Results of a phase I/II study investigating belantamab mafodotin with lenalidomide and dexamethasone as frontline therapy

At the European Hematology Association (EHA)2022 Congress, updated safety and efficacy data from the ongoing phase I/II BelaRd study (EAE-2020; NCT04808037) were presented by Evangelos Terpos on behalf of the Hellenic Society of Hematology.¹ The BelaRd study is assessing the safety and efficacy of belantamab mafodotin (belamaf) in combination with lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma who are ineligible for transplant, and it is the first study to evaluate belamaf as an upfront treatment.¹

Previously, belamaf has shown anti-myeloma activity as a single agent in patients with relapsed/refractory multiple myeloma, and it was granted accelerated approval by the U.S. Food and Drug Administration (FDA) in August 2020² and approved by the European Medicines Agency (EMA) also in August 2020.³

Study design¹

At the point of data cut-off, the BelaRd study had recruited 36 patients who were randomized equally into the three dosing cohorts below.

• Cohort 1 received 2.5 mg/kg belamaf
• Cohort 2 received 1.9 mg/kg belamaf
• Cohort 3 received 1.4 mg/kg belamaf

All cohorts received belamaf every 8 weeks, with 25 mg/day lenalidomide given orally on Days 1–21 of each 28-day cycle and 40 mg/day dexamethasone given orally or intravenously on Days 1, 8, 15, and 22 of each 28-day cycle. Key selection criteria for the study are shown in Table 1.

Table 1. Inclusion and exclusion criteria for the BelaRd study*

ASCT, autologous stem cell transplant; ECOG PS, Eastern Cooperative Oncology Group performance status; eGFR, estimated glomerular filtration rate. *Data from ClinicalTrials.gov.4 †As defined by the National Cancer Institute Common Terminology Criteria for Adverse Events  Version 5.
Inclusion criteria	Exclusion criteria
Ineligible for high-dose chemotherapy with ASCT	Peripheral neuropathy or neuropathic pain of Grade 2 or higher†
ECOG PS 0–2	Current corneal epithelial disease (except for mild punctate keratopathy)
Adequate organ function
eGFR ≥30 mL/min/1.73m2

The primary endpoint of the study is to evaluate the safety and tolerability of belamaf plus Rd, with the aim to establish a recommended phase II dose. Other endpoints include efficacy, pharmacokinetics, and corneal and ocular adverse events.

Results¹

Patient characteristics of all three cohorts are shown in Table 2.

Table 2. Baseline patient characteristics*

ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International staging system. *Adapted from Terpos.1 †Defined as del 17p, t(14:16), or t(4:14)
Characteristic, % (unless otherwise stated)	Cohort 1 (2.5 mg/kg)	Cohort 2 (1.9 mg/kg)	Cohort 3 (1.4 mg/kg)
Median age (range), years	75.0 (66.0–86.0)	74.5 (68.0–82.0)	69.0 (64.0–79.0)
Male	66.7	41.7	50.0
ECOG PS
0	33.3	25.0	66.7
1 or 2	66.7	75.0	33.3
ISS stage
I	33.3	25.0	33.3
II	41.7	58.3	58.3
III	25.0	16.7	8.3
Presence of high-risk cytogenetics†	8.3	16.7	0.0
Ocular comorbidities
Cataract, any grade	83.3	83.3	91.7
Abnormal fundoscopic findings	100.0	91.7	91.7
Abnormal intraocular pressure/glaucoma	8.3	25.0	16.7

Safety

At the time of data cut-off (April 13, 2022), the following safety results were observed.

• The median duration of therapy was
  • 3.9 months in cohort 1;
  • 6.6 months in cohort 2; and
  • 5.6 months in cohort 3.
• Two patients from cohort 1 and two patients from cohort 3 discontinued treatment.
• Two patients from cohort 1 and one patient from cohort 3 died, including one case caused by pneumonia and two cases due to COVID-19, not related to belamaf treatment.
• All but three patients experienced at least one treatment-emergent adverse event (TEAE) of any grade related to belamaf treatment, all of which were ocular AEs.
• The number of patients with ≥1 Grade 3/4 TEAE related to belamaf treatment was
  • 6 in cohort 1 (4 TEAEs were ocular);
  • 2 in cohort 2 (1 TEAE was ocular); and
  • 3 in cohort 3 (all TEAEs were ocular).
• The most common non-ocular TEAEs (any grade) included fatigue, rash, diarrhea, neutropenia, leukopenia, and COVID-19 infection.

Efficacy

After a median follow-up of 4.2 months, the overall response rate was 91.7% in cohorts 1 and 2, and 100% in cohort 3. Response rates are shown in Figure 1.

Belamaf, belantamab mafodotin; CR, complete response; ORR, overall response rate; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
*Adapted from Terpos.

Conclusions and future perspectives

Given the low incidence of Grade 3/4 ocular TEAEs in cohort 2, the recommended phase II dose in this setting has been set at 1.9 mg/kg every 8 weeks. At this dose, the safety profile was considered manageable, with a complete response rate of 16.7% and overall response rate of 91.7%, suggesting belamaf plus Rd could be used in patients with newly diagnosed multiple myeloma not eligible for transplant.

The efficacy of belamaf seen in the relapsed setting has provided rationale to initiate several clinical trials in the first-line setting, as listed below.

• DREAMM 9 (NCT04091126) is phase I trial of belamaf in combination with bortezomib and Rd to determine the dosing schedule for a phase III trial.

• GEM-BELA-VRd (NCT04802356) is a phase II trial investigating belamaf as part of induction, consolidation, and maintenance therapy for patients with newly diagnosed multiple myeloma who are eligible for transplant.
• The NCT04876248 trial is studying belamaf as consolidation and maintenance therapy for patients with minimal residual disease after autologous transplant.
• EAE 120 (NCT05280275), another trial run by the Hellenic Society of Hematology, is investigating belamaf combined with daratumumab plus Rd.

These and additional ongoing studies should provide further insight into preventing the ocular toxicities associated with belamaf and enhancing its efficacy.