Multiple Myeloma — Clinical Case

DCE Long Case

Patient profile

Mr M is a 66-year-old accountant who presents to the emergency department with three months of progressive lower back pain, fatigue and a five-kilogram weight loss, with acute worsening of his renal function and hypercalcaemia found on bloods ordered by his general practitioner. [1]

Presenting concern: For three months he has had progressive lower back pain, initially attributed to prolonged sitting at his desk, worse at night and unrelated to activity. Over the same period he has felt increasingly tired and has noticed his trousers are looser. Two weeks ago his general practitioner prescribed ibuprofen 400 mg three times daily for the back pain, and last week ordered bloods which showed anaemia, renal impairment and hypercalcaemia. He was sent to the emergency department today. He describes mild constipation and increased urinary frequency. [1]

Past medical history: Mild hypertension (on amlodipine 5 mg daily, well controlled). No prior haematological or malignant disease. Cholecystectomy at age 50. Appendicectomy at age 22. No known allergies. He has never smoked; alcohol 6 standard drinks per week. [1]

Medications: Amlodipine 5 mg daily, ibuprofen 400 mg three times daily (started two weeks ago for back pain), paracetamol as needed. No over-the-counter or herbal products. [1]

Family history: Father with type 2 diabetes (died age 78 of a stroke); mother alive age 88 with hypertension; one brother (age 70) well; two adult sons, both well. No family history of haematological malignancy. [1]

Social: Accountant, works full time. Lives with his wife (a retired nurse) in their own home. Two adult children and four grandchildren. Independent in all activities of daily living; walked 5 km daily until the past month. Has private health insurance. [1]

Examination:

• Alert, pale, comfortable at rest. Temperature 36.9. Pulse 88 regular. Blood pressure 138/82. Respiratory rate 16. SpO2 98 per cent room air.
• Marked conjunctival and palmar pallor. No jaundice. No periorbital purpura.
• No lymphadenopathy. No macroglossia. Mouth: no mucosal bleeding, no oral candidiasis.
• Cardiovascular: normal heart sounds, no murmur, JVP not elevated.
• Respiratory: clear.
• Abdomen: soft, non-tender, no organomegaly. Bladder not palpable.
• Spine: focal tenderness over L1 and L2 on percussion, no step deformity or gibbus.
• Neurological: normal motor power in all four limbs, normal tone, normal reflexes, no sensory level, anal tone normal, no saddle anaesthesia, post-void residual 50 mL on bladder scan.
• Fundoscopy: normal, no retinal venous engorgement. [1]

Investigations:

• Haemoglobin 86 g/L (MCV 89 fL); white cell count 5.2; platelets 180. Film: normocytic normochromic anaemia, rouleaux formation.
• ESR 118 mm/hour; CRP 14 mg/L.
• Sodium 138; potassium 4.2; urea 18; creatinine 240 (baseline 90 six months ago); eGFR 26 mL/min/1.73 m2.
• Corrected calcium 3.0 mmol/L; phosphate 1.1; albumin 30 g/L; total protein 118 g/L.
• Liver function normal; LDH 320 (upper limit 250); beta-2 microglobulin 8.2 mg/L.
• Serum protein electrophoresis: IgG kappa paraprotein 42 g/L; immunofixation confirms IgG kappa.
• Serum free light chains: kappa 920 mg/L, lambda 16 mg/L, ratio 58 (normal 0.26 to 1.65).
• Urine protein electrophoresis (24-hour collection): monoclonal kappa light chains 1.8 g per 24 hours (Bence-Jones protein positive).
• Bone marrow aspirate and trephine: 55 per cent clonal plasma cells (CD138+, CD38+, aberrant CD56+, kappa light-chain restricted). FISH cytogenetics pending (requested for del(17p), t(4;14), t(14;16), t(14;20), gain 1q, t(11;14)).
• Whole-body low-dose CT: multiple lytic lesions in the skull, ribs, thoracic and lumbar vertebrae (including L1 and L2), and proximal femora; no cord compression.
• ECG: normal sinus rhythm, normal voltages (no low-voltage pattern to suggest amyloid).
• Echocardiogram: normal left ventricular ejection fraction, normal wall thickness (no amyloid). [1]

Candidate's opening statement (SASPOP)

