DREAMM-9: Phase III study of belantamab mafodotin plus VRd versus VRd alone in transplant-ineligible newly diagnosed multiple myeloma (TI NDMM).

Abstract

TPS8556 Background: Bortezomib, lenalidomide, and dexamethasone (VRd) is the standard of care for transplant-eligible and TI NDMM, but relapse is usually inevitable. The median progression-free survival (PFS) is ~3 years for patients with TI NDMM, and with each relapse, the duration of response (DoR) diminishes, highlighting the need for novel, effective, targeted agents. Single-agent belantamab mafodotin is a first-in-class B-cell maturation antigen–binding, humanized, afucosylated, monoclonal immunoconjugate, showing deep and durable responses in heavily pretreated patients with relapsed/refractory multiple myeloma ( Lancet Oncol2020). Preclinical work suggests belantamab mafodotin plus bortezomib or lenalidomide enhances anti-myeloma activity. Therefore, studying clinical activity of belantamab mafodotin in combination with these agents is warranted. Methods: DREAMM-9 (NCT04091126) is a two-part, open-label study to determine efficacy and safety of single-agent belantamab mafodotin with VRd vs. VRd alone in patients with TI NDMM. Patients aged ≥18 years with ECOG status 0–2 and adequate organ system functions will be eligible. Part 1 (dose selection) will evaluate safety/tolerability of belantamab mafodotin with VRd administered by single (Day 1) or split dosing (Days 1 and 8) in ≤5 cohorts (n = 12/cohort): 1.9 mg/kg, 2.5 mg/kg split and single, and 3.4 mg/kg split and single. Six more patients may be added to cohort(s) most likely to be selected as recommended Phase III dose (RP3D). Dose-limiting toxicities and adverse events (AEs) will be assessed, and belantamab mafodotin RP3D determined through modified toxicity probability interval criteria. Part 2 (randomized Phase III) will determine efficacy and safety of belantamab mafodotin at RP3D with VRd vs. VRd alone (n = 750) in two arms randomized 1:1. Dual primary endpoints will be rate of minimal residual disease (MRD) negativity and PFS. Secondary endpoints will be response rates (overall response, complete response, very good partial response or better, sustained MRD negativity), DoR, time to progression, and overall survival. Safety assessment will include AEs, serious AEs and ocular findings. In both parts, belantamab mafodotin will be given with VRd for eight induction cycles and then with Rd for maintenance until disease progression or unacceptable toxicity. Funding: GlaxoSmithKline (209664). Drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Clinical trial information: NCT04091126 .

Antibody-drug conjugate therapies in multiple myeloma—what’s next on the horizon?

“…Currently, Bela is being evaluated in clinical trials in earlier lines of therapy and in combination with prior approved regimens such as PIs and IMiDs ( Table 1 ). Examples of such ongoing phase III clinical trials include DREAMM-8, evaluating Bela in combination with pomalidomide (Pom) and dexamethasone (Dex) as second-line therapy; DREAMM-9 evaluating Bela with bortezomib (Bor), lenalidomide (Len), and Dex in newly diagnosed MM (NDMM) [ 7 , 9 , 16 ]. Phase II trials involving Bela combinations include DREAMM-4 evaluating Bela with pembrolizumab in RRMM [ 17 ]; DREAMM-5, evaluating Bela in combination with several other agents in the fourth-line setting RRMM [ 18 ], and DREAMM-6 comparing Bela in combination with Len and Dex versus Bela with Bor and Dex in RRMM [ 19 ].…”

Belantamab Mafodotin to Treat Multiple Myeloma: A Comprehensive Review of Disease, Drug Efficacy and Side Effects

“…The focuses of these upcoming trials include the efficacy and safety of belamaf in comparison to pomalidomide plus low-dose dexamethasone (DREAMM-3), belamaf in combination with pembrolizumab (DREAMM-4), and belamaf in combination with lenalidomide or bortezomib plus dexamethasone (DREAMM-6) [ 93 , 94 , 95 ]. The DREAMM-5 trial aims to analyze the efficacy of belamaf plus various anti-cancer drugs, including GSK335609 (inducible T-cell costimulatory agonist), nirogacestat (gamma secretase inhibitor), and GSK317498 (selective OX40 agonist) [ 96 , 97 , 98 ]. At the time of this review, no direct head-to-head comparisons of belamaf vs. other agents have been performed; however, the DREAMM-7 trial plans to study the clinical efficacy of belamaf in combination with bortezomib plus dexamethasone versus daratumumab in combination with bortezomib plus dexamethasone.…”

“…DREAMM-8 plans to compare the safety and efficacy of belamaf in combination with pomalidomide and dexamethasone versus bortezomib in combination with pomalidomide and dexamethasone. The DREAMM-9 and 10 trials plan to compare belamaf versus the standard of care for multiple myeloma [ 98 ]. DREAMM-12 and 13 trials will assess safety and tolerability of belamaf in patients with normal or impaired renal or hepatic function, respectively, So far, belamaf has provided promising evidence of clinical efficacy with manageable adverse effects for patients with progressive and refractory multiple myeloma; however, future DREAMM trials are required to determine an optimal treatment approach and effective risk-management strategies.…”

Emerging Monoclonal Antibodies for the Treatment of Multiple Myeloma

“…In addition to these two milestone studies, a phase II trial (NCT04126200; DREAMM-5) has been initiated that includes belantamab mafodotin monotherapy with two T-cell costimulatory agonist mAbs -the OX40-targeting GSK3174998 and the inducible co-stimulator (ICOS) GSK3359609, along with nirogacestat (PF-03084014), a γ-secretase inhibitor [56]. The ADC plus low-dose dexamethasone also is incorporated into four phase III investigations that include standard therapies such as: pomalidomide (NCT04162210; DREAMM-3, RRMM); bortezomib and daratumumab (NCT04246047; DREAMM-7, RRMM); pomalidomide and bortezomib (NCT04484623; DREAMM-8, RRMM); and lenalidomide and bortezomib (NCT04091126; DREAMM-9, NDMM) [57].…”