DREAMM-2 | Belantamab mafodotin for relapsed or refractory multiple myeloma

Despite emerging therapies for the treatment of relapsed or refractory (R/R) multiple myeloma (MM; RRMM) improving patient prognosis considerably, caveats remain. Uncovering novel targets for therapeutic intervention is imperative for the treatment of patients that have depleted all currently available treatment options.

B-cell maturation antigen (BCMA) has been identified as a cell-surface receptor unique to plasma cells. The fact that BCMA is virtually absent on naïve and memory B cells makes it a promising target for MM cell-directed therapy. Belantamab mafodotin (GSK2857916) is a first-in-class antibody drug conjugate consisting of an anti-BCMA monoclonal antibody bound to the microtubule-disrupting agent, monomethyl auristatin F (MMAF).¹ Following the targeted release of MMAF into BCMA-expressing cells, MM cells undergo apoptosis. The binding of belantamab mafodotin to BCMA also enhances antibody-dependent cellular cytotoxicity, antibody-dependent phagocytosis and immunogenic cell death. BCMA is also the target of several immunotherapies currently in development such as chimeric antigen receptor (CAR) T-cell therapies and bispecific antibodies.¹

The first-in-human DREAMM-1 (NCT02064387) study, conducted in adult patients with RRMM who had progressive disease after stem cell transplantation (SCT), alkylators, proteasome inhibitors (PIs), and immunomodulatory drugs (IMiDs®), uncovered impressive single-agent activity of belantamab mafodotin.^2,3 Therefore, Sagar Lonial, Emory Winship Cancer Institute, and colleagues conducted a phase II, open-label, two-arm study, DREAMM-2 (NCT03525678), to investigate the efficacy and safety of belantamab mafodotin at two dose levels in patients with RRMM and recently published the results in The Lancet Oncology.¹

As a result of the positive data from the DREAMM-2 study, the U.S. Food & Drug Administration (FDA) has granted Priority Review to the Biologics License Application for belantamab mafodotin and the European Medicines Agency (EMA) have accepted marketing authorization application for its use in the treatment of RRMM.^4,5

Study design

• The DREAMM-2 study was conducted across 58 MM specialty centers in eight countries
• Patients were randomly assigned with permuted blocks (block size four)
• Patients were stratified by previous lines of therapy (≤ 4 vs > 4) and cytogenetic characteristics
• Patients were randomly assigned (1:1) to receive 2.5 mg/kg (n= 97) or 3.4 mg/kg (n= 99) belantamab mafodotin intravenously over ≥ 30 minutes every three weeks on Day one of each cycle. Values are henceforth given as 2.5 mg/kg versus4 mg/kg cohorts
• Treatment continued until disease progression or unacceptable toxicity
• Patients received a median of three treatment cycles (range, 1–11 vs 1–10)
• The median duration of follow-up was 6.3 months (interquartile range [IQR], 3.7–7.7) vs9 months (IQR, 4.8–7.9)

Outcomes

• Primary outcomes: percentage of patients with an overall response when assessed every three weeks after Cycle one (defined as partial response or better [≥PR]) confirmed using the International Myeloma Working Group (IMWG) uniform response criteria for MM
• Secondary outcomes:
  • Efficacy: duration and time to response, progression-free survival (PFS), overall survival (OS), proportion of patients achieving clinical benefit
  • Safety: adverse events (AEs), serious AEs (SAEs) and AEs of special interest

Results

Patient characteristics

• Patients with RRMM (N= 196) were recruited (Table 1)
• Inclusion criteria:
  • Aged ≥ 18 years
  • Prior autologous SCT (> 100 days before enrollment) or ineligible for a transplant
  • Disease progression after ≥ 3 lines of therapy
  • Refractory to a PI and IMiD
  • Refractory, intolerant, or both, to an anti-CD38 monoclonal antibody
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0–2
  • Adequate organ system function
• Patients had received on average seven vs six prior lines of therapy, with 84% vs 83% receiving four or more
• Discontinuation of treatment occurred in 73 vs 74 patients as a result of progressive disease in 59 vs 56 patients and AEs in 7 vs 10 patients

Table 1. Characteristics of study sample defined by belantamab mafodotin dose cohort

*Data available for 47 patients in the 2.5mg/kg cohort and 36 patients in the 3.4mg/kg cohort. IMiD; immunomodulatory drug, IQR; interquartile range, ISS=International Staging System, mAb; monoclonal antibody, PI; proteasome inhibitor.
Dose of belantamab mafodotin	2.5mg/kg (n= 97)	3.4mg/kg (n= 99)
Age, median (IQR), years  ≥ 75 years, %	65 (60–70) 13	67 (61–72) 17
Sex Male, % Female, %	53 47	57 43
Time from initial diagnosis, median (IQR), years*	5.49 (4.01–7.02)	5.08 (4.16–7.48)
ISS disease stage at screening, % Stage I Stage II Stage III Unknown	22 34 43 1	18 52 30 0
High-risk cytogenetics, %	42	47
Type of myeloma, % IgG Non-IgG or unknown	67 33	74 26
Extramedullary disease, %	23	18
Refractory to previous therapies, % Proteasome inhibitor Bortezomib Carfilzomib IMiD Lenalidomide Pomalidomide Anti-CD38 monoclonal antibody Daratumumab Isatuximab	76 65   90 87   100 3	75 58   89 78   92 1