"This is Mr M, a 66-year-old accountant presenting with a three-month history of progressive marrow failure and bone disease — back pain from lytic vertebral and skull lesions, fatigue from anaemia, and weight loss — found on marrow and serology to have multiple myeloma, an IgG kappa disease with clonal plasma cells at 55 per cent, a paraprotein of 42 g/L, and an extremely high kappa free light chain of 920 mg/L. His main problems are the acute kidney injury from cast nephropathy (creatinine 240 from a baseline of 90, accelerated by the ibuprofen his GP prescribed — he must never take an NSAID again), the symptomatic hypercalcaemia at 3.0 mmol/L, the anaemia, the extensive lytic bone disease with no cord compression, and the pending cytogenetic risk stratification. My priorities are to stop the ibuprofen, treat the hypercalcaemia aggressively with intravenous fluids and a bisphosphonate, achieve rapid cytoreduction with a bortezomib-based regimen to lower the free light chain and recover renal function, and then engage the haematology multidisciplinary team and the patient in a shared decision on the transplant pathway — he is 66, working full time, and likely transplant-eligible subject to a fitness assessment." [1]

Structured problem list (numbered, prioritised)

1. Newly diagnosed symptomatic multiple myeloma — IgG kappa, clonal plasma cells 55 per cent, meeting the IMWG 2014 criteria on the CRAB features of hypercalcaemia (3.0 mmol/L), renal impairment (creatinine 240), anaemia (haemoglobin 86), and lytic bone lesions (skull, ribs, vertebrae, femora) [1].
2. Acute kidney injury from presumed cast nephropathy — creatinine 240 from baseline 90, kappa free light chain 920 mg/L with involved-to-uninvolved ratio 58, Bence-Jones proteinuria 1.8 g per 24 hours. A reversible emergency.
3. NSAID-related nephrotoxicity — ibuprofen 400 mg three times daily for two weeks, accelerating the cast nephropathy. Stop immediately and counsel lifelong avoidance.
4. Symptomatic hypercalcaemia — corrected calcium 3.0 mmol/L, contributing to dehydration, renal impairment and constipation.
5. Anaemia — haemoglobin 86 g/L, from marrow infiltration, hypercalcaemia and renal impairment.
6. Extensive lytic bone disease — skull, ribs, thoracic and lumbar vertebrae, proximal femora; no cord compression on imaging.
7. Pending cytogenetic risk stratification — FISH for del(17p), t(4;14), t(14;16), t(14;20), gain 1q; will drive treatment intensity and prognosis.
8. Psychosocial impact — the shock of the diagnosis on him, his wife (a retired nurse, who will understand the implications acutely), and his work.

Integrated management plan

Step 1 — Immediate stabilisation: [1]

First, stop the ibuprofen immediately and counsel him never to take an NSAID again — the cardinal rule in myeloma. NSAIDs reduce renal blood flow and precipitate or worsen cast nephropathy. [1]

For the hypercalcaemia, I would give aggressive intravenous normal saline (3 to 6 litres over 24 hours, guided by his volume status and JVP, with a urinary catheter to monitor output, targeting at least 100 mL/hour), then intravenous zoledronic acid 4 mg (the calcium is high enough to justify immediate bisphosphonate; given his renal function I would dose-adjust and give slowly, or use denosumab 120 mg subcutaneously which is not renally cleared). I would add calcitonin 4 to 8 IU/kg subcutaneously every 12 hours for the first 24 to 48 hours for symptomatic relief while the bisphosphonate works over 48 to 72 hours. I would avoid thiazides (they retain calcium) and use a loop diuretic only for volume overload. [1]

For the renal failure, the priority is rapid cytoreduction (see Step 3). I would manage the hypercalcaemia aggressively (calcium is nephrotoxic), continue the intravenous hydration, hold any nephrotoxins, and involve nephrology early — high-cutoff haemodialysis may be considered if he becomes dialysis-dependent, to remove the free light chains and improve the chance of renal recovery. [1]

Step 2 — Complete the diagnostic and staging workup: [1]

The diagnosis is confirmed. I would complete the staging with the beta-2 microglobulin (8.2 mg/L) and LDH already done for the R-ISS stage [2], the urine protein electrophoresis (Bence-Jones positive), the whole-body low-dose CT (extensive lytic disease, no cord compression), and the pending FISH cytogenetics. I would also assess his fitness for transplant — ECOG performance status 0 to 1 (he worked until last month and walked 5 km daily), cardiac function (echocardiogram normal), pulmonary function, and a careful comorbidity review (only mild hypertension). He is likely transplant-eligible.

