What are the diagnostic and treatment approaches for a patient presenting with multiple myeloma?

Multiple Myeloma: Presentation, Diagnosis, and Treatment

Clinical Presentation

Multiple myeloma typically presents with CRAB criteria: hypercalcemia (calcium >11.5 mg/dL), renal failure (creatinine >2 mg/dL or clearance <40 mL/min), anemia (hemoglobin <10 g/dL or ≥2 g/dL below normal), and bone lesions (lytic lesions, severe osteopenia, or pathologic fractures). 1

Key Presenting Features

• 79% of patients have osteolytic bone disease at presentation, manifesting as bone pain 2
• 73% present with anemia 2
• 19% have acute kidney injury at diagnosis 2
• Recurrent infections, weakness, malaise, nausea, vomiting, and weight loss are common nonspecific symptoms 3
• Median age at diagnosis is 73 years, with 44% of patients ≥75 years old 4

Diagnostic Workup

The diagnosis requires ≥10% clonal plasma cells in bone marrow PLUS at least one myeloma-defining event: any CRAB criterion, ≥60% bone marrow plasma cells, involved/uninvolved serum free light chain ratio ≥100, or >1 focal lesion ≥5mm on MRI. 1

Essential Laboratory Tests

• Serum protein electrophoresis with immunofixation to detect monoclonal protein 5, 1
• 24-hour urine protein electrophoresis with immunofixation—random urine samples are insufficient and cannot replace 24-hour collection 5, 1
• Serum free light chain assay with kappa/lambda ratio, especially critical when standard SPEP is negative 5, 1
• Nephelometric quantification of IgG, IgA, and IgM immunoglobulins 5, 1
• Complete blood count to assess for anemia 5
• Serum creatinine, calcium, albumin, LDH, and beta-2 microglobulin for end-organ damage assessment and staging 5, 1

Bone Marrow Assessment

• Bone marrow aspiration and biopsy with immunohistochemistry and/or flow cytometry to confirm ≥10% clonal plasma cells 5, 1
• Cytogenetic testing via fluorescence in situ hybridization (FISH) is mandatory—high-risk features including del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation fundamentally alter treatment approach and prognosis 1

Imaging Studies

• Full skeletal X-ray survey remains the standard approach for detecting lytic bone lesions 5, 1
• MRI of spine and pelvis provides superior detail and is mandatory if spinal cord compression is suspected 5, 1
• CT or PET/CT helps distinguish between MGUS, smoldering myeloma, and overt myeloma, and is valuable for detecting extramedullary disease 5, 1

Risk Stratification

The International Staging System (ISS) stratifies patients based on β2-microglobulin and albumin levels: Stage I (β2-microglobulin <3.5 mg/L and albumin ≥3.5 g/dL), Stage II (neither Stage I nor III), and Stage III (β2-microglobulin ≥5.5 mg/L). 1

• Stage I patients (28% at diagnosis) have a median 5-year survival of 82% 2
• High-risk cytogenetics including del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation define high-risk disease requiring intensified treatment 1

Treatment Approaches

Transplant-Eligible Patients (Age ≤65, Good Performance Status, No Renal Failure)

Transplant-eligible patients should receive induction with bortezomib, lenalidomide, dexamethasone (VRd) for 3-4 cycles, followed by autologous stem cell transplantation with high-dose melphalan 200 mg/m² IV, then lenalidomide maintenance. 5, 1

• Peripheral blood progenitor cells should be used as the stem cell source rather than bone marrow 5
• This approach is associated with median progression-free survival of 41 months 2

Transplant-Ineligible Patients (Elderly, Poor Performance Status, Comorbidities)

Transplant-ineligible patients should receive either VRd for 8-12 cycles followed by lenalidomide maintenance, or daratumumab, lenalidomide, dexamethasone (DRd) until progression. 1

Evidence for Daratumumab-Based Therapy

• The MAIA trial demonstrated that DRd achieved median PFS of 61.9 months versus 34.4 months with Rd alone (44% reduction in risk of disease progression or death, HR=0.56, p<0.0001) 4
• DRd showed 32% reduction in risk of death compared to Rd (HR=0.68, p=0.0013) 4
• Overall response rate was 92.9% with DRd versus 81.3% with Rd (p<0.0001) 4
• Complete response or better was achieved in 47.6% with DRd versus 24.9% with Rd (p<0.0001) 4
• MRD negativity rate was 24.2% with DRd versus 7.3% with Rd (p<0.0001) 4

Supportive Care (All Patients)

• Long-term bisphosphonates reduce skeletal events and should be administered to patients with advanced disease 5

Monitoring and Follow-Up

Laboratory Monitoring Every 3-6 Months

• Complete blood count, serum chemistry (creatinine, albumin, calcium, LDH, β2-microglobulin), quantitative immunoglobulins, SPEP, SIFE, and serum FLC assay 6

Imaging Follow-Up

• Annual bone survey or as clinically indicated 6
• MRI, CT, or PET/CT as clinically indicated, especially for suspected disease progression or extramedullary disease 6

Response Assessment Criteria

• Stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) as defined by International Myeloma Working Group 5

Critical Pitfalls to Avoid

• Never use random urine samples for protein electrophoresis—only complete 24-hour urine collections are acceptable 5, 1, 6
• Never miss spinal cord compression—obtain urgent MRI when clinically indicated 1
• Never overlook cytogenetic testing—high-risk features fundamentally alter treatment approach and prognosis 1
• Never miss extramedullary disease progression by failing to utilize appropriate imaging 6
• Never overlook early signs of disease progression such as rising free light chain levels 6
• Always perform immunofixation even if there is no measurable protein on electrophoresis 5

Treatment of Relapse

For progressive or relapsed disease, perform comprehensive reassessment including bone marrow examination and imaging, with more frequent monitoring initially (every 4 weeks). 6