DREAMM-10 (Study 214828)

Adult TI-NDMM requiring treatment (IMWG criteria), measurable disease, transplant-ineligible, ECOG 0-2, adequate organ function, protocol-specified contraception/pregnancy prevention, informed consent.

Participants are eligible only if all criteria are met: 1) Age: - At least 18 years (or legal age of consent in jurisdiction) at informed consent. 2) Informed consent: - Capable of giving signed informed consent and complying with protocol/ICF requirements. 3) Diagnosis and disease status: - Newly diagnosed MM requiring treatment per IMWG criteria. - Monoclonal BM plasma cells >=10% or biopsy-proven plasmacytoma plus at least one CRAB criterion. 4) Measurable disease: - Serum M-protein >=0.5 g/dL (>=5.0 g/L), and/or - Serum FLC: involved FLC >=10 mg/dL (>=100 mg/L) with abnormal serum FLC ratio (<0.26 or >1.65). 5) Transplant ineligibility (TI-NDMM): - Not candidate for high-dose chemotherapy with ASCT due to: a) Country/site-specific age restriction for ASCT, and/or b) Comorbid condition(s) likely to negatively impact high-dose chemotherapy with ASCT tolerability. 6) ECOG performance status: - ECOG PS 0 to 2. 7) Adequate organ function: - Hematologic: ANC >=1.0x10^9/L; platelets >=75x10^9/L. - Hepatic: total bilirubin <=1.5xULN (isolated bilirubin >1.5xULN acceptable if fractionated and direct bilirubin <35%); ALT/AST <=2.5xULN. - Renal: eGFR >=30 mL/min/1.73 m^2. - Urine protein criteria per protocol (dipstick negative/trace, or albumin/creatinine ratio threshold if dipstick 1+). 8) Reproductive criteria and pregnancy prevention: - Must meet protocol-defined criteria for male/female contraception and pregnancy prevention. - WOCBP must have 2 negative highly sensitive serum pregnancy tests before treatment (first within 14 days of C1D1, second within 24 hours before first dose). - Additional lenalidomide-specific pregnancy prevention requirements apply (including two reliable birth-control methods if not continuously abstinent).

Prior systemic MM therapy, plasma-cell dyscrasia variants (e.g., plasma cell leukemia/AL amyloidosis/POEMS), CNS MM involvement, major uncontrolled comorbidities/infection risks (including active HBV/HCV unless protocol exceptions), significant cardiac risk, corneal epithelial disease (except mild punctate keratopathy), contraindications to required prophylaxis, and selected recent therapies/vaccination.

Participants are excluded if any apply: 1) Diagnosis of systemic AL amyloidosis, Waldenstrom disease, POEMS, or primary plasma cell leukemia (circulating plasma cells >5%). 2) Prior systemic therapy for MM or smoldering MM. - Note: emergency short steroid course allowed per protocol limits. - Note: focal palliative radiation allowed if protocol timing/recovery criteria met. 3) Signs of meningeal or CNS involvement with MM. 4) Major surgery within 2 weeks prior to first dose, or not fully recovered (kyphoplasty not considered major surgery). 5) Serious/unstable pre-existing medical or psychiatric disorder/other condition (including lab abnormalities) that could interfere with safety, consent, or compliance. 6) Current active liver or biliary disease (except Gilbert syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator). 7) Previous/concurrent malignancies other than MM, except allowed low-risk exceptions and/or medically stable >=2 years after discussion with GSK Medical Monitor; no active therapy other than hormonal therapy. 8) Cardiovascular risk conditions including: a) Clinically significant untreated arrhythmias or ECG abnormalities (including Mobitz II or third-degree AV block). b) MI/acute coronary syndrome/coronary intervention within 3 months. c) NYHA class III/IV heart failure. 9) Known HIV infection unless all protocol criteria met (stable ART, viral load <400 copies/mL during screening, CD4+ >=350 cells/µL, no AIDS-defining opportunistic infections within last 12 months). 10) Positive HCV antibody or positive HCV RNA at screening/within 3 months before first dose unless protocol-defined criteria met (negative RNA and successful antiviral treatment with required washout and repeat negative RNA). 11) HBV exclusion unless protocol-defined serology/DNA/antiviral criteria are met; includes required monitoring and antiviral management for eligible HBV-risk participants. 12) Current corneal epithelial disease except mild punctate keratopathy. 13) Intolerance or contraindication to antiviral prophylaxis. 14) Unable to tolerate antithrombotic prophylaxis. 15) Known immediate/delayed hypersensitivity or idiosyncratic reaction to belantamab mafodotin or study intervention components. 16) Plasmapheresis within 7 days prior to first study intervention dose. 17) Live or live-attenuated vaccine within 30 days prior to first belantamab mafodotin dose.