FDA Approval Summary: Belantamab Mafodotin for Patients with Relapsed or Refractory Multiple Myeloma

Abstract

On August 5, 2020, the Food and Drug Administration granted accelerated approval to belantamab mafodotin-blmf (BLENREP; GlaxoSmithKline) for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. Substantial evidence of effectiveness was obtained from the phase 2, multicenter DREAMM-2 trial. Patients received belantamab mafodotin 2.5 mg/kg or 3.4 mg/kg intravenously once every 3 weeks until disease progression or unacceptable toxicity. The trial demonstrated an overall response rate of 31% in the 2.5 mg/kg cohort and 34% in the 3.4 mg/kg cohort. Keratopathy was the most frequent adverse event, occurring in 71% and 77% of patients, respectively. Other ocular toxicities included changes in visual acuity, blurred vision, and dry eye. The U.S. prescribing information for belantamab mafodotin includes a boxed warning for ocular toxicity, and belantamab mafodotin is available only through a restricted program under a Risk Evaluation and Mitigation Strategy. This article summarizes the data and the FDA review process supporting accelerated approval of belantamab mafodotin 2.5 mg/kg intravenously once every 3 weeks. This approval may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Introduction

Multiple myeloma (MM) is the second most common hematologic malignancy, accounting for 1.8% of cancers and 10% of hematologic malignancies (1). The diagnosis is most common in the 6th and 7th decades of life, with a median age at diagnosis of 69 years (1). Multiple drugs are approved for patients diagnosed with MM, and combination induction regimens, followed by autologous stem cell transplantation for eligible patients, are considered standard of care for newly diagnosed patients. Despite the availability of multiple therapies, treatment of relapsed or refractory MM (RRMM) remains challenging and the disease remains incurable, with a 5-year survival rate of 55.6% (1). In general, the duration of remission shortens with each subsequent line of therapy, and patients who have received multiple lines of therapy and become refractory to the major classes of available therapies have poor outcomes. Patients who are relapsed or refractory to proteasome inhibitors (PI), immunomodulatory agents (IMID), and anti-CD38 monoclonal antibodies (mAb) demonstrate low response rates and have a poor prognosis (2,3). At the time the belantamab mafodotin marketing application was submitted, selinexor, an XPO-1 inhibitor, in combination with dexamethasone, had previously been granted accelerated approval in July 2019 for patients with RRMM who have received at least 4 prior therapies including two PIs, two IMIDs and an anti-CD38 mAb. In the pivotal single arm trial (n=83), the combination of selinexor plus dexamethasone had an overall response rate (ORR) of 25.3% with a duration of response (DOR) of 3.8 months.

Belantamab mafodotin is a first-in-class antibody-drug conjugate (ADC) consisting of an anti-B-cell maturation antigen (BCMA)-directed antibody conjugated to a microtubule inhibitor, monomethyl auristatin F (MMAF), that has not previously received marketing approval for any indication by any regulatory agency. It was granted breakthrough therapy designation in October 2017 based on preliminary evidence suggesting that belantamab mafodotin may demonstrate substantial improvement over available therapy on a clinically significant endpoint. The Application was submitted under the Oncology Center of Excellence Real-Time Oncology Review pilot program and received priority review designation (4). Priority review designation is granted if a drug demonstrates evidence of a significant improvement in safety or effectiveness and sets an 8-month PDUFA timeline for FDA review for applications submitted under The Program.

Belantamab mafodotin received accelerated approval on August 5, 2020, for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies including an anti-CD38 mAb, a PI, and an IMID. The U.S. Prescribing Information (USPI) for belantamab mafodotin includes a Boxed Warning to communicate the risks of ocular toxicity and the need for ophthalmic monitoring, as well as dose modifications for ocular toxicity. In addition, a Risk Evaluation and Mitigation Strategy (REMS) with elements to assure safe use (ETASU) is in place to ensure the risk of ocular toxicity with belantamab mafodotin will be adequately managed in the post-marketing setting (5). Belantamab mafodotin was discussed at the Oncologic Drug Advisory Committee (ODAC) meeting on July 14, 2020. The ODAC advised that belantamab mafodotin demonstrated benefit which outweighed the risks of ocular toxicity in the proposed patient population with RRMM (6). This article discusses the FDA’s analysis of the marketing application that led to the approval of belantamab mafodotin for patients with RRMM and the considerations for implementing the REMS.

