows:
(one) inclusion criterion:
patients who met all of the following criteria were eligible for inclusion in the study:
1. subjects were fully informed of the study, voluntarily attended and signed an Informed Consent Form (ICF);
2. the age is 18-75 years old, and male and female are not limited;
3. patients who are relapsed or refractory to cytological or histological biopsy that meet the diagnostic criteria for multiple myeloma (according to the IMWG criteria) and have received at least first line therapy;
4. at least one of the following evaluable criteria:
(1) The blood M protein level is more than or equal to 10g/L
(2) Urinary M protein level of more than or equal to 200mg in 24 hours
(3) The difference between the free light chains of affected and unaffected serum (dFLC) is more than or equal to 100mg/L;
5. ECOG score is 0-2 points;
6. laboratory examinations met the following criteria:
(1) Absolute value (ANC) of neutrophil not less than 1.5x10 9 L (not treated with G-CSF within 1 week prior to examination);
(2) Platelet (PLT) is not less than 75x10 9 L (no treatment of platelets infused within 1 week prior to examination);
(3) Total bilirubin is less than or equal to 1.5 times the upper limit of normal value (ULN);
(4) Alanine Aminotransferase (ALT) and aspartate Aminotransferase (AST) are less than or equal to 2.5 times ULN;
(5) Creatinine clearance rate (Ccr) is more than or equal to 30ml/min;
7. female subjects must be negative for blood HCG test prior to enrollment in this trial and agree from signing ICF to taking an approved very effective contraceptive measure at least 7 months after the end of the last dose [ for example: combination hormones (containing estrogen and progestin) in combination with ovulation inhibition, progestin contraception in combination with ovulation inhibition, intrauterine devices, intrauterine hormone release systems, bilateral tubal ligation, vasectomy, etc. (ii) except those who have been menopausal (have at least 1 year of menopause); except those who have undergone hysterectomy or bilateral ovariectomy;
8. the male subject and his partner agreed to take one of the contraceptive measures described in clause 8 at least 4 months after signing for ICF to the end of the last dose.
(II) exclusion criteria:
the study was not eligible for inclusion in any of the following exclusion criteria:
1. subjects with amyloidosis or central nervous system invasion or dialysis treatment;
2. the estimated survival time is less than 3 months;
3. has a history of allergy to mitoxantrone or liposome drugs; or the total accumulated dose of the anthracycline medicines is converted into adriamycin more than or equal to 350mg/m after the anthracycline medicines are treated before 2 (conversion of anthracycline equivalent dose: 1mg doxorubicin =2mg epirubicin/pyrane doxorubicin/daunorubicin =0.5mg demethoxydaunorubicin =0.45mg mitoxantrone; except for doxorubicin liposomes);
4. a history of allergy (except for local injection reactions) or intolerance to bortezomib; or one of the following occurs with the previous bortezomib-containing regimen standard treatment: no therapeutic response (no MR achieved); disease progression within 6 months after the end of the last dose;
5. use contraindications or intolerance to dexamethasone;
6. any clinical routine anti-myeloma medication (thalidomide 3 weeks prior to first administration and systemic glucocorticoid 2 weeks prior to first administration) or radiation therapy was received within 4 weeks prior to first administration of the study drug; or the study drug is treated with a study anti-myeloma drug within 3 months before the first administration;
7. autologous hematopoietic stem cell transplantation is received within 6 months before screening;
8. after allogeneic hematopoietic stem cell transplantation or allogeneic organ transplantation;
9. the toxicity of the prior anti-tumor treatment is not recovered to be less than or equal to grade 1 (except alopecia and pigmentation);
10. the continuous existence of the peripheral neuropathy with grade 2 or more or the pain accompanied by the grade 1 peripheral neuropathy;
11. impaired cardiac function or significant heart disease, including but not limited to:
(1) Myocardial infarction and viral myocarditis occur within 6 months before screening;
(2) Heart diseases needing to be treated exist during screening, such as unstable angina, chronic congestive heart failure (NYHA is more than or equal to grade 2), arrhythmia, valvular disease and the like or persistent cardiomyopathy;
