Multiple Myeloma — Causes, Symptoms & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Multiple myeloma is a malignancy of plasma cells — antibody-producing B lymphocytes residing in the bone marrow. Clonal plasma cells accumulate in the marrow, producing abnormal monoclonal immunoglobulin (M-protein or paraprotein) and suppressing normal haematopoiesis. It is the second most common haematological malignancy, affecting approximately 6 per 100,000 people annually and representing 1% of all cancers. Median age at diagnosis is 65–70 years; it is rare under 40. Myeloma is characterised by the CRAB criteria: hypercalCaemia, Renal failure, Anaemia, and Bone disease. Smouldering multiple myeloma (SMM) is a precursor state without end-organ damage. Treatment has advanced dramatically — with modern triplet/quadruplet regimens and immunotherapy, median overall survival now exceeds 5–10 years in transplant-eligible patients. Myeloma remains incurable with current therapies in most patients, but the treatment landscape has been dramatically transformed over the past decade by the introduction of proteasome inhibitors, IMiDs, anti-CD38 monoclonal antibodies, and more recently CAR-T cell therapies, extending median overall survival from approximately 3 years to more than 8-10 years in many trials.

Myeloma arises from a plasma cell clone with accumulated genetic abnormalities including translocations involving the immunoglobulin heavy chain locus (most commonly t(4;14), t(14;16), t(11;14)) and deletions of chromosome 17p (TP53). Virtually all cases are preceded by monoclonal gammopathy of undetermined significance (MGUS), which progresses to myeloma at approximately 1% per year. Risk factors include age over 60, male sex, Black African ancestry (2–3 times higher incidence), prior MGUS, family history of myeloma, obesity, radiation exposure, and occupational exposure to pesticides, petroleum products, or leather dust. MGUS affects 3–4% of adults over 50 and 5% over 70 — it does not always progress to myeloma but requires monitoring.

The mnemonic CRAB describes cardinal features. Hypercalcaemia: nausea, constipation, confusion, polyuria, and lethargy from excess bone calcium release. Renal failure (in 20–30%): elevated creatinine from light chain cast nephropathy, hypercalcaemia, or dehydration — may present as acute kidney injury. Anaemia (70%): fatigue, pallor, and breathlessness from marrow infiltration suppressing red cell production. Bone disease: bone pain (most common symptom, especially back and ribs), pathological fractures from osteolytic lesions, and vertebral compression fractures. Additional features: recurrent bacterial infections (immunoparesis — reduced normal immunoglobulins), peripheral neuropathy (especially with bortezomib), and hyperviscosity syndrome (confusion, visual disturbance, bleeding — mainly with IgM). Rouleaux formation on blood film is characteristic.

Diagnosis requires: (1) bone marrow biopsy showing ≥10% clonal plasma cells; (2) serum or urine M-protein on protein electrophoresis (SPEP/UPEP) and immunofixation — or light chain ratio abnormality; and (3) CRAB criteria or biomarkers (serum FLC ratio >100, >1 focal lesion on MRI, ≥60% plasma cells in marrow). Serum protein electrophoresis detects the M-protein 'spike'. Serum free light chain assay (kappa/lambda ratio) is essential. Full blood count, calcium, LDH, creatinine, and beta-2 microglobulin (B2M) are prognostic markers. Whole-body low-dose CT or PET-CT identifies lytic lesions and plasmacytomas. FISH cytogenetics on marrow defines prognostic risk — t(4;14), del(17p), gain(1q) confer high risk. International Staging System (ISS/R-ISS) uses B2M, albumin, LDH, and FISH.

Transplant-eligible patients (generally age <70, good performance status): induction with daratumumab-VRd (daratumumab + bortezomib + lenalidomide + dexamethasone) for 4 cycles, then high-dose melphalan + autologous stem cell transplant (ASCT), then lenalidomide maintenance indefinitely — achieves MRD (minimal residual disease) negativity in 60–70%. Transplant-ineligible patients: daratumumab-VMP or daratumumab-Rd are standard induction and maintenance regimens. Bortezomib (proteasome inhibitor), lenalidomide (IMiD), and daratumumab (anti-CD38 monoclonal antibody) are the backbone agents. Relapsed/refractory myeloma: carfilzomib, pomalidomide, elotuzumab, isatuximab, belantamab mafodotin, idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) — CAR-T cell therapies — are approved for heavily pretreated patients. Radiation for painful bone lesions. Bisphosphonates (zoledronic acid) prevent skeletal-related events. All myeloma patients should receive monthly intravenous zoledronic acid to reduce skeletal-related events regardless of whether bone lesions are evident on standard imaging, as subclinical bone destruction is present throughout the skeleton even in apparently normal-appearing areas on plain radiograph.

Untreated myeloma causes severe and progressive CRAB-related organ damage. Vertebral collapse from osteolytic bone disease causes spinal cord compression — epidural plasma cell deposits compress the spinal cord producing paralysis, incontinence, and loss of sensation below the lesion level; this is a surgical emergency requiring radiotherapy within 24-48 hours. Acute kidney failure from light chain cast nephropathy (myeloma kidney) or severe hypercalcaemia can necessitate emergency dialysis; sustained renal failure significantly impairs quality of life and treatment options. Recurrent severe bacterial infections (pneumonia, septicaemia) from immunoparesis — profound suppression of normal polyclonal immunoglobulin production — are a leading cause of myeloma mortality. Severe hypercalcaemia (corrected calcium above 3.0 mmol/L) causes confusion, coma, and cardiac arrhythmias. Pathological fractures of the femur, humerus, and vertebrae cause severe pain, immobility, and fat embolism risk. Progressive anaemia from marrow infiltration reduces quality of life and performance status, limiting tolerance of chemotherapy. Without treatment, median survival is approximately 12 months.

Multiple myeloma cannot be prevented. Patients with MGUS require monitoring: low-risk MGUS (IgG <15 g/L, non-IgG or light chain, normal FLC ratio) — repeat SPEP and FLC at 6 months, then every 1–2 years if stable; high-risk MGUS (≥2 risk factors) — 6-monthly monitoring. Smouldering myeloma should be monitored every 3–6 months by a haematologist; clinical trials of early treatment for high-risk SMM are ongoing. For patients on treatment: adequate hydration protects kidneys, bisphosphonates reduce fractures (monthly zoledronic acid IV), prophylactic aciclovir during bortezomib therapy (herpes zoster prevention), and G-CSF during chemotherapy to reduce neutropenic infection. Pneumococcal, influenza, and COVID-19 vaccines are recommended.

Seek emergency medical attention immediately for: new or worsening back pain following minor trauma (vertebral fracture risk), severe bone pain with leg weakness or bladder/bowel dysfunction (spinal cord compression from vertebral collapse — surgical emergency), confusion or drowsiness (hypercalcaemia or hyperviscosity), or signs of serious infection (fever, rigors — myeloma patients are highly immunosuppressed). See your GP or haematologist promptly if persistent unexplained bone pain, fatigue, recurrent infections, or unexplained kidney impairment occurs — especially in adults over 50. MGUS patients should attend all monitoring appointments as myeloma is far more treatable at early diagnosis. Myeloma patients should report any new back pain, lower limb weakness, or bladder and bowel dysfunction to their haematology team immediately, as these symptoms may indicate spinal cord compression — a neurosurgical emergency requiring urgent radiological evaluation and expedited treatment to prevent permanent paralysis.