Belantamab Mafodotin-blmf (Blenrep)

Number: 0981

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses belantamab mafodotin-blmf (Blenrep) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Effective July 1, 2026, precertification of belantamab mafodotin-blmf (Blenrep) is required of all Aetna participating providers and members in applicable plan designs. For precertification of belantamab mafodotin-blmf (Blenrep), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

1. Criteria for Initial Approval

   1. Multiple Myeloma

      Aetna considers belantamab mafodotin-blmf (Blenrep) medically necessary for the treatment of relapsed or refractory multiple myeloma in the following settings:

      1. In combination with bortezomib and dexamethasone, when the member has received at least two lines of prior therapy, including a proteasome inhibitor and an immunomodulatory agent; or 
      2. As a single agent for maintenance therapy after completing 8 cycles of combination treatment with bortezomib and dexamethasone, when the member has received at least two lines of prior therapy including a proteasome inhibitor and an immunomodulatory agent; or 
      3. As a single agent, when the member has received at least three lines of prior therapy;

   2. Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) syndrome, Plasma-cell related monoclonal immunoglobulin deposition disease (MIDD), and Plasma cell-related monoclonal gammopathy of renal significance (MGRS)

      Aetna considers belantamab mafodotin-blmf (Blenrep) medically necessary, as a single agent or in combination with bortezomib and dexamethasone, for the treatment of POEMS syndrome, plasma cell-related MIDD, or plasma cell-related MGRS.

   Aetna considers all other indications as experimental, investigational, or unproven.

2. Continuation of Therapy

   Aetna considers continuation of belantamab mafodotin-blmf (Blenrep) therapy medically necessary in members (including new members) requesting reauthorization for an indication listed in the Criteria for Initial Approval section when there is no evidence of disease progression or unacceptable toxicity while on the current regimen.

Dosage and Administration

Belantamab mafodotin-blmf is available as Blenrep 70 mg as a lyophilized powder in a single-dose vial for reconstitution and further dilution.

Multiple Myeloma

The recommended dosage of Blenrep, in combination with bortezomib and dexamethasone, is 2.5 mg/kg as an intravenous infusion over 30 minutes once every 3 weeks for 8 cycles, followed by Blenrep 2.5 mg/kg every 3 weeks as a single agent until disease progression or unacceptable toxicity. 

Source: GlaxoSmithKline, 2025

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
96413 - 96417	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
Belantamab mafodotin-blmf (Blenrep)-no specific code
Other HCPCS codes related to the CPB:
Ixazomib, Lenalidomide, Pomalidomide - No specific code:
J1100	Injection, dexamethasone sodium phosphate, 1 mg
J8540	Dexamethasone, oral, 0.25 mg
J8541	Dexamethasone (hemady), oral, 0.25 mg
J9041	Injection, bortezomib, 0.1 mg
J9046	Injection, bortezomib, (dr. reddy's), not therapeutically equivalent to J9041, 0.1 mg
J9047	Injection, carfilzomib, 1 mg
J9048	Injection, bortezomib (fresenius kabi), not therapeutically equivalent to J9041, 0.1 mg
J9049	Injection, bortezomib (hospira), not therapeutically equivalent to J9041, 0.1 mg
J9051	Injection, bortezomib (maia), not therapeutically equivalent to j9041, 0.1 mg
J9054	Injection, bortezomib (boruzu), 0.1 mg
J9145	Injection, daratumumab, 10 mg
ICD-10 codes covered if selection criteria are met:
C90.00 - C90.02	Multiple myeloma
D47.2	Monoclonal gammopathy [ renal significance (MGRS)]] [POEMS]
D47.Z9	Other specified neoplasms of uncertain behavior of lymphoid, hematopoietic and related tissue [MIDD]

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Blenrep is indicated, in combination with bortezomib and dexamethasone, for the treatment of adults with relapsed or refractory multiple myeloma who have received at least two prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent. 

