Daratumumab Plus KRd Regimen for Myeloma Results in Favorable MRD Negativity Rates

The addition of daratumumab (Darzalex) to the carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) regimen led to strong responses in patients with newly diagnosed multiple myeloma, including minimal residual disease (MRD) negativity in nearly three-quarters of the population, according to new research.

In a new report in JAMA Oncology,¹ corresponding author Ola Landgren, MD, PhD, of the University of Miami, and colleagues, outlined the results of the MANHATTAN nonrandomized trial, which was designed to evaluate how adding daratumumab to weekly KRd would affect patient outcomes in the absence of high-dose melphalan chemotherapy and autologous hematopoietic cell transplant (HDM-AHCT).

Landgren and colleagues explained that patients with newly diagnosed multiple myeloma have generally done well with standard therapy of bortezomib (Velcade), with lenalidomide and dexamethasone (VRd). The VRd regimen has led to 50-month progression-free survival in patients who did not undergo HDM-AHCT and 4-year overall survival (OS) in most patients who did receive HDM-AHCT.

However, the GRIFFIN trial (NCT02874742) recently showed that adding the human immunoglobulin G κ (IgGκ) CD38-targeting monoclonal antibody daratumumab could improve outcomes of patients on VRd who underwent HDM-AHCT.² In that study, 51% of patients who received 4 cycles of daratumumab-VRd followed by HDM-AHCT and an additional round of daratumumab-VRd achieved MRD negativity compared with 20% of patients who had the same treatment without the addition of daratumumab.

In the new study, Landgren and colleagues sought to examine whether a similar effect would be found by adding daratumumab to KRd. Their primary end point was acheivement of at least a 40% MRD negativity rate.

The investigators recruited 41 evaluable patients with newly diagnosed multiple myeloma. The patients had a median range of 59 years, 61% were female, and nearly half (20 patients) had high-risk disease. The patients underwent 8 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 through 21; weekly dexamethasone at 40 mg either orally or intravenously in the first 4 cycles with a lower 20-mg dose thereafter; and intravenous daratumumab at 16 mg/kg on days 1, 8, 15, and 22 in the first 2 cycles, days 1 and 15 on cycles 3 through 6, and day 1 in the final 2 cycles.

The therapy proved effective in a high percentage of patients. Seventy-one percent of patients achieved MRD negativity in the bone marrow at 10^-5 sensitivity (95% CI, 54%-83%), with a median time to MRD negativity of 6 cycles. All 41 patients achieved a very good partial response, with all but 2 (95%) achieving a complete response.

“The observed MRD results are approximately 20% higher than previously reported MRD rates among patients with newly diagnosed multiple myeloma treated with KRd, which indicates that the addition of daratumumab to an existing backbone combination therapy was associated with a clinically meaningful benefit,” the authors wrote.

The study had a median follow-up of 11 months. Ninety-eight percent of patients were progression free at 1 year. The 1-year OS rate was 100%.

The regimen’s safety profile was similar to that of KRd, and no patients developed grade 3 or higher peripheral neuropathy. There were 45 dose reductions among the 41 patients, most of which were for lenalidomide and dexamethasone. The most common grade 3 or 4 adverse events were neutropenia (12 patients; 27%), rash (4 patients; 9%), lung infection (3 patients; 7%), and increased alanine aminotransferase levels (2 patients; 4%). No patients died in the trial.

Given the promising results, Landgren and colleagues said a larger, randomized, multicenter trial is warranted. They said such a study, the ADVANCE trial (NCT04268498), is already underway.

References

1. Landgren O, Hultcrantz M, Diamond B, et al. Safety and Effectiveness of Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab Combination Therapy for Patients With Newly Diagnosed Multiple Myeloma: The MANHATTAN Nonrandomized Clinical Trial. JAMA Oncol. April 15, 2021. doi:10.1001/jamaoncol.2021.0611
2. VoorheesPM,KaufmanJL,LaubachJ,et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945. doi:10.1182/blood. 2020005288