Long-Term Follow-Up Shows Survival Benefit Maintained for Daratumumab Added to SOC in Newly Diagnosed Myeloma

Thierry Facon, MD

Daratumumab (Darzalex) added to the standard of care with lenalidomide (Revlimid) and dexamethasone (D-Rd) continued to show a survival benefit over Rd alone in patients with transplant-ineligible, newly diagnosed multiple myeloma (MM) after almost 5 years of follow-up, updated results from the phase 3 MAIA trial show.¹

“These results strongly support upfront daratumumab with lenalidomide and dexamethasone as a new standard of care for patients with transplant-ineligible newly diagnosed multiple myeloma,” Thierry Facon, MD, professor of haematology in the Department of Haematology, Lille University Hospital, Lille, France, said during a presentation of the data of updated efficacy and safety results from a prespecified interim overall survival (OS) analysis during the 2021 European Hematology Association (EHA) Annual Meeting.

The estimated 5-year OS rate was 66.3% in the D-Rd arm compared with 53.1% in the Rd arm (HR, 0.68; 95% CI, 0.53-0.86; P = .0013), “which will likely lead to a substantial improvement in median OS in this patient population,” Facon said. Median OS was not reached in either arm.

Facon noted that the significant progression-free survival (PFS) benefit of D-Rd, compared with Rd, was maintained, with a 47% reduction in the risk for disease progression or death. Median PFS was not reached with the addition of daratumumab, compared with 34.4 months with Rd.

The estimated 5-year PFS rate was 52.5% with D-Rd, compared with 28.7% with Rd (HR, 0.53; 95% CI, 0.43-0.66; P < .0001).

“These data provide a new PFS benchmark in patients with newly diagnosed multiple myeloma who are transplant ineligible,” Facon said.

Also of note, Facon added, these PFS and OS results were achieved in a study population aged 75 to 90 years.

Lastly, there were no new safety signals observed with continuous therapy and follow-up. The most common grade 3/4 adverse events (AEs) in the D-Rd and RD arms were neutropenia (54% vs. 37%, respectively), anemia (17% vs. 22%), lymphopenia (16% vs. 11%), leukopenia (12% vs. 6%), thrombocytopenia (9% each), pneumonia (19% vs. 11%), hypokalemia (13% vs. 10%), cataract (11% each), diarrhea (9% vs. 6%), fatigue (9% vs. 5%), hypertension (9% vs. 4%), hyperglycemia (8% vs. 4%), pulmonary embolism (7% vs. 5%), asthenia (5% each), acute kidney injury (5% vs. 3%), and chronic kidney disease (5% vs. 3%).

Of note, a lower percentage of grade 3/4 and serious treatment-emergent adverse events (TEAEs) occurred after 24 months, compared with the first 24 months, in both treatment arms.

Previously, in the phase 3 SWOG S0777 study, designed to evaluate the addition of bortezomib (Velcade) to Rd (VRd) in patients with newly diagnosed multiple myeloma without the intent for immediate transplant to establish VRd as a standard of care for elderly patients.2

In the trial, at a median follow-up of 84 months, the median PFS was 41 months with VRd, compared with 29 months for Rd alone (HR, 0.742). Median OS was not reach, compared with 69 months, respectively (HR, 0.709).

A subgroup of patients aged 65 or older comprised 43% of the total population; however, a significant OS benefit was not observed in older adults treated with VRd compared with RD (median, 65 months vs. 56 months; HR, 0.769; P = .168).

“Real-world data indicate that more than 50% of nontransplant elderly patients with newly diagnosed multiple myeloma do not receive any subsequent therapy, suggesting that the most effective therapy should be used upfront and not saved for relapse, at which time additional genetic mutations conferring resistance may have been acquired,” Facon explained.

Meanwhile, additional studies have established a PFS benefit of daratumumab in combination with the standard of care for patients with newly diagnosed multiple myeloma, he added.

Therefore, in the multicenter, randomized, open-label, active-controlled phase 3 MAIA trial, the researchers randomized 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation (ASCT) to receive either daratumumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone until disease progression or unacceptable toxicity.3

All patients received 28-day cycles of Rd (lenalidomide 25 mg orally once daily on days 1‐21 plus dexamethasone 40 mg orally on days 1, 8, 15, and 22) with or without daratumumab 16 mg/kg intravenously once weekly for cycles 1 through 2, once every 2 weeks for cycles 3 through 6, and once every 4 weeks thereafter. Patients were treated until disease progression or unacceptable safety events.

PFS served as the primary end point. Secondary end points included OS, PFS2, overall response rate, compete response (CR) and stringent CR, and minimal residual disease.

Patients were enrolled in the trial from March 2015 to January 2017.

In previously reported data, at a median follow-up of 28 months, disease progression or death occurred in 97 patients (26.4%) in the daratumumab arm and 143 patients (38.8%) in the control arm. The estimated percentage of patients alive without disease progression at 30 months was 70.6% (95% CI, 65.0%-75.4%) in the daratumumab arm, compared with 55.6% (95% CI, 49.5%-61.3%) in the control arm (HR, 0.56; 95% CI, 0.43-0.73; P < .001).

In total, 47.6% of the daratumumab arm experienced a CR or better, compared with 24.9% in the control group (P < .001).

Moreover, 24.2% of the patients in the daratumumab arm, compared with 7.3% of the control arm, had results below the threshold for minimal residual disease (P < .001).

The most common grade 3/4 AEs in the daratumumab and control arms included neutropenia (50.0% vs. 35.3%, respectively), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%).

_References:

_{1. Facon T, Kumar SK, Plesner T, et al. OVERALL SURVIVAL RESULTS WITH DARATUMUMAB, LENALIDOMIDE, AND DEXAMETHASONE VERSUS LENALIDOMIDE AND DEXAMETHASONE IN TRANSPLANT- INELIGIBLE NEWLY DIAGNOSED MULTIPLE MYELOMA: PHASE 3 MAIA STUDY. Presented at: European Hematology Association Annual Meeting; June 9-17, 2021; Virtual. Abstract LB1901.}

_{2. Durie BGM, Hoering A, Abidi M, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519-527. doi: 10.1016/S0140-6736(16)31594-X.}

_{3. Facon T, Kumar SK, Plesner T, et al. Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma. N Engl J Med. 2019;380:2104-2115. doi:10.1056/NEJMoa1817249.}