Compendial Uses

• Relapsed or refractory multiple myeloma
• Polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) syndrome
• Plasma cell-related monoclonal gammopathy of renal significance (MGRS)
• Plasma-cell related monoclonal immunoglobulin deposition disease (MIDD)

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in the bone marrow, leading to bone destruction and marrow failure. Multiple myeloma accounts for about 1.8% of all cancers and slightly over 17% of hematologic malignancies in the United States. The American Cancer Society has estimated about 32,270 new cases of multiple myeloma in the United States in 2020, with an estimated 12,830 deaths (American Cancer Society, 2020).

On August 5, 2020, the Food and Drug Administration granted accelerated approval to belantamab mafodotin-blmf (Blenrep) for 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. Belantamab mafodotin-blmf is a B-cell maturation antigen (BCMA)-directed antibody and microtubule inhibitor conjugate that directly targets a B-cell maturation antigen (BCMA) a protein on the surface on myeloma cells. The efficacy of belantamab mafodotin-blmf was evaluated in DREAMM-2 (NCT 03525678), an open-label, multicenter trial. Eligible patients had relapsed or refractory multiple myeloma, had previously received 3 or more prior therapies, including an anti-CD38 monoclonal antibody, and were refractory to an immunomodulatory agent and a proteasome inhibitor. Patients had measurable disease by International Myeloma Working Group (IMWG) criteria. Patients with corneal epithelial disease, except mild punctate keratopathy, at baseline were excluded from the study. Patients with mild or moderate renal impairment (eGFR 30 to 89 mL/min/1.73 m2) at baseline were also eligible for the study. Patients received either belantamab mafodotin-blmf 2.5 mg/kg or 3.4 mg/kg intravenously once every 3 weeks until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall response rate as evaluated by an Independent Review 18 Committee (IRC) based on the IMWG Uniform Response Criteria for Multiple Myeloma. A total of 97 patients received belantamab mafodotin-blmf at a dose of 2.5 mg/kg administered intravenously once every 3 weeks. The median age was 65 years (range of 39 to 85 years), 53 % were male, 74 % were White, and 16 % were Black. Most patients (77 %) were International Staging System (ISS) Stage II or III, 87 % had received prior autologous stem cell transplantation (ASCT), and 16 % had an Eastern Cooperative Oncology Group (ECOG) performance status of 2. High-risk cytogenetic factors (presence of t[4;14], t[14;16] and 17p13del) were present in 27 % of patients. The median number of prior lines of therapy was 7 (range of 3 to 21). The median time to first response was 1.4 months (95 % CI: 1.0 to 1.6). The overall response rate (ORR) was 31 % (97.5 % CI: 21 % to 43 %); 73 % of responders had response durations of greater than or equal to  6 months. These results were observed in patients receiving the recommended dose of 2.5 mg/kg. The authors noted that 2.5 mg/kg was selected as the recommended dose for future studies with belantamab mafodotin, given the similar efficacy and a more favorable safety profile compared with the 3.4-mg/kg dose. Overall, the median duration of response (DOR) was not reached.

There is a boxed warning in the prescribing information cautioning that belantamab mafodotin-blmf causes changes in the corneal epithelium resulting in alterations in vision, including severe vision loss and corneal ulcer, and symptoms, such as blurred vision and dry eyes. Therefore, ophthalmic exams at baseline, prior to each dose, and promptly for worsening symptoms should be conducted. Because of the risks of ocular toxicity, belantamab mafodotin-blmf is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), called the BLENREP REMS.

Adverse reactions in 20 % or more of patients who received belantamab mafodotin-blmf were keratopathy, decreased visual acuity, nausea, blurred vision, pyrexia, infusion-related reactions, and fatigue.

The recommended belantamab mafodotin-blmf dose is 2.5 mg/kg as an intravenous infusion over approximately 30 minutes once every 3 weeks.

