Oncologic Emergencies — DCE Clinical Case

Long Case — Multiple myeloma with hypercalcaemia, acute kidney injury and incipient cord compression

Patient scenario

Mrs Margaret O'Brien is a 59-year-old schoolteacher who presents to the emergency department with a three-month history of progressive fatigue, a six-week history of back pain, and a three-day history of confusion, polyuria and constipation. [1]

History of presenting complaint: [1]

• Three months ago: onset of fatigue and exertional dyspnoea, attributed to menopause and work stress.
• Six weeks ago: progressive lower thoracic back pain, initially attributed to a lifting injury, becoming constant, waking her at night, and unresponsive to over-the-counter paracetamol and ibuprofen.
• Three days ago: confusion, polyuria and polydipsia, constipation, and nausea. She has become increasingly drowsy. Her husband called an ambulance.
• Yesterday: a transient episode of right leg weakness that has since partially resolved. [1]

Past medical history: Hypertension (on amlodipine 5 mg daily). Cholecystectomy. No previous malignancy. [1]

Medications: Amlodipine 5 mg daily. Ibuprofen 400 mg as required for the back pain (started six weeks ago). No over-the-counter calcium or vitamin D supplements. [1]

Family history: Mother with type 2 diabetes. No family history of myeloma or haematological malignancy. [1]

Social history: Married, two adult children. Schoolteacher. Former smoker (20 pack-years, ceased 15 years ago). Minimal alcohol. No illicit drug use. [1]

Examination findings: [1]

• Afebrile, heart rate 96, blood pressure 104/64, respiratory rate 18, oxygen saturation 96 per cent on room air. Glasgow Coma Scale 14 (confused, obeys commands).
• Pale, dry mucous membranes. No jaundice, no clubbing, no lymphadenopathy.
• Cardiovascular: no signs of heart failure.
• Respiratory: clear.
• Abdomen: constipation, no organomegaly.
• Neurological: bilateral leg weakness (Medical Research Council grade 4 of 5 in the hip flexors, 4 of 5 in the knee flexors and extensors, normal distally), brisk reflexes in the legs, extensor plantar responses, a sensory level at T10 on the trunk, normal perineal sensation, normal anal tone.
• Spine: tenderness over the lower thoracic spine; no gibbus.
• Fundoscopy: normal (no hyperviscosity retinopathy). [1]

Investigations: [1]

Candidate's opening statement (model answer — SASPOP format)

"Mrs O'Brien is a 59-year-old schoolteacher presenting with a three-month history of multiple myeloma — bone pain, anaemia, hypercalcaemia and renal impairment — now complicated by three concurrent oncologic emergencies: symptomatic hypercalcaemia of malignancy (corrected calcium 3.2, causing the confusion, polyuria and constipation), acute kidney injury from a combination of cast nephropathy, hypercalcaemic nephropathy and an NSAID (the ibuprofen she started six weeks ago for the back pain), and incipient malignant spinal cord compression at T10 with a sensory level and leg weakness. [1]

She has an IgG kappa myeloma with a high paraprotein, a markedly elevated kappa free light chain, a high erythrocyte sedimentation rate, lytic bone lesions and a compression fracture. The IMWG diagnostic criteria are met [6].

My problem list is: (1) symptomatic hypercalcaemia of malignancy — a medical emergency contributing to her confusion and her renal failure; (2) incipient malignant spinal cord compression at T10 — a time-critical neurological emergency; (3) acute kidney injury from cast nephropathy, hypercalcaemic nephropathy and the NSAID; (4) newly diagnosed multiple myeloma — the unifying diagnosis and the target of definitive therapy; (5) normocytic anaemia; (6) bone pain and the risk of further pathological fractures; and (7) the psychosocial impact of a new diagnosis of a serious chronic illness on a working woman and her family. [1]

My immediate management is intravenous dexamethasone 16 mg for the cord compression, aggressive intravenous normal saline for the hypercalcaemia and the AKI, stop the ibuprofen immediately, urgent MRI whole spine — which I have — and zoledronic acid after rehydration. I am involving haematology, nephrology, clinical oncology and neurosurgery as a single team." [1]

