Belantamab Mafodotin Quadruplet Shows Promise in Myeloma

Shebli Atrash, MD, MS, FACP

Belantamab mafodotin-blmf (Blenrep) in combination with carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) was linked with a manageable safety profile, including manageable keratopathy, and early evidence of deep responses in patients with multiple myeloma who had received 1 prior line of therapy, according to findings from a phase 1 trial (NCT04822337) presented at the 21st International Myeloma Society Annual Meeting.¹

Investigators determined the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of belantamab mafodotin in this regimen to be 1.9 mg/kg every 8 weeks.

The most common gastrointestinal (GI) adverse effects (AEs) seen with the combination across all treated patients (n = 19) included diarrhea (grade 1, 31.6%; grade 2, 15.8%), constipation (21.1%; 5.3%), vomiting (10.5%; 15.8%), nausea (10.5%; 21.1%), dysgeusia (5.3%; 5.3%), oral mucositis (5.3%; 5.3%), and anorexia (0%; 15.8%). No grade 3 or higher GI AEs were reported. Grade 3 and 4 hematological and infectious AEs included decreased platelet counts (grade 3, 5.3%; grade 4, 21.2%), decreased neutrophil counts (21.1%; not available [NA]), and all infections (15.8%; NA). Grade 1, 2, and 3 keratopathy was observed in 21.1%, 42.1%, and 31.6% of patients, respectively.

“Eye toxicity was reversible in all cases,” Shebli Atrash, MD, MS, FACP, said in the presentation. “It seems that the duration [of eye toxicities] was less than the previously seen eye toxicity in [the phase 2] DREAMM-2 [trial (NCT03525678)] …It’s important to note that [the rate of infections] sets this regimen apart from other BCMA-targeted approaches, including CAR T[-cell therapy] and bispecific [antibodies], given lower infection risks [with those agents].”

Atrash is a hematologist at the Atrium Health Levine Cancer Institute in Charlotte, North Caroline, as well as a clinical associate professor of hematology and oncology at the Wake Forest University School of Medicine in Winston-Salem.

Rationale for Investigating Belantamab Mafodotin-Based Quadruplets in Myeloma

Prior research has shown the feasibility of quadruplet regimens containing KRd plus transplant in patients with transplant-eligible, newly diagnosed multiple myeloma. For instance, in the phase 2 FORTE trial (NCT02203643), KRd in combination with autologous stem cell transplant (ASCT; n = 315) elicited at least a very good partial response (VGPR) after induction in 70% of patients vs 53% of patients who received carfilzomib plus cyclophosphamide and dexamethsone plus ASCT (odds ratio [OR], 2.14; 95% CI, 1.44-3.19; P = .0002).²

Furthermore, in the phase 3 IsKia trial (NCT04483739), rates of minimal residual disease (MRD) negativity at a sensitivity of 10–6 improved over time throughout all trial phases in patients who received Isa-KRd (n = 151) vs those who received KRd alone (n = 151).³ The post-induction, post-ASCT, and post-consolidation MRD-negativity rates in the Isa-KRd arm were 27%, 52%, and 67%, respectively. These respective rates were 14% (OR, 2.36; P = .004), 27% (OR, 3.01; P < .001), and 48% (OR, 2.29; P < .001) in the KRd alone arm.

“All those results make us ask the question: Can we improve on the triplet regimen further?” Atrash asked.

Studies have also shown the efficacy of belantamab mafodotin in patients with relapsed/refractory multiple myeloma. In DREAMM-2, efficacy-evaluable patients who received the agent at 2.5 mg/kg (n = 97) achieved a median duration of response (DOR) of 11 months and an overall response rate (ORR) of 31% (97.5% CI, 20.8%-42.6%).⁴ Moreover, in the phase 3 DREAMM-7 trial (NCT04246047), belantamab mafodotin plus bortezomib (Velcade) and dexamethasone improved progression-free survival (PFS; HR, 0.41; 95% CI, 0.31-0.53; P < .001) and OS vs daratumumab (Darzalex) plus bortezomib and dexamethasone in patients with multiple myeloma who had progressed on at least 1 prior line of therapy.⁵

“Those results support the use of a quadruplet regimen with KRd with the addition of belantamab mafodotin,” Atrash noted.¹

Although DREAMM-2 showed that belantamab mafodotin is effective when administered every 3 weeks, the trial also demonstrated that the agent is associated with keratopathy, with similar rates of this AE observed regardless of the dose level.⁴ Among safety-evaluable patients who received the agent at 2.5 mg/kg (n = 95), grade 3 keratopathy or changes to the corneal epithelium was observed was observed in 27% of patients. Among safety-evaluable patients who received the agent at 3.4 mg/kg (n = 99), grade 3 keratopathy or changes to the corneal epithelium was observed was reported in 21% of patients.

“The rates of blurred vision and dry eye improved with lower doses of belantamab mafodotin, suggesting better tolerability with lower doses,” Atrash said.¹

Design of the Phase 1 Trial

Multiple myeloma cells: © David A Litman - stock.adobe.comMultiple myeloma cells: © David A Litman - stock.adobe.com

This phase 1 study of belantamab mafodotin plus KRd enrolled patients with relapsed/refractory multiple myeloma who had received at least 1 prior line of therapy and had measurable disease. Patients needed to have an ECOG performance status of 0 to 2; an ANC of at least 1.5 x 103/mm3 if their marrow burden was less than 50% or an absolute neutrophil count (ANC) of at least 1.0 x 103/mm3 if their marrow burden was higher than 50%; a platelet count of at least 100,000 cells/mm3; total bilirubin levels at or below 1.5 times the upper limit of normal (ULN); aspartate aminotransferase and alanine aminotransferase levels at or below 2.5 times the ULN; creatinine clearance levels of at least 30 mL/min; and a left ventricular ejection fraction higher than 40%.