Nonclinical Pharmacology and Toxicology

BCMA, is a non-glycosylated integral membrane type I protein expressed on normal mature B lymphocytes and MM cells. Upon binding to BCMA, belantamab mafodotin is internalized, followed by release of MMAF intracellularly, leading to disruption of the microtubule network, cell cycle arrest, and apoptosis. Belantamab mafodotin acts through multiple mechanisms to kill MM cells, including MMAF-induced apoptosis, tumor cell lysis through antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis.

In toxicology studies modeling the clinical dosing regimen, treatment of animals with belantamab mafodotin resulted in pro-inflammatory responses as indicated by hematology parameters (e.g., increased WBCs and/or differentials) and histopathology observations (multi-organ immune cell (mononuclear and mixed) infiltration). Based on FDA review of nonclinical studies, belantamab mafodotin-related toxicities were seen in the kidneys, liver, male and female reproductive organs, organs of the hematopoietic system, lung, eye, teeth, mammary gland, and injection site. Ocular findings in animal studies included increased mitoses of corneal epithelial cells with bilateral single cell necrosis (7).

Clinical Pharmacology

Dose Selection

The Sponsor initially proposed to evaluate belantamab mafodotin 3.4 mg/kg every 3 weeks in DREAMM-2 based on the results from the phase 1, first-in-human DREAMM-1 trial. Following discussion with the FDA regarding the incidence of ocular toxicity and frequency of dose modifications with the 3.4 mg/kg dose in DREAMM-1, the Sponsor amended the DREAMM-2 trial to include evaluation of belantamab mafodotin 2.5 mg/kg every 3 weeks in addition to the 3.4 mg/kg dose. Based on the assessment of efficacy and safety of the two dose levels in DREAMM-2, the Sponsor proposed 2.5 mg/kg every 3 weeks as the monotherapy dose for the population of patients with RRMM.

Clinical Trial Design

DREAMM-2 was a phase 2, open-label, two-arm, multicenter trial in patients with RRMM who had received at least 3 prior lines of therapy that included a PI, an IMID and an anti-CD38 mAb (Figure 1). Patients with corneal epithelial disease, except for mild punctate keratopathy, were excluded. Patients were randomized 1:1 to receive belantamab mafodotin 2.5 mg/kg or 3.4 mg/kg every 3 weeks and treatment was continued until disease progression or unacceptable toxicity. A subset of patients (N=30) participated in an ocular sub-study to evaluate the prophylactic use of steroid eye drops. An additional cohort of patients (N=24) was included to evaluate the lyophilized presentation of belantamab mafodotin planned for commercialization.

Figure 1: DREAMM-2 Study Schema.

Abbreviations: mAb=monoclonal antibody, PI=proteasome inhibitor, IMID=immunomodulatory agent, Q3W=once every 3 weeks, IRC=independent review committee, DOR=duration of response, PFS=progression-free survival, OS=overall survival, TTR=time to response, TTP=time to progression, CBR=clinical benefit rate.

(Source: Adapted from FDA BLA 761158 ODAC Presentation, July 14, 2020; ref 6)

Results

Demographics and Baseline Characteristics

DREAMM-2 was a global trial that enrolled patients at sites in North America, Europe, and Australia. Fourteen percent (14%) of patients were Black or African American. Overall, the demographic characteristics of patients in DREAMM-2 were representative of the general population of patients with RRMM in the U.S., with several exceptions. The median age of patients in DREAMM-2 was 66 years, which is younger than the median age at diagnosis of 69 for patients with MM in the U.S. (1). Only 15% of patients were 75 years or older.

