A Phase 2 Study of Extended Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone in Newly Diagnosed Multiple Myeloma
Authors: Derman Ben A , Major Ajay , Rosenblatt Jacalyn , Avigan David , Rampurwala Murtuza M. , Alcantar Luis , Libao Bernadette M. , McIver Amanda , Andreatos Evangelia , Major Sarah , Wolfe Brittany , Gorski Martha , Karrison Theodore G. , Stefka Andrew , Jakubowiak Andrzej 
Published: November 2021

Abstract
Introduction: The combination of carfilzomib, lenalidomide, and dexamethasone (KRd), with and without autologous stem cell transplantation (ASCT) is an effective regimen for newly diagnosed multiple myeloma (NDMM) (Jakubowiak et al., Blood 2012 and Jasielec et al., Blood 2020). The addition of daratumumab to KRd (Dara-KRd) for 8 cycles led to a measurable residual disease (MRD)-negativity rate of 71% (flow cytometry, limit of detection [LoD] &lt;10 -5); some patients received post-protocol ASCT (Landgren et al., JAMA Oncology, 2021). An MRD-adaptive design of Dara-KRd with ASCT led to high MRD-negativity rates by next generation sequencing (NGS) (Costa et al., EHA 2020). In this phase 2 study, we evaluate the safety and efficacy of extended Dara-KRd without ASCT in patients (pts) with NDMM regardless of transplant eligibility.
Methods: This is an open-label, single arm, Multiple Myeloma Research Consortium phase 2 study enrolling pts with NDMM, regardless of transplant eligibility. Subjects requiring urgent therapy may receive 1 cycle of therapy (Rd and/or Bortezomib) prior to enrollment. Pts receive Dara-KRd for 24 cycles: daratumumab 16 mg/kg IV Days 1, 8, 15, 22 for cycles 1 & 2, days 1 and 15 for cycles 3-8, then day 1 for cycles 9-24; carfilzomib 20/36 mg/m2 on days 1,2,8,9,15,16 for cycles 1-8, then 36 mg/m2 on days 1, 2, 15, 16 for cycles 9-24; lenalidomide 25 mg PO days 1-21 of a 28 day cycle for 24 cycles; dexamethasone 40 mg PO weekly (20 mg if age &gt; 75) for cycles 1-9, and 20 mg PO weekly for cycles 9-24. ASCT-eligible pts had the option to harvest stem cells to permit ASCT in the future if desired.
All subjects undergo testing for MRD using NGS (clonoSEQ, Adaptive Biotechnologies) with a lower LoD of &lt; 10 -6 at the end of cycles 8 (C8) and 24 (C24). The primary endpoint is the rate of stringent CR and/or MRD-negativity (sensitivity threshold &lt;10 -5) by NGS at the end of C8. The target sample size of 40 subjects will be used to test the hypothesis that the addition of Dara to KRd will increase the rate of sCR and/or MRD-negativity by NGS after C8 from 30% (as observed with KRd) to + &gt;50% with Dara-KRd (85% power using a one-sided alpha=0.10).
Results: Of the 29 pts who have been enrolled from March 2019- July 2021, 18 (62%) are evaluable at the C8 timepoint and of which 7/18 are evaluable at C24 by intention-to-treat analysis. The remaining 11 pts are on therapy but have not yet reached C8.
19 pts have an identifiable clone to enable MRD testing by NGS (one sequencing failure, one not performed, eight tests pending). Median age is 57 years (range 42-79; 5 pts &gt;70 years of age). Eight (28%) pts identify their race as Black and 5 (17%) as Hispanic ethnicity. High-risk cytogenetics (per IMWG criteria) is present in 16/29 (55%). 18 pts (62%) have undergone stem cell collection; median stem cell yield is 8.06x10 6 CD34+/kg.
For the 18 pts evaluable for the primary endpoint at C8, the overall response rate is 94% (13 sCR, 4 VGPR, 1 PD) (Figure 1). There are 13 MRD-evaluable pts at C8; the sCR and/or MRD-negativity rate (&lt;10 -5) is 13/18 (72%). The sCR+MRD-negativity rate by NGS (10 -5 threshold) is 7/13 (54%) and 3/13 (23%) at a threshold of 10 -6.
Responses deepened over time; 4/9 (56%) pts converted from MRD-positive at C8 to MRD-negative (10 -6 threshold) at either C12 or C24. One patient withdrew from the study after C12 to pursue ASCT (VGPR at time of withdrawal). One patient had primary refractory disease after one cycle of therapy and subsequently died from disease progression and CNS involvement. Grade 3+ leukopenia and thrombocytopenia occurred in 21% and 24%, respectively; notable grade 3+ nonhematologic adverse events were hypertension (14%) and a single case of thrombotic microangiopathy leading to discontinuation of carfilzomib. There were no other grade 3 cardiovascular toxicities.
Conclusions: The combination of Dara-KRd as extended frontline therapy for NDMM without employing ASCT can induce high rates of MRD-negativity within 8 cycles, exceeding the historical sCR rate of KRd without Dara. Importantly, the rate and depth of MRD-negativity improve beyond cycle 8, suggesting that extended Dara-KRd without ASCT may generate rates of sCR and MRD-negativity comparable to KRd with ASCT. Yearly longitudinal determinations of MRD after completion of 24 cycles of Dara-KRD protocol treatment will generate information on the durability of MRD and the role of ASCT compared to shorter treatments with Dara-KRd, with and without ASCT.
Figure 1 Figure 1.

Disclosures
Derman: Sanofi: Membership on an entity's Board of Directors or advisory committees. Rosenblatt: Wolters Kluwer Health: Consultancy, Patents & Royalties; Attivare Therapeutics: Consultancy; Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imaging Endpoints: Consultancy; Bristol-Myers Squibb: Research Funding. Avigan: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Aviv MedTech Ltd: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Parexcel: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. Jakubowiak: Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.