Isatuximab regimen a possible ‘new standard’ for newly diagnosed multiple myeloma
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The addition of isatuximab to a standard three-drug induction regimen improved outcomes for certain patients with multiple myeloma, according to randomized phase 3 study results presented at ASH Annual Meeting and Exposition.
Half of patients with transplant-eligible, newly diagnosed disease who received isatuximab (Sarclisa, Sanofi) — a CD38-directed monoclonal antibody — plus standard induction therapy with lenalidomide (Revlimid, Bristol Myers Squibb), bortezomib (Velcade, Millennium/Takeda) and dexamethasone (RVd) achieved minimal residual disease (MRD)-negative status, results of the GMMG-HD7 trial showed.
“The MRD negativity rate achieved by the combination of isatuximab and RVd is the highest ever described after induction therapy [for multiple myeloma] in the setting of a randomized phase 3 study,” Hartmut Goldschmidt, MD, professor of medicine and head of the myeloma division at Heidelberg University Hospital and National Center of Tumor Diseases Heidelberg in Germany, said during a press conference. “The addition of isatuximab to RVd induction therapy should be considered as a new standard of care in patients with newly diagnosed multiple myeloma who are transplant eligible.”
Treatment regimens incorporating CD38-directed monoclonal antibodies are becoming the new standard for patients with multiple myeloma, Goldschmidt said. Maximizing the efficacy of early treatments is vital for maintaining long-term remissions, he added.
The GMMG-HD7 trial is the first phase 3 study to evaluate isatuximab plus RVd as induction therapy for adults with newly diagnosed multiple myeloma who are eligible for autologous hematopoietic stem cell transplant.
The intention-to-treat analysis included 660 patients.
Researchers randomly assigned 331 patients (median age, 59 years; range, 37-70; 61.6% men) to induction therapy with isatuximab plus RVd over three 6-week cycles. The other 329 (median age, 60 years; range, 26-70; 62.6% men) received RVd alone.
Patient characteristics — including age, performance status, renal impairment and high-risk cytogenetics — appeared well-balanced between treatment groups.
The study design also included an ongoing second randomization to maintenance therapy with isatuximab plus RVd or RVd alone after HSCT, Goldschmidt said.
Improvement in MRD negativity rate as determined by next-generation flow cytometry after the 18-week induction period served as the study’s primary endpoint. Secondary endpoints included complete response rate and safety.
The study achieved its primary endpoint, as a significantly higher percentage of patients assigned isatuximab plus RVd achieved MRD-negativity status (50.1% vs. 35.6%; OR = 1.83; 95% CI, 1.34-2.51).
Researchers observed the MRD-negativity benefit across clinically relevant subgroups, Goldschmidt said.
The effect of isatuximab on complete response rate will require further analysis after the maintenance therapy phase is complete; however, preliminary results showed a significantly higher of rate of very good partial responses or better among patients assigned isatuximab plus RVd (77.3% vs. 60.5%; P < .001).
Safety results showed comparable rates of serious treatment-related adverse events between the RVd alone and isatuximab-RVd groups (36.3% vs. 34.8%).
A comparable number of patients from each group discontinued therapy because of adverse events, Goldschmidt said.
“The addition of isatuximab to induction therapy did not affect the overall safety profile,” Goldschmidt said. “Leukocytopenia and neutropenia occurred more frequently with the addition of isatuximab, but this did not translate into an increased rate of infections during induction treatment.”
Perspective
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Joshua Richter, MD
These are extremely impressive and encouraging data. From an academic standpoint, we always say that you cannot compare trial to trial. In the next breath, we compare trial to trial. Here, we have to compare to some degree with the GRIFFIN study, which evaluated the addition of daratumumab (Darzalex, Janssen) to RVd among newly diagnosed, transplant-eligible patients with multiple myeloma.
Although one key difference is the duration of the induction portion, what is most important to me in clinical practice is that this schema has great potential to integrate into the current standard of care. GRIFFIN utilized a post-transplant consolidation portion of therapy, whereas this study did not. Post-transplant consolidation is not common in the U.S.
Further, the MRD-negative rate of 50% after induction is extremely impressive; however, this was assessed by next-generation flow (1 × 10-5) as opposed to next-generation sequencing.
Data continue to mount regarding the role of quadruplet therapy for induction. This adds to that pool of knowledge and offers another option.
The two big unanswered questions are: Who needs a four-drug regimen over a three-drug regimen, and, in a world where both isatuximab and RVd and daratumumab and RVd are approved, how would we decide which one to use?
I am interested particularly in the high-risk patients. We recently published a paper on the role of isatuximab among patients with gain or amplification of 1q21.
We need to know how best to overcome the negative impact of high-risk disease. GRIFFIN has not yet shown this, but if isatuximab and RVd does, that would be a game changer.
References:
Bisht K, et al. Expert Rev Hematol. 2021;doi:10.1080/17474086.2021.1983427.
Voorhees PM, et al. Blood. 2020;doi:10.1182/blood.2020005288.
Icahn School of Medicine at Mount Sinai
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Goldschmidt H, et al. Abstract 463. Presented at: ASH Annual Meeting and Exposition; Dec. 11-14, 2021.
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