What are the diagnostic and treatment approaches for multiple myeloma?

Diagnostic and Treatment Approaches for Multiple Myeloma

The diagnosis of multiple myeloma requires ≥10% clonal bone marrow plasma cells or a biopsy-proven plasmacytoma plus evidence of multiple myeloma defining events such as CRAB features (hypercalcemia, renal failure, anemia, or bone lesions), ≥60% bone marrow clonal plasmacytosis, serum involved/uninvolved free light chain ratio ≥100, or >1 focal lesion on MRI. 1

Diagnostic Workup

Essential Laboratory Tests

• Detection and measurement of monoclonal (M) protein by serum protein electrophoresis (SPEP) and immunofixation (SIFE) 2
• 24-hour urine collection for protein electrophoresis (UPEP) and immunofixation (UIFE) to detect Bence Jones proteins 3
• Quantification of IgG, IgA, and IgM immunoglobulins 2
• Serum free light chain (FLC) assay with kappa/lambda ratio, especially important when standard SPEP is negative 4
• Complete blood count to assess for anemia 2
• Serum creatinine, calcium, albumin, LDH, and beta-2 microglobulin for end-organ damage assessment and staging 2, 4

Bone Marrow Assessment

• Bone marrow aspiration and biopsy with immunohistochemistry and/or flow cytometry to confirm ≥10% clonal plasma cells 2, 4

Imaging Studies

• Full skeletal survey using X-ray is recommended as the standard approach 2
• MRI provides greater detail and is recommended if spinal cord compression is suspected 2
• CT or PET/CT may help distinguish between MGUS, smoldering, and overt myeloma 2, 4

Diagnostic Criteria and Staging

Diagnostic Criteria

• ≥10% clonal plasma cells on bone marrow examination or biopsy-proven plasmacytoma 1
• Evidence of end-organ damage (CRAB criteria): hypercalcemia, renal insufficiency, anemia, or bone lesions 1
• An abnormal serum free light chain ratio with elevated involved light chain is a diagnostic criterion 4

Staging Systems

• The Durie-Salmon classification has been traditionally used for staging 2
• The International Staging System combines beta-2 microglobulin and serum albumin 2
• Cytogenetic abnormalities provide additional prognostic information 2
• High-risk features include del(17p), t(4;14), t(14;16), t(14;20), gain 1q, or p53 mutation 1

Treatment Approaches

Initial Treatment Decision

• Immediate treatment is not recommended for patients with smoldering (indolent) myeloma 2
• Treatment approach differs based on transplant eligibility 1

Transplant-Eligible Patients

• Induction therapy with bortezomib, lenalidomide, and dexamethasone (VRd) for 3-4 cycles followed by autologous stem cell transplantation 1
• For high-risk patients, daratumumab, bortezomib, lenalidomide, dexamethasone (Dara-VRd) is an alternative to VRd 1
• High-dose melphalan 200 mg/m² IV is the preferred preparative regimen prior to transplantation 2
• Peripheral blood progenitor cells should be used as the source of stem cells, rather than bone marrow 2
• Lenalidomide maintenance is recommended for standard-risk patients after transplant, while bortezomib-based maintenance is needed for high-risk patients 1

Transplant-Ineligible Patients

• Oral combination of melphalan (9 mg/m²/day for 4 days) and prednisone (30 mg/m²/day for 4 days) has been the standard treatment, repeated every 4-6 weeks until stable response 2
• Newer approaches include VRd for approximately 8-12 cycles followed by lenalidomide maintenance 1
• Daratumumab with lenalidomide and dexamethasone (DRd) has shown significant improvement in progression-free survival compared to lenalidomide and dexamethasone alone 5
• Long-term administration of bisphosphonates reduces skeletal events and should be proposed for patients with advanced disease 2

Monitoring and Follow-up

Laboratory Monitoring

• Complete blood count, serum chemistry, quantitative immunoglobulins, SPEP, SIFE, and serum FLC assay should be monitored every 3-6 months 6
• Involved free light chain (iFLC) can detect response or progression significantly earlier than SPEP (median 1.94 months vs. 5.39 months) 7

Imaging Follow-up

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

Response Assessment

• Response criteria include stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) 4
• Minimal residual disease (MRD) assessment provides deeper response evaluation 5

Common Pitfalls to Avoid

• Failing to collect a complete 24-hour urine sample can lead to false-negative results 3
• Random urine samples are insufficient and cannot replace a 24-hour urine collection 3
• Immunofixation should be performed even if there is no measurable protein on electrophoresis 3
• Missing extramedullary disease progression by not utilizing appropriate imaging 6
• Overlooking early signs of disease progression such as rising free light chain levels 6

Treatment of Relapse

• Most patients require a triplet regimen at relapse, with the choice of regimen varying with each successive relapse 1
• Comprehensive reassessment including bone marrow examination and imaging should be performed for progressive or relapsed disease 6