A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma

Abstract

Key Points• Isatuximab (anti-CD38 monoclonal antibody) given with lenalidomide/ dexamethasone is active in heavily pretreated relapsed/ refractory myeloma • Overall, the safety profile of this combination is similar to the characteristic safety profiles of the individual agents. remained on treatment at data cutoff. Isatuximab-lenalidomide-dexamethasone was generally well tolerated with only 1 dose-limiting toxicity reported (grade 3 pneumonia at 20 mg/kg QW/ Q2W); the MTD was not reached. The most common isatuximab-related adverse events were infusion-associated reactions (IARs) (56%), which were grade 1/2 in 84% of patients who had an IAR and predominantly occurred during the first infusion. In the efficacy-evaluable population, the overall response rate (ORR) was 56% (29/52) and was similar between the 10 mg/kg Q2W and 10 and 20 mg/kg QW/Q2W cohorts. The ORR was 52% in 42 evaluable lenalidomide-refractory patients. Overall median progression-free survival was 8.5 months. Isatuximab exposure increased in a greater than dose-proportional manner; isatuximab and lenalidomide pharmacokinetic parameters appeared independent. These data suggest that isatuximab combined with lenalidomide and dexamethasone is active and tolerated in heavily pretreated patients with RRMM. This trial was registered at www.clinicaltrials.gov as #NCT01749969. (Blood. 2017;129(25):3294-3303)

Isatuximab Plus Pomalidomide/Dexamethasone Versus Pomalidomide/Dexamethasone in Relapsed/Refractory Multiple Myeloma: Icaria Phase Iii Study Design

“…Overall, the safety profile of this combination was consistent with the safety profile of single-agent ISA and the combination of Len/dex alone [31,38]. Treatment of this heavily pretreated patient population (median five prior lines) with ISA plus Len/dex resulted in an ORR of 56%, including 17 (32.7%) VGPRs and two (3.8%) stringent complete responses (sCRs) [31]. The ORRs among patients refractory to Len, or both an IMiD and a PI were 52% (n = 42) and 45% (n = 38), respectively.…”

“…Therapy options in these patients are limited, and therefore new treatments which improve outcomes and survival are required. ISA has previously demonstrated anti-MM activity in patients who are refractory to currently available IMiDs and/ or PIs, and those with high-risk cytogenetic abnormalities [31,39,46]. At the dose selected for the ICARIA-MM study (10 mg/kg once a week/every 2 weeks), ISA in combination with Pom/dex showed clinical efficacy in a heavily pretreated population [44].…”

“…The ORR of the heavily pretreated population (≥3 prior lines) was 48% (n = 44). The pharmacokinetics (PK) of Len was not affected by co-administration with ISA [31].…”

“…The combination of ISA 10 mg/kg every 2 weeks with Len/dex (NCT01749969) was also associated with an acceptable safety profile [31]. The most common ISA-related AEs were IARs, which occurred mostly during cycle 1; no IARs were observed after the fourth infusion.…”

“…Preclinical assessment suggests that NK cell-mediated antibody-dependent cellular cytotoxicity is the most important mechanism of action contributing to ISA efficacy [30]. In addition, ISA appears to be unique among anti-CD38 mAbs, in that it is able to induce apoptosis without crosslinking and may be better tolerated, with a shorter infusion time [22,31]. Furthermore, ISA demonstrated significant inhibition of CD38 ectoenzyme activity in MM and other hematologic cancer cell lines [32].…”