Multiple myeloma
Description
- Clonal post-germinal-centre plasma cell malignancy in the marrow + monoclonal immunoglobulin
- **Always preceded by MGUS** - a preceding paraprotein is demonstrable in essentially every case
The spectrum
| Clonal marrow PC | M-protein | End-organ | |
|---|---|---|---|
| MGUS | <10% | <30 g/L | None |
| Smouldering | >=10% | >=30 g/L | None |
| Myeloma | >=10% (or plasmacytoma) | Any | CRAB or SLiM |
- Related entities: solitary plasmacytoma (bone or extramedullary), plasma cell leukaemia (circulating clonal PC >=5% / 0.5 x10^9/L), AL amyloidosis, POEMS, MGRS
Paraprotein isotype
- IgG ~60%, IgA ~20-25% (worse prognosis), light-chain only ~15% (no spike on SPEP - needs free light chains)
- IgD, IgE, non-secretory rare
- *IgM paraprotein = Waldenström or lymphoma, not myeloma*
Epidemiology
- 2nd commonest haematological malignancy (~10-15%)
- ~2,500 new diagnoses/yr in Australia; incidence ~7/100,000
- Median age at diagnosis ~70; <2% under 40
- M>F ~1.4:1
- 2-3x incidence and earlier onset in people of African ancestry
- Progression: MGUS ~1%/yr; smouldering ~10%/yr for the first 5 years, then falls
Aetiopathogenesis
Primary genetic events - mutually exclusive
- IGH translocations at 14q32 (~40%)
- t(11;14) - CCND1. Favourable, and predicts venetoclax response
- t(4;14) - FGFR3/NSD2(MMSET). High risk
- t(14;16) MAF, t(14;20) MAFB. High risk
- Hyperdiploidy (~55%) - trisomies of odd-numbered chromosomes. Standard risk
Secondary events - drive progression
- 1q21 gain/amplification, del(1p)
- del(17p) / TP53 mutation
- MYC rearrangement, RAS/NRAS/BRAF mutation
- del(13)/monosomy 13, hypodiploidy
Bone disease
- inc RANKL, dec OPG -> osteoclast activation
- DKK-1 inhibits Wnt -> osteoblasts switched off
- -> purely lytic lesions with no reparative response
- -> **normal ALP, and lesions are cold on bone scintigraphy**
Renal disease
- Cast nephropathy ("myeloma kidney") - filtered free light chains + Tamm-Horsfall protein precipitate in distal tubule; direct proximal tubular toxicity. Tubulointerstitial picture
- Monoclonal immunoglobulin deposition disease (usually light chain) - glomerular, nephrotic range
- AL amyloidosis - glomerular, nephrotic range
- Acquired Fanconi syndrome - proximal tubulopathy from light chain crystals
- Hypercalcaemia, dehydration, NSAIDs, contrast
Other
- Anaemia: marrow replacement + renal EPO deficiency + inflammatory block
- Infection: hypogammaglobulinaemia of uninvolved isotypes + neutropenia + therapy
Diagnosis
IMWG criteria for active myeloma
- Clonal marrow plasma cells >=10% or biopsy-proven plasmacytoma, PLUS >=1 of:
CRAB (attributable end-organ damage)
- C - corrected Ca >2.75 mmol/L (or >0.25 above ULN)
- R - creatinine >177 micromol/L or eGFR <40
- A - Hb <100 g/L or 20 g/L below normal
- B - >=1 lytic lesion on skeletal survey, CT or PET-CT
SLiM (myeloma-defining biomarkers - treat before organ damage)
- S - clonal marrow plasma cells >=60%
- Li - involved:uninvolved serum free light chain ratio >=100 (involved >=100 mg/L)
- M - >1 focal lesion >=5 mm on MRI
High-risk smouldering myeloma
- "20-2-20": marrow PC >20%, M-protein >20 g/L, FLC ratio >20
- Other adverse features: FLC ratio 8-100, absent polyclonal plasma cells on flow, high-risk cytogenetics (del(17p), t(4;14), 1q21 gain), IgA isotype, circulating plasma cells
Laboratory traps
- Normal ALP despite extensive lytic disease
- Normal urine dipstick despite heavy proteinuria - dipstick detects albumin, not light chains
- Rouleaux, very high ESR, normocytic anaemia; macrocytosis from paraprotein osmotic effect
- Spuriously low B12; pseudohyponatraemia; narrowed anion gap (cationic IgG)
Workup
- SPEP + immunofixation, serum free light chains, quantitative immunoglobulins, urine EPG/IFE
- Marrow aspirate + trephine: flow (CD138+, CD38+, CD56+, cytoplasmic light chain restriction) + FISH on sorted plasma cells
- Whole-body low-dose CT, PET-CT or whole-body MRI - plain skeletal survey is obsolete (insensitive until 30% bone loss)
- Congo red (fat pad / marrow) if amyloid suspected; NT-proBNP + troponin, echo
Staging and risk
| Basis | |
|---|---|
| ISS | Albumin + beta-2 microglobulin only. Superseded |
| R-ISS (2015) | + LDH + FISH |
| R2-ISS (2022) | + 1q21 gain/amp, weighted |
| IMS-IMWG 2025 | Binary high vs standard risk - now the reference classification |
- 2025 high-risk = any of: del(17p) and/or TP53 mutation (clonal fraction >=20%); t(4;14)/t(14;16)/t(14;20) with 1q gain/amp or del(1p); biallelic del(1p); beta-2 microglobulin >=5.5 mg/L with normal creatinine
- ~20% of patients; outperforms R-ISS/R2-ISS in the quadruplet era
Management
Axis: transplant eligibility, then line of therapy. Supportive care runs alongside from day one.
