A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma’Â is a study intended to assess the safety, efficacy and pharmacokinetics of the anti-CD38 monoclonal antibody isatuximab given in 2 different regimens in combination with lenalidomide and dexamethasone. The study included 57 patients in total with a confirmed diagnosis of multiple myeloma who had progressed or failed to respond after at least 2 lines of therapy. The study was completed in two parts, with the first part with IV isatuximab fortnightly in dose-escalation cohorts (3,5, or 10mg/kg). This was then amended in the second part to assess isatuximab in 10-20mg/kg weekly doses for 4 doses and then followed by fortnightly doses thereafter. In both parts patients also received standard doses of oral lenalidomide (10mg days 1-21) and dexamethasone (40mg days 1,8,15 and 22) in 28 day cycles. The primary objective was to determine the maximum tolerated dose (MTD) of isatuximab in this combination with secondary objectives to evaluate safety, pharmacokinetics and efficacy.
In terms of safety, in the dose-escalation part of the study, only one dose-limiting toxicity (DLT) was observed (bilateral pneumonia in the 20mg/kg cohort) which resolved with treatment discontinuation. Overall 88% of all patients suffered at least 1 grade 3/4 adverse events (AE). Infusion-associated reactions (IARs) were the most common isatuximab-related AE and occurred in 56% of patients, with 88% of these IARs only occurring during the first infusion. Apart from IARs the most common AEs were diarrhoea (53%), fatigue (49%), upper respiratory tract infection (40%) and nausea (35%). There were five on-treatment deaths, none of which were related to treatment and three of which were related to treatment progression.
With an overall median follow up of 9 months, the overall response rate (ORR) for the population was 51% including 2 patients with complete response (CR), 17 with very good partial response (VGPR), 10 with partial response (PR) and 8 with minimal response. Notably, in patients who had previously been refractory to lenalidomide-based therapy the ORR was 52% and in those refractory to IMiD based therapy the ORR was 51%. Additionally all patients who had received 1-2 lines of previous therapy attained at least a VGPR and in patients with high-risk cytogenetics the ORR was 31%. In terms of time to response, the median time to first response was 0.95 months and was similar across the cohort with a median duration of response of 10.9 months. Overall median progression free survival (PFS) was 8.5 months. Significantly, patients who received 10mg/kg isatuximab had a longer PFS when initially receiving weekly treatments than those started on fortnightly regimens.
The results of this study found that the combination of isatuximab, lenalidomide and dexamethasone demonstrated promising activity with similar activity between 10mg/kg and 20mg/kg doses (although it was not powered to detect differences between groups). It also demonstrated a similar level of activity in both lenalidomide naive patients as well as previously lenalidomide refractory patients. The study also demonstrated that the regimens were well-tolerated with only one case of a dose-limiting toxicity and the maximum tolerated dose was not reached. The 10mg/kg dose transitioning from weekly to fortnightly doses has been selected for further phase 3 trials of isatuximab combination therapies.