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Optimizing the Outcome of Anti-Myeloma Treatment with Daratumumab.

ABSTRACT: A search of the scientific literature for Daratumumab and myeloma gives more than 600 results (January 2021), which reflects the interest and activity around this antibody, an interest that was also reflected by the assignment of breakthrough designation for Daratumumab as a treatment for multiple myeloma by FDA in 2013. The high expectations have been supported and met due to a very active clinical development program, and our insight into Daratumumab's modes of action have been expanded by a concomitant, systematic activity of translational research. The scope of this article is to point to some areas where the outcome of treatment with Daratumumab for multiple myeloma may be improved with a focus on areas such as when to initiate treatment with Daratumumab, the use of supportive treatment, duration of therapy and some general thoughts about anti-myeloma treatment as a two-step process involving initial de-bulking followed by reprogramming of the host's immune system and immune-mediated control of myeloma.

SUBMITTER: Plesner T

PROVIDER: S-EPMC7958124 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Optimizing the Outcome of Anti-Myeloma Treatment with Daratumumab.

Plesner Torben T

Journal of clinical medicine 20210302 5

A search of the scientific literature for <i>Daratumumab</i> and <i>myeloma</i> gives more than 600 results (January 2021), which reflects the interest and activity around this antibody, an interest that was also reflected by the assignment of breakthrough designation for Daratumumab as a treatment for multiple myeloma by FDA in 2013. The high expectations have been supported and met due to a very active clinical development program, and our insight into Daratumumab's modes of action have been e ...[more]

PMID: 33801271

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Project description:BackgroundThere is a lack of clear guidance on the appropriate next choice of therapy for patients with relapsed/refractory multiple myeloma who become refractory to daratumumab, an anti-CD38 antibody. This review aims to identify and compare treatments with published clinical trial evidence among patients with daratumumab-refractory multiple myeloma.MethodsMEDLINE, Cochrane CENTRAL, and EMBASE databases were searched for clinical trials that evaluated treatments for patients with multiple myeloma who were refractory to daratumumab from November 2015 to October 2023. Eligible studies may have enrolled only patients who were refractory to daratumumab or reported findings on patients with daratumumab-refractory disease in subgroup analyses. Treatment outcomes of interest included response rates and survival outcomes. Screening and data extraction were done independently by two reviewers using covidence, and any discrepancy was resolved by a third reviewer. Qualitative synthesis was performed to describe and compare patient outcomes associated with different treatments.ResultsA total of 33 papers/published studies, representing 23 clinical trials, were eligible/included. Interventions from the eligible trials include chimeric antigen receptor (CAR)-T cell therapy, B-cell maturation antigen (BCMA)-directed antibodies, other monoclonal antibodies, cereblon E3 ligase modulators, a peptide-drug conjugate, and other targeted therapies. CAR T-cell therapy demonstrated the highest overall response rates, longer median overall, and progression-free survival in addition to significantly lower risk of death and higher odds of response compared to standard of care. Similarly, high response rates and/or long-term survival was also observed for other BCMA-directed treatments, such as elranatamab and teclistamab.ConclusionBased on the results of this systematic review, BCMA-directed therapies such as CAR-T cell therapy and bispecific antibodies demonstrate promising efficacy among patients with anti-CD38 refractory disease. However, additional evidence from randomized clinical trials is necessary to establish best practice guidelines.

Project description:On November 21, 2016, the U.S. Food and Drug Administration granted regular approval to daratumumab in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was based on two randomized, open-label trials in which daratumumab was added to these backbone therapies. The MMY3003 trial demonstrated substantial improvement in progression-free survival (PFS) when daratumumab was added to lenalidomide and dexamethasone compared with lenalidomide and dexamethasone alone. The estimated median PFS had not been reached in the daratumumab arm and was 18.4 months in the control arm (hazard ratio [HR] = 0.37; 95% confidence interval [CI]: 0.27-0.52; p < .0001), representing a 63% reduction in the risk of disease progression or death. Similar results were observed in the MMY3004 trial comparing the combination of daratumumab, bortezomib, and dexamethasone with bortezomib and dexamethasone. The estimated median PFS was not reached in the daratumumab arm and was 7.2 months in the control arm (HR = 0.39; 95% CI: 0.28-0.53; p < .0001), representing a 61% reduction in the risk of disease progression or death. The most frequently reported adverse reactions (greater than or equal to 20%) in MMY3003 were infusion reactions, diarrhea, nausea, fatigue, pyrexia, upper respiratory tract infection, muscle spasm, cough, and dyspnea. The most frequently reported adverse reactions (greater than or equal to 20%) in MMY3004 were infusion reactions, diarrhea, peripheral edema, upper respiratory tract infection, and peripheral sensory neuropathy. Neutropenia and thrombocytopenia have been added to the Warnings and Precautions of the drug label.Implications for practiceDaratumumab, the first monoclonal antibody targeted against CD38, received U.S. Food and Drug Administration accelerated approval in 2015 based on data from single-agent, single-arm trials that provided response rate information. Results of the MMY3003 and MMY3004 trials established that daratumumab can be combined synergistically with some of the most highly active agents used to treat multiple myeloma, leading to daratumumab's regular approval in 2016. Daratumumab added to lenalidomide and dexamethasone, or bortezomib and dexamethasone, provides a substantial improvement in progression-free survival in previously treated patients with multiple myeloma. These combinations will likely improve the survival outlook for patients with multiple myeloma.

Dataset Information

Optimizing the Outcome of Anti-Myeloma Treatment with Daratumumab.

Publications

Optimizing the Outcome of Anti-Myeloma Treatment with Daratumumab.

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