Multiple Myeloma — Written Clinical Reasoning

SAQ 1 — Multiple myeloma presenting with cast nephropathy and hypercalcaemia (20 marks, 30 minutes)

Prompt: Outline your immediate assessment, the investigations you would order, your integrated management plan addressing each problem, and the shared decision-making framework. Justify each decision with reference to evidence. [1]

Model Answer

Problem list (4 marks): [1]

1. Newly diagnosed symptomatic multiple myeloma — clonal marrow plasma cells at 55 per cent, IgG kappa paraprotein 42 g/L, with multiple myeloma-defining events under the IMWG 2014 criteria [1].
2. Acute kidney injury from presumed cast nephropathy — creatinine 240 (from baseline 90), with an extremely high free light chain (kappa 920 mg/L) and a markedly abnormal involved-to-uninvolved ratio (about 58). A reversible emergency.
3. Symptomatic hypercalcaemia — corrected calcium 3.0 mmol/L, contributing to the renal impairment, dehydration and constipation.
4. Likely accelerating nephrotoxicity from the NSAID — ibuprofen 400 mg three times daily for two weeks, reducing renal blood flow and worsening cast nephropathy. Must be stopped immediately.
5. Anaemia — haemoglobin 86 g/L, contributing to the fatigue, from marrow infiltration, hypercalcaemia and renal impairment.
6. Back pain — the presenting symptom; lytic bone disease suspected.
7. Pending cytogenetic risk stratification — which will refine the prognosis and the treatment intensity.

Step 1 — Immediate stabilisation (5 marks): [1]

First, stop the ibuprofen immediately and counsel the patient never to take NSAIDs again — the cardinal rule in myeloma. NSAIDs reduce renal blood flow and precipitate or worsen cast nephropathy by reducing the filtered load clearance. [1]

For the hypercalcaemia, I would give aggressive intravenous normal saline (3 to 6 litres over 24 hours, guided by his volume status and jugular venous pressure, 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, dose-adjusted for his renal function — zoledronic acid is reduced in renal impairment; an alternative is 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 thiazide diuretics (they retain calcium) and use a loop diuretic only for volume overload. [1]

For the renal failure, the priority is rapid cytoreduction to lower the filtered free light chain burden (see Step 3). I would also treat the hypercalcaemia aggressively (calcium is nephrotoxic), check the volume status, and involve the nephrology team 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 workup (3 marks): [1]

The diagnosis is essentially confirmed by the marrow and the paraprotein. I would complete the staging workup: beta-2 microglobulin and LDH for the R-ISS stage [2], urine protein electrophoresis on a 24-hour collection for Bence-Jones protein (quantification, though the serum free light chain is the key assay), whole-body low-dose CT or PET-CT for the full extent of lytic bone disease (the back pain suggests vertebral involvement), and FISH cytogenetics on the marrow for del(17p), t(4;14), t(14;16), t(14;20), gain 1q and t(11;14). The cytogenetics will refine the risk group and the treatment — del(17p) and t(4;14) are high-risk and drive more intensive therapy. I would also assess his fitness for transplant: ECOG performance status, cardiac and hepatic function, and pulmonary function.

Step 3 — Definitive therapy: induction with a bortezomib-based regimen (4 marks): [1]

For a 66-year-old who is likely transplant-eligible (subject to a fitness assessment), the standard induction is a bortezomib-based regimen. In the setting of acute renal failure from cast nephropathy, I would use bortezomib, cyclophosphamide and dexamethasone (VCd or CyBorD) as the induction, because bortezomib 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. The goal is a 50 per cent reduction in the serum free light chain within 21 days — the best predictor of renal recovery. Bortezomib is given subcutaneously (to reduce peripheral neuropathy) at 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle, with aciclovir prophylaxis for herpes zoster reactivation. Reduced-dose dexamethasone (20 mg weekly rather than 40 mg) is appropriate given his age and to limit steroid toxicity. [1]

If he proves transplant-eligible (subject to fitness), the pathway is: 3 to 4 cycles of VCd or VRd induction, then peripheral stem cell collection, then high-dose melphalan with autologous stem cell transplant, then lenalidomide maintenance [4][5][6]. SWOG S0777 established VRd as superior to Rd; IFM 2009 and EMN02/HO95 confirmed the additional progression-free survival benefit of autologous transplant; CALGB 100104 established the overall survival benefit of lenalidomide maintenance [3][4][5][6].

If he proves transplant-ineligible, the modern standard is a daratumumab-based regimen (DRd, the MAIA trial), though in the acute renal failure setting bortezomib remains the urgent first agent for cytoreduction [7].

