Response-Adaptive Phase II Study of Daratumumab Combined with Carfilzomib, Lenalidomide and Dexamethasone in Newly Diagnosed Multiple Myeloma

Background Studies combining Daratumumab with a proteasome inhibitor and/ or an immunomodulatory drug have shown to increase the duration and depth of response in patients with newly diagnosed multiple myeloma (NDMM). While assessment of minimal residual status (MRD) after different stages of treatment is increasingly being evaluated in clinical trials as sensitive measure of depth of response and improved survival, published data on its utility as a tool to select the optimal post-induction therapy are not yet available. Study Design This ongoing single arm, two-stage, Phase II trial is designed with the primary objective to evaluate the efficacy in terms of rate of ≥ CR after 8 cycles of Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara + KRd) induction therapy in patients with NDMM. Induction treatment cycles consist of daratumumab per standard dosing, carfilzomib 56 mg/m2 IV days 1,8,15 (per latest amendment), lenalidomide 25 mg PO days 1-21 and dexamethasone 40 mg PO/IV days 1,8,15,22 repeated every 28 days. After induction, all subjects will undergo disease evaluation. Those who experience ≥very good partial response (VGPR) will undergo an assessment of MRD and will be classified as MRD(+) or MRD(-) as determined by next generation sequencing at 10-5 sensitivity (clonoSEQ®, Adaptive Biotechnologies), with further therapy guided by MRD-based algorithm (Figure). Those with