Introduction. In newly diagnosed multiple myeloma (NDMM) patients (pts) eligible for autologous stem-cell transplant (ASCT), the phase 3 GMMG-HD7 trial (NCT03617731) Part 1 demonstrated that isatuximab, lenalidomide, bortezomib and dexamethasone (Isa-RVd) induction significantly improved minimal residual disease negativity (MRD-) rates (odds ratio: 1.82; p<0.001) and prolonged progression-free survival (PFS) compared with RVd (hazard ratio, 0.70; p=0.0184), regardless of the maintenance therapy received post-ASCT. Consequently, the 2025 EHA-EMN guidelines recommended Isa-RVd as standard of care for induction in patients with NDMM eligible for ASCT. This analysis evaluated the effect of Isa-RVd vs RVd induction on patient-reported outcomes (PROs) and health-related quality of life (HRQoL) from first random assignment through post-ASCT.

Methods. Patient-reported outcomes (PROs) were recorded using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30), the EORTC QLQ Multiple Myeloma Module 20-item (MY20), and the EuroQol 5-dimensional (EQ-5D-5L) visual analog scale (VAS) at baseline (BL), after induction, 60-90 days post-ASCT, and at the end of treatment (EOT). Prespecified analyses were conducted in the intent-to-treat population. Mixed model repeated measures (MMRM) analyzed the mean change from BL to post-ASCT. Time to first deterioration (TTFD) and time to first improvement (TTFI) were assessed using Kaplan-Meier methods and Cox proportional hazard models.

Results. A total of 662 patients were randomized to Isa-RVd (n=331) or RVd (n=329) induction, followed by single or tandem ASCT and second randomization to maintenance with Isa-lenalidomide or lenalidomide alone. PRO completion rates were high across time points in both arms (≥90% at BL, ≥87% after induction, and ≥92% 60-90 days post-ASCT). At BL, patients in both arms reported similar functioning and symptom burden, QLQ-C30 Global Health Status (GHS/QoL), and EQ-5D-5L VAS.

Pts on Isa-RVd reported a statistically significant reduction in fatigue vs RVd (overall mean [95% CI] difference in LS mean change from BL: -4.02 [-7.68, -0.37]; p=0.0312). Median TTFD in fatigue was longer in the Isa-RVd arm vs RVd (8.48 mo vs 5.22 mo; HR=0.78; p=0.0340), while median TTFI was shorter for Isa-RVd vs RVd (8.84 mo vs 10.05 mo; HR=1.26; p=0.0611). Clinically meaningful reduction in pain occurred in both arms, with Isa-RVd showing a numerically greater reduction vs RVd (overall mean [95% CI] difference in LS mean change from BL: -3.39 [-7.43, 0.64]; p=0.0991). Median TTFD in pain was 12.62 mo for Isa-RVd vs. 12.16 mo for RVd (HR=0.83; p=0.2336), while median TTFI was 5.06 mo for Isa-RVd vs 5.26 mo for RVd (HR=1.18; p=0.1393). No clinically meaningful deterioration in other symptom scales were observed in either arm.

Both Isa-RVd and RVd showed a small improvement in physical functioning (LS mean change [SE] from BL: 4.95 [2.00] vs 3.91 [2.00]; p=0.5189) and a clinically meaningful improvement in emotional functioning (LS mean change [SE]: 13.27 [1.97] vs 12.94 [1.97]; p=0.8380). No notable differences between arms were observed for the other functional scales.

Both treatments showed clinically meaningful improvement in future perspective, as measured by MY20 after induction and post-ASCT. The overall difference between arms significantly favored Isa-RVd over RVd (overall mean [95% CI] difference in LS mean change from BL: +5.64 [2.15, 9.13], p=0.0016). Each arm demonstrated clinically meaningful improvement in QLQ-C30 GHS/QoL post-ASCT, with no statistically significant difference between Isa-RVd and RVd (LS mean change [SE]: 10.17 [1.82] vs 9.22 [1.81]; p=0.5197). Similarly, pts in both treatment arms experienced a clinically meaningful improvement in EQ-5D-5L VAS post-ASCT, with numerical trend in favor of Isa-RVd (overall mean [95% CI] difference in LS mean change from BL: +1.47 [-1.28, 4.21], p=0.2939).

Conclusions. The addition of isatuximab to RVd significantly improves the likelihood of achieving MRD- and prolongs PFS in transplant-eligible NDMM pts. This enhanced efficacy is observed without compromising overall HRQoL, and importantly, is associated with significant improvement in fatigue and a favorable trend in pain reduction, compared to RVd alone. These findings underscore the favorable benefit-risk profile and value of Isa-RVd quadruplet for transplant eligible NDMM pts.

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2025
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