Approximately 27% of patients in the 2.5 mg/kg cohort had high risk cytogenetics (t(4;14), t(14;16) or del(17p)) and 23% had extramedullary disease. All patients enrolled in DREAMM-2 were double-refractory to a PI and an IMID and had received prior therapy with an anti-CD38 mAb. All patients in the 2.5 mg/kg cohort were also refractory to an anti-CD38 mAb. Prior therapies included stem cell transplantation in 75% of patients. Patients in the 2.5 mg/kg cohort had received a median of 7 prior lines (range 3 to 21) of anti-myeloma therapy.

Efficacy

The determination of efficacy was based on ORR evaluated by an independent review committee (IRC) using the International Myeloma Working Group response criteria and DOR. Among the 97 patients in DREAMM-2 who were randomized to receive the recommended dose of belantamab mafodotin 2.5 mg/kg every 3 weeks, the ORR was 31% (97.5% confidence interval [CI]: 21%, 43%; based on exact method). Best overall response included stringent complete response (sCR) in 2 patients, CR in 1 patient, very good partial response (VGPR) in 15 patients and partial response (PR) in 12 patients. With a median follow-up of 6.3 months, the median DOR was not reached (95% CI: not reached, not reached) and 73% of responders had a DOR ≥6 months. The subgroup analysis results were consistent with the primary analysis, except for the subgroups of patients with extramedullary disease and patients who were 75 years or older, in which the ORR appears to be lower compared to the overall population.

Safety

FDA’s review of the safety of belantamab mafodotin included evaluation of data from a total of 291 patients across the DREAMM-1 and DREAMM-2 trials, with a focus on patients in DREAMM-2 who received at least one cycle of the recommended dose of belantamab mafodotin 2.5 mg/kg every 3 weeks (N=95).

With the belantamab mafodotin 2.5 mg/kg every 3 weeks dosing regimen (N=95), serious adverse reactions (ARs) occurred in 40% of patients, with pneumonia (7%) and pyrexia (6%) being the most common serious ARs. Severe (grade 3–4) ARs occurred in 82% of patients, with keratopathy (44%), decreased visual acuity (28%), pneumonia (7%), and sepsis (5%) being the most common severe ARs based on FDA analysis using grouped preferred terms (7). Fatal ARs occurred in 3% of patients and included sepsis, cardiac arrest, and lung infection (1% each). Dose modifications due to ARs included dose interruptions in 54% of patients, dose reductions in 29%, and permanent discontinuation in 8%. The most common ARs of any grade (≥20% incidence), excluding laboratory abnormalities, were keratopathy, decreased visual acuity, nausea, blurred vision, pyrexia, infusion-related reactions, and fatigue (Table 1).

Table 1:

Adverse Reactions in ≥20% of Patients in DREAMM-2 (2.5 mg/kg Cohort)

Adverse Reaction	Belantamab mafodotin 2.5 mg/kg (N=95)
	Any Grade (%)	Grade 3 or 4 (%)
Eye disorders
Keratopathy a	71	44
Decreased visual acuity b	53	28
Blurred vision c	22	4
Gastrointestinal disorders
Nausea	24	0
General disorders and administration site conditions
Pyrexia	22	3
Fatigue d	20	2
Procedural complications
Infusion-related reactions e	21	3

^aKeratopathy was based on slit lamp eye examination, characterized as corneal epithelium changes with or without symptoms.

^bVisual acuity changes were determined upon eye examination

^cBlurred vision included diplopia, vision blurred, visual acuity reduced, and visual impairment.

^dFatigue included fatigue and asthenia.

^eInfusion-related reactions included infusion-related reaction, pyrexia, chills, diarrhea, nausea, asthenia, hypertension, lethargy, and tachycardia.

(Source: Adapted from Belantamab mafodotin USPI; ref 5)

As noted in Table 1, keratopathy (71% all grades, 44% grade 3 or 4), characterized by changes in the corneal epithelium based on slit lamp examination, was the most frequent AR, followed by decreased visual acuity (53% all grades, 28% grade 3 or 4). Keratopathy was also the most frequent AR leading to dose modifications, including dose interruption (47%), dose reduction (23%), and permanent discontinuation (2%).

