Lucan · Conditions

Multiple myeloma

Australian guidance: Cancer Council Victoria / Cancer Australia Optimal Care Pathway for People with Multiple Myeloma (publisher attribution pending verification — see source list) + eviQ Cancer Treatments Online + HealthPathways WA

1. Definition and epidemiology

Multiple myeloma is a malignant clonal proliferation of terminally differentiated plasma cells within the bone marrow, characterised by secretion of a monoclonal immunoglobulin or immunoglobulin fragment (the paraprotein, or M-protein) and by end-organ damage attributable to that clonal process. It is the second most common haematological malignancy in Australia after non-Hodgkin lymphoma, with a median age at diagnosis in the late sixties to early seventies and a slight male predominance. Myeloma sits at the malignant end of a biological continuum that begins with monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic clonal plasma cell population present in a meaningful proportion of the older population, and progresses through an intermediate smouldering (asymptomatic) myeloma stage before becoming symptomatic, treatment-requiring disease. Because the disease is essentially incurable with current standard therapy but highly responsive to modern agents, the clinical goal in almost every Australian patient is durable disease control and quality of life rather than cure, and the disease course is typically one of remission and relapse over years.

2. Pathophysiology

Malignant transformation occurs in a post-germinal-centre B lymphocyte that has undergone immunoglobulin class-switch recombination and somatic hypermutation before terminally differentiating into a plasma cell; the resulting clone retains the capacity to secrete a single immunoglobulin heavy and light chain combination, which is what produces the monoclonal paraprotein. Two broad cytogenetic pathways drive this transformation: hyperdiploid myeloma, characterised by trisomies of odd-numbered chromosomes and a generally more favourable prognosis, and non-hyperdiploid myeloma, driven by immunoglobulin heavy chain (IGH) translocations at 14q32, most commonly t(11;14) (upregulating cyclin D1, standard risk), t(4;14) (dysregulating FGFR3 and MMSET, high risk under R-ISS), and t(14;16) (dysregulating MAF, high risk). Risk classification has evolved: current mSMART criteria (2022) treat t(4;14) alone as intermediate risk, reserving high-risk status for del(17p), t(14;16), t(14;20), and gain/amp(1q), so t(4;14)'s risk tier depends on which staging framework is applied. Malignant plasma cells are critically dependent on the bone marrow microenvironment, particularly interleukin-6 secreted by marrow stromal cells, for growth and survival, which is why myeloma classically remains confined to the marrow (extramedullary disease is a late or high-risk feature) and why disease burden correlates so closely with the volume of marrow involved.

The lytic bone disease that defines myeloma arises because the clone disturbs the normal coupling of bone remodelling: myeloma cells and the surrounding stroma upregulate RANKL and Dickkopf-1 while suppressing osteoprotegerin, driving unopposed osteoclast activation and osteoblast suppression. The result is pure bone resorption without the reactive osteoblastic healing response seen in most other bony metastatic disease, which is why myeloma lesions are purely lytic and why a technetium bone scan, which depends on osteoblastic uptake, is an unreliable and inappropriate investigation in this disease. The paraprotein itself drives several of the other hallmark findings: at sufficiently high concentration it coats circulating red cells and reduces the normal negative surface charge (zeta potential) that keeps them apart, causing the red cells to stack together in linear aggregates on a blood film, a phenomenon called rouleaux, and the same effect drives a markedly elevated erythrocyte sedimentation rate and, at high paraprotein burden, symptomatic hyperviscosity.

3. Clinical presentation and diagnostic criteria

The classic teaching mnemonic for myeloma-defining organ damage is CRAB: hyperCalcaemia from osteoclastic bone resorption, Renal impairment from light-chain-mediated tubular injury, Anaemia from marrow infiltration and cytokine suppression of erythropoiesis, and Bone disease (lytic lesions, osteopenia, or pathological fracture). Presenting symptoms follow directly from these: bone pain (classically axial, in the spine, ribs, or pelvis, worse with movement) is the most common presenting complaint and may culminate in a pathological fracture or vertebral collapse; fatigue and pallor reflect anaemia; polyuria, thirst, confusion, and constipation reflect hypercalcaemia; and unexplained renal impairment, sometimes the presenting feature in an otherwise well patient, reflects myeloma kidney. Recurrent or unusual infections are common, because the malignant clone suppresses production of normal, functional polyclonal immunoglobulin (a phenomenon termed immunoparesis), leaving patients profoundly hypogammaglobulinaemic for organisms other than the paraprotein's own irrelevant specificity.

