Deep responses and durable outcomes in patients treated with belantamab mafodotin plus pomalidomide and dexamethasone from long-term follow-up of the Phase 3 dreamm-8 study

Abstract Introduction: Triplet or quadruplet regimens, combining proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies, are standard of care for newly diagnosed multiple myeloma (MM); however, most patients (pts) eventually experience relapse. At first relapse, there remains a lack of effective treatment options that have durable outcomes and are accessible for all pts, particularly those who have been exposed to or have disease refractory to lenalidomide and/or anti-CD38 monoclonal antibodies. In the phase 3 DREAMM-8 trial (NCT04484623) in pts with relapsed/refractory MM (RRMM) who had received ≥1 prior line of treatment including lenalidomide, belantamab mafodotin in combination with pomalidomide and dexamethasone (BPd) significantly improved progression-free survival (PFS; median follow-up, 21.8 months; hazard ratio [HR], 0.52; 95% CI, 0.37-0.73; P<0.001) vs pomalidomide, bortezomib, and dexamethasone (PVd), a standard of care in this population. Here, we report long-term follow-up from the DREAMM-8 trial to better characterize the durability of BPd treatment benefit. Methods: As previously reported, pts who had received ≥1 prior line of therapy including lenalidomide were randomized 1:1 to receive BPd or PVd. Treatment continued until progressive disease, unacceptable toxicity, withdrawal of consent, or death, whichever occurred first. Efficacy assessments occurred every 4 weeks in the intention-to-treat population. The primary endpoint was PFS; secondary endpoints included overall survival, independent review committee–assessed response rates, minimal residual disease (MRD)–negative status, duration of response (DOR), PFS2 (ie, time from randomization to disease progression or death from any cause after initiation of new antimyeloma therapy), and safety. Results: Overall, 302 pts were randomized to receive BPd (n=155) or PVd (n=147). At the data cutoff (July 7, 2025), median follow-up was 35.8 months (range, 0.03-56.5 months). Median PFS (95% CI) with BPd vs PVd was 32.6 months (21.1 months-not reached [NR]) vs 12.5 months (9.1-17.6 months), respectively (HR, 0.49; 95% CI, 0.36-0.67). BPd led to a substantial benefit in response depth, with a complete response or better (≥ CR) reported in 43% (67/155) of pts receiving BPd vs 17% (25/147) receiving PVd. Moreover, pts treated with BPd achieved ≥ CR MRD negativity at almost 5 times the rate observed in those receiving PVd (28% [43/155] vs 6% [9/147]). MRD negativity was durable, with 15% (24/155) of pts in the BPd arm having ≥ CR MRD negativity sustained for ≥12 months, compared with 3% (4/147) in the PVd arm. Consistent with the reported depth of response, responses with BPd were durable, with a median DOR (partial response or better; 95% CI) that was NR (29.5 months-NR) with BPd vs 16.4 months (11.1-22.5 months) with PVd; the proportion of pts with a 24-month DOR was 65% (95% CI, 55%-73%) vs 40% (95% CI, 29%-50%), respectively. PFS benefit was maintained following subsequent antimyeloma therapy, with a median PFS2 (95% CI) of 47.1 months (28.4 months-NR) in pts receiving BPd vs 21.7 months (13.8-28.6 months) in those receiving PVd (HR, 0.52; 95% CI, 0.38-0.70). Follow-up for overall survival is ongoing. Overall, grade 3/4 adverse events (AEs) and fatal serious AEs were experienced by 91% (136/150) and 14% (21/150) of pts in the BPd arm, respectively, compared with 74% (108/145) and 13% (19/145) of pts in the PVd arm; AEs leading to permanent discontinuation of any treatment component occurred in 22% (33/150) of pts receiving BPd vs 14% (21/145) receiving PVd. Conclusions: After extended follow-up of the DREAMM-8 trial,BPd led to a substantial increase in response depth and durability vs PVd in a population of pts with RRMM, most of whom had lenalidomide-refractory disease and a quarter of whom had disease refractory to anti-CD38 monoclonal antibodies. The updated safety profile of BPd was broadly consistent with the primary analysis. BPd resulted in a median PFS of >30 months and a maintained PFS benefit following subsequent antimyeloma therapy; as a combination that can be easily administered in the outpatient setting, these results support BPd as a potential new standard of care in RRMM. Funding statement: GSK (study ID 207499).Drug-linker technology licensed from Seagen Inc; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa.