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

Multiple myeloma is a malignancy of terminally differentiated B-lymphocytes (plasma cells), characterised by clonal proliferation of malignant plasma cells within the bone marrow producing a monoclonal immunoglobulin (M-protein or paraprotein) detectable in serum and/or urine by protein electrophoresis and immunofixation. It is the second most common haematological malignancy after non-Hodgkin lymphoma, with approximately 176,000 new cases and 117,000 deaths annually worldwide. The median age at diagnosis is 69 years; fewer than 5% of cases occur in adults under 45. Myeloma is classified on the International Staging System (ISS) and Revised ISS (R-ISS) using serum beta-2 microglobulin, albumin, LDH, and cytogenetics to stratify prognosis into three risk groups. Active (symptomatic) myeloma requiring treatment is defined by the SLiM-CRAB criteria: sixty percent or more clonal plasma cells in bone marrow (S60); serum free light chain ratio of 100 or more (Li); more than one focal MRI lesion (M); or the classic CRAB criteria: hyperCalcaemia (corrected calcium above 2.75 mmol/L), Renal failure (creatinine above 177 micromol/L or eGFR below 40), Anaemia (haemoglobin below 100 g/L), and Bone lesions (one or more osteolytic lesions on X-ray, CT, or PET-CT). Nearly all myeloma evolves from the premalignant precursor state monoclonal gammopathy of undetermined significance (MGUS), which progresses to myeloma at approximately 1% per year.

Virtually all cases of multiple myeloma arise through a stepwise progression from MGUS (monoclonal gammopathy of undetermined significance — clonal plasma cells below 10%, M-protein below 3g/dL, no CRAB features) to smouldering myeloma (plasma cells 10-60% without CRAB features, M-protein above 3g/dL) to active myeloma. MGUS affects approximately 3% of adults over 50 and progresses at 1% per year. Risk factors for developing myeloma from MGUS: non-IgG isotype (IgA, IgM), M-protein above 1.5g/dL, and abnormal serum free light chain ratio — the presence of all three risk factors carries a 58% 20-year progression risk compared with 5% for none. Demographic risk factors: Black or African-American ethnicity (2-3x higher incidence than White populations — the reasons are partially genetic and partially related to MGUS prevalence); male sex; age above 65; first-degree family history of myeloma or MGUS; occupational exposure to pesticides or radiation; obesity (adipokines promote myeloma cell survival). Primary chromosomal events in myeloma: hyperdiploidy (good prognosis, involves trisomies of odd-numbered chromosomes) and immunoglobulin heavy chain (IgH) translocations at chromosome 14q32 — t(11;14)(IgH-CCND1), t(4;14)(IgH-FGFR3/MMSET), t(14;16)(IgH-MAF). High-risk cytogenetics associated with poor prognosis: del(17p13) — TP53 deletion; t(4;14); t(14;16); 1q21 gain/amplification; and del(1p32). These are detected by FISH on bone marrow samples and critically inform treatment intensity.

The clinical manifestations of multiple myeloma reflect plasma cell infiltration of bone marrow and the pathological effects of the secreted M-protein. Bone pain is the most common presenting symptom, occurring in 60-70% of patients at diagnosis — typically in the lower back, ribs, pelvis, or proximal long bones, corresponding to the sites of osteolytic lesions driven by RANKL-mediated osteoclast activation and osteoblast suppression; nocturnal or rest pain distinguishes myeloma bone pain from mechanical back pain. Pathological fractures, including vertebral compression fractures causing acute back pain, height loss, and kyphosis, are hallmark complications. Fatigue and pallor from normochromic normocytic anaemia (haemoglobin below 100 g/L) — caused by bone marrow replacement, direct suppression of erythropoiesis, and reduced EPO production — affect 70-75% of patients. Recurrent infections from immunoparesis (suppression of normal immunoglobulin production by the malignant clone causing functional antibody deficiency) — particularly pneumococcal, Haemophilus, and viral infections — are a frequent presenting feature. Renal dysfunction (acute or chronic) in 25-50% at diagnosis — most commonly from light chain cast nephropathy (Bence Jones proteins occluding tubules), but also from hypercalcaemia-induced tubular injury, dehydration, and NSAIDs. Hypercalcaemia (corrected calcium above 2.75 mmol/L) causes polyuria, polydipsia, constipation, confusion, and nausea. Hyperviscosity syndrome from high M-protein concentrations (particularly IgM, IgG3) causes visual disturbance, headache, epistaxis, and neurological symptoms. Spinal cord compression from vertebral collapse or extradural plasmacytoma is a haematological emergency. Many patients are diagnosed incidentally following routine blood tests showing elevated total protein, ESR, or anaemia.

