Multiple Myeloma — Viva Defence

Long Case Viva Defence

The scenario

A 66-year-old man presents with three months of progressive lower back pain, fatigue and a five-kilogram weight loss. His general practitioner prescribed ibuprofen 400 mg three times daily two weeks ago. Full blood count shows haemoglobin 86 g/L, creatinine 240 micromol/L (baseline 90 six months ago), corrected calcium 3.0 mmol/L, albumin 30 g/L, total protein 118 g/L. Serum protein electrophoresis shows an IgG kappa paraprotein of 42 g/L. Serum free light chains show kappa 920 mg/L, lambda 16 mg/L. Bone marrow shows 55 per cent clonal plasma cells. FISH cytogenetics are pending. He works as an accountant, lives with his wife, has two adult children, and has mild hypertension (on amlodipine) but no other significant past history. ^[1]

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 bone lesions, fatigue from anaemia, and weight loss — found to have multiple myeloma on marrow and serology, with an IgG kappa paraprotein of 42 g/L, clonal plasma cells at 55 per cent, and an extremely high kappa free light chain of 920 mg/L. His main problems are the acute kidney injury from cast nephropathy (precipitated and worsened by the NSAID his GP prescribed for the back pain — he must never take NSAIDs again), the symptomatic hypercalcaemia at 3.0 mmol/L, the anaemia, the bone disease, and the pending cytogenetic risk stratification which will refine his prognosis and treatment intensity. 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 burden and recover renal function, then engage the haematology multidisciplinary team and the patient in a shared decision on the transplant pathway — he is 66 and likely transplant-eligible subject to a fitness assessment." ^[1]

Problem list (numbered, prioritised)

1. Newly diagnosed symptomatic multiple myeloma — meeting the IMWG 2014 criteria on multiple myeloma-defining events (CRAB features: hypercalcaemia, renal impairment, anaemia; and likely bone lesions pending imaging) ^[1].
2. Acute kidney injury from presumed cast nephropathy — creatinine 240 from baseline 90, with kappa free light chain 920 mg/L and an abnormal involved-to-uninvolved ratio of about 58. A reversible emergency if treated promptly.
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. Bone disease — back pain; lytic lesions likely pending whole-body 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 and his work.

Integrated management plan

Pillar 1 — Immediate stabilisation: "First, stop the ibuprofen immediately and tell him never to take an NSAID again — they reduce renal blood flow and precipitate or worsen cast nephropathy. For the hypercalcaemia, I would give aggressive intravenous normal saline — 3 to 6 litres over 24 hours, guided by his volume status, with a urinary catheter to monitor output, targeting at least 100 mL/hour — then intravenous zoledronic acid 4 mg, dose-adjusted for his renal function, with calcitonin 4 to 8 IU/kg subcutaneously every 12 hours for the first 24 to 48 hours for symptomatic relief while the bisphosphonate works. I would avoid thiazides (they retain calcium) and use a loop diuretic only for volume overload. For the renal failure, the priority is rapid cytoreduction — see Pillar 3. I would involve nephrology early, because high-cutoff haemodialysis may be considered if he becomes dialysis-dependent." ^[1]

Pillar 2 — Complete the diagnostic and staging workup: "The diagnosis is essentially confirmed. I would complete the staging with beta-2 microglobulin and LDH for the R-ISS stage ^[2], urine protein electrophoresis on a 24-hour collection, whole-body low-dose CT or PET-CT for the full extent of the bone disease, and FISH cytogenetics on the marrow. I would also assess his fitness for transplant — ECOG performance status, cardiac and pulmonary function, and a careful comorbidity review."

Pillar 3 — Induction with a bortezomib-based regimen: "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 it is the most effective agent for rapidly lowering the free light chain burden. I would use bortezomib, cyclophosphamide and dexamethasone (VCd) as the induction, with bortezomib subcutaneously at 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle, and aciclovir prophylaxis for herpes zoster. Reduced-dose dexamethasone (20 mg weekly) given his age. The goal is a 50 per cent reduction in the serum free light chain within 21 days — the best predictor of renal recovery. ^[1]

Subject to a fitness assessment, he is likely transplant-eligible — he is 66, working full time as an accountant, with only mild hypertension. The pathway would be: 3 to 4 cycles of induction, then peripheral stem cell collection, then high-dose melphalan 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 in the modern era ^[4][5]; CALGB 100104 established the overall survival benefit of lenalidomide maintenance ^[6]. If he proves transplant-ineligible, the modern standard is a daratumumab-based regimen (DRd, MAIA) ^[7], though bortezomib remains the urgent first agent in the renal failure setting."

