DISCUSSION
death, infections/sepsis
EVENTS, PROLIFERATIVE
This Phase 1/2 study was designed to evaluate the safety, preliminary efficacy, and PK of the combination of Isa and cemiplimab in patients with RRMM, and is the largest randomized trial investigating the combination of anti‐CD38 and anti‐PD‐1 agents to date. The study population was representative of the global population with RRMM, including important subgroups of patients with poor prognosis characteristics (ISS Stage III [26.4%], renal function impairment with creatinine clearance <60 mL/min [31.1%], high‐risk cytogenetics [25.5%], and bone marrow plasma cells at baseline ≥50% [27.4%]). Patients were heavily pretreated, with a median (range) of 4 (2–11) prior lines of therapy. In the total randomized population, 37.7% of patients received ≥5 previous lines of therapy and 84.0% were refractory to the last regimen. Most patients were refractory to PIs and IMiDs. Overall, 26.4% of patients had received prior daratumumab, including 3.8% who received daratumumab within the last line of therapy.No new safety signals were observed with Isa plus cemiplimab, which is consistent with other safety experiences with this combinationIn the present study, we did not observe death due to cardiovascular or ischemic reasons, and there were few infections/sepsis events reported. Concomitant administration of cemiplimab did not appear to alter Isa exposure. With further follow‐up, the OS curves were overlapping when comparing Isa alone with Isa plus cemiplimab. This may be due to the different mechanism of action of isatuximab versus immunomodulatory drugs.As assessed by Investigators, four patients (11.8%) in the Isa arm, nine patients (25.0%) in the Isa + CemiQ2W arm, and eight patients (22.2%) in the Isa + CemiQ4W arm were responders. Though response rates were numerically higher among cemiplimab‐containing arms, differences were not statistically significant and did not translate to improved PFS or OS. These findings of a modest improvement in ORR and lack of translation to PFS benefit are in contrast to what was shown previously with isatuximab in combination with pomalidomide and dexamethasone (ICARIA) and with carfilzomib and dexamethasone (IKEMA), which demonstrated significant benefits in PFS and response or depth of response.In the present study, an Isa dose of 10 mg/kg was chosen to allow for the assessment of cemiplimab contribution. This dose was also used for the Isa‐only arm monotherapy studies. The lower response rates in Isa‐only arm of this study could be due to the use of the 10 mg/kg Isa dose versus the now‐recommended single‐agentWhether benefit can be gained from an alternate anti‐CD38 agent (or even retreatment with the same anti‐CD38 agent) and the appropriate timing of reintroduction of CD38 inhibition remain important clinical questions, particularly as anti‐CD38 therapy moves into earlier lines of treatment. It is becoming increasingly clear that single‐agent anti‐CD38 treatment with isatuximab or daratumumab is insufficiently active in patients with prior anti‐CD38 exposure. In the present study, 28 of 106 (26.4%) patients in the overall randomized population had previously received daratumumab treatment, of whom four had received daratumumab as the last line of therapy, with no objective responses observed. In ICARIA‐MM, 22 of 92 (23.9%) patients treated with further anti‐myeloma therapy in the Isa‐Pd arm went on to receive daratumumab in any subsequent line of therapy, of whom seven received monotherapy (+/−steroids). The ORR for daratumumab as further anti‐myeloma treatment (in monotherapy) was lower after Isa‐Pd than after Pd treatment (14% vs 38%, respectively).Treatment with isatuximab with or without cemiplimab induced the expected pharmacodynamic effects, consistent with the mechanism of action of each drug as shown in previous studies.Target engagement was shown to be similar in the population pretreated with or naïve to daratumumab, so there was no lack of target engagement that could explain the lack of response in the daratumumab‐pretreated population.The baseline immune microenvironment in daratumumab‐pretreated patients appears to be consistent with what is known to happen after treatment with an anti‐CD38 molecule, that is, an increase in activated PD‐1+ CD8 T cells and proliferative Ki67+ CD8 T cells as well as a decrease in CD38+ CD8 T cells. The other baseline immune parameters, including natural killer cell counts, were similar between groups and did not explain the lack of response in daratumumab‐pretreated patients.The current study has several limitations and strengths. Limitations of the current study include the small number of patients enrolled in each study arm, the heavily pretreated population, and the short washout period after prior exposure to anti‐CD38 agents. Strengths of the current study include biomarker data and continued demonstration of a manageable safety profile with the combination of isatuximab plus cemiplimab and of no effect of cemiplimab on isatuximab PK, which confirms experiences from other Isa plus cemiplimab studies.In conclusion, this study evaluating isatuximab in combination with cemiplimab in patients with RRMM indicates a marginal benefit on clinical outcomes with the addition of cemiplimab to isatuximab. The numerical increase in ORR seen with the addition of cemiplimab was not statistically significant and did not translate into an improvement in PFS or OS. No major changes in the safety or PK profile were observed with the addition of cemiplimab.