To complement The ASCO Post’s comprehensive coverage of the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition, here are several abstracts selected from the meeting proceedings focusing on novel therapeutic regimens including the monoclonal antibody daratumumab in combination with three drug combinations for patients newly diagnosed with multiple myeloma. For full details of these study abstracts, visit hematology.org/Annual-Meeting.
ABSTRACT 860: Daratumumab plus carfilzomib, lenalidomide, and dexamethasone (KRd) induction (× 4 cycles), hematopoietic cell autologous transplantation (auto-HCT) and posttransplant, response-adapted, measurable residual disease (MRD) (clonoSEQ method, sensitivity 10-6)-based daratumumab plus KRd consolidation (0, 4, or 8 cycles based on MRD status) in patients (median age, 61 [range, 38–79] with newly diagnosed multiple myeloma (ClinicalTrials.gov identifier NCT03224507)1
Methods: MRD was evaluated by next-generation sequencing (clonoSEQ) at the end of induction, after transplant, and during each 4-cycle block of daratumumab plus KRd consolidation. The primary endpoint was achievement of MRD-negative remission (< 10-5) as defined by International Myeloma Working Group (IMWG) consensus. Secondary endpoints included MRD < 10-6, complete response by IMWG criteria at the end of induction and upon completion of consolidation, and the rate of imaging (assessed by positron-emission tomography/computed tomography) plus MRD-negative complete response.
Syed Ali Abutalib, MD
Ola Landgren, MD, PhD
Patients received therapy until achievement of two consecutive MRD reads < 10-5 (confirmed MRD-negative remission, eg, post-induction and post-transplant or post-transplant and during consolidation). Confirmed MRD-negative patients received no further therapy and were observed with surveillance for MRD resurgence 6 and 18 months after treatment discontinuation. Patients completing consolidation without confirmed MRD-negative remission received standard lenalidomide maintenance.
Results: Currently, 69 patients have been enrolled, 38 have completed induction, and 22 have completed post-transplant assessment. A total of 66 patients (96%) had MRD, and 100% of the expected MRD data points were successfully obtained. All patients responded by the end of induction cycle 2, 92% of patients obtained a very good partial response or better after induction, and 91% of patients who have reached transplant obtained complete response/stringent complete response as the best response on therapy. The MRD-negative remission (< 10-5) rate was 34%, 70%, and 80% after induction, at transplant, and at best response, respectively. The rates of MRD < 10-6 were 28%, 45%, and 65%, respectively.
No patient discontinued therapy due to toxicity. One patient died of metapneumoviral pneumonia after transplant, which was considered not to be related to the investigational agents. Most common grade 3 and 4 adverse events were neutropenia, infection, insomnia, hyperglycemia, and rash. There were 15 serious adverse events, including pneumonia (n = 5), fever and neutropenia (n = 2), pulmonary embolism (n = 1), and atypical hemolytic uremic syndrome (n = 1). All 11 patients who achieved confirmed MRD-negative remission and discontinued therapy also achieved imaging plus MRD-negative complete response, and none had relapse or resurgence of MRD with short follow-up (0.8–7.3 months).
Clinical Implications: This is the first study designed to form the basis for MRD-driven cessation of therapy. Daratumumab plus KRd induction, auto-HCT, and daratumumab plus KRd consolidation guided by MRD is feasible, safe, and leads to a high proportion of patients achieving complete response/stringent complete response, IMWG MRD-negative complete response, imaging plus MRD-negative complete response, and MRD < 10-6. This approach can form the basis for clinical efforts to reduce the burden of continuous therapy in those with confirmed MRD-negative (× 2) remissions. Of note, the clonoSEQ test is approved by the U.S. Food and Drug Administration, and results are unique to individual patients. Therefore, this test must be performed prior to therapy on an optimal marrow specimen.
ABSTRACT 862: Phase II study of daratumumab plus KRd × 8 cycles (n = 41; vs KRd × 8 cycles, n = 41) provides unprecedented MRD negativity without front-line auto-HCT in newly diagnosed multiple myeloma2
Methods: The primary endpoint of the study was to rule out MRD of 60% and to target up to 80% MRD negativity rate. In “medically fit” patients (median age, 59 years [range, 36–70 years]), hematopoietic progenitor cell collection was recommended after 4 to 6 cycles of therapy; daratumumab plus KRd therapy is resumed after apheresis collection. Treatment responses are being assessed with parallel bone marrow-based MRD assays (10 color single-tube flow cytometry and in vivo scribe IgHV sequencing); per IMWG guidelines, both MRD assays allow detection of 1 myeloma cell in 100,000 bone marrow cells (10-5).
Results: At the submission of this abstract, 28 patients have completed at least one cycle of daratumumab plus KRd; among them, 10 patients have completed therapy. Of the 10 patients, 7 who completed study treatment are MRD-negative. An additional eight patients have become MRD-negative while on therapy. The study reported MRD negativity in 15 of 18 patients.
The investigators found no added or major clinical toxicities in the experimental arm compared with the Memorial Sloan Kettering Cancer Center experience with KRd (weekly vs biweekly carfilzomib, respectively). With a comparable efficacy and safety profile coupled with a substantial reduction in the number of infusions with weekly carfilzomib (27 vs 51), daratumumab plus KRd offers an attractive treatment modality.
