What is multiple myeloma?

What is Multiple Myeloma

Multiple myeloma is a hematologic malignancy characterized by the neoplastic proliferation of clonal plasma cells that accumulate in the bone marrow, producing monoclonal immunoglobulin (M-protein) detectable in serum and/or urine, and causing end-organ damage including bone destruction, renal failure, anemia, and hypercalcemia. 1

Epidemiology and Demographics

• Multiple myeloma accounts for approximately 1.8% of all cancers and more than 15% of hematologic malignancies in the United States 1
• In 2020, an estimated 32,270 new cases were diagnosed in the United States, with approximately 12,830 deaths 1
• The median age at diagnosis is 69 years, with the disease most frequently diagnosed among people aged 65-74 years 1

Pathophysiology

• The disease results from malignant plasma cell clones that proliferate uncontrollably in the bone marrow 1, 2
• These abnormal plasma cells produce monoclonal immunoglobulin (M-protein) that can be detected in serum and/or urine 1
• The interaction between myeloma cells and the bone marrow microenvironment through soluble cytokines and cell adhesion molecules activates multiple signaling pathways (PI3K/AKT/mTOR, RAS/MAPK, JAK/STAT, Wnt/β-catenin, and NF-κB) that promote proliferation, survival, migration, and drug resistance 2

Clinical Presentation (CRAB Criteria)

At presentation, patients typically manifest end-organ damage defined by the CRAB criteria 1, 3:

• Hypercalcemia: Serum calcium >11.5 mg/dL 3
• Renal insufficiency: Serum creatinine >2 mg/dL or creatinine clearance <40 mL/min 3
• Anemia: Hemoglobin <10 g/dL or ≥2 g/dL below lower limit of normal 3
• Bone lesions: Lytic lesions, severe osteopenia, or pathologic fractures 3

Approximately 73% of patients have anemia, 79% have osteolytic bone disease, and 19% have acute kidney injury at presentation 4

Diagnostic Criteria

The International Myeloma Working Group requires clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma PLUS evidence of end-organ damage (CRAB criteria) or specific myeloma-defining biomarkers for diagnosis. 1, 3

Myeloma-Defining Biomarkers (Beyond CRAB)

• ≥60% clonal plasma cells in the bone marrow 1
• Involved/uninvolved free light chain ratio of ≥100 1
• More than one focal lesion on MRI 1

Required Diagnostic Workup

• Complete blood count with differential and platelet counts 1
• Blood chemistry including serum calcium, creatinine, and β2-microglobulin 1
• Serum and urine protein electrophoresis with immunofixation 1, 3
• 24-hour urine collection for protein electrophoresis (not random sample) 3
• Serum free light chain assay with kappa/lambda ratio 1, 3
• Nephelometric quantification of IgG, IgA, and IgM immunoglobulins 3
• Bone marrow aspiration and biopsy with CD138 staining 1, 3
• Cytogenetic/FISH studies for risk stratification 1, 3
• Skeletal imaging with low-dose CT, MRI, or PET/CT 5, 4

Disease Classification

Monoclonal Gammopathy of Undetermined Significance (MGUS)

• Serum monoclonal protein <3 g/dL 3
• Clonal bone marrow plasma cells <10% 3
• Absence of end-organ damage (no CRAB criteria) 3
• No immediate treatment required, but lifelong follow-up needed 3

Smoldering Multiple Myeloma (SMM)

• Serum monoclonal protein ≥3 g/dL and/or clonal bone marrow plasma cells 10-60% 1, 3
• No CRAB criteria or myeloma-defining biomarkers 3
• Risk of progression is 10% per year for first 5 years 3
• Requires closer monitoring than MGUS but immediate treatment is not currently recommended 3

Symptomatic Multiple Myeloma

• Clonal plasma cells ≥10% and evidence of end-organ damage (CRAB criteria) or myeloma-defining biomarkers 1
• Treatment should be initiated in all patients with active myeloma fulfilling CRAB criteria 3

High-Risk Multiple Myeloma

• Characterized by specific cytogenetic abnormalities: t(4;14), t(14;16), t(14;20), del(17p), or hypodiploidy 1
• These genomic features are identified through FISH studies and significantly impact prognosis 4

Risk Stratification

The Revised International Staging System combines serum biomarkers (β2 microglobulin, albumin, lactate dehydrogenase) with genomic features from FISH to assess prognosis 4:

• Stage I patients (28% at diagnosis) have a median 5-year survival of 82% 4
• Cytogenetic abnormalities including t(4;14), del(17p), and t(14;16) identify high-risk disease 4

Treatment Overview

• Standard first-line induction therapy consists of a proteasome inhibitor (bortezomib), an immunomodulatory agent (lenalidomide), and dexamethasone, associated with median progression-free survival of 41 months 4
• For eligible patients, induction therapy is followed by autologous hematopoietic stem cell transplantation and maintenance lenalidomide 4
• Bortezomib-based regimens can be safely administered without dose adjustment in renal impairment 6
• Novel therapies include monoclonal antibodies (anti-CD38, anti-BCMA), bispecific antibodies, and CAR T-cell therapies 5, 2

Critical Distinctions to Avoid Misdiagnosis

• MGUS has <10% plasma cells and no end-organ damage, requiring no immediate treatment 3
• SMM has ≥10% plasma cells or ≥3 g/dL M-protein but no end-organ damage, requiring monitoring but not immediate treatment 3
• Only symptomatic MM with CRAB criteria or myeloma-defining biomarkers requires immediate treatment 3
• Bone marrow examination is not routinely recommended for IgG MGUS if serum M-protein ≤15 g/L without end-organ damage, but is recommended for all IgA and IgM M-proteins 3