Subgroup Analysis of the FORTE Study by Risk Categories of Carfilzomib-Based Induction/Consolidation with or without Autologous Transplant and Lenalidomide or Carfilzomib-Lenalidomide Maintenance

2021 Year in Review - Multiple Myeloma

A subgroup analysis of the FORTE study found that carfilzomib-lenalidomide-dexamethasone induction/consolidation (KRd) plus ASCT and carfilzomib-lenalidomide maintenance provided survival benefit to patients of all cytogenetic risk groups, including patients at high risk.

The randomized, open-label, phase 2 FORTE study (NCT02203643) evaluated the efficacy and safety of different carfilzomib-based induction and consolidation therapies with or without autologous stem-cell transplantation (ASCT), followed by maintenance treatment with carfilzomib plus lenalidomide versus lenalidomide alone in newly diagnosed multiple myeloma. The regimens evaluated were carfilzomib-lenalidomide-dexamethasone induction/consolidation (KRd) plus ASCT (KRd-ASCT) versus KRd without ASCT (KRd12) or carfilzomib-cyclophosphamide-dexamethasone (KCd) plus ASCT (KCd-ASCT). The present subgroup analysis evaluated the impact of the induction and consolidation treatments on progression-free survival (PFS) and 1-year minimal residual disease negativity rates based on patient cytogenetic risk; results of this analysis were presented at the 2021 International Myeloma Workshop and summarized here.

The study enrolled patients aged ≤65 years with transplant-eligible newly diagnosed multiple myeloma with a Karnofsky Performance Status of ≥60% across 42 Italian academic and community practice centers. Eligible patients were randomized 1:1:1 to receive KRd-ASCT versus KCd-ASCT versus KRd12, followed by carfilzomib-lenalidomide versus lenalidomide maintenance. Stratification was by International Staging System stage (I vs II/III) and age (<60 years vs 60-65 years). Three patient cytogenetic risk categories were considered: high risk (presence of ≥1 high-risk cytogenetic abnormalities including del17p, t[4;14], t[14;16], del1p, and gain1q [3 copies] or amp1q [≥4 copies]), double hit (≥2 high-risk cytogenetic alterations), and standard risk (absence of any cytogenetic abnormalities).

A total of 474 patients were enrolled in the study; of these, 396 patients were evaluable for cytogenetic analysis (complete fluorescence in situ hybridization data). Of the 396 evaluable patients, 243 patients were classified as high risk, 105 as double hit, and 153 as standard risk. Among high-risk patients, 60 patients had del17p, 65 patients had t(4;14), 20 patients had t(14;16), 44 patients had del1p, 126 patients had gain1q, and 49 patients had amp1q.

Patients in all risk categories derived clinical benefit with the KRd-ASCT approach. In the standard-risk cohort, KRd-ASCT resulted in PFS improvement versus KRd12 (hazard ratio [HR], 0.47; P = .05) and KCd-ASCT (HR, 0.38; P = .01), with a 4-year PFS of 80% with KRd-ASCT, 67% with KRd12, and 57% with KCd-ASCT treatment strategies. In the high-risk cohort, KRd-ASCT improved PFS versus KRd12 (HR, 0.6; P = .04) and KCd-ASCT (HR, 0.57; P = .01), with a 4-year PFS rate of 62% with KRd-ASCT, 45% with KRd12, and 45% with KCd-ASCT treatment strategies. In the double-hit cohort, PFS improvement was observed with KRd-ASCT versus KRd12 (HR, 0.53; P = .07) and KCd-ASCT (HR, 0.49; P = .03), with a 4-year PFS rate of 55% with KRd-ASCT, 31% with KRd12, and 33% with KCd-ASCT treatment strategies. By type of cytogenetic abnormalities, a trend toward a PFS benefit from KRd-ASCT versus KRd12 was observed in patients with del17p (HR, 0.61; P = .3), t(4;14) (HR, 0.59; P = .2), and gain1q (HR, 0.45; P = .02), albeit small sample sizes. In the del1p cohort, both KRd-ASCT (HR, 0.24; P = .06) and KRd12 (HR, 0.33; P = .09) were superior to KCd-ASCT; patients in the amp1q cohort had no benefit with treatment (KRd-ASCT vs KCd-ASCT; HR, 1.16; P = .73; KRd12 vs KCd-ASCT; HR, 1.34; P = .45).

With regard to maintenance therapy, carfilzomib/lenalidomide improved PFS compared with lenalidomide in the standard-risk (3-year PFS, 90% vs 73%, respectively; HR, 0.42; P = .06), high-risk (3-year PFS, 69% vs 56%, respectively; HR, 0.6; P = .04), and double-hit (3-year PFS, 67% vs 42%; HR, 0.53; P = .1) cohorts. By cytogenetics, a trend favoring carfilzomib-lenalidomide compared with lenalidomide was observed in patients with del17p (HR, 0.59; P = .37), t(4;14) (HR, 0.59; P = .3), gain1q (HR, 0.54; P = .07), and del1p (HR, 0.23; P = .08), with amp1q patients showing no benefit from carfilzomib-lenalidomide versus lenalidomide (HR, 0.83; P = .7).

Subgroup analysis of the FORTE study found that KRd-ASCT and KR maintenance provided survival benefit to patients of all cytogenetic risk groups, including patients at high risk.

Source: Mina R, Zamagni E, Rota-Scalabrini D, et al. Carfilzomib-based induction/consolidation with or without autologous transplant and lenalidomide (R) or carfilzomib-lenalidomide (KR) maintenance: efficacy in high-risk patients of the FORTE study. Clin Lymphoma Myeloma Leuk. 2021;21(suppl 2):S3.

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