What are the common symptoms and treatment options for an older adult with suspected multiple myeloma?

Multiple Myeloma: Clinical Presentation and Management

Common Presenting Symptoms

Multiple myeloma typically presents with bone pain, fatigue, weakness, and recurrent infections, with the classic CRAB criteria defining end-organ damage that triggers treatment initiation. 1, 2

Cardinal Features (CRAB Criteria)

• Hypercalcemia: Serum calcium >11.0-11.5 mg/dL, causing fatigue, confusion, constipation, excessive thirst, and altered mental status 1, 2
• Renal insufficiency: Serum creatinine >2.0 mg/dL or creatinine clearance <40 mL/min, leading to kidney dysfunction and potential acute renal failure 3, 1
• Anemia: Hemoglobin <10 g/dL or ≥2 g/dL below normal (normochromic, normocytic), resulting in profound weakness, fatigue, and dyspnea 1, 2, 4
• Bone lesions: Lytic lesions, severe osteopenia, or pathologic fractures causing severe bone pain, particularly in the spine, ribs, and long bones 1, 2

Additional Common Symptoms

• Bone pain (most common): Particularly thoracic spine involvement with osteolytic changes and compressive fractures; pain is typically persistent and worsens with movement 5, 6
• Recurrent infections: Due to suppression of normal immunoglobulin production and immune dysfunction 6, 7
• Neurologic symptoms: Spinal cord compression (medical emergency), peripheral neuropathy, cranial nerve involvement (particularly nerves II, V, VI, VII, VIII), and rarely intracranial plasmacytomas 5
• Constitutional symptoms: Malaise, weight loss, and fever 6, 7

Metabolic Complications

• Hyperviscosity syndrome: Headache, blurred vision, drowsiness, vertigo, ataxia, and potential progression to precoma/coma 5
• Tumor lysis syndrome risk: Particularly in patients with high tumor burden, renal insufficiency, or elevated LDH 2

Diagnostic Evaluation

Essential Laboratory Tests

All patients require serum and urine protein electrophoresis with immunofixation, complete blood count, comprehensive metabolic panel, and serum free light chain assay. 1, 8

• Serum protein electrophoresis (SPEP) with immunofixation: Detects and characterizes monoclonal protein (M-protein) 1, 8
• 24-hour urine protein electrophoresis with immunofixation: Random urine samples are insufficient and cannot replace this test 8
• Serum free light chain assay: Kappa/lambda ratio particularly important when SPEP is negative 8
• Quantitative immunoglobulins: IgG, IgA, IgM levels by nephelometry 1, 8
• Complete blood count: Assess for anemia (present in 73% at diagnosis) 9
• Comprehensive metabolic panel: Creatinine (19% have acute kidney injury at presentation), calcium, albumin 4, 9
• β2-microglobulin and LDH: Required for Revised International Staging System (R-ISS) 3, 2

Bone Marrow Examination

• Bone marrow aspiration and biopsy: Required to quantify clonal plasma cells (≥10% required for diagnosis) 1, 4
• Cytogenetic analysis by FISH: Mandatory to detect high-risk features including del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p 2, 4, 9

Imaging Studies

• Full skeletal survey with plain radiographs: Standard approach including spine, pelvis, skull, humeri, femurs to detect lytic lesions (present in 79% at diagnosis) 8, 6, 9
• MRI of spine and pelvis: Provides greater detail, mandatory if spinal cord compression suspected, detects focal lesions ≥5 mm 3, 8
• PET-CT or whole-body CT: Useful for evaluating extramedullary disease and equivocal lesions 3, 2

Common pitfall: Nuclear bone scans have no role in myeloma diagnosis as lytic lesions do not show increased uptake; plain radiographs or advanced imaging (MRI/PET-CT) are required 6

Treatment Approach for Older Adults

Determining Transplant Eligibility

The critical first decision is determining transplant eligibility based on age (<65-70 years), performance status, comorbidities, and frailty assessment. 3, 2

• Frailty assessment: Use geriatric assessment factors including functional status (activities of daily living, instrumental activities of daily living) and comorbidities to stratify patients as fit, intermediate-fit, or frail 3
• High-risk cytogenetics: Presence of del(17p), t(4;14), t(14;16) affects prognosis across all age groups 3, 2

