Multiple myeloma — aetiology, diagnosis and management

Definition and epidemiology. A malignant clonal proliferation of bone marrow plasma cells producing a monoclonal immunoglobulin, with resultant lytic bone disease, marrow failure and renal impairment. It accounts for about 10% of haematological malignancies; median age at diagnosis is 70 years, and over a third of patients are above 75.

Aetiology and risk factors. All myeloma is preceded by MGUS, which progresses at 1% per year. Risk factors: increasing age, male sex, African ancestry, family history, obesity, and occupational exposure to ionising radiation, benzene, pesticides and organic solvents. Pathogenesis involves primary IgH translocations — t(11;14), t(4;14), t(14;16) — or hyperdiploidy, with secondary events (del(17p)/TP53, 1q gain, MYC rearrangement, RAS mutations) driving progression, all supported by the bone marrow microenvironment (IL-6, RANKL, VEGF).

Clinical features — the CRAB criteria. C — hyperCalcaemia (corrected calcium >11 mg/dL or >1 mg/dL above normal); R — Renal impairment (creatinine >2 mg/dL or eGFR <40 mL/min); A — Anaemia (Hb <10 g/dL or 2 g/dL below normal); B — Bone lesions (one or more lytic lesions on CT, MRI or PET-CT).

Other presentations. Bone pain, especially back pain, and pathological fracture; recurrent bacterial infection from immune paresis (the commonest cause of death); spinal cord compression; hyperviscosity; amyloidosis; peripheral neuropathy; and bleeding. In older patients, myeloma frequently presents as unexplained anaemia, fatigue, back pain attributed to osteoporosis, or acute kidney injury.

Myeloma-defining biomarkers (SLiM criteria, IMWG 2014). These allow treatment before end-organ damage occurs: S — clonal marrow plasma cells ≥60%; Li — involved:uninvolved serum free Light chain ratio ≥100 (with involved chain ≥100 mg/L); M — more than one focal lesion ≥5 mm on MRI. Diagnosis requires ≥10% clonal plasma cells or a plasmacytoma PLUS one CRAB or SLiM feature.

Investigations. Serum protein electrophoresis with immunofixation and serum free light chains (essential — light-chain-only and non-secretory myeloma have no serum M spike); 24-hour urine for Bence-Jones protein; complete blood count with film showing rouleaux and a markedly raised ESR; calcium, creatinine, albumin, LDH, β -microglobulin; bone marrow aspirate and trephine with FISH cytogenetics; and whole-body 2 low-dose CT, whole-body MRI or FDG PET-CT — the plain skeletal survey is obsolete because it misses lesions until 30–50% of bone is lost.

Staging and prognosis. Revised International Staging System (R-ISS) combines β -microglobulin and 2 albumin (the original ISS) with LDH and high-risk cytogenetics [del(17p), t(4;14), t(14;16)]: Stage I — β M 2 <3.5 mg/L and albumin ≥3.5 g/dL with normal LDH and standard-risk cytogenetics; Stage III — β M ≥5.5 mg/L with 2 high LDH or high-risk cytogenetics. The older Durie-Salmon system used tumour burden.

Management of newly diagnosed myeloma. Transplant-eligible (usually under 70–75 and fit): induction with a triplet or quadruplet — bortezomib + lenalidomide + dexamethasone (VRd), increasingly with daratumumab — followed by high-dose melphalan with autologous stem cell transplant and lenalidomide maintenance. Transplant-ineligible: daratumumab + lenalidomide + dexamethasone (D-Rd, the MAIA regimen) or VRd-lite, continued until progression, with dose reduction for frailty. Avoid melphalan before stem cell harvest in potential transplant candidates.

Supportive care (heavily examined). Bone — zoledronic acid or pamidronate monthly for at least 2 years (denosumab if renal impairment; dental review first because of osteonecrosis of the jaw); radiotherapy for pain and impending fracture; vertebroplasty/kyphoplasty. Renal — aggressive hydration, avoid NSAIDs, contrast and nephrotoxins, treat hypercalcaemia, use bortezomib-based therapy (no dose reduction needed in renal failure). Infection — vaccination, prompt antibiotics, aciclovir prophylaxis with bortezomib and daratumumab, immunoglobulin replacement for recurrent infection. Thrombosis — aspirin or LMWH prophylaxis with immunomodulatory drugs. Plus analgesia, anaemia management and early palliative input.

Relapsed disease and the geriatric approach. Relapse is inevitable; options include carfilzomib, pomalidomide, isatuximab, elotuzumab, selinexor, bendamustine and re-treatment. In older patients, use the IMWG frailty index or R-MCI (age, comorbidity, ADL/IADL) to classify fit, intermediate-fit and frail, and apply dose-adjusted regimens rather than withholding treatment — under-treatment of the fit elderly is as harmful as over-treatment of the frail. Steroid dose reduction (dexamethasone 20 mg weekly instead of 40 mg) markedly reduces toxicity without losing efficacy.

CEPHEUS trial (Nature Medicine 2025; FDA approval 2026) — in transplant-ineligible or transplant-deferred newly diagnosed myeloma, adding daratumumab to VRd (D-VRd quadruplet) nearly doubled sustained MRD negativity (60.9% vs 39.5%) and significantly improved progression-free survival, with benefit maintained irrespective of frailty status. Together with PERSEUS (NEJM 2024) in transplant-eligible patients and the MAIA benchmark of 7.5 years median overall survival with D-Rd, a daratumumab-containing quadruplet or triplet is now the standard of care for older patients.

T-cell redirecting therapy in relapsed disease. BCMA CAR T-cells (ide-cel, cilta-cel) and the bispecific antibodies teclistamab, elranatamab (anti-BCMA) and talquetamab (anti-GPRC5D) achieve response rates of 60–80% in triple-class-refractory myeloma. Bispecifics are off-the-shelf and given subcutaneously, making them more practical for older patients than CAR-T; the trade-offs are cytokine release syndrome, ICANS and a high rate of serious infection requiring routine immunoglobulin replacement and antimicrobial prophylaxis.