What are the clinical features and management of advanced multiple myeloma?

Clinical Features and Management of Advanced Multiple Myeloma

Advanced multiple myeloma is characterized by bone destruction, anemia, renal impairment, and immunological dysfunction, requiring a risk-adapted treatment approach with novel agents and supportive care to manage complications and improve survival outcomes.

Clinical Features of Advanced Multiple Myeloma

CRAB Criteria (Defining Features)

• Calcium elevation: Hypercalcemia (>11 mg/dL) 1
• Renal insufficiency: Serum creatinine >2 mg/dL or creatinine clearance <40 mL/min 1
• Anemia: Hemoglobin <10 g/dL or 2 g/dL below normal 1
• Bone disease: Lytic lesions, osteoporosis with compression fractures, or pathologic fractures 1

Additional Clinical Manifestations

• Recurrent bacterial infections due to immunodeficiency 1
• Hyperviscosity syndrome 1
• Extramedullary plasmacytomas 1
• Neurological complications (spinal cord compression) 1, 2
• Coagulation/thrombosis disorders 1

Diagnostic Workup

Laboratory Tests

• Complete blood count with differential 1
• Serum chemistry (creatinine, calcium, albumin, LDH, β2-microglobulin) 1
• Serum protein electrophoresis (SPEP) and immunofixation (SIFE) 1
• Serum free light chain assay 1
• 24-hour urine collection for protein, urine protein electrophoresis (UPEP), and immunofixation (UIFE) 1
• Serum quantitative immunoglobulins 1

Imaging Studies

• Whole-body low-dose CT (WBLD-CT): Preferred method for detecting lytic lesions (grade 1A) 1, 2
• MRI: Recommended when spinal cord compression is suspected 1, 2
• PET/CT: Useful to assess disease extent and detect extramedullary involvement 1
• Conventional skeletal survey if advanced imaging unavailable 1

Bone Marrow Assessment

• Bone marrow aspiration and biopsy to evaluate plasma cell infiltration (≥10% clonal plasma cells) 1
• Cytogenetic/FISH studies for risk stratification 1
• Multiparameter flow cytometry to assess abnormal plasma cells 1

Management Approach

Initial Assessment

1. Determine transplant eligibility based on age and comorbidities 1
2. Assess risk status based on cytogenetics and other factors 1
3. Evaluate and manage complications (bone disease, renal dysfunction, hypercalcemia) 1

Induction Therapy

For Transplant-Eligible Patients

• Bortezomib-based regimens: Bortezomib/dexamethasone or combinations 1, 3
  • Particularly valuable for patients with renal failure or adverse cytogenetics 1
• Lenalidomide/dexamethasone 1
• Thalidomide/dexamethasone 1

For Non-Transplant Eligible Patients

• Bortezomib/melphalan/prednisone: Demonstrated superior overall survival (56.4 vs 43.1 months) 3
• Lenalidomide-based regimens 1
• Reduced-intensity bortezomib-based combinations 1

Stem Cell Transplantation

• Autologous stem cell transplantation for eligible patients after induction therapy 1
• Avoid stem cell toxins (melphalan, nitrosoureas) before stem cell collection 1
• Consider maintenance therapy post-transplant 1

Management of Complications

Bone Disease

• Bisphosphonates (zoledronic acid or pamidronate) for all patients with symptomatic myeloma (grade 1A) 1, 2
• Denosumab as alternative, especially in renal dysfunction 2
• Radiation therapy for uncontrolled pain or spinal cord compression 2
• Vertebroplasty/kyphoplasty for symptomatic vertebral compression fractures 1, 2
• Surgical intervention for pathological fractures or spinal instability 2

Renal Dysfunction

• Bortezomib-based regimens are standard of care (grade 1A) 1
• Maintain hydration and avoid nephrotoxic agents (NSAIDs) 2
• Consider plasmapheresis for acute renal failure due to light chain cast nephropathy 1

Anemia

• Erythropoietic-stimulating agents for symptomatic anemia (Hb <10 g/dL) after excluding other causes (grade 1B) 1
• Discontinue if no response after 6-8 weeks 1

Hypercalcemia

• Aggressive hydration, bisphosphonates, steroids, and/or calcitonin 2

Infections

• Prophylactic aciclovir/valacyclovir for patients on proteasome inhibitors or undergoing transplantation (grade 1A) 1, 2
• Vaccination against influenza recommended; pneumococcal and H. influenzae vaccination appropriate but efficacy may be limited (grade 1C) 1

Peripheral Neuropathy

• Dose modification of neurotoxic agents (bortezomib, thalidomide) (grade 1C) 1
• Consider subcutaneous administration of bortezomib to reduce neuropathy 1

Thromboembolism

• Prophylactic anticoagulation for patients on immunomodulatory drugs (thalidomide, lenalidomide) 1

Monitoring Response and Disease Progression

• Assess response to induction therapy after 2 cycles 1
• Regular monitoring of M-protein levels in serum and urine 1
• Repeat imaging as clinically indicated 1
• Monitor for treatment-related toxicities 1

Prognosis and Outcomes

Despite significant improvements in treatment options, advanced multiple myeloma remains incurable, with most patients eventually experiencing relapse. However, the introduction of novel agents has markedly improved survival outcomes, with median overall survival now exceeding 5 years in many patients 3, 4, 5.