Integrated management plan

1. Symptomatic hypercalcaemia of malignancy (the metabolic emergency) [1]

• Aggressive intravenous normal saline — 3 to 6 litres over the first 24 hours, guided by her volume status and her cardiac function; she is dry (the hypercalcaemia has caused a nephrogenic diabetes insipidus-like concentrating defect and she has been polyuric).
• Intravenous zoledronic acid 4 mg over 15 minutes once she is rehydrated, with the dose reduced for her renal impairment (the creatinine is 280). Zoledronic acid was established as superior to pamidronate for hypercalcaemia of malignancy [4].
• Subcutaneous calcitonin 4 to 8 IU per kg every 12 hours for the first 48 hours as a rapid bridge while the zoledronic acid takes effect (48 to 72 hours).
• Stop the amlodipine (it does not affect calcium, but review the blood pressure medications in the setting of the AKI) and stop the ibuprofen immediately (NSAIDs worsen cast nephropathy by reducing renal blood flow).
• If the calcium is refractory to the bisphosphonate, or if the renal impairment makes the bisphosphonate problematic, subcutaneous denosumab 120 mg is the alternative — it is not renally cleared and is effective in bisphosphonate-refractory disease [5].
• Monitor the corrected calcium every 6 to 12 hours, the renal function, and the ECG (a short QT interval from the hypercalcaemia).

2. Incipient malignant spinal cord compression at T10 (the neurological emergency) [1]

• Intravenous dexamethasone 16 mg immediately (before any further imaging), then 16 mg daily in divided doses, tapered during radiotherapy. The steroid also helps the hypercalcaemia and the myeloma.
• Urgent MRI of the whole spine — already done, confirming the epidural mass at T10 with cord compression and multiple other vertebral lesions.
• Urgent neurosurgical and clinical oncology review. The lesion at T10 is a single compressive level, she is ambulatory (a good surgical candidate), and the Patchell trial supports direct decompressive surgery plus radiotherapy for such patients [3]. The surgery decision is made with the neurosurgeon and the radiation oncologist [2]. If surgery is not appropriate (the cord signal change suggests some irreversible injury, or she is not fit), the management is dexamethasone and radiotherapy.
• Urinary catheterisation if she is in retention; monitor the output.

3. Acute kidney injury (the reversible emergency) [1]

• Aggressive intravenous hydration — the cornerstone; isotonic saline to expand the intravascular volume and flush the cast-forming free light chains.
• Stop all nephrotoxins immediately — the ibuprofen, the amlodipine (review), any contrast (avoid unless essential), no aminoglycosides.
• Treat the hypercalcaemia — the hypercalcaemic nephropathy is contributing to the AKI.
• Start a bortezomib-based regimen urgently to lower the free light chain burden — bortezomib is the most effective agent for rapidly lowering the free light chain in cast nephropathy and is hepatically cleared (safe in renal failure).
• Consider high-cutoff haemodialysis in selected patients with very high free light chains and dialysis-dependent renal failure (the evidence is debated; discuss with nephrology).
• The best predictor of renal recovery is a 50 per cent reduction in the serum free light chain within 21 days. [1]

4. Newly diagnosed multiple myeloma — the unifying diagnosis and the target of therapy [1]

• The diagnosis is established by the IMWG 2014 criteria: clonal marrow plasma cells, a monoclonal protein, and myeloma-defining end-organ damage (the CRAB cluster — hypercalcaemia, renal impairment, anaemia, bone lesions) [6].
• Bone marrow aspirate and trephine for the plasma cell percentage, morphology, and FISH cytogenetics (del(17p), t(4;14), t(14;16), gain 1q — the high-risk lesions).
• Staging with the R-ISS (beta-2 microglobulin, albumin, LDH, FISH).
• Treatment: a fit 59-year-old is transplant-eligible. The standard induction is bortezomib-lenalidomide-dexamethasone (VRd) for 4 cycles, then autologous stem cell transplant (high-dose melphalan), then lenalidomide maintenance. The VRd lowers the free light chain rapidly (helping the renal recovery), addresses the myeloma, and is the evidence-based standard.
• Bone-targeted therapy — zoledronic acid (already given for the hypercalcaemia) or denosumab monthly, for all patients with bone disease; a dental check before starting (osteonecrosis of the jaw).

5. Normocytic anaemia [1]

• Iron studies to exclude iron deficiency; the anaemia is predominantly from the marrow infiltration.
• Transfuse only if symptomatic or if the haemoglobin is below 70 — and transfuse cautiously in the setting of the cord compression and the hypercalcaemia. Erythropoietin-stimulating agents have a role in selected patients with chemotherapy-induced anaemia. [1]

6. Bone pain and the risk of further pathological fractures [1]

• Analgesia — paracetamol, and an opioid (avoid NSAIDs); a pain service input for the neuropathic component; consider a vertebroplasty or kyphoplasty for the painful compression fracture at T11.
• Radiotherapy may be given to the painful lesions once the cord compression is addressed.
• Mobilise carefully with physiotherapy, and a thoracolumbar orthosis if the spine is unstable. [1]