Ocular ARs occurred in 77% of patients in the pooled safety population (N=218), which included patients from both the 2.5 mg/kg and 3.4 mg/kg cohorts in DREAMM-2. The most frequent ocular ARs included keratopathy (76%), decreased visual acuity (55%), blurred vision (27%) and dry eye (19%). This included grade 3 keratopathy in 45% and grade 4 in 0.5% of patients, including one case of corneal ulcer. One additional case of bilateral corneal ulcers was reported in the safety update. Among the patients with grade 2–4 keratopathy, 39% of patients had recovery to grade 1 or lower after a median follow-up of 6.2 months, and the median time to resolution was 2 months (range 11 days to 8.3 months). A clinically significant decrease in best-corrected visual acuity (BCVA) to >20/40 in the better seeing eye occurred in 19% of patients and decrease to 20/200 or worse in the better seeing eye (consistent with the definition of legal blindness in the U.S.) occurred in 1.4% of patients, though all cases (N=3) resolved after a median duration of 22 days (range 15 to 22).

Recommended dose modifications for ocular toxicity in DREAMM-2 were based on the Keratopathy and Visual Acuity (KVA) Scale, a study-specific scale developed by the Sponsor to grade severity of corneal ARs based on both corneal examination findings and changes in BCVA, considering the worst finding in the worst affected eye.

Regulatory Insights

Benefit Risk Assessment in the Context of Ocular Toxicity Risk

Belantamab mafodotin was granted accelerated approval for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. Patients in the 2.5 mg/kg cohort had received a median of 7 prior lines of therapy; 95% of patients in the 2.5 mg/kg cohort received 4 or more prior lines of therapy. The ORR (≥PR per IRC) in the 97 patients who were randomized to receive the 2.5 mg/kg dose was 31% (97.5% CI: 21%, 43%). Seventy three percent of responders had a DOR ≥6 months. The efficacy in the proposed patient population represents a treatment benefit in a patient population with no available therapies.

The primary safety concern with belantamab mafodotin is the risk of ocular toxicity. The ocular toxicity with belantamab mafodotin is a unique toxicity among anti-myeloma agents. The mechanism by which belantamab mafodotin causes ocular toxicity is not completely understood; however, ocular toxicity, including keratopathy, is a known class-effect associated with ADCs containing microtubule-inhibitor payloads such as MMAF (8). Keratopathy was associated with a clinically significant decline in visual acuity, including severe vision loss in some patients. Keratopathy and vision loss occurred despite frequent monitoring (ophthalmic examination before each cycle) on the clinical trial and use of prophylactic steroid eye drops. Dose modifications due to keratopathy were frequent in DREAMM-2; approximately half of the patients required at least one dose modification due to keratopathy and nearly a quarter of patients required a dose reduction due to keratopathy.

The benefit-risk of belantamab mafodotin in the proposed patient population in the context of the observed ocular toxicity was discussed at an ODAC meeting on July 14, 2020 (6). FDA requested discussion of 1) whether the risk of ocular toxicity has been adequately characterized in DREAMM-2 to allow for an assessment of the benefit-risk profile, and 2) the impact of ocular toxicity on the benefit-risk profile for belantamab mafodotin. The Applicant outlined a proposed REMS with ETASU to address the ocular toxicity with belantamab mafodotin.

The ODAC voted on the question, “Does the demonstrated benefit of belantamab mafodotin outweigh the risks in the proposed patient population with multiple myeloma?” The ODAC unanimously agreed that the benefit of belantamab mafodotin in the indicated population (ORR 31%) in conjunction with the proposed REMS program outweighed the risks (6).

Implementation of a REMS with ETASU was necessary to ensure the risks of ocular toxicity with belantamab mafodotin can be adequately managed in the post-marketing setting in the proposed patient population with RRMM. As part of the REMS with ETASU for belantamab mafodotin, prescribers must be certified with the program and counsel patients regarding the risk for ocular toxicity and need for ophthalmic monitoring, patients must enroll in the program and comply with monitoring, and healthcare facilities must be certified and verify that patients are authorized to receive belantamab mafodotin. The REMS also includes a communication plan.

