Belantamab mafodotin versus pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma

The pomalidomide plus dexamethasone (Pd) doublet is an established treatment regimen for patients with relapsed/refractory multiple myeloma. The DREAMM-3 trial investigated the efficacy and safety of the antibody-drug conjugate belantamab mafodotin (belamaf) as an alternative to this regimen. Although belamaf did not demonstrate progression-free survival (PFS) superiority when compared to Pd, patients receiving belamaf monotherapy displayed a longer median PFS with deeper and more durable responses and an overall good tolerability.

The combination of the immunomodulatory agent pomalidomide with low-dose dexamethasone (Pd) is approved for patients with relapsed/refractory multiple myeloma (RRMM). Belantamab mafodotin (belamaf) is a first-in-class humanised antibody-drug conjugate (ADC) that targets plasma cells that express the B-cell maturation antigen (BCMA), effectively triggering cell death through direct cell killing and immune-mediated mechanisms. In this context, the phase III DREAMM-3 trial aimed to compare the efficacy and safety of belamaf monotherapy compared with the standard of care Pd regimen in adult patients with RRMM at second relapse or later, providing valuable insights into the potential of belamaf as an alternative treatment option for these patients.

Study design

The phase III DREAMM-3 study enrolled RRMM patients who had received two or more previous therapies, including lenalidomide and a proteasome inhibitor. In total, 325 patients were randomly assigned (2:1) to receive belamaf 2.5 mg/kg every 3 weeks (21-day cycle) (N= 214), or Pd on standard dosing, i.e., pomalidomide 4 mg orally daily on days 1-21 of each 28-day cycle and dexamethasone, 40 mg orally (20 mg if >75 years old) weekly (N= 106), until progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), while overall survival (OS) was the secondary endpoint.

Results

After a median follow-up of 11.5 and 10.8 months in the belamaf and Pd arms, respectively, the median PFS was numerically longer in those patients receiving belamaf (11.2 vs. 7.0 months), but no statistically significant difference was obtained (HR[95%CI]: 1.03[0.72-1.48]; p= 0.558). Of note, this study was initially designed with the assumption that the HR for PFS would remain constant over time, and that the Kaplan-Meier (KM) curves would not intersect. However, the belamaf KM curve showed a more pronounced initial drop compared to Pd but, over time, the belamaf curve stabilised while the Pd curve continued to decline. This resulted in the crossing of the curves at approximately four months, contributing to the non-significant PFS HR. Overall response rate was similar between the two treatment groups (41% in the belamaf group vs. 36% in the Pd group). However, a higher percentage of very good partial response (VGPR) was achieved with belamaf (25% vs. 8%). Notably, minimal residual disease negativity was only observed in patients treated with belamaf (7% vs. 0%). Belamaf also exhibited a longer duration of response (not reached vs. 8.5 months), with a clear separation of the KM curves from the beginning. At 18 months, 63% of patients who responded to belamaf remained free from disease progression, compared to 50% in the Pd group. Additionally, the median PFS2 was also longer for belamaf compared to Pd (18.7 vs. 12.7 months), indicating that previous treatment with belamaf did not lead to worse outcomes in subsequent lines of therapy. At the time of the primary analysis, OS data had only achieved 37.5% overall maturity. Median OS was 21.2 and 21.1 months for belamaf and Pd, respectively, with an HR of 1.14.

The incidence of adverse events (AEs) was equally distributed between the two arms. Fatal serious AEs occurred in 7% vs. 11% of patients in the belamaf and Pd groups, respectively, while AEs leading to dose interruption or delay occurred in 61% vs. 51% of patients. Severe neutropenia and infections were more common with Pd, while severe thrombocytopenia was more common with belamaf. Severe decreases in visual acuity were infrequent and resolved upon follow-up, and ocular AEs were predominantly mild or moderate. Regarding the impact on quality of life (QoL), over 70% of patients in both treatment arms reported being "not bothered at all" or only "a little bothered" by the side effects of treatment, and the global health status showed a trend towards improvement at later time points. Remarkably, there was a trend for improved fatigue scores in the belamaf arm compared to Pd.

Conclusions

In conclusion, while the study did not meet its primary objective of demonstrating PFS superiority, single-agent belamaf appeared to show similar levels of clinical activity as Pd in RRMM. Patients receiving belamaf monotherapy displayed a longer median PFS compared to those receiving Pd, as well as deeper and more durable responses. Additionally, belamaf demonstrated good tolerability and had a positive impact on patients' QoL. Ongoing studies are investigating belamaf in combination regimens and exploring its efficacy in earlier lines of therapy.

Reference

Dimopoulus MA. Hungria V, Radinoff A, et al. A phase 3, open-label, randomized study evaluating the efficacy and safety of single agent belantamab mafodotin vs pomalidomide plus dexamethasone in relapsed/refractory multiple myeloma (DREAMM-3). Presented at EHA 2023; Abstract S199.