Multiple Myeloma & Plasmacytoma

Multiple myeloma (MM) is a malignant plasma cell dyscrasia characterised by clonal proliferation of plasma cells in the bone marrow, producing a monoclonal immunoglobulin (paraprotein). It is the most common primary malignancy of bone in adults, and the orthopaedic surgeon frequently encounters myeloma as lytic bone lesions, pathological fractures, and spinal cord compression. Solitary plasmacytoma is a localised form of plasma cell neoplasm — bone or soft tissue — without systemic myeloma involvement.

• Incidence: approximately 6–7 per 100,000 population; median age at diagnosis 65–70 years; slightly more common in males; more common in Black populations
• Skeletal involvement at diagnosis: approximately 80% of MM patients have bone lesions; MM is the most common cause of a lytic bone lesion in patients over 40 years of age — always consider MM in any adult with multiple lytic lesions
• Sites: vertebral column (most common, especially thoracolumbar), ribs, skull, proximal femur, proximal humerus, pelvis
• Pathophysiology: myeloma cells produce RANKL and suppress OPG → osteoclast activation → osteolysis; simultaneously inhibit osteoblast function → absent or minimal periosteal/sclerotic reaction (unlike other bone metastases)
• Classic teaching: MM lesions show NO periosteal reaction and NO bone scan uptake on isotope bone scan — this is because osteoblast activity is suppressed; bone scan is therefore unreliable for staging MM; use skeletal survey or whole-body MRI / PET-CT instead

• Diagnostic criteria (IMWG 2014): ≥10% clonal bone marrow plasma cells OR biopsy-proven plasmacytoma PLUS one or more myeloma-defining events (CRAB criteria or biomarkers)

• Blood tests: serum protein electrophoresis (SPEP) for paraprotein (M-band); serum free light chains; β2-microglobulin (prognostic); LDH; calcium; creatinine; FBC (anaemia)
• Urine: Bence Jones protein (free light chains in urine); 24-hour urine protein electrophoresis
• Bone marrow aspirate and trephine biopsy: definitive diagnosis — percentage and morphology of plasma cells; flow cytometry; cytogenetics (FISH for del(17p), t(4;14), t(14;16) — high-risk features)
• Imaging: whole-body low-dose CT (WBLDCT) is the recommended first-line imaging for bone involvement — more sensitive than skeletal survey; PET-CT or whole-body MRI for functional assessment, extramedullary disease, and staging; bone scan NOT recommended (false negatives due to absent osteoblastic reaction)
• Skeletal survey (plain X-rays): still used where CT not immediately available; characteristic "punched-out" lytic lesions; "pepperpot skull"

• Solitary bone plasmacytoma (SBP): single biopsy-proven plasma cell lesion in bone; no evidence of systemic MM; bone marrow biopsy at a remote site shows <10% plasma cells; no CRAB features
• Solitary extramedullary plasmacytoma (SEP): plasma cell tumour in soft tissue, most commonly the upper respiratory tract (nasopharynx, paranasal sinuses); lower risk of progression to MM than SBP
• Progression to MM: SBP progresses to MM in approximately 70–80% of cases at 10 years — patients require long-term surveillance; SEP has lower progression rate (approximately 15–30%)
• Treatment of SBP: radiotherapy is the primary treatment — plasma cells are radiosensitive; dose 40–50 Gy; local control achieved in approximately 80–90%; surgery for pathological fracture or spinal cord compression before or after radiotherapy; biphosphonates to reduce skeletal events

The orthopaedic surgeon`s primary role in MM is managing the skeletal complications — pathological fractures, impending fractures, and spinal cord compression.

