Which Therapy Has the Best Efficacy in Transplant-Ineligible NDMM?

Daratumumab (Darzalex; D) plus bortezomib (Velcade; V), lenalidomide (Revlimid; R), and dexamethasone (d; D-VRd) demonstrated the highest probability of attaining the best progression-free survival (PFS), overall survival (OS), and minimal residual disease (MRD)-negative complete response (CR) rate outcomes compared with other standard of care regimens reflected in clinical guidelines for patients with transplant-ineligible newly-diagnosed multiple myeloma. These results were presented in a systematic literature review and network meta-analysis shared in a poster at the Society of Hematologic Oncology 2025 Annual Meeting.

When comparing D-VRd with other regimens for PFS, there was a 72% chance it was superior vs isatuximab (Sarclisa) plus VRd (Isa-VRD; HR, 0.85), an 88% chance it was superior vs DRd (HR, 0.71), and a 91% chance it was greater than daratumumab, bortezomib, melphalan (Alkeran), and prednisone (DVMP; HR, 0.63). There was a 100% probability that D-VRd was favorable vs the remaining 8 combinations, ranging from VRd (HR, 0.51) to melphalan and prednisone (HR, 0.15). PFS heterogeneity was moderate (I², 45.8%; 95% credible intervals [CrIs0, 0.0%-82.0%).

When conducting a similar comparison for OS, there was a 66% chance D-VRd was favorable vs Isa-VRd (HR, 0.85), a 79% chance it was superior vs DRd (HR, 0.77), a 97% chance it was superior vs VRd (HR, 0.66), an 85% chance it was superior vs DVMP (HR, 0.58), and a 99% chance it was superior vs continuous Rd (HR, 0.51). There was a 100% probability that D plus VRd was favorable vs the remaining 5 combinations, which ranged from melphalan, prednisone, and thalidomide (HR, 0.39) to melphalan and prednisone (HR, 0.26). OS heterogeneity was low (I², 0%; 95% CrI, 0.0%-79.2%)

In the analysis comparing D-VRd with other regimens for MRD-negative CR rate, there was an 81% probability that it was favorable vs Isa-VRd (OR, 1.31), and a 100% probability that it was favorable vs VRd (OR, 2.37).

“These comparative efficacy data may inform treatment selection for maximum benefit in the [transplant-ineligible newly diagnosed multiple myeloma] population; findings should be considered alongside differences in trial timing and baseline characteristics,” wrote lead study author Saad Z. Usmani, MD, MBA, FACP, FASCO, chief of Myeloma Service at Memorial Sloan Kettering Cancer Center, with coauthors in the presentation.

From November 30, 2020, to August 6, 2024, a systematic literature review was conducted to identify large randomized controlled trials that published efficacy and safety outcomes in the transplant-ineligible newly diagnosed multiple myeloma population. When trials that used both transplant-eligible and transplant-ineligible patients were included, subgroup data for patients who were transplant-eligible were used, if available.

The regimens included in the analysis were endorsed by the American Society of Clinical Oncology/Clinical Care Options, NCCN, European Hematology Association/European Society of Medical Oncology, or European Myeloma Network.

Specifically, the regimens included in the network meta-analysis base case were: cyclophosphamide, thalidomide, and dexamethasone; D plus Rd; DVMP; Isa-VRd; carfilzomib (Kyprolis) plus Rd; melphalan and prednisone; melphalan, prednisone, and thalidomide; Rd; Vd; VMP; and VRd.

A total of 134 records were used for 95 unique studies; 90 were from databases, 43 were from other sources, and 1 was results from the phase 3 CEPHEUS trial (NCT03652064). Of note, 14 randomized controlled trials were included in the final PFS/OS evidence networks, and 14 each reported OS and PFS.

The analyzed outcomes included PFS, OS, and MRD negativity with CR.

Regarding limitations, comparability may have been limited by differences in trial timing, as some regimens reflected outdated clinical practice. Further, some guideline-recommended regimens were excluded from the network due to insufficient connectivity.

Reference

Usmani SV, Facon T, Hungria V, et al. Daratumumab-bortezomib-lenalidomide-dexamethasone vs contemporary treatment alternatives in transplant-ineligible patients with newly diagnosed multiple myeloma: results of a systematic literature review and network meta-analysis. Presented at the Society of Hematologic Oncology 2025 Annual Meeting; September 2-5, 2025; Houston, TX. Poster MM-1193.