Phase II Study of Isatuximab, and Weekly Carfilzomib + Dexamethasone in Relapsed and Refractory Multiple Myeloma (RRMM)

Background: Isatuximab (Isa) is a humanized anti-CD38 monoclonal antibody that has been shown to have multiple direct antitumor and immunomodulatory activities.1 Isatuximab is approved for use in combination with pomalidomide and dexamethasone (ICARIA) and twice weekly carfilzomib (K) and dexamethasone (IKEMA) as salvage treatment for patients with RRMM. In the IKEMA study the PFS was 35.7 months in patients with early relapsed MM (1-3 prior LOT).2 Multiple three-drug combination studies have demonstrated the safety and efficacy of using once weekly, high-dose K at 70 mg/m2 Day 1, 8, 15.3,4 Objectives: The aim of this study was to assess the safety and efficacy of Isa-Kd utilizing standard Isa-dosing (10 mg/kg QWk x4, then QOWk) and weekly high-dose K (70 mg/m2) plus dexamethasone (d) in patients with early relapsed MM (1-3 prior LOT). (NCT-02332850) Methods: Eligible patients (pts) had disease progression after 1-3 prior LOT, an ECOG <3, no prior CD38 therapy, and adequate organ function. Therapy included Isa IV weekly (QW) for 4 doses then Q2W together with K (20mg/m2 Day 1, =>70 mg/m2: Day 8, 15 Q28d and for all subsequent K doses) and d (40 mg PO QW). Pts continued therapy until disease progression, undue toxicity or physician/patient choice. Results: As of July 14, 2024,50 pts have been enrolled and are evaluable for safety and response. Pts were ECOG <2, had a median age of 64 (range 39-78) yrs, received a median of 1 LOT (range 1-3) and 90% had received prior SCT. All pts were IMiD and PI exposed, 50% Len refractory (Refr), and 22% had received prior K. Median follow-up is 14 months (range 2-43m), and a median of 16 cycles of Isa-Kd have been administered. The ORR is 90% (sCR/CR 8, VGPR 21, PR 16), responses occur rapidly (median 1 cycle) and responses deepen over time. The median progression free and overall survival have not been reached. Disposition: 14 patients have progressed; 3 patients have died (1 from PD, 1 sudden death attributed to K, 1 sudden death off treatment), 17 pts stopped treatment in response (7 due to toxicity (3 SOB, 1 MI, 1 FTT, 1 colitis, 1 fatigue); 6 for treatment holiday; 4 due to physician choice, and 16 remain on therapy). The most frequent occurring treatment-related toxicity (AEs-all grades, incidence ≥ 20%), were infusion related reactions (IRR; 58%), hypertension (52%), nausea (50%), cough (42%), fatigue (40%), dyspepsia (40%), insomnia (38%), diarrhea (38%), thrombocytopenia (34%), fever (26%), headache (24%), constipation (22%), and anemia (20%). Infections were also common; 30 pts (60%) experienced an URI, 10 pts (20%) had covid, and an additional 17 pts experienced a presumed bacterial infection (5 sinusitis, 4 UTI, 3 pneumonia, 3 cellulitis, 2 colitis). The IRRs were all attributable to Isa, all were Grade 1-2 and only 2 pts had a subsequent or second IRR. Conclusion: The triplet combination of Isa-Kd incorporating weekly high-dose K70 mg/m2 appears safe; with no unexpected toxicity and AEs consistent with the toxicity profile of the individual agents. Encouraging anti-MM activity has been demonstrated with an ORR of 90% in patients with early RRMM (1-3 PLOT) and the median PFS and OS have not been reached (NCT 02332850).