The diagnostic workup in suspected myeloma is comprehensive and integrative. Serum protein electrophoresis (SPEP) identifies and quantifies the M-protein spike; serum immunofixation electrophoresis (SIFE) confirms the isotype (IgG, IgA, IgM, IgD, IgE, or free light chain only). Urine protein electrophoresis (UPEP) and urine immunofixation (UIFE) detect Bence Jones protein (free light chains) — positive in over 70% of myeloma cases. Serum free light chain (SFLC) assay measures kappa and lambda light chain concentrations and ratio — critical for monitoring non-secretory and light chain-only myeloma, and for risk stratification in MGUS. Bone marrow trephine biopsy and aspiration are essential: immunohistochemistry and flow cytometry quantify the clonal plasma cell percentage, determine aberrant immunophenotype (CD38+, CD138+, CD56+, CD19−, CD45−), and FISH cytogenetic analysis identifies high-risk chromosomal abnormalities (del17p, t(4;14), t(14;16), 1q21 gain). Whole-body low-dose CT (WBLDCT) is the current EHA/IMWG-recommended first-line imaging, replacing the historical skeletal survey, with superior sensitivity for lytic lesions; PET-CT (FDG-PET/CT) is preferred for equivocal lesions and assessing metabolic response; MRI whole-spine is essential for spinal cord compression and cord monitoring. Full blood count (anaemia, thrombocytopenia), renal function (eGFR, creatinine, 24-hour urine protein), calcium, LDH, beta-2 microglobulin, albumin — all required for R-ISS staging.

Treatment of active myeloma is stratified by transplant eligibility (performance status, age — typically under 70-75 years with adequate organ function) and risk cytogenetics. Transplant-eligible patients: induction therapy with VRd (bortezomib 1.3mg/m² SC, lenalidomide 25mg, dexamethasone 20-40mg — SWOG S0777 trial) or Dara-VRd (daratumumab + VRd — GRIFFIN/PERSEUS trials demonstrating superior MRD negativity rates) for 4-6 cycles; stem cell harvest after adequate response; high-dose melphalan (200mg/m²) conditioning followed by autologous stem cell transplant (ASCT) — the ASCT significantly improves progression-free survival (PFS 50 months vs 28 months for chemotherapy alone in IFM 2009 trial); maintenance lenalidomide (10mg daily) post-ASCT indefinitely until progression (CALGB 100104 and IFM 2005-02 trials — reduces relapse risk by 50-60%); a second ASCT (tandem) benefits high-risk patients. Transplant-ineligible patients: daratumumab-lenalidomide-dexamethasone (DRd — MAIA trial) or VRd (continuous dosing). Bone protection: bisphosphonate therapy (zoledronic acid 4mg IV every 3-4 weeks or monthly — MRC Myeloma IX trial — reduces skeletal-related events by 35% and may have direct anti-myeloma activity). Relapsed/refractory myeloma: multiple lines of therapy are available — pomalidomide-dexamethasone, daratumumab-pomalidomide-dexamethasone (DPd), carfilzomib combinations (KRd, KPd), selinexor, isatuximab; bispecific T-cell engager antibodies (teclistamab, talquetamab, elranatamab — targeting BCMA or GPRC5D — achieve deep responses in heavily pre-treated patients with single-agent response rates of 60-70%); CAR-T cell therapies (idecabtagene vicleucel [ide-cel] and ciltacabtagene autoleucel [cilta-cel] targeting BCMA — KarMMa and CARTITUDE-1 trials — achieve ≥60-70% objective response including stringent complete responses in late-line disease).