Step 3 — Induction with a bortezomib-based regimen: [1]

For the acute renal failure, bortezomib is the agent of choice because it is hepatically cleared (not nephrotoxic, no dose adjustment for renal failure) and is the most effective agent for rapidly lowering the free light chain burden. I would use bortezomib, cyclophosphamide and dexamethasone (VCd or CyBorD) as the induction, with bortezomib 1.3 mg/m2 subcutaneously on days 1, 4, 8 and 11 of a 21-day cycle, cyclophosphamide, and reduced-dose dexamethasone 20 mg weekly (given his age, to limit steroid toxicity), with aciclovir prophylaxis for herpes zoster. The goal is a 50 per cent reduction in the serum free light chain within 21 days — the best predictor of renal recovery. [1]

Once his renal function recovers, if he proves transplant-eligible (which I expect), the pathway is: 3 to 4 cycles of induction, then peripheral stem cell collection, then high-dose melphalan 200 mg/m2 with autologous stem cell transplant, then lenalidomide maintenance. SWOG S0777 established VRd as superior to Rd [3]; IFM 2009 and EMN02/HO95 confirmed the additional progression-free survival benefit of transplant [4][5]; CALGB 100104 established the overall survival benefit of lenalidomide maintenance [6].

If he proves transplant-ineligible (unlikely given his fitness), the modern standard is a daratumumab-based regimen (DRd, MAIA) [7].

Step 4 — Supportive care: [1]

• Bisphosphonates — zoledronic acid 4 mg monthly for bone health, hypercalcaemia prevention and skeletal event reduction (the MRC Myeloma IX trial established a survival benefit); dose-adjusted for his renal function. Denosumab is the alternative in renal failure. Calcium and vitamin D supplementation to prevent hypocalcaemia, and a dental review before the first dose (osteonecrosis of the jaw risk).
• VTE prophylaxis — aspirin 100 mg daily on lenalidomide-containing regimens once he transitions to VRd; LMWH for high-risk patients.
• Infection prophylaxis — aciclovir for herpes zoster on bortezomib; cotrimoxazole if on heavy steroids; vaccination (influenza, COVID-19, pneumococcal, recombinant zoster) ideally before treatment starts, since response is blunted during therapy.
• Renal protection — aggressive hydration, strict avoidance of NSAIDs, avoid nephrotoxic contrast, manage the hypercalcaemia, monitor creatinine and free light chains closely.
• Transfusion for symptomatic anaemia (haemoglobin 86 — I would transfuse if he becomes symptomatic or if it falls further); erythropoiesis-stimulating agents have a limited role (thrombotic risk in myeloma).
• Analgesia — paracetamol, opioids for bone pain, and local radiotherapy for focal painful lesions (though his pain is multifocal, favouring systemic therapy and bisphosphonates). [1]

Step 5 — Monitor for and manage the complications: [1]

I would specifically watch for and treat: malignant epidural spinal cord compression (any new back pain with neurological signs triggers urgent MRI whole spine and dexamethasone), recurrent hypercalcaemia, bortezomib-related peripheral neuropathy (subcutaneous route, dose modification), infection (neutropenic, hypogammaglobulinaemic), and VTE (on lenalidomide, with aspirin prophylaxis). [1]

Step 6 — Communication, follow-up and safety: [1]

I would break the news with the haematologist and a clinical nurse specialist, in plain language, framing myeloma as a serious but treatable disease. I would address his wife directly — as a retired nurse she will understand the implications acutely and will be a key support. I would set out the immediate priorities (reversing the kidney injury and the calcium, then induction and the transplant pathway), the prognosis (median overall survival over 8 to 10 years for standard-risk disease in the modern era, with the R-ISS stage and cytogenetics to refine it), and the practicalities of prolonged treatment. I would document the shared decision, give written information, arrange a named contact in the haematology team, and arrange follow-up. I would discuss contraception (relevant if he has not completed his family — he has adult children, so likely not), and address his concerns about work, finances and quality of life. I would also, sensitively, ask about his wishes regarding intensive care in the event of a severe complication — not because we expect the worst, but because honest advance care planning is part of good practice. [1]

