P943: outcome analysis by cytogenetic risk group after randomization to krd or ktd followed by k maintenance or control in patients with nte ndmm (agmt mm-02)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Recent data suggest cytogenetic aberrations determined by FISH have a major impact on outcomes in pts with multiple myeloma (MM). Aims: To investigate whether a carfilzomib-based regimen (KRd or KTd) can overcome the negative impact of high-risk cytogenetics, defined by the presence one or more of either t(4;14), t(14;16), del 17p, or ampl1q21 on response rates, PFS, and OS in non-transplant eligible (NTE) pts with newly diagnosed MM (NDMM). Methods: 123 pts (median age: 75 years, range 55-84) with NTE NDMM were enrolled in this randomized phase 2 study. Treatment regimen: K 20mg/m2 on day 1 + 2, 27mg/m2 on day 8, 9, 15 and 16; cycle 2: 27mg/m2 on day 1,2,8,9,15 and 16; K was switched to once weekly dosing (56mg/m2, d1, 8, 15) from cycle 3 to cycle 9. Pts received weekly dexamethasone (20mg in pts ≥75 years) and either lenalidomide 25mg d 1-21, or thalidomide 100mg/day, d 1-28 (50mg in pts ≥75 years). Pts with ≥SD after 9 cycles were randomized again to K 56mg/m2 on days 1 and 15, q 4 weeks, or to observation for one year. FISH was performed according to recommended standards on selected CD138+ cell populations. NGF MRD testing (sensitivity 10-6) was performed in pts who achieved CR or VGPR. FISH cytogenetic data at baseline were available in 100 pts. Survival estimates of the ITT population were calculated using the Kaplan-Meier method; differences in OS were assessed using the log-rank test. This study is registered on clinicaltrials.gov (NCT02891811). Results: The median follow-up time was 30.2 mos. A previous comparison between the two treatment arms (KRd and KTd) found no statistically significant differences in ORR, MRDneg rates, PFS, and OS (ASH 2022, abstract 4572), so we combined the two arms for this analysis. Response rates were as follows: CR: 37.8%, VGPR: 35.7%, PR 14.3%, MR 5.1% (ORR: 87.8%). MRD status was assessed in 65 pts (54 pts with available cytogenetic data) and MRDneg results were found in 46.3%. Median PFS in the overall pt population was 33.4 mos and 36.3, 27.0, and 13.2 mos, respectively, in pts without, with one, or with two or more cytogenetic aberrations (p<0.001) (Figure 1A). Median survival was not reached in the entire pt group and was not reached, not reached and 44.6 mos in pts with no, one, or two or more cytogenetic risk factors, respectively (p=0.025)(Figure 1B). Pts with ampl 1q21 had significantly shorter PFS (median 26.4 vs 36.3, p=0.027) compared to 1q21 negative pts, but OS was similar (median not reached vs not reached, p=0.668). In pts without a cytogenetic risk factor a tendency for a higher MRDneg rate (55.2% vs 37.5%, p=0.199) was noted. PFS was significantly longer in MRDneg pts (not reached vs 24.4 mos, p< 0.001), while the difference observed for OS was not statistically significant (not reached vs not reached, p=0.053). Comparison of PFS in MRD-negative pts with no, one or more risk factors revealed no significant difference (not reached vs. 36.6 mos, p=0.227) and of OS (not reached vs. not reached, p=0.157), but this comparison is limited by the small pt numbers. Summary/Conclusion: KRd and KTd with once-weekly K (56mg/m2) resulted in a high response rate and deep responses including MRDneg status in 46.3% of elderly pts with NDMM. Response rates were similar in the three cytogenetic risk groups, but PFS differed significantly between pts without, with one, or with two or more cytogenetic risk factors; a similar but less pronounced difference was noted for OS. Figure 1: Outcome of patients with no, 1, or ≥2 cytogenetic aberrations. A: progression-free survival, 1A 1BB: overall survival Keywords: Proteasome inhibitor, Multiple myeloma, Cytogenetics