Belantamab Mafodotin Moves Into Lenalidomide-Refractory Myeloma in Updated NCCN Guidelines

The National Comprehensive Cancer Network (NCCN) added belantamab mafodotin-blmf (Blenrep; GSK) plus bortezomib (Velcade; Takeda) and dexamethasone (BVd) as a category 1 recommendation for patients with lenalidomide-refractory multiple myeloma (MM).¹ The change appears in Version 1.2027 of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma, released September 9, 2026.²

Two other belantamab triplets—with pomalidomide (Pomalyst; Bristol Myers Squibb) and dexamethasone (BPd), and with carfilzomib (Kyprolis; Amgen) and dexamethasone (BKd)—now appear under "Useful in Certain Circumstances" for patients who have received 3 or more prior lines of therapy.¹ The BVd listing also appears to reach past the drug's FDA label, a gap with practical consequences for pharmacists managing access.

The update is part of a broader restructuring of the relapsed/refractory section, which now separates treatment strategies by number of prior lines of therapy.¹ It also arrives roughly 1 year after the antibody-drug conjugate returned to the US market.

From Withdrawal to Category 1

The FDA approved BVd on October 23, 2025, for adults with relapsed or refractory MM who have received at least 2 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.³ That approval returned the drug to the US market after GSK withdrew its earlier single-agent indication in 2022, when the confirmatory DREAMM-3 (NCT04162210) trial did not demonstrate a sufficient progression-free survival (PFS) benefit.⁴

The approval rests on the phase 3 DREAMM-7 trial (NCT04246047), which randomly assigned 494 patients with relapsed/refractory disease after at least 1 prior line of therapy to BVd (n = 243) or daratumumab, bortezomib, and dexamethasone (DVd; n = 251).⁵ In the labeled population of patients with 2 or more prior lines, median PFS was about 31.3 months with BVd vs 10.4 months with DVd (HR, 0.31).³ Overall survival (OS) also favored BVd in that population, with median OS not reached vs 35.7 months (HR, 0.49; 95% CI, 0.32-0.76).³

An updated descriptive analysis with more than 4 years of median follow-up (52.9 months) showed a continued OS benefit for BVd in the intention-to-treat population (HR, 0.62; 95% CI, 0.46-0.82) and in patients with 3 or more lines of therapy (HR, 0.49; 95% CI, 0.33-0.74), with no new safety signals.⁶

Where the Guidelines and the Label Diverge

The guideline language matters because lenalidomide refractoriness is no longer a late-line phenomenon. With lenalidomide-based induction and maintenance now standard, many patients are lenalidomide refractory at first relapse—exactly the population DREAMM-8 was designed around.⁷ By anchoring BVd to lenalidomide-refractory disease rather than to a prior-line threshold, the NCCN recommendation appears to extend to patients who do not yet meet the FDA indication's 2-prior-line requirement.^1,3

The BPd and BKd recommendations go further: neither regimen carries a US approval. The FDA indication covers BVd only and does not include BPd.³ BPd is supported by the phase 3 DREAMM-8 clinical trial (NCT04484623), in which 302 lenalidomide-exposed patients with at least 1 prior line of therapy were randomly assigned to BPd or pomalidomide, bortezomib, and dexamethasone (PVd). The 12-month PFS rate was approximately 71% with BPd vs 51% with PVd (HR for progression or death, 0.52; 95% CI, 0.37-0.73; P < .001).⁷ BKd evidence comes from the smaller, single-arm phase 1/2 BelaCarD study (ACTRN12620000490976), in which the combination produced an overall response rate of about 83% and a median PFS of 22.6 months.⁸

Ocular Toxicity Still Sets the Pace

Guideline expansion does not change the drug's defining toxicity. In DREAMM-7, ocular toxicity occurred in 92% of patients receiving belantamab mafodotin, including grade 3 or 4 events in 77%, and 83% required dosage modification because of ocular toxicity.³ Belantamab mafodotin is available only through the BLENREP Risk Evaluation and Mitigation Strategy (REMS).³ Ocular events were also common with BPd in DREAMM-8 but were controllable with belantamab mafodotin dose modification.⁷

Hematologic toxicity deserves equal attention. Grade 3 or 4 thrombocytopenia occurred in 56% of patients receiving BVd vs 35% receiving DVd in DREAMM-7, and serious adverse events occurred in 53% vs 38%, respectively, with pneumonia the most common.⁵

The labeled BVd schedule is 2.5 mg/kg every 3 weeks with bortezomib and dexamethasone for the first 8 cycles, followed by single-agent belantamab mafodotin until progression or unacceptable toxicity.³

In DREAMM-8, belantamab mafodotin was given at 2.5 mg/kg on cycle 1, day 1, then 1.9 mg/kg every 4 weeks,⁷ while BelaCarD dosed belantamab mafodotin on day 1 of every second 28-day cycle.⁸ Order sets, REMS-linked eye examination scheduling, and patient counseling on blurred vision, dry eye, and driving safety all need to match the regimen actually chosen.

A Crowded BCMA Sequence

Belantamab mafodotin also re-enters a field in which B-cell maturation antigen (BCMA) is targeted by CAR T-cell therapies and bispecific antibodies. The NCCN panel noted that the optimal sequencing of BCMA-targeted therapies remains under investigation, and the update adds a new Principles of T-Cell Redirecting Therapy page, including the option of talquetamab-tgvs (Talvey; Johnson & Johnson) as a bridge to BCMA-directed CAR T-cell therapy.¹ Because BVd can be infused in the community setting, where most patients with myeloma are treated, it may be the first BCMA exposure for many patients—making documentation of prior BCMA therapy part of every hand-off to a referral center.

REFERENCES

1. Updated NCCN myeloma guidelines include NDMM treatment updates, changes to treatment strategies for RRMM, and MRD testing. International Myeloma Foundation. September 24, 2026. Accessed November 11, 2026. https://www.myeloma.org/nccn-updated-myeloma-guidelines

2. NCCN Clinical Practice Guidelines in Oncology. Multiple myeloma, version 1.2027. Accessed November 12, 2026. https://www.nccn.org

3. Blenrep (belantamab mafodotin-blmf). Prescribing information. GSK; 2025. Accessed November 12, 2026. https://www.accessdata.fda.gov/scripts/cder/daf/

4. Withdrawal of Blenrep from the US Market. International Myeloma Society. November 23, 2022. Accessed November 12, 2026. https://www.myeloma.org/news-events/withdrawal-blenrep-us-market

5. Hungria V, Robak P, Hus M, et al. Belantamab mafodotin plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (DREAMM-7): updated overall survival analysis from a global, randomised, open-label, phase 3 trial. Lancet Oncol. 2025. doi:10.1016/S1470-2045(25)00330-4

6. Belantamab mafodotin, bortezomib, and dexamethasone vs daratumumab, bortezomib, and dexamethasone in relapsed/refractory multiple myeloma: updated 4-year results of the phase 3 DREAMM-7 trial. Abstract PO15. HMP Global Learning Network. Accessed November 11, 2026. https://www.hmpgloballearningnetwork.com/node/392615

7. Dimopoulos MA, Beksac M, Pour L, et al. Belantamab mafodotin, pomalidomide, and dexamethasone in multiple myeloma. N Engl J Med. 2024;391(5):408-421. doi:10.1056/NEJMoa2403407

8. BKd produces robust responses in relapsed/refractory multiple myeloma. OncLive. Accessed November 11, 2026. https://www.onclive.com/view/bkd-produces-robust-responses-in-relapsed-refractory-multiple-myeloma