Nooka and colleagues (2021) noted that belantamab mafodotin (belamaf) is a BCMA-targeted antibody-drug conjugate recently approved as monotherapy for adults with relapsed/refractory multiple myeloma (MM) who have received greater than or equal to 4 prior therapies.  Belamaf binds to BCMA and eliminates myeloma cells by multi-modal mechanisms of action.  The cytotoxic and potential immunomodulatory properties of belamaf have led to novel combination studies with other anti-cancer therapies.  These researchers described the rationale and design of DREAMM-5, an ongoing phase-I/II platform study examining the safety and efficacy of belamaf combined with novel agents, including GSK3174998 (OX40 agonist), feladilimab (an ICOS; GSK3359609), nirogacestat (a gamma-secretase inhibitor; PF-03084014) and dostarlimab (a PD-1 blocker) versus belamaf monotherapy for patients with relapsed/refractory MM.

As of February 6, 2023, the U.S. Food and Drug Administration (FDA) revoked the biologics license application (BLA) for belantamab mafodotin-blmf (Blenrep) powder for injection. Blenrep withdrawal from the U.S. market was based upon the previously announced outcome of the DREAMM-3 phase III confirmatory trial which did not meet the requirements of the FDA Accelerated Approval regulations.

Belantamab mafodotin-blmf is available as Blenrep (GlaxoSmithKline LLC.) an antibody-drug conjugate (ADC) that targets the B-cell maturation antigen (BCMA). It consists of three primary components: an afucosylated, humanized immunoglobulin G1 monoclonal antibody; the microtubule inhibitor mcMMAF; and a protease-resistant maleimidocaproyl linker, which covalently binds the antibody to the inhibitor. The antibody is produced using recombinant DNA technology in a Chinese Hamster Ovary cell line, while the microtubule inhibitor and linker are synthesized chemically. The antibody component of Blenrep specifically targets BCMA, a protein found on both normal B lymphocytes and multiple myeloma cells. Once the ADC binds to BCMA, it is internalized by the cell, where proteolytic cleavage releases the active cytotoxic agent, cys-mcMMAF. This released cys-mcMMAF intracellularly disrupts the microtubule network, causing cell cycle arrest and triggering apoptosis. Additionally, the ADC exhibits antitumor effects by killing multiple myeloma cells through both cys-mcMMAF-induced apoptosis and immune-mediated mechanisms such as antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis (GlaxoSmithKline, 2025).

According to the prescribing information, Blenrep carries the following boxed warning for ocular toxicity:

• Blenrep causes changes in the corneal epithelium resulting in changes in vision, including severe visual impairment, and symptoms such as blurred vision and dry eyes. In the clinical study, corneal ulcers, including cases with infection, also occurred.
• Conduct ophthalmic exams at baseline, before each dose, promptly for new or worsening symptoms, and as clinically indicated. In the clinical study, 83% of patients required a dosage modification due to ocular toxicity. Withhold Blenrep until improvement and resume or permanently discontinue, based on severity.

Additionally, the prescribing information notes the following information about warnings and precautions, adverse reactions, and use in specific populations:

Warnings and precautions:

• Thrombocytopenia: Monitor complete blood counts at baseline and periodically during treatment. Withhold or reduce the dosage based on severity.
• Embryo-fetal toxicity: Can cause fetal harm. Advise patients of the potential risk to fetus and to use effective contraception.

Adverse reactions:

• The most common adverse reactions (≥20%) with BLENREP in combination with bortezomib and dexamethasone are reduction in best-corrected visual acuity (BCVA), corneal exam findings, blurred vision, dry eye, photophobia, foreign body sensation in eyes, eye irritation, upper respiratory tract infection, hepatotoxicity, eye pain, diarrhea, fatigue, pneumonia, cataract, and COVID-19. The most common Grade 3 or 4 (≥10%) laboratory abnormalities are decreased platelets, decreased lymphocytes, decreased neutrophils, increased gamma-glutamyl transferase, decreased white blood cells, and decreased hemoglobin.

Use in specific populations:

• Lactation: Advise not to breastfeed.

On October 23, 2025, the U.S. Food and Drug Administration (FDA) approved belantamab mafodotin-blmf (Blenrep) in combination with bortezomib and dexamethasone for the treatment of adults with relapsed or refractory multiple myeloma who have received at least two prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent. Blenrep is a conjugate product composed of a B-cell maturation antigen (BCMA)-directed antibody linked to a microtubule inhibitor. The FDA approval was based on supporting data from the DREAMM-7 trial (NCT04246047) (FDA, 2025).

