Upfront Therapy for Non‑transplantable Multiple Myeloma in 2026: Decision‑making in an Increasingly Complex Therapeutic Landscape

Abstract

Multiple myeloma (MM) is an age-related disease with a median age at diagnosis of approximately 70 years. While quadruplet regimens, such as daratumumab, bortezomib, lenalidomide, and dexamethasone (Dara-VRd), followed by autologous hematopoietic stem cell transplantation (HSCT), as demonstrated in the Perseus trial, have recently become a standard for transplant-eligible patients, optimal first-line therapy remains challenging in older, frail individuals with comorbidities and reduced functional reserve. This challenge is driven less by biological differences in the disease and more by heterogeneity in treatment tolerance, comorbidity burden, and real-world care conditions.

Historically, non‑transplant‑eligible patients were treated with doublets, such as melphalan/prednisone or lenalidomide/dexamethasone (Rd). With the introduction of proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs), triplet regimens, including VRd and later DRd (daratumumab, lenalidomide, dexamethasone), became the new standard of therapy.

A major advance was the incorporation of monoclonal CD38 antibodies. Network meta‑analyses have shown that anti-CD38 monoclonal antibody-based combinations significantly improve progression-free survival (PFS) and response rates compared with regimens lacking anti-CD38 therapy. However, increasing efficacy has also led to greater treatment complexity and toxicity, which is particularly relevant for older and frail patients.

For this population, first-line therapy must balance effective disease control with minimizing treatment-related morbidity and preserving quality of life. In addition, regional differences in access to modern therapies—especially to anti‑CD38 monoclonal antibodies and quadruplet combinations—further widen the gap between evidence-based recommendations and real‑world practice.

This review provides practical guidance on selecting first-line therapy for patients with MM who are not eligible for transplantation, focusing on efficacy, toxicity profiles, and key clinical decision factors.