Discussion
renal impairment
RENAL IMPAIRMENT
Results of this prespecified PFS updated analysis from IKEMA, at 44-month follow-up, are consistent with the prior interim analysis [In other reports, updated analysis of PFS in the ITT population of the randomized phase 3 study CANDOR, which evaluated a combination of daratumumab with Kd (D-Kd) vs Kd in patients with RRMM, has shown a mPFS of 28.6 months (95% CI: 22.7–not estimable) with D-Kd vs 15.2 months (95% CI: 11.1–19.9) in the Kd arm (HR, 0.59 [95% CI: 0.45–0.78]), at a median follow-up of 27.8 months for D-Kd and 27.0 months for Kd [All the PFS sensitivity analyses undertaken in IKEMA using different censoring rules, as per IRC or investigator assessment, strongly favored Isa-Kd over Kd, with HRs ranging from 0.57 to 0.64, adding to the robustness of the study findings. Further analysis showed consistent PFS benefit across all patients subgroups, including patients with poor prognosis, such as older patients (≥65 years of age), patients with renal impairment at baseline (eGFR <60 mL/min/1.73 mIn this updated analysis of IKEMA, both the MRD negativity rate (10The PFS2 observed in IKEMA favoring Isa-Kd vs Kd (HR: 0.68 [95% CI: 0.50–0.94]) further supports a sustained treatment effect with this Isa triplet combination through subsequent therapies. Consistently, although OS analysis is planned for 3 years after the PFS interim analysis, at a median follow-up of 44 months, results showed a higher probability of survival at 36 and 42 months with Isa-Kd vs Kd: 68.7% vs 62.9% and 66.3% vs 54.5%, respectively.Median treatment duration with Isa-Kd was longer by ~32 weeks (94.0 vs 61.9 weeks with Kd), with a median relative dose intensity for Isa of 93.2%. The longer treatment in Isa-Kd did not affect the median relative dose intensity for carfilzomib, which was comparable between treatment arms (89.5% in Isa-Kd vs 90.8% in Kd), thus supporting Isa-Kd as a combination regimen that can be given continuously in a feasible manner, without discontinuation of key therapeutic agents. To facilitate treatment administration, a once-weekly schedule of carfilzomib is currently being evaluated in a multi-arm Phase 1b study (NCT02332850) in combination with Isa and dexamethasone in patients with RRMM and in a Phase 2 study (NCT04430894) in combination with Isa-Rd in transplant-eligible patients with newly diagnosed MM. Anti-CD38 therapy with Isa was administered in this trial by IV infusion rather than the subcutaneous (SC) route. However, in this particular regimen, the combination with carfilzomib, which also requires IV administration, would limit the convenience of an Isa SC delivery. Nonetheless, SC administration of Isa is currently being evaluated in combination with pomalidomide-dexamethasone in a Phase 1b study with promising, preliminary results [After 2 additional years of follow-up and notwithstanding the risks associated with the Covid-19 pandemic, the safety profile of treatment with Isa-Kd remains similar to the results previously reported in the interim analysis [A limitation of our study was the open-label design. However, central laboratory assessments for M-protein, MRD, and baseline cytogenetics (with cytogenetic information available for almost 90% of the patients) contributed to homogenous assessments across study sites and a reduction in the potential bias related to the open-label design. In addition, PFS, best overall response, MRD negativity rate, TTNT, and PFS2 analyses were all performed in the ITT population, and the efficacy analyses conducted per blinded IRC assessment. Utilizing the Hydrashift Isa immunofixation assay, response rates were adjusted after the assessment of residual serum M-protein without Isa interference.In conclusion, the improvement in PFS observed in this updated analysis of IKEMA, with a mPFS of nearly 3 years, achievement of MRD negativity in a third of Isa-Kd treated patients, reaching MRD negativity and CR in >25% of them, and a manageable safety profile, further support Isa-Kd as a standard of care treatment for patients with relapsed MM.