Updated Results from a Phase Ib Study of Isatuximab Plus Pomalidomide (Pom) and Dexamethasone (dex) in Relapsed/Refractory Multiple Myeloma (RRMM)

Background: Isatuximab (ISA) is an anti-CD38 monoclonal antibody with multiple modes of action for killing tumor cells through immune cell engagement and direct tumor targeting. We previously presented data from the dose-escalation cohort, and the first 3 patients (pts) of the expansion cohort, of a Phase Ib study of ISA plus Pom and dex in pts with RRMM (Mikhael et al. ASCO 2017, Abs 8007) (NCT02283775). Here, we report updated results including data from 10 additional pts from the expansion cohort.

Methods: Pts with RRMM (≥2 prior MM therapies, including lenalidomide [Len] and a proteasome inhibitor [PI]) with adequate bone marrow reserve/organ function were sequentially enrolled to ISA 5, 10, or 20 mg/kg (4 weekly doses, then every 2 weeks [wks]) plus Pom 4 mg (Days 1-21) and dex 40 mg (Days 1, 8, 15, and 22; 20 mg if ≥75 yrs old), in 28-day cycles until disease progression or intolerable toxicity. Pom or dex dose reductions were permitted after Cycle 1, or during Cycle 1 in response to dose-limiting toxicities (DLTs). The primary objective was to determine the recommended dose of ISA in combination with Pom/dex. Secondary objectives included evaluation of efficacy (IMWG criteria), safety, and pharmacokinetic (PK) parameters.

Results: Based on initial safety, efficacy, and PK data, ISA 10 mg/kg was chosen as the recommended dose for the expansion cohort. At data cut-off (Mar 1, 2017), 36 pts had been treated (5 mg/kg [n=8]; 10 mg/kg [n=22, 9 in the dose-escalation; 13 in the dose-expansion (shorter follow-up time)]; 20 mg/kg [n=6]). Overall, median age was 66 (42-80) yrs and median time from diagnosis was 4.25 (1-14) yrs. Median number of prior treatment regimens was 4.0 (2-11); 14 (39%) pts had received ≥5 prior regimens; 4 (11%) pts had received prior Pom. Overall, 29 (81%) pts were refractory to their last regimen; 26 (72%), 25 (69%), and 21 (58%) pts were refractory to an immunomodulatory drug, PI, or both, respectively. Twenty-five (69%) pts had received ≥1 prior stem cell transplant. At cut-off, median duration of treatment was 20.4 wks; 21 (58%) pts remained on treatment. Two pts (10 mg/kg) discontinued therapy due to adverse events (AEs) (grade [Gr] 5 perforated bowel due to underlying MM; Gr 3 infusion-associated reaction [IAR]). Twelve pts withdrew due to disease progression, including 1 unconfirmed disease progression, and 1 pt requested to stop treatment due to an IAR. Three DLTs were reported: prolonged Gr 4 neutropenia (5 mg/kg), Gr 4 neutropenic infection (10 mg/kg) (both Pom related), and Gr 3 confusional state (20 mg/kg) (ISA and Pom related); all DLTs resulted in study treatment dose omission/reduction. The maximum tolerated dose has not been reached. Overall, Gr ≥3 AEs were reported in 28 (78%) pts and serious AEs in 17 (47%) pts. The most frequent AEs (any Gr), besides IARs and hematologic AEs, were fatigue (47%), dyspnea (36%), constipation, diarrhea, and upper respiratory tract infection (28% each). The most frequent Gr 3/4 hematologic abnormalities (laboratory assessment) were neutropenia (Gr 3, 29%; Gr 4, 54%), lymphopenia (63%; 11%), and leukopenia (60%; 14%). All cases were manageable with dose reduction/delay or granulocyte-colony stimulating factor use, and none resulted in treatment discontinuation. Eighteen (50%) pts experienced an IAR (Gr ≥3 in 1 pt), primarily during the first infusion (17 pts). Three (8%) pts experienced IARs at a subsequent infusion (all Gr <3). The overall response rate (ORR) was 56% (20/36), including 1 stringent complete response, 1 complete response, 7 very good partial responses, and 11 partial responses. ORR was 63% (5/8), 55% (12/22), and 50% (3/6) at 5, 10, and 20 mg/kg, respectively. At data cut-off, duration of follow-up for newly enrolled pts at 10 mg/kg was short, and the ORR calculation excluded 2 pts with unconfirmed responses. The ORR for pts refractory to Len or with high-risk cytogenetics was 58% (15/26) and 40% (2/5), respectively. Median time to first response was 4.1 wks; median duration of response was 33.1 wks. The PK parameters of ISA appeared unaffected by co-administration with Pom/dex. The PK profile of Pom was consistent with published data.

Conclusions: The combination of ISA and Pom/dex is clinically active in heavily pre-treated RRMM, with manageable AEs. Long-term follow-up data will be presented at the meeting. A Phase III trial of this combination in RRMM is ongoing.

Funding: Sanofi