Add-on isatuximab improves outlook for seniors with relapsed/refractory multiple myeloma

Use of isatuximab (Isa) in combination with pomalidomide and dexamethasone (PomDex) appears to lead to more favourable outcomes in elderly patients with relapsed/refractory multiple myeloma (RRMM) as compared with PomDex alone, according to the results of a subgroup analysis of the ICARIA-MM trial presented at the 61st Annual Meeting of the American Society of Hematology (ASH 2019).

The benefits observed were consistent with the overall study population but came with increased rates of treatment-emergent adverse events (TEAEs) and serious TEAEs (SAEs), the investigators said. Then again, the addition of Isa did not elevate the risk of fatal AEs.

In ICARIA-MM, 307 patients with RRMM after ≥2 prior lines of therapy, including lenalidomide and a proteasome inhibitor, were randomly assigned to receive PomDex alone (n=153; median age, 66 years) or in combination with Isa (n=154; median age, 68 years). In the respective treatment arms, there were 54 (35 percent) and 70 (46 percent) patients aged <65 years, 68 (44 percent) and 54 (35 percent) aged 65–74 years, and 32 (21 percent) and 29 (19 percent) aged ≥75 years.

Compared with PomDex alone, the addition of Isa significantly prolonged progression-free survival (PFS)—the primary study endpoint—in the overall population (median, 11.53 vs 6.47 months; hazard ratio [HR], 0.596; 95 percent confidence interval [CI], 0.436–0.814; p=0.001). This PFS benefit remained significant across the following age groups: ≥75 years (median, 11.40 vs 4.47 months; HR, 0.479, 95 percent CI, 0.242–0.946), 65–74 years (median, 11.57 and 8.58 months; HR, 0.638, 95 percent CI, 0.385–1.059) and <65 years (median, 11.53 vs 5.03 months; HR, 0.656, 95 percent CI, 0.401–1.074). [ASH 2019, abstract 1893]

Treatment with Isa-PomDex also yielded better
results for other outcomes compared with PomDex. For one, the odds of response were more than twice as great for patients receiving add-on Isa; overall response rates (ORRs) were 60.4 percent vs 35.3 percent (odds ratio [OR], 2.80) in the entire population, 53.1 percent vs 31.0 percent (OR, 2.52) in the ≥75-years group, 64.7 percent vs 38.9 percent (OR, 2.88) in the 65–74-years group, and 59.3 percent vs 34.3 percent (OR, 2.79) in the <65-years group.

Likewise, significantly more patients in the Isa-PomDex vs PomDex achieved at least a very good partial response (≥VGPR): 31.8 percent vs 8.5 percent (OR, 5.03) in the entire population, 31.3 percent vs 0 percent (OR not calculated) in the ≥75-years group, 32.4 percent vs 13.0 percent (OR, 3.21) in the 65–74-years group, and 31.5 percent vs 8.6 years (OR, 4.90) in the <65-years group. There were eight patients with negative minimal residual disease at 10⁻⁵, and two of them were ≥75 years old.

“At the time of analysis, overall survival (OS) data are not yet mature,” the investigators noted.

Regardless, in the elderly population, eight of 32 patients (25 percent) treated with Isa-PomDex had died with median OS not reached, whereas 15 of 29 PomDex-treated patients (51.7 percent) had died with a median OS of 10.25 months (HR, 0.404, 95 percent CI, 0.171–0.956).

In terms of safety, all-grade TEAEs occurred in 98.1 percent of patients aged <65 years and in all those (100 percent) aged 65–74 or ≥75 years. There was a trend toward greater toxicity for older (≥75 years) vs younger (<65 years) patients, irrespective of treatment.

The corresponding incidence rates of AEs for older vs younger patients in Isa-PomDex and PomDex arms were as follows: grade ≥3 TEAEs, 93.8 percent vs 85.2 percent and 75.0 percent vs 64.7 percent; TEAE-related treatment discontinuation, 15.6 percent vs 7.4 percent and 14.3 percent vs 10.3 percent; SAEs, 68.8 percent vs 57.4 percent and 57.1 percent vs 47.1 percent.

Interestingly, the incidence of TEAEs with fatal outcome was lower in older than younger patients who received add-on Isa (6.3 percent vs 11.1 percent), while the opposite trend was observed in those treated with PomDex alone (14.3 percent vs 5.9 percent).

Isa (10 mg/kg IV) was administered on days 1, 8, 15 and 22 (cycle 1), and days 1 and 15 in subsequent 28-day cycles. All patients received pomalidomide 4 mg on days 1–21 of each cycle and dexamethasone 40 mg (20 mg for older patients) on days 1, 8, 15, and 22 of each cycle.