Multiple Myeloma: Overview, Bone Disease, Treatment Advances and Prognosis — Overview, Diagnosis & Treatment Options | MyMedicPlus

Multiple myeloma (MM) is a clonal malignancy of terminally differentiated plasma cells that accumulate in the bone marrow, produce a monoclonal immunoglobulin (M-protein), and cause systemic end-organ damage. It accounts for approximately 10% of all hematological malignancies. MM exists on a disease continuum: monoclonal gammopathy of undetermined significance (MGUS) → smoldering myeloma (SMM) → active (symptomatic) myeloma. Active myeloma is defined by the presence of clonal bone marrow plasma cells ≥10% plus CRAB features (hypercalcaemia, renal insufficiency, anaemia, or bone disease) or myeloma-defining biomarkers (bone marrow plasma cells ≥60%, serum free light chain ratio ≥100, or >1 focal lesion on MRI) per IMWG 2014 criteria. MM is predominantly a disease of older adults; the median age at diagnosis is 65 years. African American populations have a two-to-three-fold higher incidence than white Americans. Advances in treatment — proteasome inhibitors (bortezomib, carfilzomib, ixazomib), immunomodulatory drugs (thalidomide, lenalidomide, pomalidomide), CD38-targeting monoclonal antibodies (daratumumab, isatuximab), and BCMA-directed therapies (belantamab mafodotin, bispecific antibodies, CAR-T) — have dramatically improved outcomes, with median overall survival of 6–8 years in contemporary series.

Multiple myeloma arises from MGUS through progressive acquisition of genomic events. The earliest events include primary IgH translocations (most commonly t(11;14) — anti-apoptotic via BCL2 upregulation; t(4;14) — FGFR3/MMSET overexpression; t(14;16) and t(14;20) — MAF transcription factor overexpression) and hyperdiploidy (gains of odd chromosomes). Secondary genomic events — KRAS/NRAS mutations, BRAF V600E, MYC dysregulation, del(17p)/TP53 mutations, 1q21 gain, del(1p) — drive progression to symptomatic disease and drug resistance. The strongest epidemiological risk factor is MGUS — present in 3–4% of adults over 50 and progressing at 1% per year. Black race confers 2–3 times higher incidence than white race — the reason is incompletely understood but may reflect higher MGUS prevalence. Family history of MM or MGUS increases personal risk 2–4 fold. Obesity is associated with a modestly elevated risk. Immune dysfunction (post-transplant, HIV) predisposes. Occupational exposure to pesticides, asbestos, wood dust, and solvents has been inconsistently associated.

The CRAB mnemonic captures the cardinal clinical features of active myeloma requiring treatment. Bone disease: Osteolytic lesions — punched-out lytic lesions on plain radiography most common in the skull, spine, ribs, pelvis, and proximal long bones — cause bone pain (present in 70%), pathological fractures (20%), and vertebral compression fractures with associated cord compression (~5%). Bone disease results from myeloma plasma cell activation of osteoclasts (via RANKL overexpression) and suppression of osteoblasts. Renal impairment: Bence-Jones proteinuria (free light chains) causes cast nephropathy ('myeloma kidney'), the most common renal manifestation; hypercalcaemia impairs tubular function. Haemoglobin <10g/dL reflects bone marrow infiltration and inflammatory suppression of erythropoiesis. Hypercalcaemia causes nausea, constipation, polyuria, confusion, and coma. Immunoparesis — suppression of normal immunoglobulin production — leads to recurrent bacterial infections (pneumonia, sinusitis, urinary tract infections) from polyclonal immunoglobulin deficiency and impaired neutrophil function. Peripheral neuropathy may be disease-related or treatment-related (thalidomide, bortezomib).

The diagnostic workup for myeloma includes: serum protein electrophoresis (SPEP) and immunofixation to identify and characterize the M-protein; quantitative immunoglobulins; serum free light chains (FLC assay — essential for non-secretory and light-chain-only myeloma); 24-hour urine protein electrophoresis and immunofixation for Bence-Jones proteins; full blood count, renal function, calcium, LDH, and beta-2 microglobulin (prognostic markers); bone marrow aspirate and trephine biopsy with: plasma cell percentage, immunohistochemistry (CD138, CD38, CD56, cyclin D1), cytogenetics, and FISH (del17p, t(4;14), t(14;16), 1q21 gain, t(11;14)); and imaging — whole-body low-dose CT or PET-CT (replacing skeletal survey as standard per IMWG/NICE guidance) to identify lytic lesions and extramedullary disease; whole-body MRI for spinal cord compression assessment or spinal plasmacytoma. The revised International Staging System (R-ISS) integrates: ISS stage (beta-2 microglobulin + albumin), serum LDH, and FISH high-risk cytogenetics (del17p, t(4;14), t(14;16)) into three risk groups with significantly different median OS.

