Summary
Multiple myeloma is frequently diagnosed in patients aged 65 years or older. For these patients, there are often significant negative prognostic implications for their disease. Combination therapies have been the hallmark of treatments for multiple myeloma. One recent addition to those therapies has been the use of the CD38-targeting monoclonal antibody daratumumab, which was initially approved by the FDA in 2015 for the treatment of multiple myeloma in patients who had received prior therapy.
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Original Article
The ICARIA-MM Trial: Efficacy Data for Isatuximab With Pomalidomide & Dexamethasone
Oncology Times
Richard Simoneaux
Multiple myeloma is frequently diagnosed in patients aged 65 years or older. For these patients, there are often significant negative prognostic implications for their disease. Combination therapies have been the hallmark of treatments for multiple myeloma. One recent addition to those therapies has been the use of the CD38-targeting monoclonal antibody daratumumab, which was initially approved by the FDA in 2015 for the treatment of multiple myeloma in patients who had received prior therapy.
Another CD38-targeting monoclonal antibody that is being evaluated as a potential therapy for relapsed or refractory multiple myeloma is isatuximab. One such trial is the randomized, open-label, multicenter phase III ICARIA-MM study (NCT02990338). This study is evaluating use of the anti-CD38 monoclonal antibody isatuximab plus the immunomodulatory agent pomalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. Participation was limited to patients with relapsed or refractory multiple myeloma after two or more prior lines of therapy, including a proteasome inhibitor and lenalidomide.
Recently, a subgroup analysis of the elderly participants (i.e., age 75 years or greater) in ICARIA-MM was presented at the 2019 ASH Annual Meeting (Abstract 1893) by Fredrik H. Schjesvold, MD, PhD, from the Oslo Myeloma Center at Oslo University Hospital in Norway. Regarding their findings, he noted, “The benefits that we observed in the elderly participants in this study were at least the same that were obtained for the general trial population.”
Methodology
Patients were randomly assigned in a 1:1 fashion to receive either combination of isatuximab plus pomalidomide and dexamethasone (Isa-Pd arm) or pomalidomide and dexamethasone (Pd arm), which served as an active comparator. All patients received 4 mg pomalidomide orally (PO) on days 1–21 of each 28-day treatment cycle and 40 mg dexamethasone PO (20 mg for patients aged 75 years or older) on days 1, 8, 15, and 22 of each 28-day treatment cycle. Isatuximab was administered intravenously (10 mg/kg) on days 1, 8, 15, and 22 (cycle 1), and subsequently, on days 1 and 15 of each treatment cycle.
“The primary endpoint,” Schjesvold noted, “was progression-free survival (PFS), which was assessed by an independent response committee.” Subgroup analyses were stratified according to age with the following delineations: less than 65 years, 65 to 74 years, and 75 years or older.
Study Results
A total of 307 patients who comprised the intention-to-treat population were randomized to the Isa-Pd experimental arm (n=154) or the Pd active comparator arm (n=153). The median patient ages of the Isa-Pd and Pd arms were 68.0 years and 66.0 years, respectively. The distribution by age for the patients in the Isa-Pd arm was as follows: < 65 years – 54 patients (35%); 65 to 74 years – 68 patients (44%); and 75 years or older – 32 (21%). Correspondingly, the age distribution for those in the Pd arm was as follows: < 65 years – 70 patients (46%); 65 to 74 years – 54 patients (35%); and 75 years or older – 29 (19%).
PFS was significantly improved in the overall population for the isatuximab-containing regimen, with median figures of 11.53 and 6.47 months for the Isa-Pd and Pd arms, respectively, affording a hazard ratio (HR) of 0.596 (95% CI: 0.436–0.814; p=0.001). Similarly, those patients 75 years or older in the Isa-Pd and Pd arms had median PFS values of 11.40 months and 4.7 months, respectively, giving a HR of 0.479 (95% CI 0.242–0.946). For those patients ages 65-74 years in the Isa-Pd and Pd groups, the median PFS figures were 11.57 and 8.58 months, with a HR of 0.638 (95% CI: 0.385–1.059). In patients younger than 65 years, the median PFS was 11.53 and 5.03 months, providing a HR of 0.656 (95% CI: 0.401–1.074).
For the overall patient population, the overall response rate (ORR) was 60.4 percent for the Isa-Pd arm and 35.3 percent for the Pd arm, affording an odds ratio (OR) of 2.80 (95% CI: 1.72–4.56). The ORR data for the different age groups, with the respective OR values, are shown in the Table.
| Age Group | Isa-Pd Arm | Pd Arm | Odds Ratio |
| <65 years | 59.3% | 34.3% | 2.79 (95% CI: 1.26-6.20) |
| 65-74 years | 64.7% | 38.9% | 2.88 (95% CI: 1.29-6.46) |
| >75 years | 53.1% | 31.0% | 2.52 (95% CI: 0.79-8.26) |
“At the time of analysis,” Schjesvold noted, “overall survival (OS) data are not yet mature.” In the elderly population, one-fourth of the patients (8/32) in the Isa-Pd arm had died with median OS that had not been reached. While in the Pd arm, more than half (15/29) died, providing a median OS of 10.25 months, giving a HR of 0.404 (95% CI: 0.171– 0.956).
“Generally, there were more grade 3 or greater treatment-emergent AEs with Isa-Pd in patients aged 75 years or older (93.8%) compared with those younger than 65 years (85.2%), with a similar trend being observed for the patients in the Pd arm (75.0% and 64.7%, respectively),” Schjesvold stated. “In addition, there were also more treatment discontinuations resulting from TEAEs in patients 75 years or older compared to those younger than 65 years in both the Isa-Pd and Pd arms.
“Interestingly, the incidence of TEAEs resulting in death in the Isa-Pd arm was lower in patients 75 years or older than in those younger than 65 years. However, this trend was reversed in the Pd arm, where there were more TEAEs leading to death in the elderly patients.”
Conclusion
Summarizing his observations from the trial to date, Schjesvold stated, “The addition of isatuximab to Pd improved a number of parameters, including the PFS, ORR, rates of VGPR or better.” OS in the overall population was not mature. The benefit was consistent for the elderly patients (i.e., aged 75 years or older) in this study.” To this, he also noted, “There was a consistent trend toward higher rates of serious AEs and discontinuation due to TEAEs in the elderly; however, the change was small and was present in both study arms.
“In terms of next steps for this trial, we have to wait for the OS data to mature, although we have every reason to be optimistic about those results, looking at the preliminary readout of overall survival presented in this poster” Schjesvold said.
When asked if there was a larger lesson that could be drawn from these findings, he answered, “The results of this trial show the importance of having well-tolerated combination therapies available for elderly patients.”
Richard Simoneaux is a contributing writer.