At the 64th American Society of Hematology Annual Meeting and Exposition, Paul G Richardson, MD, and colleagues spoke on “Isatuximab plus pomalidomide/low-dose dexamethasone versus pomalidomide/low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (ICARIA-MM): Characterization of subsequent antimyeloma therapies.”

The anti-CD38 monoclonal antibody isatuximab (Isa) is approved as part of a combination therapy along with pomalidomide and dexamethasone (Pd) in several countries for the treatment of patients with relapsed/refractory multiple myeloma (RRMM) who have received at least two previous treatments, including lenalidomide and a proteasome inhibitor.

“The objectives of this analysis were to look at the sequencing of antimyeloma therapies in this particular setting,” Dr Richardson said. “But here we are going to describe some updated, longer-term data which I hope helps to understand the efficacy following subsequent therapy and then informs everyone in regard to potential treatment choices.”

Patients were randomized in a 1:1 ratio to Isa-Pd (n = 154) or Pd (n = 153) and were stratified by age (<75 vs ≥75 years) and by number of prior lines of therapy (2–3 vs >3). In the first treatment cycle, Isa 10 mg/kg was administered every week for 4 weeks, then every 2 weeks thereafter for the second cycle. In both treatment cycles, all patients received pomalidomide 4 mg on days 1 to 21 and weekly dexamethasone 40 mg on days 1, 8, 15, and 22. Treatment continued until progressive disease, unacceptable adverse events, or patient choice. Researchers conducted the final overall survival analysis once 220 deaths occurred.

Sixteen (10.4%) patients in the Isa-Pd group and 3 (2.0%) in the Pd group were still on treatment as of March 14, 2022. Treatment had been discontinued in 101 (65.6%) patients receiving Isa-Pd and 117 (76.5%) receiving Pd due to progressive disease. Median treatment duration was longer with Isa-Pd than with Pd (47.6 vs 24.0 weeks). After a median 52.4 months of follow-up, the researchers found a clinically meaningful overall survival rate in favor of Isa-Pd over Pd (as of January 27, 2022; median: 24.6 vs 17.7 months; hazard ratio 0.776 [95% confidence interval: 0.594–1.1015]; one-sided P = .0319; significance level: P = .02).

A total of 102 (66.2%) patients in the Isa-Pd arm and 119 (77.8%) in the Pd arm received additional antimyeloma treatment, with a median of 2 and 1 additional regimens, respectively. Of these patients, 22.5% (23/102) in the Isa-Pd arm and 59.7% (71/119) in the Pd arm received daratumumab. The most common further subsequent antimyeloma treatments for Isa-Pd patients were corticosteroids (86.3%), alkylating agents (69.6%), and proteasome inhibitors (68.6%); a proteasome inhibitor was the most common treatment in the first subsequent treatment line (52.9%).

The most common further antimyeloma treatments for patients in the Pd arm were corticosteroids in 79% (94/119), monoclonal antibodies in 63% (75/119), and proteasome inhibitors in 58% (69/119); the most common treatment received in the first subsequent line was daratumumab in 43.7% (52/119).

The overall response rate (ORR) for the first subsequent line of therapy in the Isa-Pd arm was 28.8% vs 35.3% in the Pd arm. The ORR in patients receiving daratumumab-based regimens as the first subsequent line of therapy was 25% for the Isa-Pd arm and 40.5% for the Pd arm. In patients receiving daratumumab as monotherapy or with steroids in any subsequent line, the ORR was 12.5% for the Isa-Pd arm and 36.7% for the Pd arm. Daratumumab in combination with immunomodulatory agents, alkylating agents, or proteasome inhibitors in any subsequent line resulted in an ORR of 28.6% for the Isa-Pd arm and 44.8%. For patients receiving daratumumab, progression-free survival (PFS) on the first subsequent line of therapy was 2.2 months for patients in the Isa-Pd arm vs 5.7 months for those in the Pd arm. Comparatively, the PFS on first subsequent line for patients that excluded daratumumab was 4.6 and 5.2 months, for the Isa-Pd and Pd arms, respectively.

This analysis demonstrates that the majority of patients with RRMM require multiple lines of subsequent therapy, even after receiving a triplet combination that includes a monoclonal antibody, concluded the authors.

“We’ve got really mature follow-up now with more than 50 months in both arms,” Dr Richardson said. “Most patients continue on the triplet vs the doublet, and the primary reason for discontinuation of the Pd arm is progressive disease, and the adverse events are relatively evenly balanced.”

The authors note that, given the sample size, the more frequent subsequent use of daratumumab in Pd vs Isa-Pd may have affected the ability to detect statistically significant overall survival. 

“We obviously have to recognize limitations to this analysis,” Dr Richardson said. “The relatively small sample size, and obviously the open-label nature of the study does in fact influence the outcome. But I do think these results provide initial information on the potential efficacy differences related to treatment sequencing. The new targets that we now have deployed in this setting will likely change this playing field. As we go forward, we hope this information is helpful.

“When we think of future directions, if we focus on isatuximab, it’s important to note that this approval is relatively broad and now with the approval with the combination of carfilzomib and dexamethasone, what you can tell here is the PFS differences are real and the survival differences are sustained and impressive, pointing to the value of long-term follow-up of these studies.”

Richardson P, Perrot A, San-Miguel J, et al. Isatuximab plus pomalidomide/low-dose dexamethasone versus pomalidomide/low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (ICARIA-MM): Characterization of subsequent antimyeloma therapies. Presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022. Abstract 247. Funded by Sanofi.