(3) QTc interval at screening is >480ms or has long QTc syndrome;
(4) When in screening, the cardiac ejection fraction is lower than 50% or lower than the lower limit of the range of the detection value of the research center;
12. HBsAg or HBcAb is positive, HBV-DNA titer is higher than the lower limit of the detection value of a research center, or HCV antibody is positive, HCV-RNA titer is higher than the lower limit of the detection value of the research center, or HIV antibody is positive;
13. obvious dysfunction of the digestive system can affect the intake, transportation and absorption of the medicine (such as inability to swallow, gastrectomy, intestinal obstruction and the like);
14. study drug administration within 1 week before suffering from a bacterial, fungal or viral infection that requires systemic treatment;
15. those who have undergone major surgery within 6 weeks prior to the first dose, or who are scheduled to undergo major surgery during study treatment;
16. other malignancies (except for cured locally curable tumors such as basal or squamous cell skin cancer or carcinoma of the prostate, cervix or breast in situ) have been encountered within 5 years ago;
17. patients with other diseases judged by researchers to be inappropriate for participation in the study, including but not limited to, hypertension for which drug control does not meet standards (systolic pressure is greater than or equal to 140mmHg and/or diastolic pressure is greater than or equal to 90mmHg by multiple measurements), diabetes for which drug control does not meet standards (fasting blood glucose is greater than 7mmol/L or glycosylated hemoglobin is greater than or equal to 7.0%), chronic obstructive pulmonary disease, pulmonary embolism, cerebral thrombosis or cerebral hemorrhage within 6 months;
18. a pregnant or nursing woman;
19. there are cases where other researchers decide that they are not appropriate to participate in the study.
3. Results of the study
Evaluation of therapeutic effects
The efficacy was evaluated according to the IMWG criteria and classified into strict complete remission (sCR), complete Remission (CR), very Good Partial Remission (VGPR), partial Remission (PR), disease Stability (SD) and disease Progression (PD).
Total remission rate (ORR) = (sCR + CR + VGPR + PR)/total number of evaluable cases 100%.
By 8 and 17 days 2022, the program included 12 multiple myeloma subjects. At least one efficacy assessment was performed in 5 subjects, of which 1 subject assessed PR (partial remission), 3 subjects assessed VGPR (very good partial remission), 1 subject assessed sCR (complete remission in the strict sense), or =100% (5/5).
The above results indicate that the regimen of mitoxantrone hydrochloride liposome in combination with bortezomib and dexamethasone significantly improved the ORR in relapsed/refractory MM patients.
Typical cases
Case 1: after multiple myeloma is confirmed, thalidomide is given with poor effect, a TD (thalidomide + dexamethasone) scheme is given to evaluate VGPR, a clinical trial is participated after PD is reviewed and evaluated, a CPT/placebo + thalidomide + dexamethasone scheme is given for 4 courses of treatment, mitoxantrone liposome + bortezomib + dexamethasone is given for 2 courses of treatment after disease progression is evaluated, and sCR is evaluated.
Case 2: after multiple myeloma diagnosis is confirmed, CR is evaluated after 4 treatment courses of bortezomib + doxorubicin liposome + dexamethasone, 1 treatment course of ixabepilide + doxorubicin liposome + dexamethasone, and 2 treatment courses of mitoxantrone liposome + bortezomib + dexamethasone are evaluated after disease progression, VGPR is evaluated.
Case 3: after multiple myeloma diagnosis is confirmed, a TBCD (thalidomide + bortezomib + cyclophosphamide + dexamethasone) regimen is given for 1 course, a BCD (bortezomib + cyclophosphamide + dexamethasone) regimen is evaluated as PR after 3 courses, a BCD regimen is continued for 4 courses, a BD (bortezomib + dexamethasone) regimen for 2 courses, a BRD (bortezomib + lenalidomide + dexamethasone) regimen for 1 course, disease relapse is evaluated, a BRD regimen is given for 2 courses, mitoxantrone liposomes + bortezomib + dexamethasone are given for 2 courses after disease progression is evaluated, and VGPR is evaluated.