The International Myeloma Working Group (IMWG) diagnostic criteria, adopted in Australian practice, require clonal bone marrow plasma cells of 10% or more (or a biopsy-proven plasmacytoma) plus at least one myeloma-defining event. A myeloma-defining event is either a CRAB feature (corrected serum calcium >2.75 mmol/L or >0.25 mmol/L above the upper limit of normal; creatinine >177 micromol/L or creatinine clearance <40 mL/min; haemoglobin <100 g/L or more than 20 g/L below the lower limit of normal; one or more lytic bone lesion on imaging) or one of the SLiM biomarkers added in the 2014 IMWG revision to capture patients at very high imminent risk of progression before CRAB damage occurs: clonal bone marrow plasma cells ≥60%, a serum free light chain ratio ≥100 (with the involved light chain ≥100 mg/L), or more than one focal lesion on MRI. MGUS, by contrast, is defined by a serum paraprotein <30 g/L, clonal bone marrow plasma cells <10%, and no myeloma-defining event; it progresses to overt myeloma at roughly 1% per year and requires no treatment, only periodic monitoring. Smouldering (asymptomatic) myeloma sits between the two, with a paraprotein ≥30 g/L and/or clonal plasma cells 10 to 60%, again without a myeloma-defining event; its risk of progression is highest in the first five years (of the order of 10% per year) and declines thereafter, and it too is managed with active surveillance rather than treatment outside a clinical trial, unless SLiM criteria are met.

4. Investigations and AU-specific cutoffs

Initial work-up in primary care or hospital combines a full blood count and film (normochromic normocytic anaemia with rouleaux, and a background blue tinge on the film from the elevated paraprotein), urea, electrolytes and creatinine, corrected calcium, and lactate dehydrogenase, together with serum protein electrophoresis (SPEP) with immunofixation to identify and type the paraprotein. IgG paraproteins are most common (roughly half of cases), followed by IgA (around a fifth), with the remainder split between light-chain-only disease and rare IgD, IgE, biclonal, or non-secretory myeloma. The serum free light chain (SFLC) assay, measuring free kappa and lambda light chains and their ratio, is essential in Australian practice because it detects light-chain-only and oligosecretory or non-secretory disease that SPEP alone can miss, and because it is the most sensitive marker for monitoring response in light-chain-predominant disease; a 24-hour urine collection for protein electrophoresis (detecting Bence Jones protein) complements this. Serum beta-2 microglobulin and albumin are measured for staging.

Whole-body low-dose CT has replaced the traditional plain film skeletal survey as the first-line imaging investigation for myeloma bone disease in Australian practice, because conventional radiographs only become positive once roughly 30 to 50% of trabecular bone has been lost, whereas low-dose CT detects lytic disease earlier with a substantially lower radiation dose than a full-body diagnostic CT. Whole-body MRI or PET-CT is used where low-dose CT is negative but clinical suspicion remains, to characterise diffuse marrow infiltration, to detect extramedullary disease, and for baseline staging when available, consistent with eviQ and Myeloma Australia guidance. Bone marrow aspirate and trephine biopsy confirms clonal plasma cell infiltration by morphology and flow cytometry (light chain restriction) and provides tissue for fluorescence in situ hybridisation (FISH) cytogenetics, which risk-stratifies the disease and directly informs treatment intensity; the Revised International Staging System (R-ISS) combines beta-2 microglobulin, albumin, LDH, and the presence of high-risk cytogenetics (t(4;14), t(14;16), or del(17p)) into three prognostic stages.

5. Management

Management is coordinated through a specialist haematology service and staged according to symptomatic status, transplant eligibility, and cytogenetic risk, following protocols set out on eviQ and the Cancer Council Australia / Myeloma Australia Optimal Care Pathway. Asymptomatic MGUS and low-risk smouldering myeloma are managed with active surveillance alone. Symptomatic myeloma meeting diagnostic criteria is treated with induction combination chemotherapy, most commonly a triplet of a proteasome inhibitor (bortezomib), an immunomodulatory drug (lenalidomide or, in earlier lines, thalidomide), and dexamethasone (VRd or, where lenalidomide is unsuitable, CyBorD substituting cyclophosphamide). Fit, transplant-eligible patients (broadly those under about 70 to 75 without significant comorbidity) proceed to autologous stem cell transplantation after induction, using high-dose melphalan conditioning, followed by maintenance lenalidomide to prolong remission. Transplant-ineligible or frail patients receive the same drug classes at reduced intensity and duration, with anti-CD38 monoclonal antibody (daratumumab)-based combinations increasingly used in the first-line setting as PBS listings have expanded. Relapsed disease is retreated with a different drug combination, drawing on the same three drug classes (proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies) in new combinations, since myeloma characteristically relapses after each remission and second- and subsequent-line therapy is standard rather than exceptional.

