What is multiple myeloma?

What is Myeloma?

Myeloma (multiple myeloma) is a malignant cancer of plasma cells that accumulate in the bone marrow, producing abnormal monoclonal proteins (M-protein) and causing bone destruction, kidney damage, anemia, and elevated calcium levels. 1, 2

Disease Characteristics

Multiple myeloma is a hematologic malignancy representing approximately 1.8% of all cancers and more than 15% of blood cancers in the United States. 1

• The disease results from neoplastic proliferation of clonal plasma cells that accumulate in the bone marrow 1, 3
• These malignant plasma cells produce monoclonal immunoglobulin (M-protein) detectable in serum and/or urine 1
• The median age at diagnosis is 69 years, most frequently diagnosed in people aged 65-74 years 1
• In 2020, approximately 32,270 new cases were diagnosed in the United States with 12,830 deaths 1

Clinical Presentation

Patients typically present with the CRAB criteria: hypercalcemia, renal insufficiency, anemia, and bone lesions. 3, 4

• Approximately 73% of patients have anemia at presentation 2
• 79% have osteolytic bone disease 2
• 19% have acute kidney injury at diagnosis 2
• Bone marrow infiltration by clonal plasma cells is a hallmark feature 1, 2

Genetic Classification

Myeloma can be divided into hyperdiploid and non-hyperdiploid subtypes at the highest hierarchical level, with distinct prognostic implications. 5

• Non-hyperdiploid myeloma mainly harbors IgH translocations, including t(11;14), t(4;14), and t(14;16), generally associated with more aggressive features and shorter survival 5
• Hyperdiploid myeloma is characterized by trisomies and a more indolent disease course 5
• High-risk cytogenetic abnormalities include t(4;14), t(14;16), t(14;20), del(17p), and hypodiploidy 1, 3
• Genetic progression factors include deletions of chromosomes 13 and 17, and chromosome 1 abnormalities (1p deletion and 1q amplification) 5

Disease Spectrum

Multiple myeloma exists on a continuum from precursor conditions to symptomatic disease requiring treatment. 3, 4

• Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition with abnormal immunoglobulin production, progressing to MM at approximately 1% per year 6
• Smoldering multiple myeloma is characterized by serum monoclonal protein ≥30 g/L and/or clonal bone marrow plasma cells 10-60% without end-organ damage 1, 4
• Symptomatic multiple myeloma requires clonal plasma cells and evidence of end-organ damage (CRAB criteria) or myeloma-defining biomarkers 1, 3
• The risk of progression from smoldering to symptomatic myeloma is 10% per year for the first 5 years, 3% per year for the next 5 years, and 1.5% per year thereafter 4

Diagnostic Requirements

Diagnosis requires clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma plus evidence of end-organ damage or specific biomarkers. 1, 3

• Myeloma-defining biomarkers include ≥60% clonal plasma cells in bone marrow, involved/uninvolved free light chain ratio ≥100, and more than one focal lesion on MRI 1, 3
• The International Myeloma Working Group updated criteria to include these biomarkers even without CRAB features 3
• Diagnostic workup includes complete blood count, serum creatinine, calcium, serum and urine protein electrophoresis with immunofixation, serum free light chain assay, bone marrow biopsy with CD138 staining, and cytogenetic/FISH studies 1

Prognosis

The disease remains incurable in most cases, though survival has improved significantly with modern therapies. 2, 7

• The 5-year survival rate increased from 25% in 1975 to 34% in 2003 3
• Median survival for newly diagnosed patients ranges from 5 to 7 years 6
• With current standard induction therapy (proteasome inhibitor, immunomodulatory agent, and dexamethasone), median progression-free survival is 41 months compared to historical reports of 8.5 months without therapy 2
• The Revised International Staging System combines β2-microglobulin, albumin, lactate dehydrogenase, and high-risk cytogenetics to predict outcomes 3, 2
• Stage I patients at diagnosis (28% of cases) have a median 5-year survival of 82% 2