Subgroup analysis of ICARIA‐MM study in relapsed/refractory multiple myeloma patients with high‐risk cytogenetics

Abstract

Summary Treatment benefit in multiple myeloma (MM) patients with high‐risk cytogenetics remains suboptimal. The phase 3 ICARIA‐MM trial (NCT02990338) showed that isatuximab plus pomalidomide–dexamethasone prolongs median progression‐free survival (mPFS) in patients with relapsed/refractory MM (RRMM). This subgroup analysis of ICARIA‐MM compared the benefit of isatuximab in high‐risk [defined by the presence of del(17p), t(4;14) or t(14;16)] versus standard‐risk patients. The efficacy of isatuximab in patients with gain(1q21) abnormality was also assessed in a retrospective subgroup analysis. In ICARIA‐MM, 307 patients received isatuximab–pomalidomide–dexamethasone (n = 154) or pomalidomide–dexamethasone (n = 153). Isatuximab (10 mg/kg intravenously) was given weekly in the first 28‐day cycle, and every other week thereafter. Standard pomalidomide–dexamethasone doses were given. Isatuximab–pomalidomide–dexamethasone improved mPFS (7·5 vs 3·7 months; HR, 0·66; 95% CI, 0·33–1·28) and overall response rate (ORR, 50·0% vs 16·7%) in high‐risk patients. In patients with isolated gain(1q21), isatuximab addition improved mPFS (11·2 vs 4·6 months; HR, 0·50; 95% CI, 0·28–0·88) and ORR (53·6% vs 27·6%). More grade ≥3 adverse events occurred in high‐risk patients receiving isatuximab (95·7%) versus the control group (67·6%); however, isatuximab did not increase events leading to discontinuation or treatment‐related mortality. Isatuximab–pomalidomide–dexamethasone provides a consistent benefit over pomalidomide–dexamethasone treatment in RRMM patients regardless of cytogenetic risk.

Targeting BCMA to Treat Multiple Myeloma: Updates From the 2021 ASH Annual Meeting

“…Two things interesting were that, the ORR of CT053 to treat the RRMM patients relapsed after three or more LOT with the extramedullary disease (EMD) being 91.7%, the CR rate being 58.3%, and the median PFS being 9.3 months, better than the results of those past treatment strategies such as combination therapy with permadomide and dexamethasone (ORR: 30%; CR rate: 15.3%) ( 69 ) and carfilzomib-based combination therapy (ORR: 27%, CR rate: 0%, median PFS: 5 months) ( 70 ). For the patients with high-risk cytogenetic abnormalities [del(17p), t(4;14), t(14;16)/1q21], the ORR and CR rate of CT053 were 84.2% and 73.3%, respectively, with the 15.6 months median PFS, better than the results of ishatuximab, permadomide, and dexamethasone combination (ORR: 50%, CR rate: 0%, median PFS: 7.5 m) ( 71 ), carfilzomib monotherapy (ORR: 25.8%, CR rate: 0%, median PFS: 3.5 m) ( 72 ), and even the infusion of bb2121 (ORR: 73%, CR rate: 33%, median PFS: 8.2 m) ( 60 ). Secondly, the relationship between the dosage and curative effect of C-CAR088 has been studied ( 52 ).…”

Joint modelling and simulation of M‐protein dynamics and progression‐free survival for alternative isatuximab dosing with pomalidomide/dexamethasone

“…40 Cytogenetics was not a significant covariate in the joint model, on either serum M-protein dynamics or PFS, in agreement with ICARIA-MM subgroup analyses, which showed that Isa-Pd provided consistent benefit versus Pd in RRMM patients, regardless of cytogenetic risk. 41 The drug-disease modelling platform established based on ICARIA-MM data was further applied to predict the impact of using a hypothetical monthly dosing regimen after 6 months of Isa QW-Q2W in RRMM patients. In patients still on treatment, simulations of a hypothetical switch to monthly dosing after 6 months predicted progression to occur 2.3 weeks earlier compared with the original Isa-Pd arm, with 42.3% of patients having their serum M-protein regrow faster.…”

Isatuximab: A Review of Its Use in Multiple Myeloma

“…The addition of isatuximab to pomalidomide–dexamethasone significantly improved PFS in patients with RRMM (Table 1 ); the risk of disease progression or all-cause death was reduced by 40% [hazard ratio (HR) 0.596, 95% CI 0.436–0.814; p = 0.001] at the time of the primary analysis [ 28 ]. A PFS benefit was seen with the addition of isatuximab to pomalidomide–dexamethasone in all prespecified subgroups, including patients aged ≥ 75 years, those at ISS stage III, those with RI, those with high-risk cytogenetics, those with 2–3 or > 3 previous lines of therapy, those refractory to lenalidomide, those refractory to a PI, and those double-refractory to lenalidomide and a PI [ 28 , 41 , 42 ]. Moreover, in retrospective analyses, PFS benefits were seen with the addition of isatuximab to pomalidomide–dexamethasone in the following subgroups of patients: those with isolated gain of chromosome arm 1q21 genomic abnormality (1q21 gain; ≥ 3 copies of 1q21); those with 1q21 gain, regardless of the presence of other high-risk cytogenetic abnormalities; those with isolated amplification of chromosome arm 1q21 genomic abnormality (1q21 amplification; ≥ 4 copies of 1q21); and those with 1q21 amplification (≥ 4 copies of 1q21), regardless of the presence of other high-risk cytogenetic abnormalities [ 42 ].…”

“…Adding isatuximab to pomalidomide–dexamethasone significantly improved ORR (Table 1 ). Consistent with the ORR benefit seen in the overall population [odds ratio (OR) 2.795, 95% CI 1.75–4.56; p < 0.0001], ORRs were numerically higher with isatuximab–pomalidomide–dexamethasone than with pomalidomide–dexamethasone in all prespecified subgroups, including patients aged ≥ 75 years, those with RI, those with high-risk cytogenetics, those with 2–3 or > 3 previous lines of therapy, those refractory to lenalidomide, and those double-refractory to lenalidomide and a PI [ 28 , 41 , 42 ]. ORRs were, respectively, 53.6% and 27.6% in isatuximab-pomalidomide–dexamethasone and pomalidomide–dexamethasone recipients with isolated 1q21 gain (one-sided p = 0.0116) [ 42 ] and 52.1% and 34.2% in isatuximab–pomalidomide–dexamethasone and pomalidomide–dexamethasone recipients classified as frail ( p < 0.05) [ 39 ].…”