Belantamab Mafodotin–Based PFS Benefits in Difficult-to-Treat R/R Myeloma Subgroups

María-Victoria Mateos, MD, PhD

The combination of belantamab mafodotin-blmf (Blenrep) in combination with bortezomib (Velcade) and dexamethasone could represent a new treatment option after first relapse for patients with relapsed/refractory multiple myeloma, including difficult-to-treat populations such as patients refractory to lenalidomide (Revlimid) and those with high-risk cytogenetics, according to María-Victoria Mateos, MD, PhD.

Findings from subgroup analyses of the phase 3 DREAMM-7 trial (NCT04246047) presented at the 2024 ASCO Annual Meeting showed that in patients who were refractory lenalidomide, the median progression-free survival (PFS) was 25.0 months (95% CI, 18.1–not reached [NR]) in the belantamab mafodotin arm (n = 79) compared with 8.6 months (95% CI, 6.4-13.5) in patients treated with daratumumab (Darzalex) plus bortezomib and dexamethasone (DVd; n = 87; HR, 0.31; 95% CI, 0.19-0.48). In patients with high-risk cytogenetics, the median PFS was 33.2 months (95% CI, 20.3-NR) in the belantamab mafodotin arm (n = 87) vs 10.5 months (95% CI, 7.6-13.4) in the DVd arm (n = 89; HR, 0.31; 95% CI, 0.18-0.52).¹

“[These data] are the reason why today I see a more clear role for this [belantamab mafodotin] combination in the patients coming from treatment with daratumumab, lenalidomide, and dexamethasone. The general population refractory to lenalidomide will also be a choice to select for this [belantamab mafodotin] combination,” Mateos said in an interview with OncLive®.

In the interview, Mateos, a hematologist/oncologist, associate professor of medicine, and director of the Myeloma Program and Clinical Trials Unit in the University of Salamanca Hospital in Spain, discussed data from the subgroup analyses presented at the 2024 ASCO Annual Meeting, expanded on prior data presented from the study, and detailed the potential implications for this belantamab mafodotin–based combination.

OncLive: What unmet needs exist for patients with relapsed/refractory multiple myeloma did DREAMM-7 aim to address?

Mateos: Multiple myeloma is a complex disease, and the treatment landscape is rapidly evolving. Today, the vast majority of [patients with] newly diagnosed myeloma are being treated with proteasome inhibitors—such as bortezomib—immunomodulatory drugs—such as lenalidomide—dexamethasone, and an anti-CD38 monoclonal antibody—basically daratumumab. This means that at the moment of the first relapse and subsequent relapses, the majority of patients are going to be triple-class exposed. This is the most relevant unmet that we have after the first relapse, and this highlights the need we have for novel drugs and novel compounds with a different mechanism of action.

This is the rationale for the incorporation of belantamab mafodotin to this space. Belantamab mafodotin is BCMA-targeted antibody-drug conjugate with monomethyl auristatin F [MMAF]. This represents a monoclonal antibody targeting something different from CD38. BCMA is highly expressed on the surface of the plasma cells in a specific way. This means that we are going to see on-target events but very few or no off-target events, and because of the mechanism of action, the release of the cytotoxic agent and MMAF result in the apoptosis of the plasma cells.
In addition, belantamab mafodotin maintains antibody-dependent cell cytotoxicity and [induces] immunogenic cell death. Immunogenic cell death is a sign [for combining balantamab mafodotin] with the proteasome inhibitor bortezomib, and this is the rationale for the experimental arm in the DREAMM-7 study of belantamab mafodotin in combination with bortezomib and dexamethasone.

What were some of the key findings from DREAMM-7 that were previously presented, and what data from subgroup analyses were presented at the 2024 ASCO Annual Meeting?

DREAMM-7 is a phase 3 clinical study in which belantamab mafodotin in combination with bortezomib and dexamethasone has been compared with a standard-of-care DVd in [patients with] relapsed/refractory multiple myeloma after at least 1 prior line of therapy. The treatment is scheduled with 8 induction cycles with belantamab mafodotin plus bortezomib and dexamethasone, followed by single-agent belantamab mafodotin, or DVd for 8 cycles, followed by daratumumab monotherapy.

The primary end point of the clinical study was a PFS, and after a medium follow-up of 28.2 months [range, 0.1-40.0], belantamab mafodotin in combination with bortezomib and dexamethasone resulted in a statistically significant and clinically meaningful [PFS] benefit in comparison with DVd [HR, 0.41; 95% CI, 0.31-0.53; P < .00001]. The median PFS was 36.6 months [(95% CI, 28.4-NR) for patients treated with belantamab mafodotin plus bortezomib and dexamethasone (n = 243) vs 13.4 months [(95% CI, 11.1-17.5) for those given DVd (n = 251)].²

This PFS superiority was sustained across a prespecified subgroup of patients, highlighting some challenging subgroups of patients, such as those patients with disease refractory to lenalidomide, which we know is a challenging population [to treat]. The benefit has been sustained in this group of patients with a median PFS of 25 months [95% CI, 18.1-NR] for the experimental arm [n = 79] vs 8.6 months [95% CI, 6.4-13.5] in the control arm [n = 87; HR, 0.31; 95% CI, 0.19-0.48].

