Shaji K. Kumar, MD
The treatment approaches to multiple myeloma have significantly changed over the past decade with the introduction of many new active agents. Among them, the monoclonal antibodies have been one of the most exciting advances in myeloma, complementing their success in other hematologic cancers. In particular, daratumumab, a monoclonal antibody directed toward CD38, has shown considerable efficacy in the treatment of newly diagnosed and relapsed myeloma, especially when used in combination with other standard-of-care myeloma therapies such as immunomodulatory drugs and proteasome inhibitors.
Clinical trials with daratumumab have validated this anti-CD38 approach in the setting of newly diagnosed myeloma when combined with standard-of-care regimens such as bortezomib with lenalidomide (D-VRd, GRIFFIN trial),1 thalidomide (D-VTd, CASSIOPEIA trial),2 and melphalan/prednisone (D-VMP, ALCYONE trial),3 as well as with lenalidomide and dexamethasone (D-Rd, MAIA trial).4 Similarly, in the relapsed setting, combinations with lenalidomide (POLLUX),5 pomalidomide (DPd, EQUULEUS),6 bortezomib (DVd, CASTOR),7 and carfilzomib (DKd, CANDOR)8 have all shown improved outcomes with the addition of the monoclonal antibody.
A Closer Look at the New Kid on the Block
It is in this context that another CD38-directed monoclonal antibody has become available in the armamentarium for treatment of multiple myeloma. Isatuximab is a monoclonal antibody that binds to a specific epitope on CD38, resulting in antimyeloma effects through several mechanisms; they include antibody-dependent cellular-mediated cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and direct induction of apoptosis—mechanisms similar to those reported for other monoclonal antibodies. Isatuximab is now approved for use in combination with pomalidomide and dexamethasone to treat adults with multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor.
The approval was based on the results of the ICARIA-MM trial—reported by Attal et al and reviewed in the April 25, 2020, issue of The ASCO Post. It evaluated the impact of adding isatuximab to pomalidomide and dexamethasone in this setting.9 The overall results appear to mirror those observed with daratumumab plus pomalidomide/dexamethasone in a similar population in the phase II EQUULEUS trial. In the ICARIA-MM trial, the median number of prior lines of therapy was three, and 97% vs 99% were refractory to the last line of therapy. Patients in the daratumumab trial may represent a more heavily pretreated population, with a median of 4 lines of therapy (range = 1–13).
The overall response rate was 60% in the isatuximab group vs 35% in the control group, and the median progression-free survival was 11.5 vs 6.5 months. In the daratumumab trial, the response rates were similar, with an overall response rate of 60%, including a rate of very good partial response or better of 25%. However, the median progression-free survival was 8.8 months, shorter than that observed with the isatuximab regimen, likely reflecting the more advanced disease of patients in the daratumumab study.
Several smaller studies have examined the combination of isatuximab with other myeloma drugs in patients with newly diagnosed or relapsed disease, and several large phase III trials are examining the addition of the antibody to other combinations, including VRd for newly diagnosed myeloma. Both the isatuximab and daratumumab combinations were well tolerated, with hematologic toxicity being the most common adverse event noted. The overall rate of serious adverse events was 62% among patients treated with isatuximab and 53% among those treated with daratumumab. It was previously suggested, based on prior studies, that infusion reactions may be less common with isatuximab; the infusion-related reaction rate in the ICARIA-MM trial was 38% in the current study, compared with 50% in the daratumumab study. Adverse events led to discontinuation of treatment in 8% vs 16% of patients.
Where Will Isatuximab Combination Fit in the Clinic?
Where does this place the isatuximab, pomalidomide, and dexamethasone combination in the management of myeloma? Although cross-trial comparisons are not always appropriate, the ICARIA-MM and EQUULEUS trials are the only way the regimens can be contrasted. Overall, there appears to be not much difference between the two CD38-directed monoclonal antibodies available in the clinic for the treatment of myeloma. The current approvals allow the use of isatuximab in a limited spectrum of patients, but this will likely change as more results come in from ongoing trials in newly diagnosed disease and other indications.
In terms of schedule, isatuximab goes to every other week starting from cycle 2 instead of cycle 3 with daratumumab. However, after six cycles, isatuximab continues every other week, whereas daratumumab goes to once a month; thus, essentially, the difference is in favor of isatuximab only when a short duration of treatment is considered.
In terms of the duration of infusion, it is shorter with isatuximab with the initial cycles, but once treatment progresses to the 90-minute infusion with daratumumab, they are comparable; once subcutaneous infusions are available, this will no longer be an advantage. So, what will drive the adoption of isatuximab in the clinic? It may end up being driven by the cost differences for the regimens.
One important aspect of both trials is the high rate of hematologic toxicity, especially neutropenia, leading to dose reduction with pomalidomide in nearly half of patients. One approach that may be reasonable in practice may be to consider starting patients on 2 mg of pomalidomide and go up to the full dose of 4 mg once tolerability is established.
Several questions remain to be answered. Will isatuximab offer better outcomes in patients previously exposed to daratumumab instead of retreatment with daratumumab (a scenario that will be quite common given the incorporation of daratumumab in the upfront setting)? Regardless of how isatuximab ends up being used in the clinic, approval of yet another drug for myeloma highlights not only the need for new drugs, but also the continuing innovation that is occurring in the field, which will eventually translate to better outcomes for all patients.
Dr. Kumar is Professor of Medicine at the Mayo Clinic College of Medicine; Consultant for the Division of Hematology; and Medical Director of the Cancer Clinical Research Office, Mayo Clinic, Rochester, Minnesota.
DISCLOSURE: Dr. Kumar has served as a consultant or advisor to Cellectar -Biosciences, GeneCentrix, and Oncopeptides; has served in an institutional consulting or advisory role for AbbVie, Amgen, Bluebird Bio, Celgene, Genentech/Roche, Janssen Oncology, Kite Pharma, Merck, Molecular Partners, and Takeda; and has received institutional research funding from AbbVie, CARsgen Therapeutics, Celgene, Janssen Oncology, Kite Pharma, MedImmune, Merck, Novartis, Roche/Genentech, Sanofi, Takeda, and TeneoBio.
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8. Usmani SZ, Quach H, Mateos MV, et al: Carfilzomib, dexamethasone, and daratumumab vs carfilzomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma. 2019 ASH Annual Meeting & Exposition. Abstract LBA-6.
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