The quadruplet regimen of daratumumab (Darzalex), lenalidomide (Revlimid), ixazomib (Ninlaro), and dexamethasone (D-RId) showed promising progression-free survival (PFS) and overall survival (OS) for patients with newly diagnosed multiple myeloma who were ineligible for or deferred autologous stem cell transplant (ASCT), according to results from the phase 2 Allian Foundation Trial 41 (NCT04009109).1
Findings presented at the
Additionally, the 12-month PFS and OS rates were 92% (95% CI, 86.1%-98.4%) and 93.6% (95% CI, 88.3%-99.2%), respectively.
“A 4-drug regimen of [D-RId] achieves initial favorable outcomes in this older, transplant-ineligible patient population,” lead study author Andrew J. Yee, MD, said during a presentation of the data. Yee is the clinical director of the Center for Multiple Myeloma at Massachusetts General Hospital and an assistant professor of medicine at Harvard Medical School in Boston.
What Was the Goal of Evaluating D-RId in Newly Diagnosed Myeloma?
Although quadruplet regimens have become a standard of care in the management of transplant-ineligible/deferred, newly diagnosed multiple myeloma, Yee explained that regimens adapted for the transplant-ineligible population stem from treatments for transplant-eligible patients with minimal modifications.
Thus, investigators sought to evaluate D-RId in an older, frailer population. Notably, this regimen used a modified dose of lenalidomide, given at 15 mg vs 25 mg. Ixazomib is a proteasome inhibitor that is currently approved by the FDA in combination with lenalidomide and dexamethasone for patients with multiple myeloma who have received at least 1 prior therapy.2
The randomized, multicenter Alliance Foundation Trial 41 enrolled patients with newly diagnosed multiple myeloma who were not considered candidates for high-dose chemotherapy and ASCT, or those who deferred ASCT.1 Patients needed to have an ECOG performance status of 0 to 2, and there was no upper limit on age for enrollment.
Although patients were randomly assigned between arms A and B, all enrolled patients received the same D-RId induction regimen, comprising subcutaneous daratumumab at 1800 mg once per week in cycles 1 and 2, days 1 and 15 in cycles 3 to 6, and once every 4 weeks from cycles 7 to 12; lenalidomide at 15 mg once per day on days 1 to 21 of cycles 1 to 12; and ixazomib at 4 mg per day on days 1, 8, and 15 of each cycle. Dexamethasone was given at 20 mg on days 1, 2, 8, 9, 15, 16, 22, and 23 of each cycle for patients under 75 years of age; it was given at the same dose on days 1, 8, 15, and 22 for patients 75 years of age and older.
During maintenance, patients in arm A received lenalidomide alone at 10 mg per day on days 1 to 21 for 24 cycles. In arm B, maintenance therapy consisted of daratumumab at 1800 mg on day 1, lenalidomide at 10 mg on days 1 to 21, and ixazomib at 3 mg on days 1, 8, and 15. Subsequent therapy after the completion of maintenance was left to investigator discretion.
PFS served as the trial’s primary end point.
In the overall population, patients had a median age of 74 years (range, 63-86; IQR, 71-79), and 55.7% of patients were 75 years of age or younger; 13.9% were over the age of 80. Most patients were female (59.5%), White (83.5%), and had an ECOG performance status of 1 (57%).
International Staging System (ISS) disease grades included I (41.8%), II (35.4%), and III (22.8%). Additionally, fluorescence in situ hybridization findings revealed that 29.1% of patients had high-risk disease per trial criteria, 11.4% had high-risk disease per International Myeloma Working Group criteria, 5.1% had high-risk disease per IMS 2025 criteria, 21.5% had 1q gain, and data were unavailable for 6.3% of patients. Overall, 43% of patients were stratified as high risk, and 41.8% of patients were considered frail.
In arm A, 41 patients received induction therapy; 13 of these patients were off treatment prior to maintenance due to adverse effects (AEs; n = 5), death (n = 3), other complicating disease (n = 1), disease progression (n = 1), and other (n = 3). Of the 28 patients who entered the maintenance portion, 12 remained on treatment at data cutoff. In the 16 patients off treatment, 10 completed maintenance therapy. Patients also discontinued treatment due to disease progression (n = 4), and other reasons (n = 2).
