Belantamab Mafodotin Plus Vd Significantly Improves PFS in Relapsed/Refractory Multiple Myeloma

Belantamab Mafodotin Plus Vd Significantly Improves PFS in Relapsed/Refractory Multiple Myeloma

Patients with relapsed/refractory multiple myeloma treated with belantamab mafodotin-blmf (Blenrep) plus bortezomib (Velcade) and dexamethasone (BVd) had significant improvements in progression-free survival (PFS) compared with daratumumab (Darzalex) plus bortezomib and dexamethasone (DVd), as demonstrated in findings from the phase 3 DREAMM-7 trial (NCT04246047) that were presented during the 2024 February ASCO Plenary Series.¹

The median PFS with BVd (n = 243) was 36.6 months (95% CI, 28.4-not reached [NR]) vs 13.4 months (95% CI, 11.1-17.5) with DVd (n = 251), translating to a 59% reduction in the risk of disease progression or death (HR, 0.41; 95% CI, 0.31-0.53; P <.00001). The 18-month PFS rates were 69% and 43% with BVd and DVd, respectively. Moreover, PFS was improved across all prespecified subgroups, including patients who were refractory to lenalidomide ([Revlimid] n = 79; HR, 0.37; 95% CI, 0.24-0.56) and those with high-risk cytogenetics (HR, 0.36; 95% CI, 0.22-0.58).

Notably, BVd also doubled the rates of complete response (CR) or better (34.6% vs 17.1% with BVd and DVd, respectively), minimal residual disease (MRD) negativity in those responders (24.7% [95% CI, 19.4%-30.6%] vs 9.6% [95% CI, 6.2%-13.9%]), and median duration of response (DOR; 35.6 months [95% CI, 30.5-NR] vs 17.8 months [95% CI, 13.8-23.6]).

“These results suggest that BVd can potentially be a new standard of care in second-line or later relapsed/refractory multiple myeloma owing to the robust efficacy, manageable safety, and ease of administration,” lead study author Maria-Victoria Mateos, PhD, of the Hospital Universitario de Salamanca, in Spain, said in a presentation of the data.

Belantamab mafodotin is a humanized, afucosylated anti-BCMA monoclonal antibody conjugated to the microtubule inhibitor monomethyl auristatin-F, by a protease-resistant cysteine linker. The agent enhances immune response through antibody-drug conjugate–mediated apoptosis, antibody-dependent cell-mediated toxicity, and antibody-dependent cellular phagocytosis, representing an attractive treatment for patients who relapse on first-line triplet or quadruplet therapy.

In November 2023, the manufacturer of belantamab mafodotin announced that the study met its primary end point of PFS.²

To be eligible for enrollment, patients had to have received at least 1 line of therapy for multiple myeloma and evidence of disease progression during or after their most recent therapy.¹ Patients could not have received prior BCMA-directed therapy or be refractory to or intolerant of daratumumab or bortezomib.

Patients were recruited between May 7, 2020, and June 28, 2021.

Eligible patients were randomly assigned 1:1 to BVd (arm A) or DVd (arm B). In arm A, patients received 2.5 mg/kg of intravenous (IV) belantamab mafodotin every 3 weeks for 8 cycles. In arm B, patients received 16 mg/kg of IV daratumumab every week for the first 3 cycles and then every 3 weeks for the remaining 5 cycles. All patients received bortezomib, which was administered subcutaneously at 1.3 mg/m2 on days 1, 4, 8, and 11 for eight 21-day cycles, and 20 mg of dexamethasone on the day of and day after treatment with bortezomib. Starting in cycle 9, patients received either belantamab mafodotin every 3 weeks or daratumumab every 4 weeks.

Disease assessments were performed every 3 weeks for PFS and every 12 weeks for overall survival (OS).

Treatment was continued until the end of the study, consent withdrawal, disease progression, death, or unacceptable toxicity.

PFS served as the primary end point. Secondary end points included OS, DOR, and MRD, as well as CR rate, objective response rate (ORR), clinical benefit rate, time to response, time to progression, time from randomization to second tumor progression on next-line therapy, adverse effects (AEs), ocular findings, and quality of life (QOL).

Patients were stratified by prior lines of treatment (1 vs 2 or 3 vs ≥4), disease stage per Revised International Staging System criteria (R-ISS; I vs II/III), and prior bortezomib (yes vs no).

The median follow-up was 28.2 months (range, 0.10-40.02), at which time 33% and 20% of patients remained on treatment with belantamab mafodotin and daratumumab, respectively. Within the BVd arm, 66% of patients discontinued treatment due to progressive disease (24%), an AE (19%), physician decision (14%), patient withdrawal (9%), being lost to follow-up (<1%), and protocol-defined criteria being met (<1%). In the DVd arm, 78% of patients discontinued therapy because of progressive disease (59%), an AE (9%), patient withdrawal (5%), physician decision (4%), being lost to follow-up (<1%), and protocol deviation (<1%).

Baseline patient characteristics and prior treatments were well balanced between the arms, Mateos said. In the BVd arm, the median patient age was 65.0 years (range, 34-86). Half of patients were under the age of 65 years; 53% of patients were male and 85% were White. The majority of patients had an ECOG performance status of 0 or 1 (96%), R-ISS stage II disease at screening (53%), standard-risk cytogenetic abnormalities (72%), and no evidence of extramedullary disease (95%). The median time since diagnosis was 4.28 years (range, 0.2-26.0).