Probing questions the examiner would ask

Q: His FISH cytogenetics return deletion 17p (TP53 loss). What changes? [1]

A: "His risk group shifts to high-risk. Del(17p) — loss of the TP53 locus — is the single most adverse cytogenetic lesion in myeloma, associated with early relapse, extramedullary disease and poorer survival even with modern therapy. The implications: I would favour an intensified induction (transition to VRd once his renal function recovers, with consideration of a daratumumab-based quadruplet such as D-VRd on a clinical trial), proceeding to autologous transplant in first remission (transplant remains beneficial even in high-risk disease), more intensive maintenance (bortezomib-based maintenance in addition to lenalidomide, explored in the BMT CTN 0702 trial for high-risk disease), and early discussion of clinical trial enrolment — including CAR-T cell therapy and bispecific antibodies at relapse. I would set realistic expectations — 5-year overall survival for R-ISS stage III disease with del(17p) is under 40 per cent. I would ensure he understands the trade-offs and would not de-escalate without his explicit choice. Allogeneic transplant is considered in selected high-risk patients on clinical trials but is not standard outside a trial." [1]

Q: On day 5 of induction he develops acute severe back pain and bilateral leg weakness with a sensory level at T6. How do you respond? [1]

A: "This is malignant epidural spinal cord compression until proven otherwise — an oncological emergency in which delay causes permanent paraplegia. I would follow the ABCDE approach, examine him immediately for motor power, a sensory level, anal tone and urinary retention (post-void residual), then order an urgent MRI of the whole spine (the lesion may be at multiple levels), and give intravenous dexamethasone 10 to 16 mg immediately to reduce spinal cord oedema. I would not wait for the MRI to start the dexamethasone. I would involve the clinical oncology team urgently for radiotherapy (myeloma is exquisitely radiosensitive and radiotherapy is the modality of choice for most cases of cord compression) or surgical decompression in selected patients with spinal instability or a single-level lesion. I would arrange a neurosurgical opinion if there is spinal instability or uncertainty about the diagnosis. The principle: back pain plus a neurological sign in myeloma equals MRI whole spine and dexamethasone now." [1]

Q: How would your induction differ if his creatinine were 900 micromol/L and he required haemodialysis? [1]

A: "The principles are unchanged — bortezomib remains the agent of choice and is given at full dose because it is hepatically cleared. I would add the consideration of high-cutoff haemodialysis — a modified dialysis that uses a high-cut-off membrane to remove circulating free light chains more efficiently than standard dialysis — in a patient with very high free light chain levels and dialysis-dependent disease, with the goal of improving the chance of renal recovery. The evidence is mixed and its routine use is debated, but in a young patient with a very high free light chain burden it is a reasonable consideration, discussed with the nephrology team. The goal remains rapid cytoreduction (50 per cent free light chain reduction within 21 days predicts renal recovery). I would also be more careful with the bisphosphonate dose in dialysis-dependent disease — zoledronic acid is significantly dose-reduced and given slowly; denosumab (not renally cleared) is the safer alternative, though it carries a higher risk of hypocalcaemia in renal failure and requires closer calcium monitoring." [1]

Q: What is the role of daratumumab in his treatment, and what practical issues does it raise? [1]

A: "Daratumumab is a monoclonal antibody against CD38 on the plasma cell surface, causing complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity and direct apoptosis. In newly diagnosed transplant-ineligible disease, the MAIA trial established daratumumab plus lenalidomide and dexamethasone (DRd) as superior to Rd [7]; in the transplant-eligible setting, daratumumab-based quadruplets (D-VRd) are increasingly used, particularly in high-risk disease. The practical issues are three. First, infusion reactions during the first dose — managed with premedication (steroid, paracetamol, antihistamine) and largely avoided with the subcutaneous formulation. Second, interference with the blood crossmatch — daratumumab binds CD48 on red cells and causes a panreactive antibody screen, so the blood bank must be notified and a sample obtained before the first dose. Third, interference with the serum paraprotein assay — the drug itself is an IgG kappa and appears as an M-spike on immunofixation, requiring the mass-spectrometry-based monitoring or the daratumumab-specific immunofixation reflex assay (DIRA) to distinguish residual disease from the drug. For this patient, who is IgG kappa, the monitoring issue is directly relevant."

