Outcomes of Patients By High-Risk Cytogenetic Abnormalities in a Phase II Study of Isatuximab, Weekly Carfilzomib, Lenalidomide, Dexamethasone in Newly Diagnosed, Multiple Myeloma (The SKylaRk Trial) Who Deferred Transplant

Background: Despite significant advances in the treatment of multiple myeloma, early relapse remains a challenge for patients with newly diagnosed multiple myeloma (NDMM) and high-risk cytogenetic abnormalities (HRCA). Current clinical data strongly support the utility and effectiveness of a combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and dexamethasone for the treatment of NDMM. The SKylaRk trial investigated the use of isatuximab (isa) in combination with weekly carfilzomib (K), lenalidomide (len), and dex in an all-risk, transplant-eligible patients with NDMM and stratified maintenance based on cytogenetic risk. Unlike many other recent investigations of 4-drug regimens, this study offered the option of deferring auto stem cell transplant (ASCT) based on patient and provider preference, with most patients, 90% (45/50), deferring ASCT.

Study Design and Methods: SKylaRk was a phase II study of isa-KRd in 50 transplant-eligible (TE) NDMM patients (NCT04430894). All patients received 4 cycles of isa-KRd followed by stem cell collection with option of upfront versus deferred ASCT. Patients who had upfront ASCT received 2 additional cycles then maintenance. Patients who deferred ASCT received 4 additional cycles then maintenance. Each 28-day cycle consisted of isa 10 mg/kg iv weekly cycles 1-2, Q2 weeks cycles 3-6, then Q4 weeks; K (20 mg/m2 cycle 1, day 1 only) 56 mg/m2 iv days 1, 8, 15; len 25 mg po days 1-21; and dex 20 mg po days 1, 2, 8, 9, 15, and 16 (and days 22, 23 cycles 1-2).

For maintenance, patients with standard-risk received len 10 mg po days 1-21, and patients with HRCA (del 17p, gain 1q, t(4:14), t(14;16), or t(14;20)) continued on Isa 10 mg/kg iv day 1; K 56 mg/m2 iv days 1, 15; len 10 mg po days 1-21. Promising results of the primary analysis were previously reported (O’Donnell E et al., Lancet Haematol 2024). In this post-hoc analysis, we report the outcomes of patients who deferred ASCT and were evaluated based on cytogenetic risk.

Results: We enrolled TE 50 patients between August 2020 and February 2022; 4 patients did not have FISH information; 5 patients received high dose melphalan and auto SCT; 3 patients came off study before stem cell collection. We therefore focused on 41 patients with FISH information who did not undergo ASCT with median follow-up 35.9 months. Median age was 59 years (range 39-70) and 56% were male. Three-year progression free survival (PFS) overall (N=41) was 79.6% (95% CI, 67-94.5%). Three-year PFS by HRCA: no HRCA (N=20), 89.5% (76.7-100%); HRCA 1 (N=16), 82.5% (63.1-100%); HRCA 2 (N=5) not assessable due to insufficient follow up for this cohort, respectively. Median PFS was not reached (NR) for HRCA 0-1 and was shorter at 33 months (32.8-NR) for HRCA 2. For high-risk FISH defined by IMWG (del 17p, t(4;14), t(14;16)), three-year PFS for standard-risk (N=31) was 93.1% (84.3-100%) and for high-risk (N=10) not assessable due to insufficient follow-up for this cohort. Median PFS in months was NR for standard-risk and was 32.8 months (30.7- NR) for high-risk.

Conclusions: This is one of the first reports of a 4-drug regimen, isa-KRd, analyzed by cytogenetic risk in TE patients who have not undergone ASCT. While median follow up remains short, with isa-KRd, patients with 0-1 HRCAs who deferred ASCT demonstrated outcomes comparable to those seen in 4-drug combinations with upfront ASCT. However, while the number of patients is limited (N=5), the poorer outcomes for patients with 2 HRCAs who deferred ASCT suggest the need for further improvement, and for whom there may be more value for ASCT in this high-risk population as well as other additional innovative strategies, such as CAR-T and/or bispecific therapies.