[The PFS benefit was] also [observed] in patients with high-risk genetic abnormalities. This is also a challenging population [to treat], and the benefit for the belantamab mafodotin [regimen (n = 67)] was also sustained with a median PFS of [33.2 months (95% CI, 20.3-NR), which [was similar to the] median PFS of 36.6 months [95% CI, 28.4-NR] observed [with the belantamab mafodotin regimen] in the standard-risk population [n = 175], indicating that this combination is able to overcome the poor prognosis [for those with] the presence of these high-risk cytogenetic abnormalities.

[Although] PFS was the primary end point and in spite of the follow-up being quite short, there was an early but strong trend toward a benefit in overall survival [in the intention-to-treat population]. The evaluation of the overall response rate [ORR] and the complete response [CR] or better rate were superior for belantamab mafodotin plus bortezomib and dexamethasone. The CR or better rate was a 34.6% [95% CI, 28.6%-40.9%] for belantamab mafodotin plus bortezomib and dexamethasone vs 17.1% [95% CI, 12.7%-22.4%] for DVd.

It's important to highlight the superiority in terms of a minimal residual disease [MRD] negativity rate. [MRD] is maybe the most powerful prognostic factor we have right now in multiple myeloma, and the MRD negativity rate in the ITT population in CR or better was 24.7% [95% CI, 19.4%-30.6%] for belantamab mafodotin plus bortezomib plus dexamethasone [vs 9.6% (95% CI, 6.2%-13.9%) for DVd].

Were there any updated safety findings presented at the 2024 ASCO Annual Meeting?

The safety profile is very important. Overall, [treatment with] belantamab mafodotin plus bortezomib and dexamethasone resulted in a higher incidence of hematological and non-hematological adverse effects [AEs] numerically; however, when [these rates] were adjusted for the time of [treatment] exposure, the difference was not so evident.

Thrombocytopenia was the most frequent [grade 3 or higher] hematological AE observed in both the belantamab mafodotin arm [55%] and the DVd arm [35%]. Anemia, by contrast, was more frequent in the DVd arm. Infection [rates] were quite compatible, although the rate of grade 3/4 infections was slightly higher in the belantamab mafodotin arm vs the DVd arm.

However, maybe the most relevant and the most important AE is ocular toxicity. This ocular toxicity is in clear relation with the mechanism of action of belantamab mafodotin. To evaluate ocular toxicity [in DREAMM-7], baseline, visual acuity was evaluated in all patients via a Snellen scale. If we select all patients in whom the visual acuity was normal [at baseline]—meaning that it was a 20/25 or better—[66%] of the patients [in the belantamab mafodotin arm] experienced a worsening in the visual acuity to 20/50. This means that these patients [experienced] only blurred vision. When we evaluated how many patients experienced [a worsening in] visual acuity 20/200, which means that the vision is impaired. This occurred in [11%] of the patients [in the experimental arm]. It is important is the vast majority of patients experienced resolved ocular keratopathy through dose modifications and dose delays.

Finally, only 9% of the patients needed to discontinue [belantamab mafodotin] because of ocular toxicity.

What are the clinical implications of this DREAMM-7 subgroup analyses?

The most important clinical implication is the [prevelance of the] triple-class exposed population is going to be a reality in the near future in our clinical practice. The possibility of having belantamab mafodotin— a BCMA-directed ADC—in combination with bortezomib and dexamethasone will represent something in order to cover the unmet medical need that we have in this population.

Today, in newly diagnosed myeloma, for example, the transplant-ineligible patients represent approximately 60% of the newly diagnosed myeloma population, are being treated right now with daratumumab in combination with lenalidomide and dexamethasone as continuous therapy. This means that patients at the moment of the relapse are going to be refractory to daratumumab and lenalidomide, but naive for a proteasome inhibitor. Therefore, belantamab mafodotin in combination with bortezomib and dexamethasone could represent a choice for this population.

In the transplant-eligible population, [the belantamab mafodotin regimen] will be another possibility, but the newly diagnosed, transplant-eligible population is currently receiving triple-drug–based combinations with anti-CD38 monoclonal antibodies, then transplant and maintenance with lenalidomide. Therefore, the vast majority of these patients are going to be refractory to lenalidomide, but maybe these patients could be treated again with an anti-CD38 monoclonal antibody.

References

1. Mateos M-V, Robak P, Hus M, et al. DREAMM-7 update: subgroup analyses from a phase 3 trial 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 16):7503. doi:10.1200/JCO.2024.42.16_suppl.7503
2. Hungria V, Robak P, Hus M, et al. Belantamab mafodotin, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. Published online June 1, 2024. doi:10.1056/nejmoa2405090