Treatment for Transplant-Ineligible Patients

For older adults ineligible for transplant, triplet therapy with daratumumab plus lenalidomide and dexamethasone (DRd) until progression is the preferred first-line treatment based on superior survival outcomes. 10, 4

Preferred Regimen: Daratumumab-Lenalidomide-Dexamethasone (DRd)

• Daratumumab 16 mg/kg IV plus lenalidomide 25 mg orally days 1-21 plus dexamethasone 40 mg weekly (20 mg weekly if >75 years) in 28-day cycles until progression 10
• Evidence: MAIA trial showed median PFS of 61.9 months vs 34.4 months with lenalidomide-dexamethasone alone (44% reduction in progression risk), with 32% reduction in death risk 10
• Overall response rate: 92.9% with DRd vs 81.3% with Rd alone 10

Alternative Regimens

• Bortezomib-Cyclophosphamide-Dexamethasone (VCD): Preferred when daratumumab unavailable; bortezomib administered subcutaneously to reduce neuropathy risk 1
• Bortezomib-Melphalan-Prednisone (VMP): 8-12 cycles; bortezomib 1.3 mg/m² subcutaneously days 1,8,15,22; melphalan 9 mg/m² orally days 1-4; prednisone 60 mg/m² days 1-4; 35-day cycles 3, 2
• Lenalidomide-Dexamethasone (Rd): Continuous until progression; approved by EMA but inferior to DRd 3

Important consideration: Avoid melphalan-containing regimens initially in patients who may become transplant-eligible later, as melphalan is stem cell toxic 1

Treatment for Transplant-Eligible Patients

Younger, fit patients should receive induction with bortezomib-lenalidomide-dexamethasone (VRd) or daratumumab-VRd, followed by high-dose melphalan 200 mg/m² with autologous stem cell transplantation, then lenalidomide maintenance. 2, 4, 9

• Induction: 3-4 cycles of VRd or daratumumab-VRd 1, 4
• Stem cell collection: After 3-4 cycles of induction 1
• High-dose therapy: Melphalan 200 mg/m² followed by autologous stem cell transplantation 2, 8, 9
• Maintenance: Lenalidomide for standard-risk; bortezomib plus lenalidomide for high-risk myeloma 4

Essential Supportive Care

Bone Health

All patients with bone disease require long-term bisphosphonates (zoledronic acid or pamidronate) to reduce skeletal-related events, pathologic fractures, and bone pain. 1, 2, 6

• Monthly infusions reduce skeletal events by altering the bone marrow microenvironment 1, 5

Hypercalcemia Management

• Aggressive IV hydration: Normal saline 150-200 mL/hour to achieve urine output >100 mL/hour 1, 8
• Bisphosphonates: Most effective therapy for severe hypercalcemia (>11.0 mg/dL) 1, 8

Tumor Lysis Syndrome Prophylaxis

Patients with high tumor burden, renal insufficiency, or elevated LDH require aggressive IV hydration with normal saline and rasburicase before initiating chemotherapy. 2

• Rasburicase: 0.2 mg/kg IV single dose (or 3-6 mg fixed dose) in high-risk patients 2
• Critical timing: Do not delay chemotherapy for extended periods; initiate tumor lysis prophylaxis immediately then begin treatment 2

Infection Prevention

• Herpes zoster prophylaxis: Acyclovir mandatory with bortezomib-based regimens 1
• Vaccinations: Pneumococcal (PCV13 followed by PPSV23) and annual influenza 1
• Broad-spectrum antibiotics: For any febrile illness due to immune suppression 6

Renal Protection

• Avoid nephrotoxic NSAIDs: Use opiates for bone pain instead 6
• Bortezomib advantage: Can be administered without dose adjustment in renal impairment 1, 2

Response Monitoring

• Initial assessment: Check M-protein (SPEP/UPEP) after 1-2 cycles to ensure no progression 2
• Ongoing monitoring: Every other cycle during active treatment 2
• Response criteria: Stringent complete response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR) per IMWG criteria 3, 2

Treatment Initiation Criteria

Treatment should be initiated immediately in all patients meeting CRAB criteria or having ≥60% bone marrow plasma cells, involved/uninvolved free light chain ratio ≥100, or ≥1 focal lesion ≥5 mm on MRI. 3, 1, 4

Critical distinction: Patients with smoldering (asymptomatic) myeloma should be observed with monitoring every 3-6 months, not treated immediately 3, 2