Belantamab Mafodotin Plus Lenalidomide/Dexamethasone Shows Efficacy, Safety in Newly Diagnosed Myeloma

Evangelos Terpos, MD, PhD

The addition of belantamab mafodotin-blmf (Blenrep) to lenalidomide (Revlimid) and dexamethasone generated responses with acceptable safety in patients with newly diagnosed multiple myeloma who were ineligible to undergo autologous stem cell transplant (ASCT), according to findings from the phase 1/2 BelaRd trial (NCT04808037).¹

Data presented during the 2022 EHA Congress showed that patients in cohort 1 who received the regimen with 2.5 mg/kg of belantamab mafodotin and achieved an overall response rate (ORR) of 91.7%, which included a stringent complete response (sCR) rate of 8.3%, a complete response (CR) rate of 16.7%, a very good partial response (VGPR) rate of 41.7%, and a PR rate of 25.0%.

In cohort 2, patients who received the regimen with 1.9 mg/kg of belantamab mafodotin experienced an ORR of 91.7%, which comprised a CR rate of 16.7%, a VGPR rate of 25.0%, and a PR rate of 50.0%. In cohort 3, patients received with regimen with 1.4 mg/kg of belantamab mafodotin and had an ORR of 100.0%, which included a CR rate of 75.0% and a PR rate of 25.0%.

Among all patients, the median time to a PR or better was 1.0 month (range, 0.9-3.9), and the median number of belantamab mafodotin infusions was 3.

“There was a manageable safety profile with a low frequency of severe ocular treatment-emergent adverse effects [TEAEs], especially in the lower-dose cohort,” lead study author Evangelos Terpos, MD, PhD, a professor of Hematology and director of the Stem Cell Transplantation Unit in the Department of Clinical Therapeutics of the National & Kapodistrian University of Athens, School of Medicine in Athens, Greece, said in a presentation of the data.

Beyond CD38-targeted immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies, agents that target BCMA could represent the fourth pillar of treatment in multiple myeloma. Belantamab mafodotin is a first-in-class immunoconjugate designed to target BCMA. Previously, in August 2020, the FDA approved belantamab mafodotin as a treatment for patients with relapsed/refractory multiple myeloma who have received 4 prior therapies, including an IMiD, a PI, and an anti-CD38 antibody.²

Belantamab mafodotin monotherapy has been shown to have meaningful antitumor activity and acceptable safety in heavily pretreated patients with relapsed or refractory multiple myeloma. Moreover, when paired with pomalidomide (Pomalyst) and dexamethasone, it was found to lead to a median progression-free survival (PFS) of 16.2 months in those refractory to IMiDs, PIs, and CD38-targeted monoclonal antibodies.

These data supported the rationale to evaluate the agent’s safety and activity when combined with lenalidomide and dexamethasone in ASCT-ineligible patients with newly diagnosed multiple myeloma as part of the BelaRd trial. Preliminary findings from part 1 the trial were shared during the 2022 EHA Congress.

BelaRd enrolled patients with documented multiple myeloma who were ineligible for high-dose chemotherapy with ASCT. To be eligible for enrollment, patients were required to have an ECOG performance status of 0 to 2, have adequate organ system function, and an eGFR of at least 30 mL/min/1.73 m².

Part 1 of the trial comprised 36 patients who were randomized 1:1:1 to cohorts 1, 2, and 3. Patients were administered 2.5 mg/kg, 1.9 mg/kg, and 1.4 mg/kg of belantamab mafodotin once every 8 weeks in cohort 1, cohort 2, and cohort 3, respectively. All patients also received 25 mg of lenalidomide daily on days 1 through 21, as well as 40 mg of dexamethasone daily on days 1, 8, 15, and 22 of every 28-day cycle. Notably, patients who were at least 75 years of age received 20 mg of dexamethasone daily on the same dosing schedule.

The primary end point of part 1 of the trial was safety and tolerability, as well as to determine the recommended phase 2 dose (RP2D) of belantamab mafodotin; this was ultimately established to be 1.9 mg/kg. Secondary end points included the efficacy of belantamab mafodotin, the management of corneal AEs, pharmacokinetics, and ocular AEs by ocular surface disease index.

