Introduction In very elderly newly diagnosed pts with multiple myeloma, data comparing induction treatment with Isatuximab plus lenalidomide-dexamethasone (Isa-Rd) followed by Isa-R maintenance therapy vs. Rd induction followed by R maintenance are not available so far. In this prospective, randomized study, we compare both treatment strategies focusing on MRDneg rates at the end of induction therapy, which is the primary endpoint of this study.

Patients and methods Pts were randomized 1:1 to 8 cycles induction therapy with either Isa-Rd or Rd; Isatuximab 10mg/kg on d 1, 8, 15, 22 in cycle 1, subsequently on d 1 and 15; lenalidomide 25mg, d 1-21 q 28 d, dexamethasone 40mg once weekly (20mg in pts aged ≥75 years).

Maintenance therapy was administered for 24 cycles; isatuximab was given at 10mg/kg q 28 d, and lenalidomide at 5-10mg, d 1-21 q 28 d. MRD was evaluated at the end of induction therapy using NGF with a sensitivity of 10-6. Additionally, MRD data were analysed using a 10-5 sensitivity threshold. Circulating tumor cells (CTC) were assessed at d 1 and 8 of the study. Survival estimates were calculated according to Kaplan-Meier, and survival curves were compared using the log-rank test. This trial is registered on ClinicalTrials.gov (NCT04891809).

Results One hundred thirty-nine pts have been enrolled. Median age was 77 yrs (range 70-91 yrs), ISS stage I/II/III: 38 (28.8%)/47 (35.6%)/47 (35.6%), ECOG status 0/1/2: 36 (25.9%)/71 (51.1%)/32 (23.0%). Cytogenetics: t(4;14) 8 (7.1%), t(14;16) 4 (3.6%), del17p 21 (18.4%), ampl1q21 31 (27.0%) of 110-115 pts with results available.

Median follow-up was 12 mos, 5 pts discontinued therapy within the first cycle due to pt (2) or investigator (1) decision, death (1), or progressive disease (1). Between cycles 2-8, disease progression or death was noted in 15 pts (3 in Isa-Rd and 12 in Rd), whereas 4 and 3 pts discontinued the study due to AE/toxicity or withdrawal of consent, respectively.

The efficacy analysis was performed on the per protocol population, which includes pts with comprehensive data from the induction phase, resulting in evaluable response data for 100 pts (50 in each study arm). The median time to best response was 7.3 mos, with no difference between the Isa-Rd (7.0 mos) and the Rd (7.3 mos) groups. All but 8 pts achieved an initial response (≥PR). Response rates were as follows: CR: 26% vs. 10%, p=0.066, VGPR: 36% vs. 20%, p=0.118, PR: 32% vs. 60%, p=0.009, and ORR: 94% vs. 90%, p=0.715, respectively. Minor response was observed in 6 (6%), and SD in 2 (2%) pts.

MRD testing was performed in 88 pts after the end of 8 induction cycles. MRDneg at 10-6 was achieved in 17/48 (35.4%) pts of the Isa-Rd and in 1/40 (2.5%) of the Rd group, resulting in a significant difference in favor of Isa-Rd (p<0.001). Using a sensitivity threshold of 10-5, MRDneg was documented in 19 (39.6%) pts of the Isa-Rd and in one (2.5%) of the Rd group. MRDneg rates were similar in pts with/without HR cytogenetics. PFS analysis shows a median PFS of not reached in the Isa-Rd vs. 20.2 mos in the Rd group, respectively (p=0.011). The PFS rate at 24 mos was 64.9% in the Isa-Rd, and 38.2% in the Rd arm. Currently, no difference in OS was observed (OS rate at 24 mos 86.0% vs 75.6%, median not reached in both groups, p=0.21). CTC data were available in 64 pts. Those with CTC detectable at d 8 had significantly shorter PFS (p=0.031). The PFS rate at 24 mos was 28.3% in CTC pos. vs. 73.9% in CTC neg. pts, respectively.

Hematologic AEs of any grade/grade≥3, which occurred in ≥10% of pts, were neutropenia (28.5%/19.0%), anemia (24.8%/8.8%), thrombocytopenia (16.8%/5.8%), hypokalemia (6.6%/2.2%) and hypocalcemia (5.8%/2.9%). Non-hematological AEs in ≥10% of pts, were infections (57.7%/19.7%), pain (43.8%/7.3%), edema (23.4%/0.7%), asthenia (22.6%/4.4%), diarrhea (19.7%/0%), constipation (15.3%/1.5%), rash (14.6%/2.2%), dyspnea (13.9%/1.5%) and polyneuropathy (10.9%/0%). Only procedural complications (9 [12.9%] vs. 0, p=0.003), and weight loss (6 [8.6%] vs. 0, p=0.028) were more frequent in the Isa-Rd group.

Conclusion Our data show a significantly higher MRDneg rate at 10-6 after 8 cycles of induction therapy with Isa-Rd compared to Rd (35.4% vs. 2.5%). Additional benefits of Isa-Rd include a higher rate of CR/VGPR, a significantly longer PFS, and a favorable safety and tolerance profile in very elderly pts with NDMM. Updated efficacy and safety data will be presented at the upcoming meeting.

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2025
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