The quadruplet combination of the anti-CD38 monoclonal antibody isatuximab with a backbone regimen of carfilzomib, lenalidomide and dexamethasone (IsaKRd) showed significant improvement in outcomes of measurable residual disease (MRD) in the treatment of newly diagnosed patients with multiple myeloma (MM).
"This [research] builds on our experience that four-drug combinations with a monoclonal antibody, proteasome inhibitor, immunomodulatory drug and steroids are superior to three-drug combinations," Joseph Mikhael, MD, chief medical officer of the International Myeloma Foundation, said in an interview on the study.
"It also demonstrates the value of CD38 antibodies, and specifically isatuximab, in the frontline setting," said Dr. Mikhael, professor at the Translational Genomics Research Institute (TGen), City of Hope Cancer Center in Goodyear, Ariz.
The findings were presented at the annual meeting of the American Society of Hematology.
The current standard of care for transplant-eligible, newly diagnosed MM consists of the quadruple combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid, followed by high-dose melphalan and autologous stem-cell transplantation (ASCT).
Isatuximab already has approval in combination with the regimen of carfilzomib and dexamethasone (KRd) in the treatment of relapsed or refractory MM patients who have received prior lines of therapy.
To investigate the efficacy and safety of addition of isatuximab in the setting of transplant-eligible, newly diagnosed MM patients, first author Francesca Gay, MD, PhD, of the Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy, and colleagues conducted the multisite, phase-3 Iskia trial, enrolling 302 transplant-eligible newly diagnosed MM patients.
The patients were randomized to groups of 151 each to treatment either with IsaKRd or KRd alone. The treatment regimen for KRd included four cycles in induction including weekly carfilzomib at 56 mg on day 1, 8 and 15, lenalidomide 25 mg at day 1-21, and dexamethasone at 40 mg weekly, and the IsaKRd group included four 28-day cycles of isatuximab 10 mg/kg IV days 1, 8, 15, and 22 in cycle 1, followed by 10 mg/kg days 1, 15 in cycles 2-4.
The induction was followed by stem cell mobilization and collection and high dose chemotherapy, followed by four cycles of full-dose consolidation at the same doses and schedule as induction, followed by a light consolidation phase of 12 28-day cycles of reduced dose KRd.
Patients had a median age of 61 and 60 in the isatuximab versus KRd group, respectively, and characteristics were similar between the two arms.
With the current follow-up of a mean of 21 months, the primary endpoint was met, with the intention-to-treat analysis showing a rate of post-consolidation MRD negativity, as assessed with a next-generation sequencing (NGS) cut-off of 10-5, of 77% with isatuximab versus 67% with KRd alone (OR 1.67; P = .049).
With an NGS cut-off of 10-6, the respective rates were 67% vs. 48% (OR 2.29; P < .001).
" This difference in MRD negativity in the depth of response was seen despite the responses analyzed according to the conventional criteria being comparable in the two arms, with more than 90% of patients achieving at least a very good partial response and more than 70% achieving at least a complete response, " Dr. Gay noted.
For the key secondary endpoint of MRD negativity over time, the rates were also significantly higher with IsaKRd vs. KRd at post-induction (10-5 cut-off, 45% vs. 26%, OR 2.34; P < .001; 10-6 cut-off, 27% vs. 14%, OR 2.36, P = .004).
IsaKRd also had greater MRD negativity post-ASCT (10-5 cutoff 64% vs. 49%; P = .006; 10-6 cutoff, 52% vs. 27%, P < .001) and post-consolidation (10-5 cutoff, 77% vs. 67%; P = .049 and 10-6 cutoff, 67% vs. 48%, P < .001).
The increase in the MRD negativity in the IsaKRd group was observed in all subgroups of patients analyzed at the 10-5 and 10-6 cut-offs.
The improved post-consolidation rate of MRD negativity with IsaKRd was also observed among patients based on all levels of cytogenetic risk, which was not the case in the KRd alone arm, which showed a reduction in MRD negativity among very high-risk patients, Dr. Gay observed.
The study's other key secondary endpoint of progression-free survival will be presented in the future, when longer-term outcomes are available.
As of the current follow-up, 17% of patients in the IsaKRd group had discontinued the study treatment versus 10% with KRd, with the leading cause of adverse events for 6% and 5%, respectively.
At least one hematologic adverse event occurred in 55% of patients treated with IsaKRd and 44% in the KRd alone group, with the most prominent grade 3-4 adverse events occurring more commonly with IsaKRd being neutropenia (36% vs. 22%) and thrombocytopenia (15% vs. 17%).
Non-hematologic grade 3-4 adverse events occurred in 41% of patients in the IsaKRd group versus 37% in KRd only, which included infections (15% vs. 11%), and gastrointestinal (7% vs. 5%), vascular (5% vs. 10%) and cardiac events (<1% vs. 3%).
Discontinuation for toxicity occurred in similar rates in both groups (6% in IsaKRd vs. 5% in KRd); with four treatment-related deaths occurring with IsaKRd (two COVID, one pneumonia, one pulmonary embolism) and one with KRd (septic shock).
"Treatment was tolerable with a toxicity profile that was similar to that in previous reports," Dr. Gay said.
"In the context of these highly effective regimens that produce a high rate of response, the 10-6 MRD cutoff might be more informative than other result categories," she added.
Longer follow-up will provide more insights in survival endpoints, and "the trial can potentially offer the opportunity to explore correlations between depth of MRD negativity and survival endpoints," Dr. Gay noted.
Further commenting on the study, Irene Ghobrial, MD, of Medical Oncology, with the Dana-Farber Cancer Institute, Boston, said the results are encouraging.
"We're seeing two phase three trials now showing us that indeed a CD38 antibody in addition to our triplet standards of care are making a huge difference in MRD response," she said in an interview.
"So, I think the main message here is that the four-drug regimen is the way to go from now on in multiple myeloma."
The study received funding from Sanofi and Amgen. Dr. Gay disclosed relationships with AbbVie; Bristol Myers Squibb/Celgene; Sanofi; Roche; GlaxoSmithKline; Pfizer; Oncopeptides; Takeda; Janssen; and Amgen. Dr. Mikhael reported ties with Amgen, BMS, Janssen, Sanofi and Takeda.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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