Regimen provides ‘unprecedented’ PFS benefit in relapsed multiple myeloma
The addition of isatuximab-irfc to carfilzomib and dexamethasone conferred a durable PFS benefit to patients with relapsed multiple myeloma, according to updated results of the randomized phase 3 IKEMA trial.
“These results show an unprecedented median PFS of 3 years [among patients who received the three-agent regimen],” Philippe Moreau, MD, head of the department of hematology at University Hospital in Nantes, France, said during a presentation in an ESMO Virtual Plenary session. “That is the longest PFS observed using a proteasome inhibitor backbone in the relapsed multiple myeloma setting. ... This regimen is now a standard of care for [patients with] relapsed multiple myeloma.”
Data derived from Moreau P, et al. VP2-2022. Presented at: ESMO Virtual Plenary; May 19, 2022.
Background
A high percentage of patients with multiple myeloma will relapse, highlighting the need for second-line treatments that can further delay progression.
Isatuximab-irfc (Sarclisa, Sanofi Genzyme) is a monoclonal antibody directed at CD38, which is expressed on multiple myeloma cells.
The multicenter, open-label IKEMA trial included 302 patients (median age, 64 years; range, 33-90;) who had received one to three prior lines of therapy but had not received carfilzomib (Kyprolis, Amgen) and were not refractory to prior anti-CD38 therapy.
More than half (59.6%) had Revised International Staging System disease; 77% had received one or two prior lines of therapy; and 24% had high-risk cytogenetics.
Researchers randomly assigned 179 patients to 10 mg/kg isatuximab-irfc via IV once weekly for 4 weeks, then every other week for 28-day cycles, plus carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1, 56 mg/m2 on days 8-9 and 15-16 of cycle 1, and 56 mg/m2 on days 1-2, 8-9 and 15-16 of all subsequent cycles) and 20 mg dexamethasone on days 1-2, 8-9, 15-16 and 22-23 of each cycle). The other 123 patients received carfilzomib and dexamethasone alone.
Treatment continued until progressive disease, unacceptable toxicity or patient request.
PFS assessed by independent review committee served as the study’s primary endpoint. Secondary endpoints included overall response rate, rate of complete response or better, rate of very good partial response or better, rate of minimal residual disease negativity, OS and safety.
Results of a preplanned interim analysis — performed after median 20.7 months of follow-up — showed a significant improvement in PFS (HR = 0.53; 99% CI, 0.32-0.98), very good partial response or better (72.6% vs. 56.1%), minimal residual disease negativity (29.6% vs. 13%) and complete response rate (39.7% vs. 27.6%) among patients who received isatuximab-irfc.
The FDA approved isatuximab-irfc in combination with carfilzomib and dexamethasone for this patient population based on these results.
Updated PFS results
During the ESMO Virtual Plenary session, Moreau presented results of a prespecified analysis performed after 159 PFS events occurred, allowing for median follow-up of 44 months.
At this time, 27.4% of patients assigned the isatuximab-irfc regimen and 8.9% of those assigned carfilzomib-dexamethasone alone remained on treatment.
Updated results showed median PFS of 35.7 months among those assigned the isatuximab-irfc combination vs. 19.2 months among those assigned carfilzomib-dexamethasone alone per independent review committee assessment (HR = 0.58; 95.4% CI, 0.42-0.79).
A PFS analysis that followed FDA recommendations on censoring rules also showed longer median PFS with the addition of isatuximab-irfc (41.7 months vs. 20.8 months; HR = 0.59; 95% CI, 27.1-not estimable).
The PFS benefit with the isatuximab-irfc regimen persisted across all subgroups, including those based on age ( 65 years vs. < 65 years) and prior treatment exposures.
Researchers reported greater depth of response with the isatuximab-irfc regimen (ORR, 86.6% vs. 83.7%; very good partial response or better, 72.6% vs. 56.1%; stringent complete response, 44.1% vs. 28.5%; minimal residual disease negativity, 33.5% vs. 15.4%).
The addition of isatuximab-irfc also extended median time to next treatment (44.9 months vs. 25 months; HR = 0.55; 95% CI, 0.4-0.76) and PFS2, defined as time from randomization to disease progression on the next line of therapy or death (47.2 months vs. 35.6 months; HR = 0.68; 95% CI, 0.5-0.94).
“The benefit with [the isatuximab-irfc regimen] was maintained late through this PFS2 analysis,” Moreau said.
OS results remained immature; however, investigators estimated a higher 42-month survival probability in the isatuximab-irfc group (66.3% vs. 54.5%).
Safety
Isatuximab-irfc exhibited a safety profile consistent with that observed in prior trials, and investigators observed no new safety signals.
The most common adverse events reported among patients assigned isatuximab-irfc included infusion-related reaction (45.8% for isatuximab-irfc vs. 3.3% for carfilzomib-dexamethasone alone), diarrhea (39.5% vs. 32%), hypertension (37.9% vs. 35.2%), upper respiratory tract infection (37.3% vs. 27%), fatigue (31.6% vs. 20.5%), dyspnea (30.5% vs. 22.1%), pneumonia (27.1% vs. 21.3%), back pain (25.4% vs. 21.3%), insomnia (25.4% vs. 24.6%) and bronchitis (24.3% vs. 12.3%).
A majority of patients assigned the isatuximab-irfc regimen and carfilzomib-dexamethasone alone experienced grade 3 or higher treatment-emergent adverse events (83.6% vs. 73%). Those assigned isatuximab-irfc appeared more likely to experience serious treatment-emergent adverse events (70.1% vs. 59.8%); however, researchers observed no difference in this rate after adjustment for treatment exposure.
Collapse
Moreau P, et al. VP2-2022. Presented at: ESMO Virtual Plenary; May 19, 2022.
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