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

Multiple Myeloma Diagnostic Criteria

Multiple myeloma requires ≥10% clonal bone marrow plasma cells (or biopsy-proven plasmacytoma) PLUS at least one myeloma-defining event: either 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

Essential Diagnostic Workup

Laboratory Testing Required

• Serum protein electrophoresis with immunofixation to identify and characterize the monoclonal protein 3, 1
• 24-hour urine protein electrophoresis with immunofixation using a concentrated 24-hour collection (never use random urine samples—this is a critical pitfall) 3, 1
• Nephelometric quantification of IgG, IgA, and IgM immunoglobulins 3, 1
• Serum free light chain (FLC) assay with kappa/lambda ratio measurement 3, 1
• Complete blood count with differential 3
• Serum creatinine and creatinine clearance 3
• Serum calcium level 3
• β2-microglobulin and albumin for International Staging System classification 1

Bone Marrow Evaluation

• Bone marrow aspiration and biopsy are mandatory to quantify clonal plasma cell percentage 3, 1
• CD138 staining must be performed to accurately determine plasma cell percentage—failure to do this can lead to underestimation 1
• Cytogenetic/FISH studies are essential for risk stratification, specifically testing for del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, and p53 mutation 1, 2

Imaging Requirements

• Full skeletal X-ray survey (spine, pelvis, skull, humeri, femurs) to detect lytic bone lesions 3, 1
• MRI of spine and pelvis provides superior detail and is mandatory when spinal cord compression is suspected or when skeletal survey is negative but symptoms suggest bone lesions 3, 1

CRAB Criteria for End-Organ Damage

Any one CRAB criterion attributable to the plasma cell disorder confirms symptomatic myeloma requiring treatment: 1

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

Additional Myeloma-Defining Events (Without CRAB)

Multiple myeloma can be diagnosed even without CRAB criteria if any of the following biomarkers are present: 1, 2

• ≥60% clonal plasma cells in bone marrow 1, 2
• Involved/uninvolved serum FLC ratio ≥100 (provided involved FLC is ≥100 mg/L) 1, 2
• >1 focal lesion ≥5mm on MRI 1, 2

Differential Diagnosis

MGUS (Monoclonal Gammopathy of Undetermined Significance)

All three criteria must be met: 3, 1

• Serum monoclonal protein <3 g/dL
• Clonal bone marrow plasma cells <10%
• Absence of CRAB criteria or myeloma-defining biomarkers

MGUS progresses to myeloma at 1% per year and requires lifelong monitoring but no immediate treatment. 3

Smoldering Multiple Myeloma (SMM)

Both criteria must be met: 3, 1

• Serum monoclonal protein ≥3 g/dL and/or clonal bone marrow plasma cells ≥10%
• Absence of CRAB criteria or myeloma-defining biomarkers

SMM progresses at 10% per year for the first 5 years, 3% per year for the next 5 years, then 1.5% per year thereafter. 3 Closer monitoring is required than MGUS, but immediate treatment is not currently recommended. 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

High-risk features include del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation. 1, 2 Presence of any two high-risk factors is considered double-hit myeloma; three or more is triple-hit myeloma. 2 These cytogenetic findings fundamentally change treatment decisions and must not be overlooked. 1

Treatment Approach

Transplant-Eligible Patients

Induction therapy consists of anti-CD38 monoclonal antibody plus bortezomib, lenalidomide, dexamethasone (VRd) followed by autologous stem cell transplantation (ASCT). 2 This is given for approximately 3-4 cycles before transplant. 5 Selected standard-risk patients can delay transplant until first relapse. 2

Transplant-Ineligible Patients

Frail patients not candidates for transplant are treated with VRd for approximately 8-12 cycles followed by maintenance or alternatively with daratumumab, lenalidomide, dexamethasone (DRd) until progression. 2, 5 The MAIA trial demonstrated that DRd improved median progression-free survival to 61.9 months compared to 34.4 months with lenalidomide-dexamethasone alone, representing a 44% reduction in risk of disease progression or death. 6

Maintenance Therapy

• Standard-risk patients need lenalidomide maintenance 2, 5
• High-risk myeloma requires bortezomib plus lenalidomide maintenance 2, 5

Relapsed/Refractory Disease

A triplet regimen is usually needed at relapse, with the choice varying with each successive relapse. 2, 5 Carfilzomib is indicated for relapsed or refractory multiple myeloma in combination with lenalidomide and dexamethasone, dexamethasone alone, or with daratumumab and dexamethasone. 7

Critical Pitfalls to Avoid

• Never use random urine samples for protein electrophoresis—only 24-hour concentrated collections are acceptable 1
• Do not perform unnecessary bone marrow biopsies in low-risk MGUS patients 1
• Do not miss spinal cord compression—obtain urgent MRI when clinically indicated 1
• Do not overlook cytogenetic testing—high-risk features fundamentally change treatment decisions 1
• Ensure CD138 staining to avoid underestimating plasma cell percentage 1
• Monitor for volume overload during hydration protocols, especially in patients at risk for cardiac failure 7