Q: How would your management differ if he were 84 rather than 66, frail, and living in supported accommodation? [1]

A: "The decision would shift toward a less intensive regimen or toward best supportive care, depending on his wishes and his overall trajectory. For a frail 84-year-old, I would consider daratumumab-lenalidomide-dexamethasone at reduced intensity (the MAIA trial included patients into their 90s, but the toxicity — cytopenias, infections, infusion reactions — is real in the very frail), or VRd-lite (a reduced-intensity bortezomib-lenalidomide-dexamethasone schedule), or a daratumumab-bortezomib-melphalan-prednisone regimen. I would assess him with a Comprehensive Geriatric Assessment where available, discuss the options honestly with him and his family, and respect his choice. For some very frail patients with high comorbidity and limited life expectancy, best supportive care with transfusion, analgesia, bisphosphonates and palliative care input is the most appropriate plan — it is not a failure of medicine but an honest alignment of therapy with the patient's goals. Autologous transplant is not offered to an 84-year-old because the toxicity (mucositis, cytopenias, infection, treatment-related mortality) outweighs the benefit in this group." [1]

Q: Six months later he is in complete remission after induction, autologous transplant and the start of lenalidomide maintenance. He asks about his long-term outlook. What do you tell him? [1]

A: "I would frame the prognosis honestly. His R-ISS stage and cytogenetics will refine the estimate, but for standard-risk disease in a fit 66-year-old, median overall survival in the modern era is over 8 to 10 years, and the trajectory continues to improve with anti-CD38 therapy, CAR-T cell therapy and bispecific antibodies entering earlier lines. The depth of response matters — complete remission and MRD (measurable residual disease) negativity are the strongest predictors of durable remission. Long-term follow-up involves surveillance for relapse (regular blood counts, paraprotein and free light chain monitoring every 1 to 3 months during maintenance, then every 3 to 6 months), bone health (continuing bisphosphonates or denosumab, monitoring for osteonecrosis of the jaw), attention to second primary malignancies (a small but real risk on lenalidomide maintenance), infection prophylaxis and vaccination, and psychosocial support — a myeloma diagnosis and its prolonged treatment affect every domain of life. I would offer him the haematology late-effects service and a primary care plan for shared surveillance." [1]

Communication and shared decision-making

"I would sit with Mr M and his wife in a quiet room, with the haematologist and a clinical nurse specialist. I would address his wife directly — as a retired nurse she will understand the implications acutely and will be a key support. I would explain in plain language what myeloma is — a cancer of the antibody-making cells in the marrow — and what the immediate plan is. I would acknowledge the shock explicitly and give them space. I would set out the immediate priorities — stopping the ibuprofen, treating the hypercalcaemia, recovering the kidney function, then starting induction — and the longer pathway of induction, transplant and maintenance if he is fit. I would address his anxiety about his kidneys directly — that the kidney injury is often reversible if we act promptly, that bortezomib is the right first agent, and that nephrology is involved. I would discuss the prognosis honestly — median overall survival over 8 to 10 years for standard-risk disease in the modern era, with the cytogenetics to refine it. I would address the practicalities of prolonged treatment (time off work, financial implications, family life), document the shared decision, and review it as the cytogenetics clarify the prognosis. I would give them written information and a named contact in the haematology team. I would also, sensitively, ask about his wishes regarding intensive care in the event of a severe induction or transplant complication — not because we expect the worst, but because honest advance care planning is part of good practice in a patient with a serious new diagnosis." [1]

DCE Short Case — Skeletal and General Examination in Multiple Myeloma

Instruction

"Examine this patient's general systems." [1]

