Interim Results of a Risk-Adaptive Phase II Study: Carfilzomib, Lenalidomide, Dexamethasone and Daratumumab (KRD-Dara) in Newly Diagnosed Multiple Myeloma (NDMM) at the Levine Cancer Institute (LCI)

Background: The combination of carfilzomib, lenalidomide and dexamethasone (KRd) has previously demonstrated deep and durable responses in patients with NDMM. A quadruplet regimen incorporating daratumumab (KRd-Dara) may further improve results. We report an interim analysis from stage 1 (Simon's optimal 2-stage design) of an ongoing minimal residual disease (MRD)-driven, single center phase 2 trial of KRd-Dara. Methods: The study design has been previously published (Bhutani et al, Blood 2020 Abstr 1388). Briefly, patients with NDMM (both transplant eligible and ineligible) were allowed one cycle of non-protocol therapy (if deemed necessary) and then 7 or 8 cycles of induction therapy with KRd-Dara (total induction cycles: 8). MRD assessment was performed by both next generation sequencing (NGS) and next generation flow cytometry (NGF) at the end of 8 cycles of induction, post- autologous stem cell transplantation (ASCT), and every 4 cycles of consolidation (maximum of 12 cycles). Post-induction treatment was dictated by an MRD-driven algorithm, using MRD (NGS, 10-5) to assign patients to one of the 3 study groups. The primary endpoint is complete response (CR) + stringent CR (sCR) at the completion of KRd-Dara induction therapy. Group A (MRD negative post-induction) proceeded directly to lenalidomide maintenance therapy deferring ASCT, if transplant eligible. Group B (MRD positive, transplant eligible) received upfront ASCT, KRd consolidation (maximum 12 cycles), and then lenalidomide maintenance. Group C (MRD positive after 8 cycles of induction, transplant ineligible) received KRd consolidation (maximum 12 cycles) followed by lenalidomide maintenance. Conversion to MRD negative status at any protocol specified time point allowed the patients to proceed to lenalidomide maintenance. Results: Stage 1 futility analysis criteria were met in November 2021 and stage 2 enrollment is actively ongoing. As of a data cutoff of 4/8/22, 30/39 patients have been enrolled. Twenty-three patients were enrolled in Stage 1. The median age of stage I patients was 60 (range 34- 76) years, 74% were male and 35% were Black. R-ISS stage 3 was present in 2 (8.7%), high-risk cytogenetics in 1 (4.4%) and gain 1q21 in 7 (30.4%). Fifteen patients (65.2%) received one cycle of pre-study treatment. All patients completed 8 total cycles of induction therapy. At the end of induction, CR + sCR was achieved in 15/23 (65.2%) patients with sCR in 52.2%, and very good partial response (VGPR) in 7 (30.4%). The MRD negativity rate was 69.6% (NGS, 10-5) and 43.5% (NGS, 10-6). The MRD negativity rate by NGF was 82.6% at 10-5and 47.4% at 10-6 sensitivity level in 23 and 19 evaluable patients, respectively; 43% of bone marrow specimen tested by NGF were hemodiluted. Concordance of MRD by NGS/ NGF at 10-5 was 16/23 (69.6% in agreement and 30.4% disagreement, Cohen's kappa: 0.183). Concordance of MRD by NGS/ NGF at 10-6 was 12/19 (63.2% in agreement and 36.8% disagreement, Cohen's kappa: 0.257). Grade 3-4 treatment related adverse events (>10% of patients) included hypophosphatemia (30%), hypertension (13%), and neutropenia (13%). Covid infection occurred in 7 (30.4%) patients; only one needed hospitalization. Other Infections (any grade) were seen in 15 (65.2%) patients. At least one dose reduction of carfilzomib was required in 5 (21.7%) patients, dexamethasone in 3 patients, and lenalidomide in 4 patients. Systemic injection reactions to subcutaneous daratumumab occurred in 5 (21.7%). Thromboembolic events happened in 3 patients. No patient discontinued treatment because of toxicity. There was no treatment-related mortality during stage 1. Post-induction, 16 patients (MRD negative) transitioned to lenalidomide maintenance, 5 patients (MRD positive) underwent ASCT, and 2 patients (MRD positive) proceeded to consolidation phase. Stem cell collection for eligible patients (n=22) was performed upon completion of induction; 5 patients failed to collect optimal target (3 million CD34+ cells/kg) during their first mobilization attempt. Survival results will be updated after stage 2 enrollment is completed, but as of data cutoff, no subjects in the Stage 1 cohort have progressed. Conclusions: The quadruplet regimen KRd-Dara as induction in NDMM leads to deep responses reflected in high rates of sCR and MRD negativity with an acceptable and well-tolerated safety profile. The stage 2 enrollment is ongoing.