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Clinical Trial
. 2021 Jun 1;7(6):862-868.
doi: 10.1001/jamaoncol.2021.0611.

Safety and Effectiveness of Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab Combination Therapy for Patients With Newly Diagnosed Multiple Myeloma: The MANHATTAN Nonrandomized Clinical Trial

Ola Landgren  1   2 , Malin Hultcrantz  1 , Benjamin Diamond  1 , Alexander M Lesokhin  1 , Sham Mailankody  1 , Hani Hassoun  1 , Carlyn Tan  1 , Urvi A Shah  1 , Sydney X Lu  1 , Meghan Salcedo  1 , Kelly Werner  1 , Jenna Rispoli  1 , Julia Caple  1 , Allison Sams  1 , Dennis Verducci  1 , Katie Jones  1 , Isabel Concepcion  1 , Amanda Ciardello  1 , Aisara Chansakul  1 , Julia Schlossman  1 , Elizabet Tavitian  1 , Tala Shekarkhand  1 , Angela Harrison  1 , Casey Piacentini  1 , Even H Rustad  1 , Venkata Yellapantula  1 , Kylee Maclaughlan  1 , Francesco Maura  1   2 , Heather J Landau  3 , Michael Scordo  3 , David J Chung  3 , Gunjan Shah  3 , Oscar B Lahoud  3 , Katie Thoren  4 , Kazunori Murata  4 , Lakshmi Ramanathan  4 , Maria E Arcila  5 , Caleb Ho  4 , Mikhail Roshal  5 , Ahmet Dogan  5 , Andriy Derkach  6 , Sergio A Giralt  3 , Neha Korde  1
Affiliations
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

Ola Landgren et al. JAMA Oncol. .

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; 10-5 sensitivity) 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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Landgren reported receiving grants from LLS, the Rising Tide Foundation, Paula and Rodger Riney Foundation, IMF, the National Institutes of Health, Glenmark, Seattle Genetics, Memorial Sloan Kettering, Amgen, and Janssen; personal fees from Amgen, Celgene, and Janssen for invited scientific talks; other fees from Takeda and Janssen for randomized clinical trials, personal fees from Karyopharm, Adaptive Biotech, The Binding Site, Bristol Myers Squibb, Cellectis, Oncopeptides, and Pfizer for invited scientific talks; grants from the Multiple Myeloma Research Foundation for genomic studies and minimal residual disease (MRD) studies in myeloma, from the Perelman Family Foundation for studies on myeloma precursor disease, from the National Cancer Institute for MRD studies in myeloma, and from the US Food and Drug Administration for racial disparities in myeloma; other fees from Theadex for randomized clinical trials and other from Merck outside the submitted work. Dr Hultcrantz reported receiving grants from the Swedish Research Council and the Karolinska Institute Foundations; and other fees from GSK, Daiichi Sankyo, the Multiple Myeloma Research Foundation, and the Memorial Sloan Kettering Cancer Center outside the submitted work. Dr Lesokhin reported receiving grants and personal fees from Janssen and Pfizer, and grants from Genentech, Bristol Myers Squibb, and Trillium Therapeutics outside the submitted work. Dr Mailankody reported receiving other fees from Takeda, Janssen, Bristol Myers Squibb, Allogene Therapeutics, PleXus Education, and Physician Education Resource outside the submitted work. Dr Hassoun reported receving grants from Janssen and Celgene and other fees from Novartis. Dr U. A. Shah reported receiving grants from the Parker Institute for Cancer Immunotherapy and research funding and a research award from Celgene/Bristol Myers Squibb, other from Janssen Research funding paid to institution for investigator initiated clinical trial, and honoraria from Physicians Education Resources Honoraria outside the submitted work. Dr Scordo reported receiving personal fees from Angiocrine Bioscience Inc, Omeros Corporation, McKinsey & Company, Kite Pharma, and i3Health outside the submitted work. Dr G. Shah reported receiving reseach funding from Janssen and Amgen outside the submitted work. Dr Lahoud reported receiving personal fees from MorphoSys for serving on an advisory board outside the submitted work. Dr Thoren reported receiving nonfinancial support from The Binding Site and personal fees and grants from Sebia Inc outside the submitted work. Dr Arcila reported receiving consulting fees from Invivoscribe, Biocartis, and AztraZeneca outside the submitted work. Dr Ho reported receiving honorarium from Invivoscribe outside the submitted work. Dr Dogan reported receiving grants from Roche and Takeda, nonfinancial support from AbbVie, and personal fees from Roche, Takeda, EUSA Pharma, PeerView, PER, and Seattle Genetics outside the submitted work. Dr Giralt reported receving grants from Amgen, Celgene/Bristol Myers Squibb, Actinuum, Miltenyi, and Sanofi during the conduct of the study; personal fees from Amgen, Sanofi, Celgene/Bristol Myers Squibb, and Novartis outside the submitted work; research support/funding from Amgen, Janssen, Celgene, Pfizer, Behring, Sanofi, Jazz Pharmaceuticals, Kite Pharma, and Actinuum; and honraria for consulting from Amgen, Celgene/Bristol Myers Squibb, Actinuum, and Sanofi during the conduct of the study. Dr Korde reported receiving funding from Amgen and Janssen during the conduct of the study and personal fees from Medimmune outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Response to Therapy, by Number of Cycles and Follow-up
During the time window of the study (up to 8 cycles of weekly 56-mg/m2 dosing of the second-generation proteasome inhibitor carfilzomib with lenalidomide and dexamethasone [wKRd-D] combination therapy), minimal residual disease (MRD) status was assessed in 39 patients as they achieved at least a very good partial response (VGPR); 29 patients were found to be MRD negative (10−5 sensitivity) in the bone marrow. Thus, overall MRD negativity (complete response [CR] or VGPR) was achieved in 29 of 41 patients (71%; 95% CI, 54%-83%). Of the 29 patients who were MRD negative, 14 had cleared their monoclonal serum protein at the time of MRD testing, and 10 had cleared their monoclonal serum protein at a median of 3 months later (range, 1-6 months); thus, an MRD-negative CR was achieved in 24 of 41 patients (59%; 95% CI, 42%-74%). Five patients achieved a VGPR at a median follow-up of 5 months after becoming MRD negative in the bone marrow. Two patients (patients 3 and 14) only achieved a partial response (PR) during the time window of the study; after 8 cycles of wKRd-D, patient 3 was given additional 2 cycles of KRd therapy followed by an autologous stem cell transplant as standard of care and became MRD negative; after 8 cycles of wKRd-D, patient 14 was given an autologous stem cell transplant as standard of care and achieved CR or MRD positivity. Patient 3 remained MRD negative at 1-year follow-up while receiving 10 mg of lenalidomide as maintenance therapy, and patient 14 remained MRD positive at 1-year follow-up while receiving 10 mg of lenalidomide as maintenance therapy. ASCT indicates autologous stem cell transplant; BL, baseline; C, cycle; FU, follow-up; PD, progressive disease; and Pt, patient.
Figure 2.
Figure 2.. Progression-free Survival
See this image and copyright information in PMC

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