The efficacy of belantamab mafodotin at the 2.5 mg/kg dose evaluated in DREAMM-2 along with the REMS with ETASU and mitigation strategies for ocular toxicity proposed in the USPI supported the FDA’s benefit-risk assessment to grant accelerated approval for belantamab mafodotin in the indicated patient population (Table 2). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a randomized confirmatory clinical trial. A post-marketing requirement (PMR) to evaluate the ocular toxicity with the lyophilized presentation and an additional PMR to further characterize the ocular toxicity were issued.

Table 2:

Summary of Belantamab Mafodotin Benefit-Risk Assessment

Dimension	Evidence and Uncertainties	Conclusions and Reasons
Analysis of Condition	• MM remains incurable with a 5-year survival rate of 56%.	• RRMM is a serious and life-threatening condition.
Current Treatment Options	• Despite availability of multiple therapies, patients eventually relapse and become refractory to available therapies. • MM remains incurable.	• There is an unmet medical need to improve outcomes of patients with RRMM who have received multiple lines of therapy and are refractory to the commonly used classes of drugs (i.e., a PI, an IMID and an anti-CD38 mAb).
Benefit	• Patients who received the 2.5 mg/kg dose in the pivotal DREAMM-2 trial (N=97) had received a median of 7 lines of therapy and were refractory to an anti-CD38 mAb, an IMID and a PI. • The ORR assessed by IRC for the 2.5 mg/kg dose was 31% (97.5% CI: 21%, 43%). As of the data cut-off, with a median follow-up of 6.3 months, median DOR was not reached.	• The efficacy in the proposed patient population represents a treatment benefit. • A PMR to confirm the benefit of belantamab mafodotin in a randomized clinical trial in patients with RRMM was issued.
Risk and Risk Management	• Key safety concerns for belantamab mafodotin include ocular toxicity, thrombocytopenia, and infusion-related reactions. • The ocular toxicity observed with belantamab mafodotin is a unique toxicity among anti-myeloma agents. • Keratopathy was the most frequent AR with belantamab mafodotin (incidence of 71% in 2.5 mg/kg cohort) and was associated with a clinically significant decline in visual acuity, including severe vision loss, and development of corneal ulcers. • Not all patients with keratopathy had associated ocular symptoms like blurred vision or dry eye. In the absence of close monitoring with frequent ophthalmic exams and appropriate management, keratopathy could go undetected, and patients could develop severe corneal ulcers that may require corneal transplant. • The mechanism of keratopathy and ocular toxicity with belantamab mafodotin has not been fully characterized.	• The Warnings and Precautions section in the USPI details the serious risks of the drug, including risks of ocular toxicity, infusion-related reactions and thrombocytopenia, and mitigation strategies. • The USPI includes a Boxed Warning to communicate the risks of ocular toxicity and need for ophthalmic monitoring and dose modifications. • A REMS with ETASU was included to ensure the risks of belantamab mafodotin can be adequately managed in the post-marketing setting.

Abbreviations: MM=multiple myeloma, RRMM=-relapsed or refractory MM, PI=proteasome inhibitor, IMID=immunomodulatory agent, mAb=monoclonal antibody, ORR=overall response rate, IRC=independent review committee, DOR=duration of response, PMR=post-marketing requirement, AR=adverse reaction, USPI=US prescribing information, REMS=risk evaluation and mitigation strategy, ETASU=elements to assure safe use. (Source: Adapted from FDA BLA761158 Multidisciplinary Review and Evaluation; ref 7)