The median ages of cohorts 1, 2, and 3 were 75.0 years (range, 66.0-86.0), 74.5 years (range, 68.0-82.0), and 69 years (range, 64.0-79.0), respectively. Additionally, 52.8% of all enrolled patients were male. Most patients in cohorts 1 and 2 had an ECOG performance status of 1 (50.0% and 75.0%, respectively), although most patients in cohort 3 had an ECOG performance status of 0 (66.7%). The majority of patients had International Staging System (ISS) stage II disease (41.7%, 58.3%, and 58.3% in cohorts 1, 2, and 3, respectively), revised ISS stage II disease (75.0%, 75.0%, and 66.7%, respectively), and intermediate fitness per the International Myeloma Working Group frailty score (score = 1; 83.3%, 91.7%, and 91.7%, respectively).

Regarding ocular comorbidities and baseline best corrected visual acuity (BCVA), most patients had a baseline BVCA of 20/25 (50.0%, 41.7%, and 33.3% in cohorts 1, 2, and 3, respectively). Additionally, most patients had cataracts of any grade (83.3%, 83.3%, and 91.7%, respectively) and abnormal fundoscopic findings (100%, 91.7%, and 91.7%, respectively). No patients had punctate keratopathy of any grade at baseline.

As of the April 12, 2022, the treatment cut-off date, 83.3%, 100.0%, and 83.3% of patients in cohorts 1, 2, and 3, respectively, remained on treatment. Of the 4 patients to discontinue treatment, 2 in cohort 1 and 1 in cohort 3 died, and an additional patient in cohort 3 withdrew. The 3 deaths were not determined to be related to study treatment; 1 fatal serious AE was pneumonia and 2 were due to COVID-19.

In cohorts 1, 2, and 3, the median duration of treatment in was 3.9 months (range, 2.1-12.0), 6.6 months (range, 3.0-11.6), and 5.6 months (range, 1.9-11.6), respectively. In these cohorts, the median number of infusions administered was 3.0 (range, 2.0-5.0), 3.0 (range, 2.0-6.0), and 3.5 (range, 2.0-7.0). The median follow-up was 5.9 months (range, 3.2-12.9), 9.3 months (range, 3.8-12.7), and 8.4 months (range, 3.5-13.1), respectively.

No new safety signals were detected with the belantamab mafodotin combination. All patients experienced at least 1 TEAE of any grade, and most patients in cohort 1 (n = 10/12), cohort 2 (n = 11/12), and cohort 3 (n = 12/12) experienced an any-grade TEAE related to belantamab mafodotin. Additionally, most patients in cohort 1 (n = 10), cohort 2 (n = 10), and cohort 3 (n = 8) reported a grade 3/4 TEAE. Three patients in cohort 1, 1 patient in cohort 2, and 2 patients in cohort 3 experienced at least 1 serious AE.

Furthermore, most patients had at least 1 ocular TEAE (10, 11, and 12 patients in cohorts 1, 2, and 3, respectively). Grade 3/4 ocular TEAEs occurred in 4, 1, and 3 patients in cohorts 1, 2, and 3, respectively. All ocular TEAEs of all grades were considered to be related to belantamab mafodotin. Notably, the only grade 3 or higher ocular TEAE observed in at least 5% of all patients was reduced visual acuity.

The study treatment was found to have a minor impact on daily life functioning, with a very low number of instances of daily life activities impacted at “half the time;” that was especially reported in the cohorts of patients who received belantamab mafodotin at 1.9 mg/kg or 1.4 mg/kg.

“Part 2 of the BelaRd study will evaluate the safety and the preliminary activity of belantamab mafodotin plus lenalidomide and dexamethasone at the RP2D and will additionally explore an alternative dose modification guideline for corneal AEs,” Terpos concluded.

References

1. Terpos E, Gavriatopoulou M, Ntanasis-Stathopoulos I, et al. A phase 1/2 dose and schedule evaluation study to investigate the safety and clinical activity of belantamab mafodotin administered in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma transplant ineligible. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S178.
2. FDA approves GSK’s Blenrep (belantamab mafodotin-blmf) for the treatment of patients with relapsed or refractory multiple myeloma. News release. GlaxoSmithKline, plc. August 5, 2020. Accessed July 6, 2022. https://bit.ly/3gxEXB1