Treatment with mezigdomide (Mezi) plus carfilzomib and dexamethasone (Kd) significantly improves progression-free survival (PFS) in patients with relapsed or refractory multiple myeloma (RRMM) compared with Kd regimen only, according to the phase III SUCCESSOR-2 trial presented at EHA 2026.
“Kd is a widely adopted standard of care in RRMM and is one of the most frequently used regimens in patients with prior anti-CD38 monoclonal antibody (mAb) and lenalidomide exposure, whereas Mezi has shown promising activity in patients with RRMM, including those with triple-class exposure and extramedullary disease,” said Prof Meletios Dimopoulos from the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens, Athens, Greece.
Stage 2 of the SUCCESSOR-2 trial evaluated 371 patients with RRMM who had received ≥1 prior line of therapy (LOT), including anti‑CD38 mAb and lenalidomide. The participants were randomized 3:2 to receive MeziKd* (n=225) or Kd alone (n=146).
At a median follow-up of 10.6 months, patients who received MeziKd had a significantly longer median PFS than those on Kd only (18 vs 8.3 months), which corresponded to a 52-percent reduction in the risk of disease progression or death (hazard ratio [HR], 0.48; p<0.0001). [EHA 2025, abstract LB5004]
The PFS benefit observed with the combination regimen over Kd alone was consistent across all prespecified subgroups, particularly among patients with ≤2 LOTs (HR, 0.54), high-risk cytogenetics (HR, 0.49), and extramedullary plasmacytomas (HR, 0.33), as well as those aged ≥75 years (HR, 0.52) and refractory to both anti-CD38 mAbs and lenalidomide (HR, 0.51).
Additional endpoints
In terms of treatment response, patients treated with MeziKd achieved a higher objective response rate (80.2 percent vs 53.4 percent) than those treated with Kd alone, as did the rates of very good partial response (VGPR; 60.1 percent vs 30.9 percent) and complete response (26.7 percent vs 8.9 percent).
“The addition of Mezi to the Kd regimen deepened the response, doubling the rate of VGPR and tripling the rate of complete response,” Dimopoulos noted.
The investigator-assessed PFS2 also favoured MeziKd over Kd alone, with a median PFS of 23.6 vs 13 months (HR, 0. 53), indicating a “sustained clinical benefit beyond first progression,” said Dimopoulos.
In addition, fewer patients on the combination regimen received any subsequent treatment than those on Kd alone (24 percent vs 49.7 percent).
Although the overall survival data were still immature at the time of analysis, a trend towards OS improvement with MeziKd vs Kd alone was observed (HR, 0.79).
Safety
Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 83.7 percent of patients receiving MeziKd compared with 56.5 percent of those receiving Kd alone.
The most common grade 3/4 TEAE was neutropenia with MeziKd (61.1 percent), but it was effectively managed through dose interruptions or modifications and/or G-CSF**, as noted by Dimopoulos.
“The safety profile of MeziKd was consistent with that of previous Mezi studies, with no new safety signals,” he added.
New standard of care
Dimopoulos highlighted that anti-CD38 mAb- and lenalidomide-exposed RRMM patients with ≥1 prior LOT enrolled in this trial represent a growing population with poor outcomes and few validated treatment options.
“MeziKd showed a clinically meaningful PFS benefit as early as first relapse in this patient population, and these data support Mezi, a potent oral treatment with a predictable and manageable safety profile, as a readily accessible, potential new standard of care for RRMM across multiple settings,” he concluded.