Synapse - Safety and effectiveness of weekly carfilzomib, lenalidomide, dexamethasone, and daratumumab combination therapy for patients with newly diagnosed multiple myeloma the MANHATTAN nonrandomized clinical trial

Safety and effectiveness of weekly carfilzomib, lenalidomide, dexamethasone, and daratumumab combination therapy for patients with newly diagnosed multiple myeloma the MANHATTAN nonrandomized clinical trial Journal Article

Authors:	Landgren, O.; Hultcrantz, M.; Diamond, B.; Lesokhin, A. M.; Mailankody, S.; Hassoun, H.; Tan, C.; Shah, U. A.; Lu, S. X.; Salcedo, M.; Werner, K.; Rispoli, J.; Caple, J.; Sams, A.; Verducci, D.; Jones, K.; Concepcion, I.; Ciardello, A.; Chansakul, A.; Schlossman, J.; Tavitian, E.; Shekarkhand, T.; Harrison, A.; Piacentini, C.; Rustad, E. H.; Yellapantula, V.; Maclaughlan, K.; Maura, F.; Landau, H. J.; Scordo, M.; Chung, D. J.; Shah, G.; Lahoud, O. B.; Thoren, K.; Murata, K.; Ramanathan, L.; Arcila, M. E.; Ho, C.; Roshal, M.; Dogan, A.; Derkach, A.; Giralt, S. A.; Korde, N.
Article Title:	Safety and effectiveness of weekly carfilzomib, lenalidomide, dexamethasone, and daratumumab combination therapy for patients with newly diagnosed multiple myeloma the MANHATTAN nonrandomized clinical trial
Abstract:	Importance: Recently, the benefit of adding daratumumab to the proteasome inhibitor-based, 3-drug combination of bortezomib, lenalidomide, and dexamethasone for patients with newly diagnosed multiple myeloma who underwent high-dose melphalan chemotherapy and autologous hemopoietic cell transplant was assessed. Here, we examine the addition of daratumumab to the second-generation proteasome inhibitor-based, 3-drug combination of carfilzomib, lenalidomide, and dexamethasone. Objective: To assess the safety and effectiveness of carfilzomib-lenalidomide-dexamethasone-daratumumab combination therapy for patients with newly diagnosed multiple myeloma, in the absence of high-dose melphalan chemotherapy and autologous hemopoietic cell transplant. Design, Setting, and Participants: Clinical and correlative pilot study at the Memorial Sloan Kettering Cancer Center in New York, New York. Patients with newly diagnosed multiple myeloma were enrolled between October 1, 2018, and November 15, 2019. The median follow-up from start of treatment was 20.3 months (95% CI, 19.2-21.9 months). Interventions: Eight 28-day cycles with intravenous carfilzomib, 20/56 mg/m2(days 1, 8, and 15); oral lenalidomide, 25 mg, (days 1-21); dexamethasone, 40 mg weekly, orally or intravenously (cycles 1-4), and 20 mg after cycle 4; and intravenous daratumumab, 16 mg/kg (days 1, 8, 15, and 22 [cycles 1-2]; days 1 and 15 [cycles 3-6]; and day 1 [cycles 7 and 8]). Main Outcomes and Measures: The primary end point was the minimal residual disease (MRD) rate, in the absence of high-dose melphalan chemotherapy and autologous hemopoietic cell transplant. Secondary end points included determining safety and tolerability, evaluating rates of clinical response per the International Myeloma Working Group, and estimating progression-free survival (PFS) and overall survival (OS) rates. Results: Forty-one evaluable patients were enrolled (median age, 59 years; range, 30-70 years); 25 (61%) were female, and 20 (49%) had high-risk multiple myeloma. The primary end point (MRD negativity in the bone marrow; 10-5sensitivity) was achieved in 29 of 41 patients (71%; 95% CI, 54%-83%), and therefore the trial was deemed successful. Median time to MRD negativity was 6 cycles (range, 1-8 cycles). Secondary end points of the overall response rate and the very good partial response or complete response rate were 100% (41 of 41 patients) and 95% (39 of 41 patients), respectively. At 11 months of the median follow-up, the 1-year PFS rate and the OS rate were 98% (95% CI, 93%-100%) and 100%, respectively. Most common (≥2 patients) grade 3 or 4 adverse events were neutropenia (12 patients [27%]), rash (4 patients [9%]), lung infection (3 patients [7%]), and increased alanine aminotransferase level (2 patients [4%]). There were no deaths. Conclusions and Relevance: In this nonrandomized clinical trial, carfilzomib-lenalidomide-dexamethasone-daratumumab combination therapy was associated with high rates of MRD negativity in patients with newly diagnosed multiple myeloma and high rates of PFS. © 2021 American Medical Association. All rights reserved.
Keywords:	adult; clinical article; treatment outcome; treatment response; aged; overall survival; lenalidomide; constipation; drug tolerability; fatigue; neutropenia; diarrhea; drug dose reduction; drug efficacy; drug safety; drug withdrawal; hypertension; follow up; low drug dose; progression free survival; multiple cycle treatment; multiple myeloma; phase 2 clinical trial; anemia; nausea; thrombocytopenia; peripheral neuropathy; dexamethasone; drug structure; high risk patient; dyspnea; fever; pruritus; rash; alanine aminotransferase; insomnia; cancer center; correlation analysis; minimal residual disease; pilot study; acetylsalicylic acid; paracetamol; thromboembolism; warfarin; peripheral edema; headache; new york; lung infection; congestive heart failure; upper respiratory tract infection; low molecular weight heparin; dysgeusia; carfilzomib; rivaroxaban; diphenhydramine; hypertransaminasemia; acute coronary syndrome; blood clotting factor 10a inhibitor; montelukast; infusion related reaction; human; male; female; article; daratumumab
Journal Title:	JAMA Oncology
Volume:	7
Issue:	6
ISSN:	2374-2437
Publisher:	American Medical Association
Date Published:	2021-06-01
Start Page:	862
End Page:	868
Language:	English
DOI:	10.1001/jamaoncol.2021.0611
PUBMED:	33856405
PROVIDER:	scopus
PMCID:	PMC8050789
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85104647505&doi=10.1001%2fjamaoncol.2021.0611&partnerID=40&md5=21c655d01f501622862bb447637170e7
Notes:	Kylee Maclachlan's name is spelled as Kylee Maclaughlan in the publication's author list -- Article -- Export Date: 2 August 2021 -- Source: Scopus