Step 4 — Supportive care (3 marks): [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). Denosumab is the alternative in renal failure. Calcium and vitamin D supplementation to prevent hypocalcaemia, and a dental review before starting (osteonecrosis of the jaw risk).
• VTE prophylaxis — aspirin 100 mg daily is standard-risk prophylaxis on lenalidomide-containing regimens; low-molecular-weight heparin 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.
• Renal protection — aggressive hydration, strict avoidance of NSAIDs, avoid nephrotoxic contrast, manage the hypercalcaemia.
• Transfusion for symptomatic anaemia; erythropoiesis-stimulating agents have a limited role (thrombotic risk).
• Analgesia — paracetamol, opioids for bone pain, and local radiotherapy for focal painful lesions. [1]

Step 5 — Monitor for and manage the complications (2 marks): [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), symptomatic hypercalcaemia (recurrent), bortezomib-related peripheral neuropathy (subcutaneous route, dose modification), and infection (neutropenic, hypogammaglobulinaemic). [1]

Step 6 — Communication, shared decision-making and prognosis (3 marks): [1]

I would break the news with the haematologist and a clinical nurse specialist in plain language, framing myeloma as a treatable but not yet curable disease. I would explain the immediate priorities — reversing the kidney injury and the calcium, then the induction and the transplant pathway if fit. I would set out the prognosis honestly: the R-ISS stage and the cytogenetics will refine the estimate, but median overall survival in the modern era is over 8 to 10 years for standard-risk disease, and the trajectory continues to improve. I would address his concerns about work, family and quality of life, document the shared decision, and arrange follow-up. I would also discuss contraception (relevant to family planning if he has not completed his family), the impact on his life, and the practicalities of prolonged treatment. I would give written information and a named contact in the haematology team. [1]

SAQ 2 — Risk-stratified treatment of newly diagnosed myeloma and the biomarker-defined diagnosis (10 marks, 20 minutes)

Prompt: A 60-year-old fit woman is found to have an IgG kappa paraprotein of 35 g/L on routine bloods. She is asymptomatic. Her full blood count, renal function and calcium are normal. Bone marrow shows 65 per cent clonal plasma cells. Whole-body low-dose CT shows no lytic lesions. Serum free light chain ratio is 25 (kappa 180 mg/L, lambda 7.2 mg/L). Outline how you establish the diagnosis, your treatment strategy, and the rationale. [1]

Model Answer

Step 1 — Establish the diagnosis using the IMWG 2014 criteria (3 marks): [1]

This patient meets the diagnostic criteria for multiple myeloma, despite being asymptomatic and despite having no CRAB features. By the IMWG 2014 update, the diagnosis requires clonal marrow plasma cells at least 10 per cent (or a biopsy-proven plasmacytoma) plus at least one myeloma-defining event [1]. The myeloma-defining events are the four CRAB features and the three biomarkers: clonal marrow plasma cells at least 60 per cent, an involved-to-uninvolved serum free light chain ratio at least 100 (provided the involved level is at least 100 mg/L), or more than one focal MRI lesion. This patient has marrow plasma cells at 65 per cent — above the 60 per cent biomarker threshold — and therefore meets the criteria for multiple myeloma requiring treatment, even though her free light chain ratio of 25 is below the 100 biomarker threshold and she has no CRAB features.

The key teaching point: The biomarker criteria were added in 2014 because patients with marrow plasma cells at least 60 per cent, or free light chain ratio at least 100, or more than one focal MRI lesion, progress to CRAB within a median of under 2 years, and treating earlier prevents irreversible end-organ damage. The older candidate trap is to label this smouldering myeloma and observe — that is incorrect. [1]

Step 2 — Complete the staging workup (2 marks): [1]

Beta-2 microglobulin and LDH for the R-ISS stage [2]; FISH cytogenetics on the marrow for del(17p), t(4;14), t(14;16), t(14;20), gain 1q and t(11;14); an echocardiogram as a baseline; and a fitness assessment for transplant. The cytogenetics are critical — del(17p) (TP53 loss) is the most adverse lesion and drives intensified therapy and consideration of clinical trial enrolment.

Step 3 — Induction and the transplant pathway (3 marks): [1]

She is 60 and, subject to fitness, transplant-eligible. The standard induction is bortezomib, lenalidomide and dexamethasone (VRd) — SWOG S0777 established that VRd improves both progression-free and overall survival over lenalidomide-dexamethasone [3]. After 3 to 4 cycles of induction, peripheral stem cells are collected, and she undergoes high-dose melphalan with autologous stem cell transplant — IFM 2009 and EMN02/HO95 confirmed the additional progression-free survival benefit of transplant after modern induction [4][5]. The transplant is followed by lenalidomide maintenance (CALGB 100104 showed an overall survival benefit) [6].

Step 4 — Prognosis and communication (2 marks): [1]

I would frame the prognosis honestly: the R-ISS stage and the cytogenetics will refine the estimate, but for standard-risk disease in a fit 60-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 and emerging CAR-T cell therapy. I would explain the two-phase pathway (induction and transplant, then maintenance), the main toxicities (neuropathy from bortezomib — given subcutaneously to reduce it; cytopenias and infection; VTE risk on lenalidomide requiring prophylaxis; mucositis and cytopenias from the high-dose melphalan transplant conditioning), and the fact that maintenance continues until progression or intolerance. I would discuss fertility if relevant, give written information, document the shared decision, and arrange follow-up. [1]

The principle: the IMWG 2014 biomarker criteria allow the diagnosis of myeloma before end-organ damage occurs, in patients with a very high risk of imminent CRAB events. The registrar's job is to apply the criteria correctly, to complete the staging workup including FISH cytogenetics, and to engage the haematology multidisciplinary team and the patient in a shared decision on the treatment pathway driven by transplant eligibility and risk. [1]