Systematic examination routine

1. End of bed — observe for pallor, cachexia, weight loss, pain posture (guarding the back), bruising, walking aid. Note any oxygen, lines, or a urinary catheter.
2. Hands — pallor of the palmar creases, finger clubbing (uncommon, suggests an alternative diagnosis), leukonychia (hypoalbuminaemia), peripheral neuropathy (from amyloid or prior bortezomib), nail-fold infarcts (hyperviscosity).
3. Face — conjunctival pallor, periorbital purpura ("raccoon eyes" of amyloidosis), macroglossia (the enlarged, indented tongue of amyloid), signs of anaemia.
4. Mouth — oral candidiasis (immunosuppression), mucosal bleeding (thrombocytopenia), dental health (relevant before bisphosphonates).
5. Neck — cervical and supraclavicular lymphadenopathy (uncommon in myeloma; prominent nodes suggest lymphoma). JVP (volume status in renal failure).
6. Chest — respiratory exam for pleural effusion; precordial exam for signs of amyloid cardiomyopathy (raised JVP, gallop rhythm, peripheral oedema with a low-voltage ECG and thick echocardiographic walls).
7. Abdomen — hepatosplenomegaly (uncommon in myeloma; prominent organomegaly suggests amyloidosis or an alternative diagnosis). Bladder (urinary retention in cord compression).
8. Spine and skeleton — palpate for a gibbus or step deformity (vertebral collapse), percuss for spinal tenderness, examine for bony tenderness over the sternum, ribs, skull and pelvis.
9. Lower limbs — motor power, tone, reflexes, a sensory level (cord compression), saddle anaesthesia, anal tone, and a post-void residual (urinary retention).
10. Fundoscopy — retinal haemorrhages (hyperviscosity, thrombocytopenia), papilloedema (hyperviscosity), retinal venous engorgement with sausage-link segmentation (hyperviscosity). [1]

Key physical signs the patient demonstrates (for this case)

• Marked conjunctival and palmar pallor
• Bony tenderness over L1 and L2 on spinal percussion
• Reduced lumbar range of movement with guarding
• No periorbital purpura, no macroglossia (amyloid absent)
• No organomegaly (in keeping with typical myeloma)
• Normal neurological examination (no cord compression)
• Normal fundoscopy (no hyperviscosity) [1]

Presentation template

"I examined Mr M, a 66-year-old man who looks pale and tired at the end of the bed, guarding his back. He has marked conjunctival and palmar crease pallor. There is focal bony tenderness on percussion over L1 and L2, with reduced lumbar range of movement, but no step deformity or gibbus. There is no periorbital purpura, no macroglossia, no oral candidiasis, no mucosal bleeding. There is no significant lymphadenopathy. The chest is clear; the precordial examination is normal. The abdomen reveals no organomegaly. There is no peripheral oedema. Lower limb neurological examination is normal with no sensory level and intact sphincter function. Fundoscopy is normal. These findings are consistent with anaemia and focal bone disease in a patient with a monoclonal gammopathy — the picture is consistent with multiple myeloma. I would specifically examine for signs of AL amyloidosis (macroglossia, periorbital purpura, restrictive cardiomyopathy, hepatomegaly) and for malignant epidural spinal cord compression (a sensory level, motor weakness, urinary retention), because these change the immediate management. I would then confirm the diagnosis with serum protein electrophoresis, serum free light chains, and a bone marrow biopsy, and complete the staging with beta-2 microglobulin, LDH, FISH cytogenetics and whole-body low-dose CT." [1]

Discussion questions

Q: What is the significance of macroglossia in a patient with a paraprotein? [1]

A: "Macroglossia — an enlarged tongue indented by the teeth — is a highly specific sign of AL amyloidosis. It is essentially never seen in uncomplicated multiple myeloma without amyloid deposition. If I see it, I would actively look for the other systemic features of amyloidosis — periorbital purpura (raccoon eyes), easy bruising, a restrictive cardiomyopathy (low-voltage ECG with thick echocardiographic walls — the opposite of hypertensive heart disease, which gives high voltages with thick walls), nephrotic-range proteinuria, hepatomegaly, and a bleeding tendency (factor X binding by amyloid). I would confirm the diagnosis with a biopsy (abdominal fat pad, bone marrow, or involved organ) showing Congo-red-positive deposits with apple-green birefringence under polarised light. Treatment is the same anti-myeloma therapy directed at the clonal plasma cell, because the amyloid fibrils are derived from the monoclonal light chain — bortezomib-based or daratumumab-based regimens. The cardiac amyloid carries the worst prognosis and the greatest constraint on treatment (fluid overload, arrhythmia, contraindication to stem cell transplant in many cases)." [1]

Q: How would you distinguish multiple myeloma from metastatic carcinoma at the bedside? [1]