This phase 1 study included a 3+3 dose-escalation portion followed by a dose-expansion cohort to identify the RP2D. The primary objective was to establish the MTD of belantamab mafodotin. Key secondary objectives included ORR, depth of response, DOR, PFS, OS, and safety.

Patients received belantamab mafodotin plus KRd for a maximum of 18 cycles, followed by lenalidomide maintenance. Patients remained on treatment until disease progression or toxicity. Intravenous (IV) belantamab mafodotin was tested at 2 doses: 1.4 mg/kg or 1.9 mg/kg each over 30 to 60 minutes every 8 weeks. A backbone regimen of KRd was administered in 28-day cycles and consisted of IV carfilzomib at 20 or 56 mg/m2 on days 1, 8, and 15; oral lenalidomide at 25 mg on days 1 through 21; and oral dexamethasone at 20 or 40 mg weekly.

During the dose-escalation portion, 3 patients received belantamab mafodotin at 1.4 mg/kg. One DLT of grade 4 thrombocytopenia was observed at this dose level.

“It’s important to note that the patient remained on the study and achieved MRD negativity later on,” Atrash added.

Three more patients were enrolled at the dose level of 1.4 mg/kg. No additional DLTs were observed at this dose level, and the dose was escalated in 3 additional patients to 1.9 mg/kg. No DLTs were observed at this dose level, and 3 more patients were enrolled at the 1.9-mg/kg dose level to identify the MTD. Investigators did not observe any DLTs at the 1.9-mg/kg dose level, and this was identified as the MTD.

Notably, patients had received a median of 1 prior line of therapy (range, 1-3), and 42.1% of patients were Black. International Staging System information was available for 15 patients, 40%, 26.7%, and 33.3% of whom had stage I, II, and III disease, respectively. High-risk cytogenetics were observed in 47.3% of patients, and included 1q gain and 1p deletion (5.3%), 17 deletion (10.5%), and 1q gain (36%). Among all patients, 42.1% were refractory to lenalidomide, 10.5% were refractory to bortezomib, 26.3% were double refractory to a proteasome inhibitor and an immunomodulatory agent, and 26.3% were refractory to daratumumab.

Additional Safety Data

Beyond keratopathy, the most common ophthalmological AEs seen at any point during treatment included blurred vision (5.2%; 42.1%; 42.1%), dry eye (36.8%; 5.3%; NA), cataract (0%; 10.5%; NA), photophobia (10.5%; 0%; NA), and conjunctivitis (0%; 5.3%; NA). No grade 4 ophthalmological AEs were observed.

Regarding the number of patients dosed in each treatment cycle, during cycle 1 (n = 19), 100% of patients were given treatment. During cycles 3 (n = 18), 5 (n = 15), 7 (n = 13), 9 (n = 11), 11 (n = 11), 13 (n = 9), 15 (n = 8), and 17 (n = 7), 61%, 47%, 58%, 36%, 64%, 44%, 25%, and 57% of patients enrolled in each cycle received treatment. Reasons for non-treatment in each cycle included dose toxicity, defined as grade 2 or higher keratopathy prior to dosing, as well as patient choice, Atrash explained.

“Keratopathy was manageable mainly with dose delays and to a lesser degree, with dose reductions,” Atrash noted.

Efficacy Data

Best responses included stringent complete response (CR; 37%), CR (16%), VGPR (5%), and PR (42%).

“Regarding MRD negativity, 10 out of 19 patients so far have MRD negativity at 10^–5, whereas 40% of the patients had MRD negativity at 10^–6,” Atrash emphasized.

At a median follow-up of 16.8 months, 3 patients had progressed. The 24-month PFS, DOR, and OS rates were 80%, 81%, and 95%, respectively.

Based on these phase 1 findings, the phase 2 portion of the trial is planned, in which patients with high-risk, newly diagnosed multiple myeloma will undergo autologous stem cell transplant following induction with 8 cycles of belantamab mafodotin plus KRd.

Disclosures: Dr Atrash reports receiving research funding from Amgen, GSK, and Karyopharm; receiving honoraria from Janssen; and receiving consulting fees from Pfizer.

REFERENCES:

1. Atrash S. Results of a phase 1 clinical trial of belantamab mafodotin combined with carfilzomib, lenalidomide, and dexamethasone for multiple myeloma after one prior line of therapy. Presented at: 2024 International Myeloma Society Annual Meeting; September 25-28, 2024; Rio De Janeiro, Brazil. Abstract OA-57.

2. Gay F, Musto P, Rota-Scalabrini D, et al. Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): a randomised, open-label, phase 2 trial. Lancet Oncol. 2021;22(12):1705-1720. doi:10.1016/S1470-2045(21)00535-0

3. Gay F, Roeloffzen W, Dimopoulos MA, et al. Results of the phase III randomized Iskia trial: isatuximab-carfilzomib-lenalidomide-dexamethasone vs carfilzomib-lenalidomide-dexamethasone as pre-transplant induction and post-transplant consolidation in newly diagnosed multiple myeloma patients. Blood. 2023;142(suppl 1):4. doi:10.1182/blood-2023-177546

4. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21(2):207-221. doi:10.1016/S1470-2045(19)30788-0

5. Hungria V, Robak P, Hus M, et al. Belantamab mafodotin, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2024;391(5):393-407. doi:10.1056/NEJMoa2405090