In arm B, 38 patients received induction, and 33 proceeded to maintenance. Reasons for discontinuation prior to maintenance included AEs (n = 2), disease progression (n = 1), other complicating disease (n = 1), and other (n = 1). In the maintenance phase, 14 were still on treatment and 13 completed treatment; patients discontinued maintenance due to disease progression (n = 3), other complicating disease (n = 1), AEs (n = 1), and other (n = 1).
What Other Efficacy and Safety Data Were Reported for D-RId?
When assessed by risk, PFS outcomes were similar between standard-risk and high-risk patients. Per trial criteria, the 12-month PFS rate was 90.9% (95% CI, 82.8%-99.8%) among standard-risk patients (n = 45) vs 93.7% (95% CI, 85.6%-100%) among high-risk patients (n = 34). Per IMWG criteria, the 12-month PFS rates were 93.6% (95% CI, 87.7%-99.9%) in standard-risk patients (n = 65) and 87.5% (95% CI, 67.3%-100%) in high-risk patients (n = 9). These respective rates were 94.0% (95% CI, 88.5%-99.9%) and 75.0% (95% CI, 42.6%-100%) in standard-risk (n = 70) and high-risk (n = 4) patients per IMS 2025 criteria.
Additionally, non-frail patients (n= 46) achieved a 12-month PFS rate of 95.4% (95% CI, 89.4%-100%), and frail patients (n = 33) experienced a 12-month PFS rate of 87.2% (95% CI, 76.3%-99.8%).
The 12-month PFS rates were 95.4% (95% CI, 89.4%-100%) in patients 80 years of age or younger who were non-frail (n = 46), 95.0% (95% CI, 85.9%-100%) in patients 80 years of age or younger who were frail (n = 22), and 72.7% (95% CI, 50.6%-100%) in patients over 80 years of age, who are all considered frail per the Simplified Frailty Index (n = 11).
Regarding safety, the most common hematologic AEs included neutropenia (all grade, 34.2%; grade ≥3, 16.5%), anemia (29.1%; 10.1%), and thrombocytopenia (25.3%; 8.9%). The most common nonhematologic AEs included infections (53.2%; 18.9%), syncope (7.6%; 7.6%), diarrhea (41.8%; 7.6%), acute kidney injury (6.3%; 6.3%), fatigue (46.8%; 5.1%), hypertension (11.4%; 5.1%), hypokalemia (21.5%; 5.1%), thromboembolic event (7.6%; 5.1%), rash (40.5%; 5.1%), and neuropathy (29.1%; 0%).
Notably, grade 3 or higher AEs were increased among frail patients (85%) compared with non-frail patients (63%); the overall incidence of grade 3 or higher AEs was 72%. This increase was most notable among non-hematologic AEs, where the rates of grade 3 or higher toxicities were 82% for frail patients and 57% for non-frail patients.
Yee concluded by noting that the 16.5% rate of grade 3 or higher neutropenia observed with D-RId was improved compared with other quadruplet regimens evaluated in previous phase 3 trials.
“This [lower rate of grade 3 or higher neutropenia] is probably due to the lower dose of lenalidomide used in our study,” Yee said.
Disclosures: Yee reported serving as a consultant for AbbVie, Adaptive Biotechnologies, Amgen, BMS, Celgene, GSK, Janssen, Karyopharm, Oncopeptides, Pfizer, Prothena, Regeneron, Sanofi, Sebia, and Takeda; and receiving institutional research funding from Amgen, BMS, GSK, Janssen, Sanofi, and Takeda.
References
- Yee AJ, O’Donnell EK, Nadeem O, et al. A randomized phase 2 study of daratumumab, lenalidomide, ixazomib, and dexamethasone in transplant-ineligible/deferred patients with newly diagnosed multiple myeloma: Alliance Foundation Trial 41. Presented at: 22nd Annual International Myeloma Society Meeting and Exposition; September 17-20, 2025; Toronto, Canada. Abstract OA-61.
- Ninlaro. Prescribing information. Takeda; 2024. Accessed September 19, 2025. https://www.ninlaro.com/sites/default/files/resources/ninlaro-prescribing-information.pdf