The CD38 mechanism is showing real benefit, and an interesting question is whether there will be differences in the pattern of disease control with isatuximab vs daratumumab, given that there are differences between these agents in epitope binding and complement activation; there is also a direct apoptotic mechanism with isatuximab. These potential mechanistic differences may impact the biology of the disease in ways that remain to be seen, and as this relates to the potential for immunomodulatory antitumor effects with CD38-directed therapy, there is still much to be learned.

Last year, we were alerted to the striking success of the phase 3 CANDOR trial, with daratumumab in combination with carfilzomib and dexamethasone in the relapsed/refractory setting. Here, in the interim analysis of the phase 3 IKEMA trial (abstract LB2603), the addition of isatuximab to carfilzomib and dexamethasone resulted in a markedly improved progression-free survival (PFS) compared with carfilzomib and dexamethasone alone. Patients in this trial had received 1 to 3 prior lines of antimyeloma therapy. At a median follow-up of nearly 21 months, the median PFS was not yet reached for the isatuximab-containing arm, while the PFS was approximately 19 months in the arm receiving carfilzomib and dexamethasone alone. To me, it was particularly striking that approximately 70% of patients in the isatuximab-containing arm appeared to be progression free at the time of follow-up, which is particularly impressive in the relapsed and refractory settings. The tolerability profile was also favorable, with no signal for additional cardiovascular or renal toxicity with isatuximab.

Several important questions await further investigation, one of which relates to the use of isatuximab after relapse post daratumumab-based therapy in the upfront setting. I could see a treatment algorithm emerging in the future, where an isatuximab-carfilzomib–based combination might be used as the next regimen, based on these data. Another question becomes: Would you go straight to an isatuximab-based regimen or would you instead deploy it in a more syncopated fashion (eg, perhaps after using a B-cell maturation antigen–targeted approach)? Nevertheless, based on the IKEMA trial data, an isatuximab-carfilzomib–based platform is an attractive option after prior exposure to daratumumab.

As relates to patterns of disease control, extramedullary disease (EMD) after daratumumab failure is a high-risk presentation, with enrichment for 17p deletion, and an active area of investigation. In the multicenter international HORIZON trial evaluating single-agent infusional melflufen combined with dexamethasone in triple class–resistant disease, a high number of patients with this presentation was included in the study, where a response rate of 24% in these patients was seen, with durability also noted. This compares favorably with response rates reported with single-agent daratumumab for daratumumab-naïve patients with EMD, which was 17% in one series. The limited efficacy of daratumumab for EMD was further described here at EHA25 Virtual, in abstract EP1030. This analysis included 42 patients with relapsed/refractory multiple myeloma who had been treated with single-agent daratumumab after 3 or more prior lines of therapy. The results indicated that the efficacy of daratumumab is very limited in these patients, with a median PFS of only 1.4 months compared with 6.8 months for the overall population. 

Unfortunately, many patients have few effective treatment options after the third relapse; however, as noted above, emerging evidence with melflufen (abstract EP945) has been encouraging, showing promising activity in EMD, and this will likely be enhanced in combination. These observations in patients with EMD are thus very important because they illustrate the need to better understand how best to sequence drugs as we move through the available choices of treatment in the face of disease progression.