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Results of the Phase 3 GMMG-HD7 Trial of Isatuximab plus Lenalidomide, Bortezomib, and Dexamethasone as Induction Therapy for Transplant-Eligible NDMM

2021 Year in Review - Multiple Myeloma

Initial primary analysis results of the ongoing phase 3 GMMG-HD7 trial demonstrated that the addition of isatuximab to the standard-of-care RVd regimen was associated with superior MRD negativity rates after induction, and the regimen was not accompanied by emergence of new safety signals or early discontinuation.

The randomized, open-label, multicenter, phase 3 GMMG-HD7 trial compared the rate of minimal residual disease (MRD) negativity with lenalidomide/bortezomib/dexamethasone (RVd) without or with the anti-CD38 monoclonal antibody isatuximab as induction therapy in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM); results of the trial were reported at the 2021 ASH Annual Meeting and summarized here.

Between October 2018 and September 2020, the study enrolled patients with transplant-eligible NDMM at 67 sites in Germany. Eligible patients were randomized 1:1 to receive three 42-day cycles of RVd (lenalidomide 25 mg daily on days 1-14 and days 22-35; bortezomib 1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32; and dexamethasone 20 mg daily on days 1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, and 32-33), plus isatuximab (10 mg/kg, cycle 1: days 1, 8, 15, 22, and 29; cycles 2-3: days 1, 15, and 29) in the experimental arm. Stratification was by revised International Staging System. Primary end point was MRD negativity (as assessed by next-generation flow cytometry, threshold of 1 × 10–5) after induction; secondary end points were complete response rates after induction, and safety. A second randomization will compare the efficacy of isatuximab versus lenalidomide maintenance (results not reported here). The data cutoff date of current analysis was April 2021.

The intent-to-treat population included 660 patients who were eligible for intent-to-treat analysis, and 658 patients started induction (RVd, 328 of 329; isatuximab plus RVd, 330 of 331). Median age was 59 years in the isatuximab plus RVd arm and 60 years in the RVd arm; baseline characteristics were well-balanced between treatment arms. The majority of patients continued study treatment after induction (89.1% RVd vs 94.3% isatuximab plus RVd). Among those who discontinued induction treatment, a higher proportion of patients in the RVd arm discontinued treatment compared with the isatuximab plus RVd arm (10.6% vs 5.4%, respectively; P = .02); however, the proportion of those who discontinued as a result of adverse events (AEs) were comparable between the 2 arms (2.4% and 2.1%, respectively).

Patients who received isatuximab plus RVd induction therapy achieved significantly higher MRD negativity rates compared with those who received RVd (50.1% vs 35.6%, respectively; odds ratio, 1.83; P <.001). While the complete response rates were similar between the RVd and isatuximab plus RVd arms (21.6% vs 24.2%, respectively; P = .46), the rate of very good partial response or better was significantly higher in patients who received isatuximab plus RVd (60.5% vs 77.3%, respectively; P <.001). Multivariate analyses (including treatment arm, Revised Multiple Myeloma International Staging System, performance status, renal impairment, age, and sex) found that isatuximab plus RVd treatment was the only significant predictor of increased MRD negativity after induction compared with RVd (odds ratio, 1.82; P <.001).

The incidence of grade ≥3 AEs on induction therapy was comparable between the RVd and isatuximab plus RVd arms (61.3% vs 63.6%, respectively; P = .57). On induction, the most common grade ≥3 AEs (by system organ class) that occurred in at least 10% of patients were investigations (23.5% vs 23.9%, respectively; P = .93), blood and lymphatic system disorders (16.8% vs 25.8%, respectively; P = .006), infections and infestations (10.4% vs 13.0%, respectively; P = .33), and nervous system disorders (10.1% vs 8.5%, respectively; P = .50). Rates of any grade serious AEs that occurred on induction were similar between RVd and isatuximab plus RVd (36.3% vs 34.8%, respectively; P = .75). During induction, a total of 6 patients on the RVd arm and 4 on the isatuximab plus RVd arm died.

Initial primary analysis results of the ongoing phase 3 GMMG-HD7 trial demonstrated that the addition of isatuximab to the standard-of-care RVd regimen was associated with superior MRD negativity rates after induction. Investigators found that the addition of isatuximab showed no new safety signals or early discontinuation.

Source: Goldschmidt H, Mai EK, Nievergall E, et al. Addition of isatuximab to lenalidomide, bortezomib and dexamethasone as induction therapy for newly-diagnosed, transplant-eligible multiple myeloma patients: the phase III GMMG-HD7 trial. Blood. 2021;138(suppl 1):463.

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