Investigators evaluated the efficacy of belantamab mafodotin-blmf (Blenrep) in the DREAMM-7 trial (NCT04246047), an open-label, randomized, multicenter study involving adult patients with relapsed or refractory multiple myeloma who had received at least one prior line of therapy. The trial excluded patients refractory or intolerant to daratumumab or bortezomib, those with previous exposure to BCMA-directed therapies, and individuals with existing corneal disease (excluding cases of mild punctate keratopathy). Participants were randomized in a 1:1 ratio to receive either the Blenrep, bortezomib, and dexamethasone (BVd) or a combination of daratumumab, bortezomib, and dexamethasone (DVd). The efficacy population comprised 217 patients (108 in the BVd arm and 109 in the DVd arm) each having been treated with at least two prior regimens that included a proteasome inhibitor and an immunomodulatory agent (FDA, 2025; GlaxoSmithKline, 2025).

Efficacy outcomes were measured by progression-free survival (PFS) and overall survival (OS). The results demonstrated that the median PFS was 31.3 months (95% confidence interval [CI]: 23.5, not reached [NR]) in the BVd arm compared to 10.4 months (95% CI: 7, 13.4) in the DVd arm, corresponding to a hazard ratio (HR) of 0.31 (95% CI: 0.21, 0.47). Additionally, the median OS was NR in the BVd group versus 35.7 months (95% CI: 21.1, NR) in the DVd group (HR 0.49, 95% CI: 0.32, 0.76) (FDA, 2025; GlaxoSmithKline, 2025).

Belantamab in Combination with Dexamethasone in Patients with Triple-class Relapsed/Refractory Multiple Myeloma

Atieh et al (2022) noted that triple-class relapsed/refractory multiple myeloma (RRMM) has a poor prognosis.  These researchers examined the clinical outcomes of belantamab plus dexamethasone (Bd) in the treatment of patients with triple-class RRMM.  They identified 35 patients with triple-class RRMM who received Bd at the University of Kansas from October 2019 to November 2021.  The median age was 66 years (42 to 85) and the median prior lines of therapy was 5 (3 to 15); 19 (54 %) patients had R-ISS stage III disease, 15 (43 %) patients had high-risk cytogenetics, and 15 patients (43 %) had extra-medullary disease (EMD); 8 patients received prior BCMA-targeted therapy.  ORR was 43 %, with 23 % achieving very good partial response (PR) and better.  At a median follow-up of 10.7 months, the median progression-free survival (PFS) and overall survival (OS) were 4.9 and 10.7 months, respectively.  The most common adverse event (AE) was keratopathy, which occurred in 30 (86 %) patients; 24 patients required dose reduction or delay due to keratopathy.  Other common toxicities included anemia (83 %), thrombocytopenia (80 %), neutropenia (34 %), and elevated liver function tests (51 %).  The authors concluded that this analysis showed belantamab plus dexamethasone exhibited good activity in triple-class RRMM; and keratopathy remains a challenging AE and the leading cause of dose reduction, delay and treatment cessation.

Belantamab for the Treatment of Light Chain Amyloidosis

Rodriguez et al (2022) noted that light chain (AL) amyloidosis is challenging to diagnose, and it should be considered a cardiac emergency.  There has been a great deal of advances in the treatment of AL amyloidosis from initial descriptions of melphalan therapy until the recent approval of the 1st AL amyloidosis specific drug (daratumumab).  Comprehension of the pathophysiology and biology of AL amyloidosis is crucial to understanding the major therapeutic targets in which light chain stability remains as a major key target of therapy.  Organ dysfunction is a result not only from disruption of organ architecture but also direct cellular toxicity.  Novel anti-plasma cell agents for AL like isatuximab (anti CD-38 monoclonal antibody), belantamab (anti-BCMA monoclonal antibody), and elotuzumab (anti-SLAMF7 monoclonal antibody) are currently under investigation.  The authors concluded that both diagnostic and therapeutic advances made the future of AL management bright while acknowledging the complexity of this patient population and focusing on a multi-disciplinary approach.

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References