Multiple Myeloma: 2026 Update on Diagnosis, Risk-Stratification and Management

Abstract

Diagnosis

The diagnosis of multiple myeloma requires ≥ 10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE): CRAB (hypercalcemia, renal failure, anemia, or lytic bone lesions) attributable to the plasma cell disorder, bone marrow clonal plasmacytosis ≥ 60%, serum involved/uninvolved free light chain (FLC) ratio ≥ 100 (provided involved FLC is ≥ 100 mg/L and urine monoclonal protein is ≥ 200 mg/24 h), or > 1 focal lesion on magnetic resonance imaging.

Risk Stratification

High-risk multiple myeloma is defined by the presence of del(17p), p53 mutation, or bi-allelic del(1p); t(4;14), t(14;16), t(14;20) in combination with gain(1q) or del(1p); or gain(1q) plus del(1p).

Initial Therapy

Initial therapy consists of a quadruplet regimen consisting of anti-CD38 monoclonal antibody (daratumumab or isatuximab) plus bortezomib, lenalidomide, dexamethasone (VRd) followed by autologous stem cell transplantation in eligible patients. Selected standard risk patients can delay transplant until first relapse. Frail patients who are not candidates for transplant are treated with a triplet regimen, either anti-CD 38 antibody plus lenalidomide and dexamethasone, or VRd.

Maintenance Therapy

Standard maintenance is lenalidomide in combination with daratumumab or isatuximab. Lenalidomide is discontinued after 2 years in standard-risk patients. Bortezomib plus lenalidomide is an alternative option for high-risk myeloma.

Management of Relapsed Disease

Major options are chimeric antigen receptor T (CAR-T) cell therapy, bispecific antibodies, various triplet regimens, and belantamab mafadotin.

Management of Smoldering Multiple Myeloma

Daratumumab for 3 years should be considered in high-risk smoldering multiple myeloma.