Supportive care runs in parallel with disease-directed treatment throughout the illness. Bone-modifying therapy, either intravenous bisphosphonate (zoledronic acid monthly, or pamidronate where renal function is impaired) or the RANKL inhibitor denosumab, is recommended for all patients with lytic bone disease to reduce skeletal-related events (fracture, cord compression, need for radiotherapy or surgery to bone), typically for around two years; denosumab is preferred over zoledronic acid in significant renal impairment because it is not renally cleared, and dental assessment before starting either agent is routine because of the risk of medication-related osteonecrosis of the jaw. Localised radiotherapy treats painful focal lesions, impending or actual pathological fracture, and cord compression, and vertebroplasty or kyphoplasty is used for symptomatic vertebral collapse. Because immunomodulatory drugs combined with dexamethasone carry a substantial venous thromboembolism risk, thromboprophylaxis (aspirin for standard risk, low molecular weight heparin for higher risk) is routine during treatment with these agents.

6. Pharmacology and AU PBS notes

Bortezomib (a reversible proteasome inhibitor) is delivered subcutaneously and is PBS-listed for induction and relapsed myeloma; its principal toxicity is peripheral sensory neuropathy, and it carries a specific risk of varicella-zoster reactivation, for which prophylactic aciclovir or valaciclovir is co-prescribed throughout treatment. Lenalidomide (an oral immunomodulatory drug, the successor to thalidomide with less neuropathy but more myelosuppression) is PBS-listed for induction, maintenance, and relapsed disease; it is teratogenic, distributed in Australia only through a mandatory pregnancy-prevention risk management program (historically the i-access program), and requires renal dose adjustment. Daratumumab (an anti-CD38 monoclonal antibody, given intravenously or subcutaneously) has PBS listings that have progressively expanded from relapsed/refractory disease into the first-line setting in combination regimens; it interferes with blood bank antibody screening (pan-reactivity on indirect antiglobulin testing) and pre-treatment typing is arranged accordingly.

Infection prophylaxis is a core part of myeloma pharmacotherapy because of the disease's intrinsic immunoparesis compounded by treatment-related lymphopenia and corticosteroid exposure: antiviral prophylaxis accompanies bortezomib and daratumumab-based regimens, co-trimoxazole Pneumocystis jirovecii prophylaxis is used with high-dose or prolonged corticosteroid exposure, and annual influenza and periodic pneumococcal vaccination are recommended, with live vaccines avoided during active treatment. Intravenous immunoglobulin replacement is reserved for patients with recurrent severe bacterial infection and confirmed hypogammaglobulinaemia rather than used routinely. NSAIDs are avoided wherever possible given the added nephrotoxic burden on a kidney already threatened by light chains.

7. Complications and monitoring

Myeloma (cast) kidney is the classic renal complication and a medical emergency: excess free light chains filtered by the glomerulus overwhelm proximal tubular reabsorption, combine with Tamm-Horsfall protein in the distal tubule, and precipitate as obstructing casts, producing acute kidney injury that is managed with aggressive intravenous hydration, avoidance of further nephrotoxins (NSAIDs, unnecessary iodinated contrast), and, crucially, urgent initiation of disease-directed therapy to shut down light chain production, since renal recovery depends on reducing the light chain load rather than on renal-specific measures alone. Hypercalcaemia of malignancy in myeloma is driven by osteoclastic bone resorption rather than PTHrP and is treated with aggressive rehydration followed by intravenous bisphosphonate. Hyperviscosity syndrome, more common with IgA and higher-concentration paraproteins, presents with visual disturbance, mucosal bleeding, and neurological symptoms and is treated with urgent plasmapheresis alongside disease-directed therapy. AL amyloidosis, in which the same clonal light chains misfold and deposit as amyloid fibrils in the heart, kidneys, and peripheral nerves, can coexist with or precede overt myeloma and should be considered when cardiac or renal involvement seems disproportionate to the paraprotein burden. Spinal cord compression from vertebral collapse or an extradural plasmacytoma is an oncological emergency requiring urgent MRI, corticosteroids, and same-day radiotherapy or surgical decompression.

Infection remains a leading cause of death in myeloma across all stages of treatment, reflecting the combination of disease-related immunoparesis and treatment-related immunosuppression, and any unexplained fever in a myeloma patient warrants prompt assessment. Prognosis has improved substantially with the sequential introduction of proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, but the disease remains characteristically relapsing and remitting rather than curable outside rare cases, and R-ISS stage at diagnosis, together with cytogenetic risk, remains the principal determinant of expected survival and the intensity of first-line therapy offered.

Written for Australian practice and grounded in the guidance named above. Study material only — not medical advice. Always check against current guidelines.