Anti-BCMA-Based Regimen Impresses in Relapsed/Refractory Myeloma

Combination treatment with belantamab mafodotin (belamaf; Blenrep) plus lenalidomide (Revlimid) and dexamethasone appeared effective for relapsed or refractory multiple myeloma, and had a tolerable safety profile, according to results from an arm of the DREAMM-6 study.

Responses were seen in 60% of the 45 patients treated with four different dosing schedules of belamaf -- an anti-B-cell maturation antigen (BCMA) monoclonal antibody -- plus lenalidomide-dexamethasone, reported Sagar Lonial, MD, of the Winship Cancer Institute of Emory University in Atlanta.

The regimen was "certainly doable," said Lonial at the Society of Hematologic Oncology annual meeting. "We saw enhanced response rates over what you would expect."

"More importantly, we did see changes in the safety profile," he added. For example, grade 2/3 blurred vision was more common in patients who were in the higher-dose belamaf cohorts (2.5 mg/kg) compared with the lower-dose cohorts (1.9 mg/kg).

"The real question," Lonial continued, "is how do you marry efficacy with safety to really come up with the optimal dose and schedule of belamaf in combination with [lenalidomide plus dexamethasone]. I think it may be different with each agent we are partnering with belamaf, but certainly these kinds of studies need to be undertaken to understand where that risk-benefit ratio can be maximized."

Lonial, who was not involved in the study, presented the results on behalf of Hang Quach, MD, of the University of Melbourne in Australia.

In the pivotal phase II DREAMM-2 study, for which Lonial was a co-investigator, single-agent belamaf given at 2.5 mg/kg every 3 weeks demonstrated deep and durable responses for patients with relapsed or refractory multiple myeloma, with an overall response rate (ORR) of 32%, median duration of response of 11.0 months, and median overall survival of 13.7 months. The trial led to the drug's accelerated approval.

DREAMM-6 investigators noted that preclinical data showed synergy between belamaf and lenalidomide, suggesting that there could be an added benefit by combining belamaf with standard of care therapies such as lenalidomide-dexamethasone.

Thus, this arm of DREAMM-6, which is a a two-part, two-arm, open-label, dose and evaluation study, was designed to assess belamaf plus lenalidomide-dexamethasone in patients with relapsed or refractory multiple myeloma at various dosing schedules.

Patients were eligible for the study if they had an ECOG performance status of 0-2, had undergone stem cell transplantation if eligible, and had previously received at least one line of therapy. The 45 patients (median age 68 years, 78% of whom were men) were treated according to four dosing schedules:

• Belamaf 1.9 mg/kg plus lenalidomide-dexamethasone every 8 weeks

• Belamaf 1.9 mg/kg plus lenalidomide-dexamethasone every 4 weeks

• Belamaf 2.5 mg/kg plus lenalidomide-dexamethasone every 4 weeks

• Belamaf 2.5 mg/kg plus lenalidomide-dexamethasone every 4 weeks, with belamaf given as two 50% doses and delivered on days 1 and 8 (split-dose group)

In the lower-dose groups, the ORR was 42% among 12 patients receiving the regimen every 8 weeks, including two very good partial responses (VGPRs). Among the four patients treated every 4 weeks, three patients responded, including one VGPR and one stringent complete response (CR); this group had a median duration of response of 11.1 months and median progression-free survival (PFS) of 8.6 months.

In the higher-dose groups, the ORR was 63% for the 16 patients receiving the regimen as a single dose every 4 weeks, including two VGPRs, four CRs, and two stringent CRs. For the 13 patients receiving the split-dose every-4-week regimen, the ORR was 69%, and included three VGPRs, one CR, and one stringent CR; this group had a median PFS of 9.0 months.

Unless noted, median durations of response and PFS were not reached in the other cohorts.

Grade ≥3 treatment-related adverse events occurred in 42-85% of patients. Grade ≥3 keratopathy occurred in fewer patients in the lower-dose cohorts (one of 16 patients total), as compared with 46-50% of patients in the higher-dose cohorts.

"We've seen this data now, not just for the combination with lenalidomide but the combination with pomalidomide (Pomalyst), and the combination with the GSI [gamma-secretase inhibitor] nirogacestat," Lonial observed. "You can actually give lower doses or less frequent administration of belamaf, and perhaps get equivalent or superior response rates, and at the same time reduce the incidence of grade 3 or 4 keratopathy or ocular toxicities."

"You see some of that here," he added. "Visual acuity, in terms of reduction, is really a very important safety measure to keep in mind, because the benefit of combination therapy is that you perhaps don't have to go full dose with each agent."

Lonial noted that spreading out the dosing, "which we know from our own experience with belamaf as a single agent in refractory myeloma, can be quite effective for patients."

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