Underrepresentation of Older Adults

The median age in DREAMM-2 was 66 years (median age of 65 years in the 2.5 mg/kg cohort) compared to a median age of 69 years for patients with newly diagnosed MM in the U.S. Furthermore, patients with RRMM who have had multiple prior lines of therapy are likely to be older compared to the median age at diagnosis. The incidence of ocular toxicity in the age 65 to <75 years was higher compared to the age <65 years subgroup (keratopathy 79% versus 67%; change in BCVA 59% versus 47%). The ORR in the 2.5 mg/kg cohort for all age subgroups combined was 31% (97.5% CI: 21%, 43%). In the 2.5 mg/kg cohort, the ORR in patients age ≥75 years was 8% (1/13). However, there was an insufficient number of patients in the ≥75 years subgroup (N=13) to draw any definitive conclusions regarding differences in safety or efficacy. A post-marketing commitment (PMC) was issued to further characterize the ocular toxicity with belantamab mafodotin in patients aged 65 to <75 and ≥75 years subgroups.

Dose Optimization

The Applicant’s proposed dosage regimen of belantamab mafodotin 2.5 mg/kg, administered as an intravenous infusion every 3 weeks until disease progression or unacceptable toxicity, was approved based upon the benefit-risk profile observed in the pivotal DREAMM-2 trial. However, there was uncertainty regarding the optimal dose of belantamab mafodotin for the indicated patient population. In DREAMM-1, responses were observed at dose levels from 0.96 mg/kg and above, ocular toxicity was observed at dose levels as low as 0.12 mg/kg. There was limited data at doses lower than 2.5 mg/kg due to evaluation of only 1–4 patients per dose level to inform the selection of the 2.5 mg/kg dose (Table 3). Ocular toxicity rates noted at the 2.5 mg/kg dose in DREAMM-2, were not different from the rates observed with the 3.4 mg/kg dose. Exposure-response (E-R) analyses indicated that increasing doses and exposures (trough concentration [C_tau] and average concentration [C_avg] at cycle 1) of belantamab mafodotin were associated with increasing probability of Grade ≥2 and Grade ≥3 corneal ARs even after adjusting by baseline soluble BCMA and history of dry eye (7). In addition, data from DREAMM-2 indicated that belantamab mafodotin maximum concentration (C_max) at Cycle 1 may also be associated with the risk of ocular toxicity. Therefore, additional data to further optimize the dose was warranted. A PMR was issued to require further evaluation of alternative dosage regimens, including lower doses.

Table 3:

Overall Response Rate and Ocular Toxicity in First-in-Human DREAMM-1 Trial

DREAMM-1 Cohort (mg/kg)	0.03 (N=1)	0.06 (N=1)	0.12 (N=4)	0.24 (N=4)	0.48 (N=4)	0.96 (N=3)	1.92 (N=4)	2.5 (N=8)	3.4 (N=3)	4.6 (N=6)
Efficacy: Investigator-Assessed Response
ORR, n (%)	0	0	0	0	0	1 (33)	1 (25)	1 (13)	3 (100)	3 (50)
Safety: Eye Disorders
Any grade, n (%)	0	0	1 (25)	1 (25)	2 (50)	1 (33)	4 (100)	3 (38)	3 (100)	6 (100)
Grade 2, n (%)	0	0	0	0	0	1 (33)	2 (50)	3 (38)	2 (67)	4 (67)
Grade 3, n (%)	0	0	0	0	0	0	1 (25)	0	1 (33)	0

Abbreviations: ORR=overall response rate

(Source: Adapted from FDA BLA761158 Multidisciplinary Review and Evaluation; ref 7)

Conclusion

Belantamab mafodotin is a first-in-class BCMA-directed ADC. Based on the observed benefit for belantamab mafodotin in the single arm trial in conjunction with the REMS with ETASU to mitigate the risk of ocular toxicity and the information in the USPI, the benefit-risk assessment supported accelerated approval of belantamab mafodotin for the treatment of adult patients with RRMM who have received at least 4 prior therapies including an anti-CD38 mAb, a PI, and an IMID. The DREAMM-3 trial, a randomized, phase 3 trial evaluating the efficacy and safety of belantamab mafodotin versus pomalidomide in combination with dexamethasone in patients with RRMM who have received at least 2 prior lines of therapy including lenalidomide and a PI, was proposed by the Sponsor to potentially serve as a phase 3 confirmatory trial.