Pillar 4 — Supportive care: "Bisphosphonates monthly for bone health and skeletal event reduction, with calcium and vitamin D supplementation and a dental review before starting (osteonecrosis of the jaw risk); denosumab is the alternative in renal failure. VTE prophylaxis with aspirin on lenalidomide-containing regimens (LMWH for high-risk patients). Aciclovir for herpes zoster on bortezomib. Vaccination — influenza, COVID-19, pneumococcal, recombinant zoster — ideally before treatment. Transfusion for symptomatic anaemia. Analgesia with paracetamol and opioids, and local radiotherapy for focal painful bone lesions." ^[1]

Pillar 5 — Communication and shared decision: "I would break the news with the haematologist and a clinical nurse specialist, in plain language, framing myeloma as a serious but treatable disease — not yet curable for most patients, but with median overall survival now over 8 to 10 years in the modern era and continuing to improve. I would set out the immediate priorities (reversing the kidney injury and the calcium, then induction), the transplant pathway if he is fit, and the maintenance phase. I would address his concerns about work, family and quality of life, document the shared decision, and arrange follow-up with a named contact in the haematology team." ^[1]

Probing questions the examiner would ask

Q: His FISH cytogenetics return a 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 (VRd rather than VCd once his renal function recovers), proceeding to autologous transplant in first remission (transplant remains beneficial even in high-risk disease), more intensive maintenance (the BMT CTN 0702 trial explored bortezomib-based maintenance in high-risk disease), and early discussion of clinical trial enrolment. I would set realistic expectations — 5-year overall survival for R-ISS stage III disease is under 40 per cent, and del(17p) places him toward the adverse end. I would not de-escalate to supportive care without his explicit choice, but I would ensure he understands the trade-offs. Allogeneic transplant is considered in selected high-risk patients in first remission on clinical trials, but it is not standard outside a trial because of the graft-versus-host disease and transplant-related mortality burden." ^[1]

Q: On day 5 of induction he develops acute severe back pain and bilateral leg weakness. 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 examine him immediately for a sensory level, motor power, 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 plain films or CT are inadequate), and give intravenous dexamethasone 10 to 16 mg immediately to reduce spinal cord oedema. I would involve the clinical oncology team urgently for radiotherapy (the modality of choice for most cases of myeloma-related cord compression, which is exquisitely radiosensitive) or surgical decompression in selected patients with spinal instability or a single-level lesion. I would not wait for the MRI to start the dexamethasone. 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 selected patients 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. The goal remains rapid cytoreduction (50 per cent free light chain reduction within 21 days predicts renal recovery). I would also be even 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." ^[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 being studied and are increasingly used in high-risk disease. The practical issues are three: (1) infusion reactions during the first dose, managed with premedication (steroid, paracetamol, antihistamine) and largely avoided with the subcutaneous formulation; (2) interference with the blood crossmatch — daratumumab binds CD38 on red cells and causes a panreactive antibody screen, so the blood bank must be notified and a sample obtained before the first dose; and (3) 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."

Q: How would your management differ if he were 84, 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 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) outweighs the benefit in this group." ^[1]

Communication and shared decision-making

"I would frame Mr M's myeloma as a serious but treatable diagnosis, with a clear immediate plan and a shared decision on the treatment pathway. I would explain that the kidney injury and the calcium are the immediate emergencies, that stopping the ibuprofen is critical, and that we will start treatment urgently to recover his kidney function. I would set out the two phases honestly — induction and (if fit) transplant, then maintenance — the expected course (prolonged but with extended survival in the modern era), the main toxicities (neuropathy, cytopenias, infection, VTE), and the fact that maintenance continues until progression or intolerance. I would address his concerns about work and family, document the shared decision, and review it as the cytogenetics refine the prognosis. I would give him 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 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]