Efficacy

• The number of patients included in the efficacy analysis was 97 vs 99
• Overall response rate (ORR): 31% (97.5% CI, 20.8–42.6) vs 34% (97.5% CI,23.9–46)
• A very good PR or better (≥VGPR) was achieved by 19% vs 20% of patients
• Clinical benefit was observed in 34% (95% CI, 24.7–44.3) vs 39% (95% CI, 29.7–49.7) of patients
• At a median follow-up of 6.3 [IQR, 3.7–7.7] vs 6.9 [IQR, 4.8–7.9] months, the median duration of response was not reached in either cohort
• At the data cut-off date (June 21^st 2019) 18 vs 24 patients had a duration of response of ≥ 4 months with PFS follow-up ongoing and treatment continuing
• At the time of data cut-off, the OS data were not mature; 58% vs 56% of patients had disease progression or died
• Median PFS was 2.9 months (95% CI, 2.1–3.7) vs 4.9 months (95% CI, 2.3–6.2)

Safety

Safety data is shown in Table 2.

Table 2. Adverse events in the safety population

AE, adverse event; SAE, serious adverse event
Belantamab mafodotin dose	2.5 mg/kg (n= 95)	3.4 mg/kg (n= 99)
≥ 1 AE, %	98	100
Dose delays due to AEs, %	54	62
Dose reductions due to AEs, %	29	41
Permanent discontinuation of treatment due to AEs, %	8	10
Most common Grade 3–4 AEs, % Keratopathy Thrombocytopenia Anemia	27 20 20	21 33 25
≥ Grade three pneumonia, %	4	11
SAEs, %	40	47
Death due to SAE, %	3	7
≥ Grade two bleeding events, %	5	17
Neutropenia, %	14	27

• The most common Grade 3–4 AEs were keratopathy, thrombocytopenia and anemia as shown in Table 2
• The incidence of upper respiratory tract infections was low (0% vs 1%)
• Two deaths were considered potentially related to study treatment and occurred as a result of sepsis (n= 1, 2.5 mg/kg cohort) and hemophagocytic lymphohistiocytosis (n= 1, 3.4 mg/kg cohort)
• Infusion-related reaction (IRR) events were predominantly Grade 1–2
• One patient (2.5 mg/kg cohort) discontinued treatment due to an IRR

Keratopathy

• Keratopathy was defined as corneal epithelium changes observed by ophthalmic examination
• Keratopathy was the main AE leading to permanent treatment discontinuation, and was the most common Grade 1–2 AE, and one of the most common Grade 3–4 AEs
• Keratopathy resulted in treatment discontinuation in one vs three patients, dose reductions in 22 vs 27 patients, and dose delays in 45 vs 48 patients

Conclusions

• The recent data from the DREAMM-2 study highlight the anti-myeloma activity of belantamab mafodotin at 2.5 mg/kg and 3.4 mg/kg dose in patients with RRMM who were refractory to a PI, IMiD and refractory/intolerant/both to an anti-CD38 monoclonal antibody
• The median duration of response in the overall patient population, and OS in patients achieving an overall response or a clinical benefit were not reached. This alludes to the idea that the clinical responses reached following belantamab mafodotin treatment extend beyond the six-month follow-up period
• No additional safety concerns were identified in the DREAMM-2 study compared to DREAMM-1
• Limitations of the DREAMM-2 study include the short duration of follow-up and the absence of a standard-of-care competitor arm
• Whilst the DREAMM-2 study was not designed to compare the two doses, the 2.5 mg/kg dose was selected as the recommended dose for future studies on the basis of its similar anti-myeloma activity with a more favourable safety profile
• At present, there has been just one additional clinical trial (STORM [NCT02336815]) to investigate a prospective therapeutic regimen for the treatment of MM patients refractory to PIs, IMiDs, and daratumumab
  • For more information on the STORM trial, see the MM Hub article here

Future Directions

Further studies of belantamab mafodotin are planned to evaluate:³

• The safety and efficacy of belantamab mafodotinvs pomalidomide plus low-dose dexamethasone in patients with RRMM (DREAMM-3; NCT04162210)
• The safety and clinical activity of belantamab mafodotin administered in combination with pembrolizumab in patients with RRMM (DREAMM-4; NCT03848845)
• Belantamab mafodotin in combination with innovative anti-cancer treatments in participants with RRMM (DREAMM-5; NCT04126200)
• The safety, tolerability, and clinical activity of belantamab mafodotin administered in combination with lenalidomide plus dexamethasone, or in combination with bortezomib plus dexamethasone in patients with RRMM (DREAMM-6; NCT03544281)
• Belantamab mafodotin, bortezomib, and dexamethasone vs daratumumab, bortezomib, and dexamethasone in participants with RRMM (DREAMM-7; NCT04246047)
• The efficacy and safety of belantamab mafodotin in combination with pomalidomide and low-dose dexamethasone vs pomalidomide plus bortezomib and low-dose dexamethasone in participants with RRMM (DREAMM-8)
• Belantamab mafodotin + bortezomib, lenalidomide and low-dose dexamethasone vs bortezomib, lenalidomide and low-dose dexamethasone in patients with newly diagnosed MM who are not eligible for transplant (DREAMM-9)⁴