What are the diagnostic criteria and treatment options for Multiple Myeloma?

Multiple Myeloma Diagnosis

Multiple myeloma requires ≥10% clonal plasma cells in bone marrow (or biopsy-proven plasmacytoma) PLUS at least one myeloma-defining event: CRAB criteria (hypercalcemia, renal failure, anemia, bone lesions), ≥60% bone marrow plasma cells, involved/uninvolved serum free light chain ratio ≥100, or >1 focal lesion ≥5mm on MRI. 1, 2, 3, 4

Essential Diagnostic Laboratory Tests

Protein Studies:

• Serum protein electrophoresis with immunofixation to detect monoclonal protein 5, 1, 6
• 24-hour urine protein electrophoresis with immunofixation (not random urine sample—this is a critical pitfall to avoid) 5, 1, 6
• Nephelometric quantification of IgG, IgA, and IgM immunoglobulins 5, 1, 6
• Serum free light chain assay with kappa/lambda ratio 1, 6, 7

Hematologic and Chemistry:

• Complete blood count with differential 5, 1
• Serum calcium (hypercalcemia defined as >11.5 mg/dL) 5, 1, 6
• Serum creatinine and calculated creatinine clearance using MDRD or CKD-EPI equations (renal failure defined as creatinine >2 mg/dL or clearance <40 mL/min) 5, 1, 6
• Serum β2-microglobulin and albumin for International Staging System 5, 1, 7
• Lactate dehydrogenase for Revised International Staging System 7

Bone Marrow Evaluation:

• Bone marrow aspiration and biopsy to quantify plasma cell infiltration 5, 1, 6
• CD138 immunohistochemical staining to accurately determine plasma cell percentage 5, 1, 6
• Cytogenetics and FISH analysis for high-risk features: del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation 5, 1, 2, 3, 4

Imaging Requirements

Skeletal Assessment:

• Full skeletal X-ray survey remains standard for detecting lytic bone lesions 5
• Whole-body low-dose CT has replaced traditional X-rays in many centers as it is more sensitive and uses lower radiation 8
• MRI of spine and pelvis provides superior detail and is mandatory if spinal cord compression is suspected 5
• MRI or PET/CT can detect focal lesions >5mm that qualify as myeloma-defining events even without CRAB criteria 5, 1, 8

CRAB Criteria for End-Organ Damage

The presence of any one CRAB criterion attributable to plasma cell disorder confirms symptomatic myeloma requiring treatment:

• C (Calcium): Serum calcium >11.5 mg/dL 1, 6, 2, 3, 4
• R (Renal): Creatinine >2 mg/dL or creatinine clearance <40 mL/min 1, 6, 2, 3, 4
• A (Anemia): Hemoglobin <10 g/dL or ≥2 g/dL below lower limit of normal 1, 6, 2, 3, 4
• B (Bone): Lytic lesions, severe osteopenia, or pathologic fractures on imaging 1, 6, 2, 3, 4

Biomarker-Based Myeloma-Defining Events (Without CRAB)

These three criteria allow diagnosis and treatment initiation even without end-organ damage:

• Bone marrow clonal plasma cells ≥60% 1, 2, 3, 4
• Serum involved/uninvolved free light chain ratio ≥100 (provided involved FLC ≥100 mg/L) 1, 2, 3
• More than one focal lesion ≥5mm on MRI 1, 2, 3, 4

Risk Stratification

International Staging System (ISS):

• Stage I: β2-microglobulin <3.5 mg/L and albumin ≥3.5 g/dL 1
• Stage II: Neither Stage I nor III 1
• Stage III: β2-microglobulin ≥5.5 mg/L (worst prognosis) 1

High-Risk Cytogenetics: The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation defines high-risk disease 5, 1, 2, 3, 4. Two high-risk factors constitute "double-hit" myeloma; three or more constitute "triple-hit" myeloma with particularly poor prognosis 2, 3, 4.

Critical Differential Diagnoses

MGUS (Monoclonal Gammopathy of Undetermined Significance):

• Serum monoclonal protein <3 g/dL 6
• Clonal bone marrow plasma cells <10% 6
• No CRAB criteria or myeloma-defining biomarkers 6
• No treatment required, but lifelong monitoring needed 6

Smoldering Multiple Myeloma:

• Serum monoclonal protein ≥3 g/dL and/or clonal bone marrow plasma cells ≥10% 6
• No CRAB criteria or myeloma-defining biomarkers 6
• 10% annual risk of progression for first 5 years 6
• No immediate treatment recommended, but closer monitoring than MGUS 6

Treatment Approach Based on Transplant Eligibility

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

• Induction with bortezomib, lenalidomide, dexamethasone (VRd) for 3-4 cycles 5, 2, 3, 4
• For high-risk patients, daratumumab-VRd is preferred over VRd alone 2, 3, 4
• Autologous stem cell transplantation with high-dose melphalan 200 mg/m² IV (preferred over melphalan 140 mg/m² plus total body irradiation) 5
• Peripheral blood progenitor cells preferred over bone marrow as stem cell source 5
• Maintenance with lenalidomide for standard-risk patients 2, 3, 4
• Maintenance with bortezomib plus lenalidomide for high-risk patients 2, 3, 4

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

• VRd for 8-12 cycles followed by lenalidomide maintenance 2, 3, 4
• Alternatively, daratumumab, lenalidomide, dexamethasone (DRd) until progression 9, 2, 3, 4
• DRd demonstrated median progression-free survival of 61.9 months versus 34.4 months with lenalidomide-dexamethasone alone in the MAIA trial 9
• Oral melphalan plus prednisone remains an option but is inferior to novel agent combinations 5

Smoldering/Indolent Myeloma:

• No immediate treatment recommended 5, 6
• Monitor at 3-month intervals for first year to establish disease evolution pattern 6

Common Pitfalls to Avoid

• Do not use random urine samples—always collect 24-hour urine for protein electrophoresis 1, 6
• Do not diagnose based on bone marrow alone—must have myeloma-defining events (CRAB or biomarkers) 1, 2, 3, 4
• Do not perform unnecessary bone marrow biopsies in low-risk MGUS (IgG M-protein ≤15 g/L without end-organ damage) 6
• Do not miss spinal cord compression—maintain high suspicion and obtain urgent MRI when clinically indicated 5
• Do not overlook cytogenetic testing—high-risk features fundamentally alter treatment approach and prognosis 5, 1, 2, 3, 4