OA-43: Analysis of sustained MRD-negativity and Progression-free Survival of Isa-KRd in High-Risk Newly Diagnosed Multiple Myeloma – Additional Data from Planned Interim Analysis of the GMMG-CONCEPT Trial

Introduction: While novel treatments have improved prognosis for most multiple myeloma (MM) patients (pts), survival remains poor for pts with high-risk (HR) disease. Achievement of minimal residual disease negativity (MRD–) correlates with better survival outcome and is particularly important for HR MM pts. The academic, multi-center phase II GMMG-CONCEPT trial (NCT03104842) investigates the quadruplet isatuximab, carfilzomib, lenalidomide, and dexamethasone in newly diagnosed (ND) HR MM pts both transplant-eligible (TE) and ineligible (TNE). The planned interim analysis (IA) on the primary endpoint (EP) demonstrated MRD– after consolidation (CONS) with 67.7% and 54.2% for TE and TNE pts, respectively (Weisel, ASH 2022 #759). Here, we show data on sustained MRD– and progression-free survival (PFS).

Methods: HR MM is defined by ISS stage 2 or 3 and any of del17p, t(4;14), t(14;16), or >3 copies 1q21 (amp1q21) as HR cytogenetic aberration (HRCA). All pts receive Isa-KRd induction, CONS, and Isa-KR maintenance. TE pts undergo high-dose therapy while TNE pts receive 2 extra cycles Isa-KRd. PFS is defined as combined EP of progressive disease or death, whichever occurs first. Data cutoff was on Dec. 1, 2022.

Results: The IA population for the primary EP consists of 125 pts (99 TE-ITT-IA, 26 TNE-ITT) according to trial design; sustained MRD– and PFS is based on the full first cohort (127 TE, 26 TNE). Median age was 58 (range 35-73) and 74 (64-87) years for the TE-ITT-IA and TNE-ITT population. All pts had HR MM, del17p was the most common HRCA (n=44, 44.4% [TE]; n=11, 42.3% [TNE]), followed by t(4;14) (n=42, 42.4% [TE]; n=6, 23.1% [TNE]) and amp1q21 (n=31, 31.3% [TE]; n=14, 53.8% [TNE]). 31 (31.3%) of 91 evaluable TE and 7 (26.9%) of 24 evaluable TNE pts had ≥2 HRCA marking ultra-HR (30.4% overall). As reported, the CONCEPT trial significantly met its primary EP (MRD– rates after CONS: 67.7% in TE and 54.2% in TNE pts [NGF, 10-5]). Of 106 TE pts reaching MRD– at any timepoint (84.4%), it was sustained for ≥6 and ≥12 months in 90 (72.0%) and 80 (64.0%) pts. Results for 18 TNE pts with MRD– (69.2%) were slightly lower (susMRD–6mo: n=14, 53.8%; susMRD–12mo: n=12, 46.2%). With a median follow-up of 40 (33) months for TE (TNE) pts, the median PFS was not reached in either study arm. Exploratory PFS analysis showed 1-Y-PFS rates of 86.4% (95% CI: 80.5-92.6) for TE-ITT and 75.1% (59.7-94.5) for TNE-ITT pts. 2-Y-PFS rates were 78.3% (71.4-85.9) for TE-ITT and 62.6% (46.0-85.3) for TNE-ITT. Additional subgroup analyses showed that pts with elevated LDH or ≥2 HRCA or del17p were least likely to reach MRD– and had shortened PFS. Since the last report, no new safety signals occurred.

Conclusions: Isa-KRd induces high rates of sustained MRD– in ND HRMM, translating into a median PFS that was not yet reached. Of the HR markers, elevated LDH, co-existence of ≥2 HRCA, and del17p are associated with lower MRD– and PFS rates, helping to identify the subgroups of HR MM at highest risk.