7. Psychosocial support [1]

• A quiet room, a senior clinician with a nurse, plain language about the diagnosis and the plan, a written summary, and a single named contact.
• Clinical psychology referral for the adjustment to a new diagnosis of a serious chronic illness.
• Myeloma Australia and the local support services. [1]

Probing questions and model answers

Examiner: How do you reconcile the need for urgent cytoreduction with the need to treat the cord compression and the hypercalcaemia? [1]

A: "They are not in conflict — they are synergistic. The dexamethasone I am giving for the cord compression is also part of the myeloma induction regimen and helps the hypercalcaemia. The bortezomib I am starting for the myeloma will lower the free light chain and recover the renal function. The zoledronic acid I am giving for the hypercalcaemia is also the bone-targeted therapy for the myeloma. The integrated plan is: dexamethasone, zoledronic acid, intravenous hydration, stop the NSAID, surgery or radiotherapy for the cord, and bortezomib-based induction for the myeloma. I would treat all three emergencies in parallel, with haematology, nephrology, oncology and neurosurgery as a single team." [1]

Examiner: What is your threshold for dialysis in this patient? [1]

A: "The dialysis thresholds are the standard ones: refractory hyperkalaemia (above 6.5 despite medical therapy, or with ECG changes — though her potassium is normal at present), severe metabolic acidosis (pH below 7.1), volume overload unresponsive to diuretics, or symptomatic uraemia. In myeloma-related AKI specifically, I would involve nephrology early because the renal recovery depends on the rapid lowering of the free light chain, and high-cutoff haemodialysis (which removes the free light chains) may improve the chance of renal recovery in selected patients with very high free light chain levels. The best predictor of renal recovery is a 50 per cent reduction in the free light chain within 21 days, so I would monitor the free light chain closely during the bortezomib induction." [1]

Examiner: Why is the parathyroid hormone suppressed, and what does the low phosphate tell you? [1]

A: "The parathyroid hormone is appropriately suppressed by the high calcium — this is the key discriminator from primary hyperparathyroidism, in which the parathyroid hormone is inappropriately normal or high in the face of hypercalcaemia. In myeloma, the hypercalcaemia is from direct osteoclast activation (the RANKL-OPG imbalance) releasing calcium from the lytic bone lesions, with no PTH-like phosphaturic effect, so the phosphate is typically normal or high (it is 1.3 here, in the normal range). In a PTHrP-mediated humoral hypercalcaemia (classically squamous cell and renal cell cancers), the phosphate is low because PTHrP has a phosphaturic effect. The suppressed PTH and the normal-to-high phosphate in a patient with myeloma and lytic lesions confirm a local osteolytic hypercalcaemia, and I would treat it with fluids and a bisphosphonate as I described." [1]

Examiner: How do you discuss the prognosis with Mrs O'Brien and her family? [1]

A: "I would speak with her and her family in a quiet room, once she is less confused, in plain language. I would explain that she has a cancer of the plasma cells called multiple myeloma, that it has caused the high calcium, the kidney problem, and the pressure on her spine, and that we are treating all of these problems together with fluids, a bone medicine, a steroid, and a chemotherapy that targets the myeloma cells. I would be honest that myeloma is treatable but, in nearly all patients, not yet curable, that the median survival with modern therapy is over 8 to 10 years, and that the aim is to control the disease, preserve her function, and give her the best quality of the years ahead. I would ask what matters most to her now, involve the palliative care team for symptom control and family support, and document the shared decisions and review them as her clinical picture evolves." [1]

Short Case — Skeletal and neurological examination: back pain and leg weakness in a cancer patient

Examination instruction

"This patient with known myeloma has back pain and difficulty walking. Examine the spine, the legs and the relevant system, and present your findings." [1]

Systematic examination routine

Step 1 — Inspect at the end of the bed:

• General appearance — pallor, cachexia, distress, a urinary catheter, a walking aid, the ability to rise from the chair.
• Look for a thoracolumbar orthosis or a surgical scar. [1]

Step 2 — Examine the hands and the general screen:

• Pallor in the palmar creases (anaemia), bruises (thrombocytopenia), peripheral neuropathy (a bortezomib effect).
• Pulse, blood pressure, respiratory rate. [1]

Step 3 — Examine the spine:

• Inspect for a gibbus, a step, or muscle spasm.
• Palpate for tenderness at each spinous process, from the cervical to the lumbar spine.
• Percuss for tenderness. [1]

Step 4 — Examine the neurological system of the legs:

