Clinical Summary: 

• Design/Population: Post hoc analysis of the phase 3 IRAKLIA trial evaluating isatuximab plus pomalidomide and dexamethasone in 67 patients with relapsed or refractory multiple myeloma previously exposed to anti-CD38 monoclonal antibodies, including 26 patients with anti-CD38–refractory disease.
• Key Outcomes: Prior anti-CD38–exposed patients achieved an overall response rate of 52.2% and median progression-free survival of 8.5 months. Outcomes were similar between anti-CD38–refractory and non-refractory patients, while patients with a washout period greater than 20.2 months achieved response rates and progression-free survival outcomes approaching those seen in anti-CD38–naïve patients.
• Clinical Relevance: These findings support retreatment with CD38-targeted therapy in selected patients with relapsed or refractory multiple myeloma and suggest that longer intervals since prior CD38 exposure may optimize outcomes.

Sikander Ailawadhi, MD, Mayo Clinic, Jacksonville, Florida, discusses post hoc analysis results from the phase 3 IRAKLIA trial evaluating the impact of prior anti-CD38 monoclonal antibody exposure on outcomes with isatuximab, pomalidomide, and dexamethasone in relapsed or refractory multiple myeloma. As CD38-targeted therapies are increasingly incorporated into frontline treatment, understanding the effectiveness of retreatment strategies has become increasingly important.

The analysis demonstrated that patients previously exposed to anti-CD38 therapy continued to derive meaningful benefit from isatuximab-based treatment, including those whose disease was refractory to prior CD38-directed therapy. Notably, patients with longer treatment-free intervals experienced outcomes that closely resembled those of anti-CD38–naïve patients, supporting the concept that CD38 retreatment remains a viable and clinically relevant option in modern myeloma care.

Dr Ailawadhi presented these results at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois. 

Transcript: 

Hello everybody, I’m Sikander Ailawadhi from Mayo Clinic in Jacksonville, Florida, and I also lead the multiple myeloma group for Mayo Clinic as a whole. I’m coming to you from the ASCO 2026 meeting in Chicago, and I’m excited to share some of the results presented today from the IRAKLIA clinical trial.

This is a clinical trial in relapsed or refractory multiple myeloma that has been presented previously, but what we discussed today was a subgroup analysis of patients who were treated with the combination of isatuximab, pomalidomide, and dexamethasone, specifically focusing on patients who had previously been treated with an anti-CD38 monoclonal antibody–based regimen. In other words, these were patients who had prior treatment with either a daratumumab- or isatuximab-based regimen. Why is that important?

In today’s practice, especially in the United States, the majority of myeloma patients are exposed to an anti-CD38 monoclonal antibody—either daratumumab or isatuximab—in the first or second line of therapy. As a result, by the time patients develop relapsed/refractory disease, many have already received a CD38-targeted therapy.  The challenge is that many clinical trials evaluating anti-CD38–based combinations excluded patients who had prior exposure to these agents. Therefore, when we use those regimens in routine clinical practice, we often do not have the same level of evidence that was available in the original trials.

The IRAKLIA study did not exclude patients with prior CD38 exposure. However, it required at least a nine-month interval between prior anti-CD38 therapy and study treatment. That allowed us to perform this analysis and better understand the role of anti-CD38 retreatment in the relapsed or refractory setting. Overall, the study enrolled 561 patients. Of those, 67 patients—approximately 13%—had previously been exposed to an anti-CD38–based regimen. Looking specifically at those patients, the subgroup analysis showed that outcomes were similar whether patients had simply been exposed to a CD38-based regimen previously or were actually refractory to it. The second important and quite exciting finding was related to the duration of washout from prior anti-CD38 therapy.

The median washout period was 20 months. Patients who had a washout period of 20 months or longer had efficacy outcomes that were remarkably similar to those seen in patients who had never received a CD38-targeted therapy. In other words, a longer washout period largely eliminated the concern that prior exposure to a CD38 monoclonal antibody would negatively affect outcomes. Importantly, there were no new safety signals observed. Although these patients were somewhat more heavily pretreated, there were no unexpected safety concerns. Putting all of this together, these findings suggest that in today’s treatment landscape, where first- and second-line CD38 exposure is very common, patients can still derive meaningful benefit from retreatment with an anti-CD38 monoclonal antibody. In this case, that retreatment involved an isatuximab-based regimen. 

Furthermore, if there is a sufficiently long washout period, patients may behave almost as though they had never been exposed to a CD38-targeted therapy in the first place. These findings help us better understand how to optimally use the therapies that are available today for our patients with relapsed/refractory multiple myeloma. Of course, patients with prior CD38 exposure may still have somewhat lower response rates, shorter progression-free survival, and shorter duration of response compared with CD38-naive patients. However, this analysis clearly demonstrates that retreatment remains a viable and clinically meaningful option for these patients.

Source: 

Rocafiguera AO, Hus M, Gazitua R, et al. Isatuximab plus pomalidomide-dexamethasone in relapsed/refractory multiple myeloma: Subgroup analysis by prior anti-CD38 exposure from the phase 3 IRAKLIA trial. Presented at the ASCO Annual Meeting. May 29 - June 2, 2026. Chicago, Illinois. Abstract 7516.