Results from the single-institution phase II MANHATTAN study were reported in JAMA Oncology recently by Ola Landgren, MD, PhD, and colleagues. The investigators found that daratumumab in combination with weekly carfilzomib, lenalidomide, and dexamethasone resulted in high rates of minimal residual disease (MRD) negativity and progression-free survival in patients with newly diagnosed multiple myeloma in the absence of treatment with high-dose melphalan and autologous hematopoietic cell transplantation (HCT).
Ola Landgren, MD, PhD
As stated by the investigators, “Recently, the benefit of adding daratumumab to the proteasome inhibitor–based, three-drug combination of bortezomib, lenalidomide, and dexamethasone for patients with newly diagnosed multiple myeloma who underwent high-dose melphalan chemotherapy and autologous HCT was assessed. Here, we examine the addition of daratumumab to the second-generation proteasome inhibitor–based, three-drug combination of carfilzomib, lenalidomide, and dexamethasone.”
In the study, 41 evaluable patients enrolled at Memorial Sloan Kettering Cancer Center between October 2018 and November 2019 received eight 28-day cycles of intravenous carfilzomib at 20/56 mg/m2 on days 1, 8, and 15; oral lenalidomide at 25 mg on days 1 to 21; and dexamethasone at 40 mg weekly orally or intravenously during cycles 1 to 4 and at 20 mg thereafter, plus intravenous daratumumab at 16 mg/kg on days 1, 8, 15, and 22 in cycles 1 to 2, days 1 and 15 in cycles 3 to 6, and day 1 in cycles 7 and 8. The primary endpoint was MRD negativity rate (MRD negativity in the marrow at 10-5 sensitivity) in the absence of high-dose melphalan chemotherapy and autologous HCT. Response was assessed using International Myeloma Working Group criteria. Overall, 49% of patients had high-risk disease.
Median follow-up from the start of treatment was 20.3 months (95% confidence interval [CI] = 19.2–21.9 months). MRD negativity was achieved in 29 (71%, 95% CI = 54%–83%) of 41 patients. Median time to MRD negativity was six cycles (range = 1–8 cycles). No significant difference in achievement of MRD negativity was observed between high-risk vs standard-risk patients (odds ratio = 1.7, P = .50). Disease progression occurred in one patient with MRD negativity at 9 months after treatment. At the time of analysis, seven of eight patients with 1-year follow up have shown sustained MRD negativity.
The overall response rate was 100%, with very good partial response or complete response seen in 95% of patients. At 11 months of the median follow-up, 1-year progression-free survival was 98% (95% CI = 93%–100%) and overall survival was 100%.
The most common grade 3 or 4 adverse events were neutropenia (27%), rash (9%), lung infection (7%), and increased alanine aminotransferase (4%). No grade 3 or 4 peripheral neuropathy was observed. Daratumumab infusion-related reactions occurred in 18 patients (40%); all were grade 2, all occurred during the first daratumumab infusion, and none resulted in discontinuation of daratumumab. Serious adverse events related to treatment occurred in eight patients (18%), with the most common being lung infection (7%). No deaths occurred during the trial.
The investigators concluded: “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 progression-free survival.”
The investigator-initiated trial was supported by a grant from the National Cancer Institute and by Janssen and Amgen Pharmaceuticals.
Dr. Landgren, of the Myeloma Program, Sylvester Comprehensive Cancer Center, University of Miami, is the corresponding author for the JAMA Oncology article.
Disclosure: For full disclosures of the study authors, visit jamanetwork.com.