Case 4: after multiple myeloma diagnosis is confirmed, the treatment is evaluated as SD after 8 courses of treatment by a VADT (vincristine + adriamycin + dexamethasone + thalidomide) regimen, is evaluated as PD after 2 courses of treatment by dexamethasone + thalidomide, is subsequently involved in clinical trials, the treatment is evaluated as VGPR after 4 courses of treatment by a CPT/placebo + thalidomide + dexamethasone regimen, and the treatment is evaluated as VGPR after 2 courses of treatment by mitoxantrone liposome + bortezomib + dexamethasone after disease progression.
Claims (10)
1. Use of mitoxantrone liposome, bortezomib and dexamethasone in the preparation of a medicament for the treatment of multiple myeloma.
2. Use of mitoxantrone liposomes in the manufacture of a medicament for improving the therapeutic effect of bortezomib and dexamethasone in the treatment of multiple myeloma.
3. Use of bortezomib and dexamethasone in the preparation of a medicament for improving the therapeutic effect of mitoxantrone liposomes in the treatment of multiple myeloma.
4. The use of any one of claims 1-3, wherein the multiple myeloma is relapsed/refractory multiple myeloma.
5. The use of any one of claims 1-3, wherein the mitoxantrone liposome is a mitoxantrone hydrochloride liposome.
6. The use as claimed in claim 5, wherein the mitoxantrone hydrochloride liposome has a particle size of 30 to 80 nm comprising: 1) Mitoxantrone, an active ingredient, which forms a poorly soluble precipitate with multivalent counter ions within the liposome, and 2) a phospholipid bilayer containing phospholipids with a phase transition temperature (Tm) above body temperature selected from phosphatidylcholine, hydrogenated soy lecithin, hydrogenated egg yolk lecithin, dipalmitoyl lecithin or distearyl lecithin or any combination thereof.
7. A pharmaceutical combination for use in the treatment of multiple myeloma, comprising mitoxantrone liposomes, bortezomib and dexamethasone.
8. The pharmaceutical combination of claim 7, wherein the multiple myeloma is relapsed/refractory multiple myeloma.
9. The pharmaceutical combination product of claim 7 or 8, wherein the mitoxantrone liposome is a mitoxantrone hydrochloride liposome.
10. The pharmaceutical combination product of claim 9, wherein the mitoxantrone hydrochloride liposome has a particle size of 30-80 nm comprising: 1) Mitoxantrone, an active ingredient, which forms a poorly soluble precipitate with multivalent counter ions within the liposome, and 2) a phospholipid bilayer containing phospholipids with a phase transition temperature (Tm) above body temperature selected from phosphatidylcholine, hydrogenated soy lecithin, hydrogenated egg yolk lecithin, dipalmitoyl lecithin or distearyl lecithin or any combination thereof.
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| CN2021110421401 | 2021-09-07 | ||
| CN202111042140 | 2021-09-07 |
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| CN202211089751.6A Pending CN115770288A (en) | 2021-09-07 | 2022-09-07 | Use of mitoxantrone liposomes, bortezomib and dexamethasone for treating multiple myeloma |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1469735A (en) * | 2000-10-16 | 2004-01-21 | ����˹��ҩ�﹫˾ | Liposomal formulation of mitoxantrone |
| EP1926489A2 (en) * | 2005-09-12 | 2008-06-04 | Alza Corporation | Liposomes for treatment of multiple myeloma |
| WO2007059078A1 (en) * | 2005-11-14 | 2007-05-24 | Dana-Farber Cancer Institute | Treatment of multiple myeloma with dasatinib |
| CN101209243B (en) * | 2006-12-29 | 2010-12-08 | 石药集团中奇制药技术（石家庄）有限公司 | Liposome medicament and preparation thereof |
| EP3291819A4 (en) * | 2015-05-05 | 2018-11-21 | The Regents of the University of California | Improved drug combinations for drug-resistant and drug-sensitive multiple myeloma |
| CN110711178A (en) * | 2018-07-11 | 2020-01-21 | 石药集团中奇制药技术（石家庄）有限公司 | Application of mitoxantrone hydrochloride liposome in treating non-Hodgkin lymphoma |
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