S824 a Phase 3 Randomized, Open‐label, Multicenter Study of Isatuximab, Pomalidomide, and Low‐dose Dexamethasone vs Pomalidomide and Low‐dose Dexamethasone in Relapsed/Refractory Multiple Myeloma (Rrmm)

Abstract

Background:Despite recent advances, multiple myeloma (MM) remains incurable, and new treatment options are needed to continue to improve patient outcomes. This is the first randomized, phase 3 trial of an anti‐CD38 antibody in combination with pomalidomide (P) and dexamethasone (d) in RRMM.Aims:The primary objective of this phase 3 trial (NCT02990338) was to demonstrate progression free survival (PFS) improvement of isatuximab (Isa), a novel anti‐CD38 monoclonal antibody targeting a specific epitope, combined with Pd versus (vs) Pd in RRMM.Methods:Patients (pts) with RRMM who received ≥2 prior lines, including lenalidomide (len) and a proteasome inhibitor (PI), refractory to last therapy were enrolled. IsaPd arm received Isa 10 mg/kg IV weekly for first 4 weeks (wks), then every 2 wks. Both arms received approved schedules of pom and dex (4 mg PO days 1–21; 40 mg [20 mg if >75 yrs] PO or IV weekly) every 28 days until progression or unacceptable toxicity.Results:307 pts (154 IsaPd, 153 Pd) were randomized and analyzed (ITT). Patient characteristics were well balanced across arms. Median age: 67 (36–86) yrs; median prior lines of therapy: 3 (2–11); estimated GFR: <60 ml/min in 33.9% pts; 92.5% refractory to len, 75.9% to PI; and 19.5% pts had high‐risk cytogenetics. At median follow‐up of 11.6 months (mos), median PFS was 11.5 mos IsaPd vs 6.5 mos Pd; HR 0.596 (95% CI 0.44–0.81), P = 0.001. PFS benefit was consistent across all major subgroups. ORR (≥PR) was 60.4% IsaPd vs 35.3% Pd, P < 0.0001. VGPR rate or better was 31.8% IsaPd vs 8.5% Pd, and MRD negativity (NGS, 10−5) was seen in 5.2% IsaPd pts vs 0% Pd. At analysis date, overall survival (OS) was immature (99 events) but a trend to OS improvement in IsaPd (vs Pd) was observed (HR 0.687; 95% CI 0.461–1.023). Median treatment duration was 41 wks IsaPd vs 24 wks Pd; median Isa infusion (inf.) duration was 3.3 h at 1st inf. and 2.8 h at subsequent inf. Grade ≥3 AEs were observed in 86.8% IsaPd vs 70.5% Pd; 7.2% IsaPd and 12.8% Pd pts discontinued due to AEs; 7.9% IsaPd and 9.4% Pd pts died due to AEs. Inf. reactions were reported in 38.2% (2.6% grade 3–4) IsaPd. Grade ≥3 infections were seen in 42.8% IsaPd and 30.2% Pd, grade ≥3 neutropenia in 84.9% (febrile 11.8%) IsaPd and 70.1% (febrile 2.0%) Pd.Summary/Conclusion:Isatuximab in combination with pomalidomide and dexamethasone significantly improved PFS and ORR vs pomalidomide and dexamethasone, with a manageable safety profile. Isatuximab in combination with pomalidomide and dexamethasone is an important new treatment option for the management of RRMM.

Treatment of Lenalidomide Exposed or Refractory Multiple Myeloma: Network Meta-Analysis of Lenalidomide-Sparing Regimens

“…Furthermore, few or no data are currently available on the activity of lenalidomide-based triplets or quadruplets (thus excluded from this analysis) in lena-refractory patients as well as on the efficacy of lenalidomide ramp-up in patients progressing during 10 mg maintenance. Along the same line, the efficacy of the new pomalidomide/mAbs combo regimens, which look very promising, could not be evaluated with this approach, mainly due to the fact that all the investigational clinical trials have been performed in more advanced settings (from the third line of therapy) by using (always) PD as control arm (12)(13)(14). Translational investigations, which shed light on the biologic interplay which take place within the bone marrow microenvironment (15)(16)(17)(18)(19) are eagerly awaited and could help to develop new therapeutic approaches in this setting.…”

Pomalidomide and Dexamethasone Are Effective in Relapsed or Refractory Multiple Myeloma in a Real-Life Setting: A Multicenter Retrospective Study in Taiwan

“…Primary lenalidomide refractoriness should not be an obstacle to Pom/Dex treatment in RRMM patients. Adding elotuzumab (19) or isatuximab (20) to Pom/Dex could be a solution to improve the efficacy of this regimen in future practice.…”

The Anti-CD38 Antibody Therapy in Multiple Myeloma

“…In the CASSIOPEIA study, 1085 transplant-eligible patients with NDMM were randomized 1:1 to receive either intravenous daratumumab with bortezomib, thalidomide, and dexamethasone (VTd) or VTd alone. In this phase III study, patients received up to four 28-day cycles as induction and two 28-day cycles as consolidation therapy, oral thalidomide (100 mg/day), bortezomib (1.3 mg/m 2 on days 1, 4, 8 and 11 of each cycle) and dexamethasone (40 mg on days 1,2,8,9,15,16,22, and 23 of cycles 1 and 2, on days 1 and 2 of cycles 3 and 4, and 20 mg on days 8,9,15, and 16 of cycles 3 and 4 of induction treatment, and on days 1, 2, 8, 9, 15, and 16 of both consolidation cycles). In addition, 543/1085 in the daratumumab group received MoAb at a dose of 16 mg/kg weekly in induction cycles 1 and 2 and then once every two weeks during induction cycles 3 and 4 and consolidation.…”

“…Among the 38.2% of IRRs, 2.6% were Grade 3-4. Data, in terms of overall survival, are not mature yet after a median treatment duration of 41 weeks (IsaPd) vs. 24 weeks (Pd), but a trend to OS improvement in IsaPd was observed (HR 0.687; 95% CI 0.461-1.023) [22].…”