Background: The multicenter phase III trial GMMG-HD7 ( NCT03617731 ) demonstrated superior minimal residual disease (MRD) negativity rate after induction therapy in patients with transplant-eligible newly-diagnosed multiple myeloma (NDMM) by addition of the anti-CD38 monoclonal antibody isatuximab (Isa) to lenalidomide / bortezomib / dexamethasone (Isa-RVd), as compared to RVd alone (Goldschmidt H et al., 2021, ASH Annual Meeting).
Aims: Here we present a subgroup analysis on patients with high-risk cytogenetics.
Methods: Patients with transplant-eligible NDMM were equally randomized to receive three 42-day cycles of RVd (lenalidomide 25 mg/d p.o., d1–14 and d22-35; bortezomib 1.3 mg/m 2 s.c. d1, 4, 8, 11, 22, 25, 29, 32; dexamethasone 20 mg/d d1-2, 4-5, 8-9, 11-12, 15, 22-23, 25-26, 29-30, 32-33) in both study arms. Isa was added to Isa-RVd as follows: 10 mg/kg i.v., cycle 1: d 1, 8, 15, 22, 29; cycles 2-3: d 1, 15, 29. Randomization for induction was stratified by Revised International Staging System. Primary endpoint of the trial was MRD negativity rate assessed by next-generation flow (NGF, cut-off 1x10 -5 ) after induction therapy. Fluorescence in-situ hybridization (FISH) analysis was performed centrally on CD138-purified plasma cells. High-risk and ultra high-risk cytogenetics were defined as at least one or two of the following aberrations, respectively: del17p, t(4;14), t(14;16), gain1q21 (≥ 3 copies). Data cut-off for the present analysis was December 2021.
Results: 660 patients (Isa-RVd: 331 and RVd: 329) were eligible for intention-to-treat analysis. The study met its primary endpoint, demonstrating superiority of NGF-MRD negativity rates with Isa-RVd compared to RVd (50.1% vs. 35.6%; odds ratio [OR]=1.82, 95% confidence interval [95% CI]: 1.33-2.48, p<0.001). High-risk cytogenetics were well balanced between the treatment arms. 264 of 584 (45.2%) and 82 of 580 (14.1%) evaluable patients had high-risk and ultra high-risk cytogenetics, respectively. Del17p, t(4;14), t(14;16) and gain 1q21 were present in 59 of 615 (9.6%), 67 of 613 (10.9%), 17 of 609 (2.8%) and 218 of 583 (37.4%) evaluable patients, respectively. Among patients with high-risk cytogenetics, MRD negativity rates were 50.4% (63/125) vs. 37.4% (52/139; OR=1.70, 95% CI: 1.04-2.79, p=0.03) with Isa-RVd vs. RVd. MRD negativity rates for ultra high-risk patients were 56.3% (27/48) vs. 44.1% (15/34; OR=1.63, 95% CI: 0.67-3.99, p=0.28) with Isa-RVd vs. RVd. Similar results were observed for Isa-RVd vs. RVd among the common major single high-risk cytogenetic features: del17p: 56.0% (14/25) vs. 35.3% (12/34), OR=2.33, 95% CI: 0.82-6.88; t(4;14): 57.6% (19/33) vs. 47.1% (16/34), OR=1.53, 95% CI: 0.58-4.06; t(14;16): 66.7% (6/9) vs. 50.0% (4/8), OR=2.00, 95% CI: 0.28-15.67; gain1q21: 48.2% (55/114) vs. 35.6% (37/104), OR=1.69, 95% CI: 0.98-2.92. Dividing evaluable patients in either standard risk (absence of any high-risk aberration; 320/578, 55.4%) vs. high-risk (exactly one high-risk aberration; 176/578, 30.4%) vs. ultra high-risk (≥2 high-risk aberrations; 82/578, 14.2%) yielded similar efficacy results. MRD negativity rates for Isa-RVd vs. RVd were 49.7% (86/173) vs. 36.7% (54/147; OR=1.70, 95% CI: 1.09-2.68) in standard risk patients, 46.7% (35/75) vs. 34.7% (35/101; OR=1.65, 95% CI: 0.90-3.05) in high-risk patients and 56.3% (27/48) vs. 44.1% (15/34; OR=1.63, 95% CI: 0.67-3.99) in ultra high-risk patients.
Summary/Conclusion: Isa-RVd induction therapy is superior to RVd in patients with transplant-eligible NDMM and high-risk or ultra high-risk cytogenetics, consistent with the benefit observed in the overall trial population.