Vertebral compression fractures from osteolytic disease cause severe back pain, progressive kyphotic deformity, height loss, and reduced lung capacity. Spinal cord compression from extradural plasmacytoma or vertebral collapse is a haematological emergency requiring immediate MRI, high-dose dexamethasone 16-32mg/day, and urgent radiotherapy or surgical decompression — delayed treatment results in permanent paralysis. Pathological fractures of the proximal femur, humerus, and ribs are common, causing significant disability and requiring orthopaedic stabilisation. Renal failure from light chain cast nephropathy develops in 25-50% of patients — acute kidney injury may be reversible with aggressive hydration, loop diuretics, and rapid reduction of the paraprotein load with bortezomib-based regimens; high-dose steroids reduce tubular inflammation. Approximately 10-15% of patients progress to end-stage renal disease requiring dialysis. Immunoparesis (suppression of normal immunoglobulin production) causes severe susceptibility to encapsulated bacteria (pneumococcus, Haemophilus), VZV reactivation, and fungal infections — prophylactic trimethoprim-sulfamethoxazole, antiviral aciclovir/valaciclovir, and vaccination are standard. Hypercalcaemia (above 3.0 mmol/L) causes acute neuropsychiatric crisis, cardiac arrhythmias, and oliguric renal failure — emergency treatment with IV saline, furosemide, and bisphosphonate is required. Secondary amyloidosis (AL) and secondary acute myeloid leukaemia (AML/MDS) from prolonged alkylator or lenalidomide therapy are rare but serious late complications.

There are no proven specific strategies to prevent multiple myeloma from arising de novo. However, managing MGUS with regular surveillance is essential to detect early progression: low-risk MGUS (IgG isotype, M-protein under 1.5g/dL, normal free light chain ratio) requires monitoring every 3-6 months initially then annually; high-risk MGUS warrants haematology referral and 6-monthly review. Smouldering myeloma surveillance is every 3-6 months; daratumumab is being studied in clinical trials (DARA-QUIREDEX) for high-risk smouldering myeloma to delay progression. Bone disease management for all active myeloma patients: zoledronic acid 4mg IV monthly for the first 2 years (then every 3 months) — NICE-recommended, regardless of whether overt bone lesions are present, to prevent skeletal-related events; dental review before starting bisphosphonate therapy to reduce osteonecrosis of the jaw risk. Vertebroplasty or kyphoplasty may be considered for symptomatic vertebral compression fractures causing pain. Infection prophylaxis and vaccination: pneumococcal vaccination (PCV13 + PPSV23 schedule), annual influenza vaccination, and aciclovir 400mg twice daily for VZV prophylaxis during active therapy. IV immunoglobulin (IVIG) replacement for recurrent severe infections with severe hypogammaglobulinaemia (IgG below 4g/L). Exercise — particularly aerobic and resistance training — is safe in myeloma patients and improves fatigue, bone density, and quality of life; NICE recommends oncology rehabilitation programmes.

See your GP urgently for: persistent unexplained back or rib pain (especially at rest or at night and not explained by trauma), fatigue with recurrent infections and pallor, unexplained elevated protein on routine blood testing, new renal impairment, or hypercalcaemia symptoms (confusion, constipation, excessive thirst, polyuria). An elevated total serum protein with depressed normal immunoglobulins on routine blood tests should prompt same-week GP review. Go to A&E immediately for: sudden severe back pain with new leg weakness, numbness, or loss of bladder or bowel control (spinal cord compression from vertebral disease — a haematological emergency requiring immediate MRI, high-dose dexamethasone, and radiotherapy or surgical decompression); severe confusion or agitation (hypercalcaemia or hyperviscosity — both acute medical emergencies); fever with known myeloma (immunoparesis renders patients highly susceptible to serious bacterial infection — sepsis requires immediate assessment). After diagnosis, contact your haematology team same-day for any new bone pain, new neurological symptom, or suspected infection — do not wait for your routine appointment.