Clinical Implications: In patients newly diagnosed with multiple myeloma, 8 cycles of weekly daratumumab plus KRd, without front-line auto-HCT, resulted in an MRD negativity rate of 83%. These promising results have prompted the development of an important, large, randomized multicenter study (ADVANCE) with a similar design, which will allow for more definitive answers, and the results might be practice changing. We anticipate that the first patient will be enrolled early in 2020.
ABSTRACT 691: Griffin study update: Depth of response with the addition of daratumumab to lenalidomide, bortezomib, and dexamethasone (daratumumab plus RVd; n = 104) improves with time (end of induction → auto-HCT → end of consolidation) compared with RVd treatment alone (n = 103) in patients with transplant-eligible newly diagnosed multiple myeloma (NCT02874742)3
Methods: The primary endpoint was the stringent complete response rate by the end of consolidation. MRD (10-5 per IMWG criteria) was assessed by next-generation sequencing (clonoSEQ).
Results: The study met its primary endpoint; daratumumab plus RVd improved the stringent complete response rate by the end of consolidation (42.4% vs 32.0%; odds ratio = 1.57; 95% confidence interval = 0.87–2.82; 2-sided P = .1359). This improvement was observed in all patient subgroups except for the small subsets with International Staging System stage 3 disease or with high-risk cytogenetics. Responses deepened with time in both arms, with superior results in the experimental arm.
Grade 3 and 4 treatment-associated adverse events (≥ 10%) with daratumumab plus RVd vs RVd included neutropenia (32% vs 15%), thrombocytopenia (16% vs 8%), and leukopenia (15% vs 7%). There was no difference in the rate of grade 3 and 4 infections between the study arms.
Clinical Implications: In newly diagnosed patients with multiple myeloma, four cycles of daratumumab plus RVd followed by auto-HCT and an additional two cycles of daratumumab plus RVd consolidation significantly improved response rates and the depth of response, including stringent complete response and MRD negativity compared with the control arm. The maintenance phase of the study is ongoing, comparing lenalidomide with or without daratumumab.
ABSTRACT 864: Phase II trial of daratumumab, ixazomib, lenalidomide, and an abbreviated course of dexamethasone (40 mg intravenously weekly for no more than 2 cycles; daratumumab plus IRd) in 40 patients with newly diagnosed multiple myeloma (NCT03012880)4
Methods: The primary objective is to determine the rate of complete response.
Results: The median age at enrollment was 64.5 years (range, 33–81 years); eight patients (20%) had high-risk cytogenetics. The median follow-up was 6.1 months. At the end of cycle 2, 88% of patients achieved at least a partial response and 33%, at least a very good partial response that improved to 52% at the end of cycle 4. The overall best confirmed response rate among all 40 patients was 95%, including 10% stringent complete responses, 5% complete responses, and 23% near complete responses (13% very good partial response excluding near complete response). CD34-positive cell collection was completed in 17 patients at the time of data cutoff.
Overall, 224 cycles have been administered across the study, with dose reduction/hold required in a subset of patients: lenalidomide (20%), dexamethasone (13%), ixazomib (10%), and daratumumab (0%). The most frequent reasons for dose adjustment were skin rash and hematologic toxicities.
Clinical Implications: Daratumumab plus IRd is well tolerated, with excellent activity, and does not adversely impact hematopoietic progenitor cell mobilization in patients with newly diagnosed multiple myeloma. The daratumumab plus IRd regimen represents another future four-drug option for patients with newly diagnosed multiple myeloma but seems therapeutically inferior to other four-drug daratumumab-based regimens (with KRd or RVd). ■
DISCLOSURE: Dr. Abutalib has served on the advisory board for AstraZeneca and Partner Therapeutics. Dr. Landgren has received grant support from Amgen, Celgene, Janssen, Takeda, Glenmark, Seattle Genetics, and Karyopharm; has received honoraria or served on ad boards for Adaptive Biotechnologies, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer; and has served on an independent data monitoring committee for Takeda, Merck, Janssen, and Theradex.
REFERENCES
1. Costa LJ, Chhabra S, Godby KN, et al: Daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) induction, autologous transplantation and post-transplant, response-adapted, measurable residual disease–based Dara-KRd consolidation in patients with newly diagnosed multiple myeloma. 2019 ASH Annual Meeting & Exposition. Abstract 860. Presented December 9, 2019.
2. Landgren O, Hultcrantz M, Lesokhin AM, et al: Weekly carfilzomib, lenalidomide, dexamethasone, and daratumumab combination therapy provides unprecedented MRD negativity rates in newly diagnosed multiple myeloma: A clinical and correlative phase 2 study. 2019 ASH Annual Meeting & Exposition. Abstract 862. Presented December 9, 2019.
3. Voorhees PM, Kaufman JL, Laubach JP, et al: Depth of response to daratumumab, lenalidomide, bortezomib, and dexamethasone improves over time in patients with transplant-eligible newly diagnosed multiple myeloma: Griffin study update. 2019 ASH Annual Meeting & Exposition. Abstract 691. Presented December 9, 2019.
4. Kapoor P, Gertz MA, Laplant B, et al: Phase 2 trial of daratumumab, ixazomib, lenalidomide and modified dose dexamethasone in patients with newly diagnosed multiple myeloma. 2019 ASH Annual Meeting & Exposition. Abstract 864. Presented December 9, 2019.
