The DREAMMs at ASCO — updates on belantamab mafodotin as a single agent

Despite significant improvements in the outcomes of patients with multiple myeloma (MM) in recent years, there is still a need for novel agents that specifically target myeloma cells, are well tolerated, and induce deep and durable responses. One of such novel agents is belantamab mafodotin (belamaf, GSK2857916), a first-in-class, antibody-drug conjugate against B-cell maturation antigen linked to cytotoxic monomethyl auristatin F. Belamaf is being evaluated in the DREAMM program consisting of several clinical trials, where belamaf is used as a single agent or in combination with other treatments in newly diagnosed or heavily pretreated patients with MM. Here is a summary of new data from the DREAMM studies using belamaf as a single agent presented during the 2020 virtual meeting of the American Society of Clinical Oncology (ASCO).

DREAMM-1¹

While the updated safety and efficacy results of the initial belamaf study, DREAMM-1 (NCT02064387) were published in 2019,² the abstract with patient-reported outcomes was presented at the ASCO20 meeting and is particularly relevant since keratopathy was identified as the most frequent adverse event reported with belamaf.

Patients who received single-agent belamaf (3.4 mg/kg intravenous once every 3 weeks for 16 cycles) were invited to participate in interviews at end-of-treatment (EOT) and 6-month follow-up. During the interviews, patients evaluated symptoms, treatment-related adverse events (AEs), treatment burden, and overall satisfaction. Each of the assessed aspects was rated 0–10 (with 0 as not severe and 10 as the most severe, or 0 as not at all satisfied and 10 as extremely satisfied).

• In total, 17/35 patients were interviewed at least once, the majority were female (53%) 
  • Four patients completed both interviews
• 94% of the interviewed patients achieved ≥ partial response
• At EOT, patients reported a reduction in bone pain (mean change in score from 6.4 to 4.0) and fatigue (8.0 to 5.5)
• The most frequent treatment-related AE was blurred vision, reported by 76% of patients
  • in 62% (8/13) of cases the problems with vison resolved or improved after EOT (mean reduction in severity rating from 7.3 to 5.3)
• Only 1/14 patients considered stopping treatment due to AEs
• The overall satisfaction with treatment was high, with a mean score of 7.9 and median 9.0

In conclusion, the satisfaction with single-agent belamaf therapy was high amongst this cohort of patients, who noticed improvements in symptoms of MM. The frequent ocular symptoms were manageable, improved/resolved after treatment, and did not contribute to the patients’ decision to stop treatment.

DREAMM-2^3,4

Two post hoc analyses of subgroups of patients from the DREAMM-2 study (NCT03525678) after a 9-month follow-up were also presented during the meeting.

Impact of cytogenetic risk on efficacy and safety of single-agent belamaf³

Adam Cohen from the University of Pennsylvania, US, presented a poster where patients were stratified by high vs standard cytogenetics risk. The researchers evaluated the impact of high-risk cytogenetics, which are associated with particularly poor prognosis, on the responses to single-agent belamaf among the heavily pretreated patients included in the DREAMM-2 study (N = 196).

In total, 45% of the enrolled patients had ≥ 1 high-risk cytogenetic abnormality. The most frequent were 1q21 gains followed by 17p deletions; other abnormalities included 4;14 and 14;16 translocations. There were no statistically significant differences in response rates between patients in the standard and high-risk groups (Table 1). Responses occurred typically within the first two cycles and deepened over time. Additionally, the responses were durable even in patients who had dose reduction or delays in belamaf administration.

Table 1. Efficacy of belamaf in DREAMM-2 study patients with RRMM stratified by cytogenetic risk and belamaf dose

In general, the frequency of AEs was similar between groups and consistent with that previously reported for the general population.^3,5 The most common AEs in both cytogenetic risk groups were keratopathy, thrombocytopenia, nausea, anemia, and blurred vision. The frequency of anemia and thrombocytopenia were greater in the high-risk vs standard-risk group. Three treatment-related deaths were reported, one patient in the high-risk group (2.5 mg/kg) and two in patients in the standard-risk group (3.4 mg/kg).

In conclusion, the data demonstrated that single-agent belamaf is equally active in patients with high-risk relapsed/refractory MM (RRMM), as in those with standard-risk and the overall population of the DREAMM-2 study. The duration of responses was also similar, and the safety profile was consistent with previous reports.

Single-agent belamaf in patients with renal impairment⁴

Hans Chulhee Lee from the MD Anderson Cancer Center, US, presented a poster at ASCO20 with results of post hoc analysis of single-agent belamaf in a subpopulation of patients with renal impairment from the DREAMM-2 study. Renal impairment is associated with reduced treatment tolerance and poor outcome in patients with RRMM.

Patients with RRMM with no active renal conditions and adequate renal function were eligible for the study (N = 196). The majority of patients in the DREAMM-2 study had mild renal impairment (eGFR ≥ 60 ≤ 90 mL/min/1.73 m²) and around a quarter had moderate impairment (eGFR ≥ 30 ≤ 60 mL/min/1.73 m²).

Single-agent belamaf demonstrated activity in patients with mild and moderate impairment (Table 2). The ORR was similar between patients with normal and mild/moderate renal function. The median duration of response for patients with normal renal function was 4.2 (1.4–NR) months for the 2.5 mg/kg dose and 6.2 (2.1–NR) months for 3.4 mg/kg vs not reached and 5.6 (2.3–NR) months in patients with mild/moderate impairment, respectively. The median PFS was similar between patients with and without renal impairment (Table 2)

Table 2. Efficacy of single-agent belamaf in DREAMM-2 study patients with RRMM and renal impairment

The rates of any grade AEs were generally similar across the groups, with keratopathy most frequently reported in all groups. Frequency of keratopathy and albuminuria were similar across the groups; while anemia, pyrexia, and thrombocytopenia were more common in patients with renal impairment vs those with normal renal function.

Signs of active renal disease occurred in patients with mild (1/45 and 2/37) and moderate renal impairment (2/20 and 5/20) who received 2.5 mg/kg and 3.4 mg/kg, respectively. While worsening of renal function was reported in ≤ 26% of patients with both doses irrespective of renal function.

Grade 3/4 AEs were generally similar across the groups. The most frequent Grade 3/4 AEs are presented in Table 3. Three treatment-related deaths were recorded, one patient with the normal renal function on the 2.5 mg/kg dose (sepsis), and two patients with mild renal impairment on the 3.4 mg/kg dose (cerebral hemorrhage and hemophagocytic lymphohistiocytosis).

Table 3. The most frequent Grade 3/4 AEs

In summary, the results of this post hoc analysis of the DREAMM-2 study patients with RRMM revealed that single-dose belamaf safety profile was not negatively affected by mild/moderate renal impairment. Moreover, the depths and duration of response of those patients were similar to patients with normal function. Further studies are needed to validate the suitability of belamaf for this challenging-to-treat group of patients.

Conclusion

In the DREAMM-2 study, this first-in-class anti-BCMA drug conjugate showed activity and manageable safety in heavily pretreated patients, including in difficult to treat populations of patients with renal impairment, and those with high-risk cytogenetics. Results of these trials are currently being evaluated by the U.S. Food and Drug Administration and the European Medicines Agency for the approval of belamaf single-agent for patients with RRMM.