Regarding prior therapy in the BVd arm, 90% of patients had received a proteasome inhibitor, most of whom had received bortezomib (86%). Eighty percent of patients had received an immunomodulatory drug in the form of thalidomide (Thalomid; 50%) and lenalidomide (52%). Only 3 patients (1%) had previously received daratumumab and 67% underwent prior autologous stem cell transplant. Notably, 12% of patients in this arm had received at least 4 prior lines of therapy; 36% received 2 or 3 prior lines.

Additional results from the trial demonstrated that OS data, although not yet mature and not reached in either arm, showed a clinically meaningful trend in favor of the BVd arm (HR, 0.57; 95% CI, 0.40-0.80; P =.00049). The 12- and 18-month OS rates with BVd were 87% and 84%, respectively, vs 81% and 73% with DVd.

Regarding responses in the BVd arm, the ORR was 82.7% (95% CI, 77.4%-87.3%), which included a stringent CR rate of 14%, CR rate of 20.6%, very good partial response (VGPR) rate of 31.3%, and a partial response (PR) rate of 16.9%. With DVd, the ORR was 71.3% (95% CI, 65.3%-76.8%), which included a stringent CR rate of 5.2%, CR rate of 12%, VGPR rate of 29.1%, and a PR rate of 25.1%. The likelihood of remaining in response at 18 months was 76% with BVd vs 49% with DVd. At the data cutoff, 53% of patients in the BVd arm remained in response vs 29% of those in the DVd arm.

Among patients who achieved VGPR or better, the rates of MRD negativity were 38.7% (95% CI, 32.5%-45.1%) and 17.1% (95% CI, 12.7%-22.4%) with BVd and DVd, respectively.

In terms of safety, all patients experienced an AE; grade 3/4 AEs occurred in 95% of patients on BVd vs 76% of those on DVd. However, the exposure-adjusted events/person-years was 68.8% vs 62.4% with BVd and DVd, respectively.

Blood and lymphatic system disorders occurred in 76% of patients in the BVd arm (grade ≥3, 62%) vs 64% in the DVd arm (grade ≥3, 44%). Infections and infestations occurred in 70% (grade ≥3, 31%) and 67% (grade ≥3, 20%) of patients, respectively.

In the BVd arm, ocular AEs of special interest included blurred vision (all grade, 66%; grade ≥3, 22%), dry eye (all grade, 51%; grade ≥3, 7%), eye irritation (all grade, 43%; grade ≥3, 5%), and visual impairment (all grade, 11%; grade ≥3, 5%).

The median time to onset of first blurred vision, which was defined as 20/50 vision, was 73.5 days (range, 16-753), and the median duration of the first event was 22 days (range, 6-257). Most events (98%) resolved to grade 1 or baseline visual acuity. For visual impairment (20/200), the median time to the first event was 105 days (range, 47-304), and the median duration was 19 days (range, 8-26)––all events resolved.

A total of 44% of patients had dose reductions, 78% had dose delays or interruptions, and 9% discontinued therapy because of an ocular event.

“The safety and tolerability of the BVd regimen was consistent with the known safety profile of the individual agents,” Mateos said. “Eye-related AEs, a known risk of belantamab mafodotin, were generally reversible, were manageable with dose modification, and led to low treatment discontinuations.”

Moreover, no difference was seen between arms over time in global QOL as quantified by the EORTC QLQ-C30 scale.

“The DREAMM-7 trial results are compelling and support the clinical efficacy of belantamab mafodotin for patients with relapsed/refractory multiple myeloma,” discussant Rachid Baz, MD, of Moffitt Cancer Center in Tampa, said. “While this data comes in a crowded field of BCMA-directed therapies, treatment considerations include efficacy, tolerability, and access to care.”

Results from the study also open a potential path forward for the agent’s development following its withdrawal from the United States market in patients with relapsed/refractory disease who have received at least 4 lines of therapy in November 22, 2022.³

References

1. Mateos MV, Robak P, Hus M, et al. Results from the randomized phase III DREAMM-7 study of belantamab mafodotin (belamaf) + bortezomib, and dexamethasone (BVd) vs daratumumab, bortezomib, and dexamethasone (DVd) in relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2024;42(suppl 36):439572. doi:10.1200/JCO.2024.42.36_suppl.439572
2. GSK announces positive results from DREAMM-7 head-to-head phase III trial for Blenrep in relapsed/refractory multiple myeloma. News release. GSK. November 27, 2023. Accessed February 6, 2024. https://www.gsk.com/en-gb/media/press-releases/gsk-announces-positive-results-from-dreamm-7-head-to-head-phase-iii-trial-for-blenrep/
3. GSK provides an update on Blenrep (belantamab mafodotin-blmf) US marketing authorization. News release. GSK. November 22, 2022. Accessed February 6, 2024. https://us.gsk.com/en-us/media/press-releases/gsk-provides-an-update-on-blenrep-belantamab-mafodotin-blmf-us-marketing-authorization/