In the MANHATTAN phase 2 pilot trial, published in JAMA Oncology, researchers led by Ola Landgren, MD, PhD, concluded that combining daratumumab with the second-generation proteasome inhibitor-based triplet therapy of carfilzomib, lenalidomide, and dexamethasone yielded high rates of measurable residual disease (MRD) and progression-free survival (PFS) in patients with newly diagnosed multiple myeloma.
This study followed previous reports that daratumumab improved outcomes when combined with bortezomib, lenalidomide, and dexamethasone triplet therapy in patients with newly diagnosed multiple myeloma who underwent high-dose melphalan chemotherapy and autologous hematopoietic cell transplantation. Comparatively, patients in this study had not undergone either chemotherapy or hematopoietic cell transplantation.
Daratumumab Shows Promise in Multiple Myeloma Treatments
From October 2018 to November 2019, researchers enrolled 41 evaluable patients (61% female) with a median age of 59 years (range, 30-70 years) and newly diagnosed multiple myeloma at the Memorial Sloan Kettering Cancer Center. Authors noted 20 (49%) participants had high-risk multiple myeloma.
Participants received eight 28-day cycles of:
- Intravenous carfilzomib 20/56 mg/m2 on days 1, 8, and 15
- Oral lenalidomide 25 mg on days 1 through 21
- Oral or intravenous dexamethasone 40 mg weekly in cycles 1 through 4, followed by 20 mg in further cycles
- Intravenous daratumumab 16 mg/kg on days 1, 8, 15, and 22 of cycles 1 and 2; days 1 and 15 of cycles 3 through 6; and day 1 of cycles 7 and 8
The primary end point was MRD negativity in bone marrow. Additional end points included safety and tolerability, response rates per International Myeloma Working Group criteria, PFS, and overall survival (OS).
Participants were followed for a median of 20.3 months (95% CI, 19.2-21.9). The researchers reported 29 (71%) of 41 patients achieved the specified MRD criteria (95% CI, 54-83), leading them to judge the pilot trial a success.
The median time to MRD negativity was 6 cycles (range, 1-8 cycles). The overall response rate was 100% (n=41), and the rate of very good partial or complete responses was 95% (n=39). At 11 months, authors estimated the 1-year rates for PFS and OS were 98% (95% CI, 93-100) and 100%, respectively.
Grade 3 or 4 adverse events included neutropenia (n=12), rash (n=4), lung infection (n=3), and increased alanine aminotransferase level (n=2), and no patients died during the study.
“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,” Landgren and colleagues concluded.
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