• Gait (spastic, foot-drop, antalgic).
• Tone (spasticity for an upper motor neuron lesion).
• Power, grade each muscle group on the MRC scale, in a pyramidal pattern.
• Reflexes (brisk, with extensor plantars for an upper motor neuron lesion).
• Sensation — light touch, pinprick, vibration, joint position; look for a sensory level on the trunk.
• Sphincter — anal tone, perineal sensation, a palpable bladder. [1]

Step 5 — Look for the other myeloma stigmata:

• Skin — bruises, purpura, amyloid purpura (periorbital).
• Eyes — fundoscopy for hyperviscosity retinopathy (sausage-link veins).
• Chest — for a pleural effusion or infection (hypogammaglobulinaemia).
• Abdomen — hepatosplenomegaly, organomegaly. [1]

Key physical signs this patient demonstrates

• Pallor from the anaemia.
• Spinal tenderness in the lower thoracic spine.
• Bilateral leg weakness in a pyramidal distribution, hyperreflexia, extensor plantar responses.
• A sensory level at T10 on the trunk.
• A high erythrocyte sedimentation rate and rouleaux on the blood film (the myeloma background). [1]

Presentation template

"I examined Mrs O'Brien, a 59-year-old woman, who is pale at the end of the bed. The pulse is 96 regular, the blood pressure 104 over 64, the respiratory rate 18, and she is afebrile but confused. The spine is tender in the lower thoracic region. The neurological examination of the legs shows increased tone, grade 4 of 5 power in a pyramidal distribution, brisk reflexes with extensor plantar responses, and a sensory level at T10 on the trunk. There is no saddle anaesthesia. The hands show pallor in the palmar creases and no peripheral neuropathy. These findings, in the setting of a known myeloma with a high corrected calcium of 3.2 and a creatinine of 280, are consistent with multiple myeloma complicated by malignant spinal cord compression at T10, hypercalcaemia of malignancy, and cast nephropathy. My immediate management is intravenous dexamethasone 16 mg, aggressive intravenous fluids, stop the ibuprofen, zoledronic acid after rehydration, and urgent neurosurgical and haematology review." [1]

Discussion questions

Examiner: What is the significance of the night pain? [1]

A: "Night pain — pain that wakes the patient from sleep and is unrelated to activity — is a red flag for a serious underlying cause, including malignancy, infection and a pathological fracture. Mechanical back pain typically improves with rest and is absent at night; malignant bone pain is typically progressive, constant, and worse at night. In a patient over 50 with night pain, a normocytic anaemia and a raised erythrocyte sedimentation rate, myeloma is high on the differential, and the workup is a serum protein electrophoresis, a serum free light chain assay, a calcium, a renal function, and a bone marrow and imaging once the myeloma is biochemically confirmed [6]."

Examiner: How do you distinguish cord compression from a cauda equina lesion? [1]

A: "By the neurological pattern. A cord lesion (above the conus, roughly above L1) produces an upper motor neuron pattern in the legs — spasticity, hyperreflexia, extensor plantar responses, and a sensory level on the trunk. A conus lesion (at the conus medullaris, around L1) produces a mix of upper and lower motor neuron signs, early and symmetrical sphincter involvement, and saddle anaesthesia. A cauda equina lesion (below the conus) produces a lower motor neuron pattern — hypotonia, hyporeflexia, fasciculation, asymmetrical leg weakness, saddle anaesthesia, and sphincter disturbance. The reflex pattern and the presence of a sensory level on the trunk are the key discriminators: a sensory level and hyperreflexia indicate a cord lesion; saddle anaesthesia and hyporeflexia indicate a cauda equina lesion. Both are emergencies requiring urgent MRI whole spine." [1]

Examiner: What is the evidence for the bisphosphonate in this setting? [1]

A: "Zoledronic acid was established as superior to pamidronate for the acute treatment of hypercalcaemia of malignancy in the Major pooled analysis — the complete response rate by day 10 was 88 per cent with zoledronic acid 4 mg versus 70 per cent with pamidronate, and the median duration of response was longer (32 versus 18 days) [4]. For myeloma bone disease, zoledronic acid reduces skeletal events, bone pain and hypercalcaemia, and the MRC Myeloma IX trial showed a survival benefit. Denosumab is non-inferior to zoledronic acid for skeletal events and is the agent of choice in renal failure (it is not renally cleared); it is also effective in bisphosphonate-refractory hypercalcaemia [5]. Both require calcium and vitamin D supplementation to prevent hypocalcaemia, and both carry a small risk of osteonecrosis of the jaw — a dental check before starting is standard."