Smoldering myeloma: no treatment outside clinical trials except for high-risk SMM (per PROMISE and GEM-CESAR trials demonstrating lenalidomide benefit). Symptomatic myeloma treatment is stratified by transplant eligibility. Transplant-eligible (generally age ≤70–75 years, adequate organ function): standard of care in 2024–2025 is Dara-VRd (daratumumab 16 mg/kg IV + bortezomib 1.3 mg/m² SC + lenalidomide 25 mg + dexamethasone 40 mg) × 4–6 cycles induction, followed by peripheral blood stem cell collection, high-dose melphalan (200 mg/m²) and autologous SCT, then maintenance lenalidomide ± daratumumab. PERSEUS trial: Dara-VRd → ASCT → Dara-R maintenance achieved 60-month PFS rate of 84.3% vs 67.7% with VRd → ASCT → R maintenance. Transplant-ineligible: Dara-Rd (daratumumab + lenalidomide + dexamethasone) — MAIA trial: median PFS 61.9 months vs 34.4 months with Rd alone; or VMP for frail patients. Bone disease: zoledronic acid 4 mg IV monthly for 24 months (MRC IX trial: significant OS benefit); radiation therapy for isolated painful lesions; vertebroplasty for vertebral compression fractures. Relapsed/refractory: isatuximab-Pd (ICARIA-MM), carfilzomib combinations, selinexor, BCMA-directed therapies — CAR-T (ide-cel, cilta-cel) and bispecific antibodies (teclistamab anti-BCMA×anti-CD3, elranatamab) achieving deep responses in heavily pretreated disease.

Multiple myeloma prognosis has markedly improved with the introduction of triplet and quadruplet induction regimens, high-dose therapy with ASCT, and novel maintenance strategies. Median overall survival for all patients is 6–8 years with modern treatment, with substantial heterogeneity by risk group. R-ISS Stage I patients have median OS not yet reached in contemporary series, while R-ISS Stage III patients have median OS of approximately 43 months. Favorable-risk disease (t(11;14), standard cytogenetics, ISS I) treated with Dara-VRd induction and ASCT achieves 60-month PFS rates of 84% (PERSEUS trial). High-risk cytogenetics — del(17p), t(4;14), t(14;16), 1q21 gain — are the most important adverse prognostic factors; their detection mandates early treatment with high-efficacy induction and potential intensification of maintenance. MRD negativity at 10⁻⁵ sensitivity after induction and ASCT is the strongest predictor of prolonged PFS and is increasingly used as a surrogate endpoint in clinical trials. CAR-T therapies (cilta-cel, ide-cel) and bispecific antibodies (teclistamab, elranatamab) have transformed the relapsed/refractory landscape, achieving deep and durable responses in heavily pretreated patients. The disease remains incurable for the vast majority, but sequential lines of effective therapy are progressively extending OS and improving quality of life. By stage: Stage I 5-year OS approaches 70–80% with modern therapy; Stage III 5-year OS approximately 40–50%. Long-term monitoring focuses on M-protein, serum free light chains, and bone marrow MRD assessment at key disease milestones.

No interventions are proven to prevent progression from MGUS or SMM to active myeloma in the general population, though lenalidomide is being evaluated in high-risk SMM. MGUS monitoring according to Mayo Clinic risk stratification model (M-protein level, non-IgG isotype, abnormal FLC ratio): low-risk (annual monitoring with SPEP, FLC, CBC), intermediate-risk (6–12 monthly monitoring), high-risk (3–6 monthly with consideration of bone marrow biopsy and imaging). Patients with MGUS should be educated about CRAB symptoms — any new back pain, fatigue, recurrent infections, or renal impairment warrants immediate reassessment. Weight management, as obesity is a modifiable risk factor, may modestly reduce myeloma incidence. Patients should avoid nephrotoxic agents (NSAIDs, contrast media without adequate hydration) given the vulnerability of myeloma kidneys to acute kidney injury.

Seek urgent haematology review for: new-onset back pain in an older adult with elevated ESR, high total protein, or proteinuria — do not assume musculoskeletal cause without excluding myeloma; unexplained hypercalcaemia; normocytic anaemia with a monoclonal band on protein electrophoresis; or recurrent bacterial pneumonia suggesting immunoparesis. Neurological emergency: any myeloma patient with acute onset back pain and bilateral leg weakness, urinary retention, or sensory level must have emergency MRI spine to exclude cord compression from vertebral plasmacytoma or pathological fracture — spinal cord compression from myeloma requires dexamethasone 10 mg IV immediately and emergency radiotherapy or surgical decompression within 24–48 hours to preserve neurological function. Patients with known MGUS must not miss annual appointments — rising M-protein, new anaemia, or CRAB symptoms during surveillance require bone marrow biopsy and imaging to exclude myeloma progression.