• Mirels score for impending pathological fracture: assesses upper and lower limb lesions; scores pain (1–3), lesion size (1–3), lesion type (lytic vs blastic vs mixed, 1–3), and site (1–3); score ≥9 = high risk; prophylactic fixation recommended; score ≤7 = low risk; radiotherapy and observation; score 8 = borderline, surgeon judgement
• Long bone pathological fractures: intramedullary nail (for diaphysis/metaphysis) or endoprosthetic replacement (for periarticular lesions); nail entire bone to prevent fracture at untreated distal lesion; post-operative radiotherapy to consolidate lesion and reduce local recurrence
• Spinal cord compression (MSCC): oncological and orthopaedic emergency; dexamethasone 8–16 mg stat; urgent MRI whole spine; decompression ± stabilisation if neurological deficit or instability; radiotherapy alone for radiosensitive tumours without significant instability (MM is radiosensitive)
• Vertebroplasty / kyphoplasty: for painful MM vertebral compression fractures without cord compression; cement (PMMA) injection stabilises vertebra; kyphoplasty also partially restores vertebral height; contraindicated with posterior wall breach or epidural disease
• Endoprosthetic replacement (EPR): for periarticular fractures (proximal femur, proximal humerus) where intramedullary fixation is inadequate due to extensive bone destruction; provides immediate stability; allows early weight-bearing; tumour implants used when bone destruction is extensive

• Induction therapy: standard regimens include VRd (bortezomib + lenalidomide + dexamethasone) or VTd (bortezomib + thalidomide + dexamethasone) as first-line in transplant-eligible patients
• Autologous stem cell transplantation (ASCT): for transplant-eligible patients (<70 years, adequate organ function); improves progression-free survival; deepens response after induction
• Bisphosphonates (zoledronic acid): reduce skeletal-related events (SREs) including pathological fractures; given IV monthly; osteonecrosis of the jaw (ONJ) is the most significant complication of bisphosphonate therapy in MM — dental review and any required dental work must be completed before starting bisphosphonates; avoid IV bisphosphonates in patients with active dental disease
• Denosumab: RANKL inhibitor; alternative to bisphosphonates for bone protection; subcutaneous injection; may be preferred in renal impairment; also associated with ONJ risk
• Daratumumab: anti-CD38 monoclonal antibody; incorporated into modern first-line regimens; significantly improves outcomes

• MGUS (monoclonal gammopathy of undetermined significance): premalignant condition; paraprotein present, <10% plasma cells, no CRAB features; approximately 1% per year risk of progression to MM or related disorder; requires monitoring but not treatment; differentiate MGUS from smouldering MM (higher plasma cell burden, no CRAB) from active MM requiring treatment
• Hypercalcaemia management in MM: IV hydration (3–4 litres normal saline) + bisphosphonate (IV zoledronic acid) + steroids; loop diuretics can be added once hydrated; urgent treatment to prevent renal failure and cardiac arrhythmia; one of the CRAB criteria
• Bone biopsy in suspected MM: biopsy must be planned to enable limb-salvage surgery if needed — core needle biopsy preferred over open biopsy; biopsy tract must be in the surgical field; frozen section to confirm plasma cell tumour before instrumentation; liaise with haematology and oncology before any biopsy
• MM and renal failure: light chain cast nephropathy is the most common renal pathology; avoid nephrotoxins (NSAIDs, IV contrast, aminoglycosides); early chemotherapy to reduce light chain burden; haemodialysis for severe renal failure; renal recovery possible with treatment

• Most common primary bone malignancy in adults over 40 = multiple myeloma; most common cause of multiple lytic bone lesions = MM
• Bone scan: unreliable in MM — NO osteoblast activity → false negative; use whole-body low-dose CT or PET-CT instead
• CRAB: hyperCalcaemia, Renal impairment, Anaemia, Bone lesions — diagnostic criteria for MM
• Punched-out lytic lesions; pepperpot skull; NO periosteal reaction — characteristic radiological appearance
• Mirels score ≥9 = prophylactic fixation; ≤7 = observe + radiotherapy; 8 = borderline
• Solitary plasmacytoma: radiotherapy primary treatment; 70–80% progress to MM at 10 years — lifelong surveillance
• Bisphosphonates: reduce SREs; osteonecrosis of jaw (ONJ) main complication; dental review before starting
• Vertebroplasty/kyphoplasty: painful vertebral compression fractures without cord compression or posterior wall breach
• MGUS: 1% per year progression to MM; monitor; no treatment required
• ONJ prevention: dental clearance before bisphosphonate or denosumab therapy; no elective dental procedures during treatment