Blenrep's Reemergence: Navigating Safety Risks and Market Dynamics in the ADC Space

The antibody-drug conjugate (ADC) market has become a battleground for pharmaceutical innovation, with GlaxoSmithKline's (GSK) Blenrep (belantamab mafodotin-blmf) standing at a crossroads. Approved in 2020 for relapsed/refractory multiple myeloma (RRMM) patients with limited options, Blenrep's journey has been marked by regulatory scrutiny, clinical setbacks, and a strategic pivot to combination therapies. As of 2025, the drug's reapproval in combination regimens in the UK and Japan, alongside ongoing U.S. regulatory reviews, raises critical questions about its long-term commercial viability.

The FDA's Safety Concerns: A Double-Edged Sword

The FDA's primary concern with Blenrep centers on its ocular toxicity profile. Keratopathy—a corneal condition causing blurred vision or blindness—occurred in over 90% of patients in pivotal trials (DREAMM-7 and DREAMM-8). While most cases resolved with dose modifications, the severity and frequency of these events prompted the FDA's Oncologic Drugs Advisory Committee (ODAC) to question whether the benefits outweigh the risks. The agency's 2022 withdrawal of Blenrep's monotherapy approval underscored the regulatory body's caution, even as GSK argued for its value in combination regimens.

The reintroduction of Blenrep in 2025 hinges on a robust Risk Evaluation and Mitigation Strategy (REMS), which includes mandatory patient monitoring and collaboration with ophthalmologists. While this mitigates some risks, the REMS adds administrative and financial burdens for healthcare providers and payers. For investors, the key question is whether the REMS can normalize Blenrep's adoption without deterring uptake due to complexity or liability concerns.

Competitive Pressures: A Crowded ADC Landscape

The ADC market for RRMM is no longer a niche space. Competitors like XPOVIO (selinexor) and newer BCMA-targeting therapies (e.g., Car-T and bispecific antibodies) are reshaping the treatment paradigm. Blenrep's combination regimens, however, offer a unique edge: in DREAMM-7 and DREAMM-8, Blenrep + bortezomib + dexamethasone (BVd) or pomalidomide + dexamethasone (BPd) demonstrated median progression-free survival (PFS) of 36.6 months and 32.6 months, respectively—far outpacing existing standards of care.

Yet, Blenrep's ocular side effects remain a differentiator in the wrong way. While other ADCs, such as Enhertu (fam-trastuzumab deruxtecan) and Padcev (enfortumab vedotin), also face safety profiles (e.g., interstitial lung disease, neuropathy), their toxicity is less likely to render patients permanently disabled. For payers and clinicians, Blenrep's safety risks could limit its use to highly selected patient populations, capping its market potential.

Strategic Reorientation: Combination Therapies as the Lifeline

GSK's pivot to combination therapies has been a masterstroke. By pairing Blenrep with bortezomib or pomalidomide, the company has not only improved efficacy but also diversified its therapeutic value. The DREAMM-7 and DREAMM-8 trials showed that Blenrep's immune-modulating properties—such as antibody-dependent cellular cytotoxicity (ADCC)—complement traditional myeloma drugs, creating a synergistic effect. This strategy has resonated in markets like the UK and Japan, where regulatory bodies have prioritized PFS and overall survival (OS) benefits over safety concerns.

However, the U.S. FDA remains skeptical. The ODAC's criticism of Blenrep's “non-optimized” dosing in combination trials suggests that GSK may need to refine its protocols further. For now, the drug's U.S. approval rests on a fragile balance between efficacy and risk management.

Financial Implications and Investment Considerations

The ADC market is projected to grow at a compound annual rate of 25% through 2030, driven by demand for targeted therapies in oncology. Blenrep's reentry into the UK and Japan could generate $200–300 million in annual revenue, but its U.S. prospects depend on FDA approval and payer reimbursement.

Investors must weigh GSK's broader portfolio against Blenrep's uncertainties. While the company's focus on respiratory and HIV treatments provides a stable base, its oncology segment—anchored by Blenrep and other ADCs—remains a high-risk, high-reward bet. The drug's long-term commercial viability will hinge on three factors:
1. Regulatory Acceptance: Will the FDA greenlight Blenrep's combination regimens in the U.S., and how will its REMS be enforced?
2. Competitive Erosion: Can Blenrep maintain its PFS/OS lead as newer BCMA-targeted therapies (e.g., teclistamab) enter the market?
3. Cost of Care: Will payers cover Blenrep's high price tag ($35,000–$40,000 per dose) given its safety risks and the availability of alternatives?

Conclusion: A Calculated Bet on Innovation

Blenrep's story is emblematic of the ADC market's duality: groundbreaking science meets regulatory and commercial friction. For GSK, the drug represents both a strategic opportunity and a reputational risk. Investors who believe in GSK's ability to navigate these challenges—through dosing refinements, payer negotiations, and continued clinical innovation—may find Blenrep a compelling long-term holding. However, those wary of regulatory overreach or competitive displacement should proceed cautiously.

In the end, Blenrep's fate will mirror the broader ADC industry's evolution: a race to balance efficacy with safety in an era of rising patient expectations and tighter regulatory scrutiny.