OAB-051: Daratumumab, Carfilzomib, Lenalidomide and Dexamethasone (Dara-KRd), autologous transplantation and MRD response-adapted treatment duration and cessation in newly diagnosed Multiple Myeloma (NDMM)

Abstract

<h3>Background</h3> Daratumumab, when combined with PI or an IMiD increases depth of response in MM. Minimal/measurable residual disease (MRD) is an important prognostic factor for long term outcome in patients (pts) with newly diagnosed MM (NDMM), but has not been used to modify therapy. We treated NDMM pts with daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) and employed MRD by next generation sequencing (NGS) to guide the use and duration of Dara-KRd post-autologous transplant (AHCT) and treatment cessation in pts with confirmed MRD negativity. <h3>Methods</h3> We enrolled pts with NDMM, CrCl ≥40 ml/min, adequate organ function, ECOG performance status 0-2 with no age limit. There was a planned enrichment for pts with high-risk cytogenetic abnormalities (HRCA). Treatment cycles consisted of daratumumab 16 mg/kg IV days 1,8,15,22 (typical reduction in frequency with subsequent cycles), carfilzomib 56 mg/m2 IV days 1,8,15, lenalidomide 25 mg days 1-21 and dexamethasone 40 mg oral/IV days 1,8,15,22 repeated every 28 days. Pts received 4 cycles of Dara-KRd induction, AHCT, and received 0, 4 or 8 cycles of Dara-KRd consolidation, according to MRD status. MRD was evaluated by NGS (ClonoSEQ®) in all pts at end of induction, post-AHCT, and during each 4-cycle block of Dara-KRd consolidation. Primary endpoint was achievement of MRD negativity (<10-5 as defined by IMWG) in the intention-to-treat population. Pts received therapy until achievement of two consecutive MRD <10-5 (confirmed MRD-negativity). Confirmed MRD-negative pts entered treatment-free observation and MRD surveillance ("MRD-SURE" phase) with surveillance for MRD resurgence 6 months after treatment cessation and yearly thereafter. Pts completing consolidation without confirmed MRD-negativity received standard lenalidomide maintenance. <h3>Results</h3> Among 123 participants, 46 (37%) had 1 and 24 (20%) had 2+ HRCA [gain 1q, t(4;14), t(14;16), t(14;20) or del(17p)]. Median age was 60 y (36-79), 20% had ECOG 2, 21% had high LDH, and 20% R-ISS3. Disease was trackable by NGS-MRD in 96% of pts. Median follow up is 25.1 mo. Most common severe adverse events were pneumonia (N=8), and venous thromboembolism (N=3). Overall, 80% of pts have achieved MRD negativity (78%, 82% and 79% of pts with 0, 1 and 2+ HRCA respectively) and 65% MRD < 10-6 (62%, 73% and 58% of pts with 0, 1 and 2+ HRCA respectively). MRD negativity was reached in 38% of patients post induction, 65% post AHCT and 80% post MRD-directed Dara-KRd consolidation. Response ≥CR was obtained in 86% of pts. Overall 84 pts (71%) have reached confirmed MRD negativity and entered MRD-SURE. <h3>Conclusion</h3> Monoclonal antibody-based quadruplet therapy, AHCT and MRD response-adapted consolidation therapy leads to high rate of MRD negativity in NDMM. For most patients with NDMM, MRD-directed adaptive treatment offers the prospect of confirmed deep responses and investigation of MRD surveillance as an alternative to indefinite maintenance.