A. Newly diagnosed, transplant-eligible (fit, broadly <70)
- Quadruplet induction: daratumumab + bortezomib + lenalidomide + dexamethasone (Dara-VRd)
- Supersedes VRd triplet - PERSEUS: 58% dec risk of progression/death
- Isatuximab-VRd an equivalent anti-CD38 backbone
- Stem cell harvest after 4 cycles (prolonged lenalidomide impairs mobilisation)
- Melphalan 200 mg/m2 + autologous SCT - TRM ~1%, deepens response
- *Not curative* - unlike lymphoma
- Maintenance lenalidomide (+/- daratumumab) until progression
B. Newly diagnosed, transplant-ineligible
- Dara-Rd (MAIA) or Dara-VRd (CEPHEUS)
- Frail: VRd-lite, or bortezomib-cyclophosphamide-dexamethasone; attenuate dexamethasone early
- Weekly subcutaneous bortezomib - as effective as IV twice-weekly with far less peripheral neuropathy
C. Relapsed / refractory
- Triplet at each relapse; switch class according to what the disease is refractory to
- Backbones: anti-CD38 (dara, isatuximab), carfilzomib, pomalidomide, elotuzumab, selinexor, venetoclax if t(11;14)
- BCMA- and GPRC5D-directed immunotherapy
- CAR-T: ciltacabtagene autoleucel, idecabtagene vicleucel (cilta-cel now from first relapse, CARTITUDE-4)
- Bispecifics: teclistamab, elranatamab (BCMA); talquetamab (GPRC5D)
- CRS + ICANS - step-up dosing, tocilizumab; profound infection risk -> antimicrobial prophylaxis + IVIG
- Allogeneic SCT - only ~5% of patients; TRM ~40%, uncertain graft-versus-myeloma effect
D. Supportive care - all patients
- Bone: monthly zoledronic acid or denosumab, ~2 years; dental review before starting (ONJ)
- Denosumab preferred if renal impairment; rebound bone loss on cessation
- Radiotherapy for uncontrolled pain, impending fracture, cord compression; vertebroplasty/kyphoplasty; prophylactic fixation
- Renal: rehydrate, stop nephrotoxics, urgent bortezomib-based therapy (renally safe, no dose adjustment)
- Plasma exchange for cast nephropathy is not standard - the light chain source must be shut off
- VTE prophylaxis mandatory with IMiDs - aspirin if low risk, LMWH or DOAC if high risk
- Infection: influenza/COVID/pneumococcal vaccination, aciclovir with any proteasome inhibitor or anti-CD38, IVIG if recurrent infection + hypogammaglobulinaemia
- Hyperviscosity (visual change, mucosal bleeding, confusion) -> plasma exchange
- *Symptomatic anaemia is treated with red cells, not plasma exchange*
- Hypercalcaemia: saline + bisphosphonate + corticosteroid
Daratumumab traps
- Human IgG-kappa antibody -> appears on SPEP/immunofixation and confounds CR assessment in IgG-kappa myeloma
- Binds CD38 on red cells -> pan-reactive indirect antiglobulin test - phenotype/genotype and notify the blood bank before the first dose
- Infusion reactions ~50%, almost all first cycle (much lower with subcutaneous); neutropenia, thrombocytopenia
IMiD class effects
- Mechanism: T/NK cell activation, anti-angiogenic, direct plasma cell kill (cereblon)
- Thalidomide: constipation, somnolence, painful sensory neuropathy (monitor SNAP amplitude), thrombosis, rash, oedema
- VTE risk rises with added dexamethasone, and further again with cytotoxic chemotherapy
- Lenalidomide: cytopenias, diarrhoea, rash, secondary malignancy; renally dosed
- All teratogenic - pregnancy prevention programme
Associations
- AL amyloidosis - cardiac, renal, neuropathy, macroglossia, periorbital purpura
- MGRS - monoclonal gammopathy of renal significance: renal lesion without myeloma-level clone
- POEMS - polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes; usually lambda, VEGF-driven, osteosclerotic lesions
- Solitary plasmacytoma; plasma cell leukaemia
- Hypogammaglobulinaemia -> encapsulated organism infection
- Acquired von Willebrand disease, acquired C1-inhibitor deficiency, cryoglobulinaemia
- Amyloid-associated acquired factor X deficiency
- Prior radiation, obesity, pesticide/benzene exposure
Natural history & complications
- Median OS now >7-10 years with quadruplet induction + ASCT; ~5 y in older/high-risk
- Remitting-relapsing - each remission shorter than the last
- Not cured by autologous SCT (CR ~25-50% vs <5% with conventional therapy; 5-yr OS ~50% vs ~10% historically)
Adverse markers
- del(17p)/TP53, t(4;14), t(14;16), t(14;20), 1q21 gain/amp, del(1p)
- del(13) and hypodiploidy on karyotype (not on FISH - reflects proliferation)
- inc LDH, inc beta-2 microglobulin, IgA isotype
- Circulating plasma cells, extramedullary disease, plasma cell leukaemia, renal failure
- *t(11;14) is favourable*
Response assessment
- MRD negativity (10^-5 to 10^-6 by NGS or next-generation flow) - strongest surrogate for PFS and OS; sustained MRD negativity at 12 months is the current endpoint
Complications
- Pathological fracture, vertebral collapse, cord compression
- Renal failure - dialysis-dependence in a minority
- Recurrent infection - commonest cause of death
- Hyperviscosity (more with IgA/IgM - polymerisation)
- Marrow failure from progressive infiltration
- Therapy-related MDS/AML - lenalidomide maintenance after melphalan
- Peripheral neuropathy - disease, amyloid, bortezomib, thalidomide
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