A: "The bedside discriminators are limited — the diagnosis is made on marrow, serology and imaging. But there are clues. Myeloma presents with bone pain, anaemia, hypercalcaemia and renal impairment in an older patient, with a monoclonal protein on serology and purely lytic bone lesions on imaging. Metastatic carcinoma often has a known primary (breast, lung, prostate, thyroid, kidney) and may produce sclerotic or mixed lytic-sclerotic lesions (prostate is typically sclerotic, breast is often mixed). The ESR is characteristically very high in myeloma (from the paraprotein — often over 100) but may be normal in metastatic disease. Hypogammaglobulinaemia with recurrent infection points to myeloma. The definitive discrimination is the marrow (clonal plasma cells in myeloma versus malignant epithelial cells in metastatic carcinoma) and serology (a monoclonal protein in myeloma). A bone scan is often falsely normal in myeloma (purely lytic lesions with no osteoblastic reaction) but typically abnormal in metastatic disease (which usually has an osteoblastic component) — a classic exam point." [1]

Q: What signs would make you concerned about hyperviscosity in a patient with a paraprotein? [1]

A: "The clinical features of hyperviscosity syndrome are visual disturbance (blurred vision), headache, mucosal bleeding (epistaxis, gum bleeding), neurological symptoms (confusion, ataxia, vertigo), and the characteristic retinal finding of venous engorgement with 'sausage-link' or 'boxcar' segmentation, with retinal haemorrhages and papilloedema. The syndrome is more typical of Waldenstrom macroglobulinaemia (IgM, a pentamer with high intrinsic viscosity at lower concentrations) than of typical IgG or IgA myeloma, but can occur with very high paraproteins — over about 100 g/L for IgG or 70 g/L for IgA. The treatment is urgent plasmapheresis (1.0 to 1.5 plasma volumes) to lower the paraprotein acutely, then definitive cytoreduction. The trigger is clinical, not a number — the plasma viscosity (above about 4 centipoise, or serum viscosity above 6) supports the decision but a symptomatic patient is treated regardless." [1]

Q: What is the role of the serum free light chain assay in monitoring myeloma, and when is it more useful than the paraprotein? [1]

A: "The serum free light chain assay has three key roles. First, in diagnosis — the involved-to-uninvolved ratio at least 100 is a myeloma-defining biomarker under the IMWG 2014 criteria, and the assay is essential to avoid missing light-chain myeloma (which has no serum paraprotein on electrophoresis). Second, in prognosis — an abnormal ratio is one of the three factors in the MGUS risk model, and a rising ratio during follow-up predicts progression. Third, in monitoring — for light-chain myeloma and oligosecretory disease (where the paraprotein is small or absent), the free light chain ratio is the primary disease marker, and it responds faster than the paraprotein to treatment. The assay is also used in the IMWG response criteria (a complete response requires a normal free light chain ratio). The caveat is that the ratio can be artefactually abnormal in renal impairment (reduced clearance of both light chains, with a disproportionate rise of the normally lower one), so it must be interpreted in clinical context. For this patient, with an extremely high kappa of 920 mg/L and a ratio of 58, the free light chain is the more sensitive marker for monitoring his response to induction, alongside the IgG kappa paraprotein." [1]

Q: What is the role of irradiated blood products in multiple myeloma, and which patients need them? [1]

A: "Irradiated blood products prevent transfusion-associated graft-versus-host disease (TA-GVHD), a rare but almost universally fatal complication in which donor T-lymphocytes in the transfused product engraft in the recipient and attack host tissues. The patients who need irradiated products are those with profound immunosuppression — patients who will have, are having, or have had an autologous or allogeneic stem cell transplant; patients treated with purine analogues (fludarabine, cladribine) or certain immunosuppressive biologics; and patients with Hodgkin lymphoma. For a newly diagnosed myeloma patient about to start induction and proceed to autologous transplant, the standard practice is to switch to irradiated products from the time of diagnosis or at least from the time of stem cell collection, because the transplant conditioning profoundly immunosuppresses the recipient. Leucodepletion (which is standard for all blood products in most countries) reduces but does not eliminate the TA-GVHD risk — irradiation is required for the high-risk groups. CMV-negative products are given to CMV-negative patients who are candidates for transplant, to prevent CMV transmission." [1]