What are the diagnostic approaches and treatment options for multiple myeloma?

Multiple Myeloma Diagnostics

The diagnosis of 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

Essential Laboratory Testing

The diagnostic workup must include a comprehensive panel of laboratory tests to detect and characterize the monoclonal protein:

• Serum protein electrophoresis (SPEP) with immunofixation to detect and characterize the M-protein 2, 1
• 24-hour urine protein electrophoresis with immunofixation on a concentrated sample—random urine samples are insufficient and cannot be used even when corrected for creatinine 1, 3
• Serum free light chain assay with kappa/lambda ratio measurement 1
• Quantification of IgG, IgA, and IgM immunoglobulins by nephelometry 2, 1

Critical pitfall: Never rely on random urine samples for protein electrophoresis, as this leads to false-negative results and missed diagnoses 1, 3. A complete 24-hour collection is mandatory 3.

Bone Marrow Evaluation

Bone marrow aspiration and biopsy are required to quantify plasma cell infiltration and detect qualitative abnormalities 2, 1. This is the gold standard for establishing the diagnosis and should not be omitted in suspected cases 2.

However, avoid unnecessary bone marrow biopsies in patients with low-risk monoclonal gammopathy of undetermined significance (MGUS) who do not meet criteria for further investigation 1.

Imaging Requirements

The skeletal evaluation follows a specific hierarchy:

• Full skeletal X-ray survey remains the standard for detecting lytic bone lesions 2, 1
• MRI of spine and pelvis provides superior detail and is mandatory when spinal cord compression is suspected 2, 1
• MRI and/or PET scan help distinguish between MGUS, smoldering myeloma, and overt myeloma when available 2

Critical pitfall: Do not miss spinal cord compression—obtain urgent MRI when clinically indicated based on neurological symptoms or back pain with red flags 1.

CRAB Criteria for Symptomatic Disease

Any one of these criteria attributable to the plasma cell disorder confirms symptomatic myeloma requiring treatment 1:

• Hypercalcemia: Serum calcium >11.5 mg/dL 1
• Renal failure: Creatinine >2 mg/dL or creatinine clearance <40 mL/min 1
• Anemia: Hemoglobin <10 g/dL or ≥2 g/dL below lower limit of normal 1
• Bone lesions: Lytic lesions, severe osteopenia, or pathologic fractures on imaging 1

Risk Stratification

After diagnosis, perform risk stratification using:

• International Staging System (ISS) based on β2-microglobulin and albumin levels 2, 1

  • Stage I: β2-microglobulin <3.5 mg/L and albumin ≥3.5 g/dL 1
  • Stage III: β2-microglobulin ≥5.5 mg/L 1
  • Stage II: Neither Stage I nor III 2

• Cytogenetic testing is mandatory—do not overlook this, as high-risk features fundamentally alter treatment approach and prognosis 1

• High-risk cytogenetics include del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation 1, 4

Additional Baseline Testing

Complete the staging workup with 2:

• Complete blood count 2
• Serum calcium 2
• Renal function assessment 2
• Prognostic markers: β2-microglobulin, C-reactive protein, LDH, serum albumin 2

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, followed by autologous stem cell transplantation with high-dose melphalan 200 mg/m² 2, 1, 4. This approach is associated with median progression-free survival of 41 months 5. After transplant, lenalidomide maintenance is required for standard-risk patients, while bortezomib-based maintenance is needed for high-risk disease 4.

For high-risk patients, daratumumab-VRd (Dara-VRd) is an alternative to standard VRd 4.

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

VRd for 8-12 cycles followed by lenalidomide maintenance, or daratumumab, lenalidomide, dexamethasone (DRd) until progression 1, 4. The MAIA trial demonstrated that DRd achieved median PFS of 61.9 months versus 34.4 months with lenalidomide-dexamethasone alone, representing a 44% reduction in disease progression risk 6. Overall survival also improved with a 32% reduction in death risk 6.

Critical pitfall: Do not use multiagent chemotherapy in elderly patients, as it has proven inferior to oral melphalan combinations 2.

Smoldering (Indolent) Myeloma

Immediate treatment is not recommended—these patients require close monitoring but should not receive therapy until progression to symptomatic disease 2.