What is multiple myeloma, particularly in older adults with a medical history of anemia, bone pain, or kidney problems?

Multiple Myeloma: Disease Overview

Multiple myeloma is a malignant hematologic cancer characterized by clonal proliferation of plasma cells in the bone marrow that produce abnormal monoclonal immunoglobulin (M-protein), leading to bone destruction, marrow failure, and end-organ damage. 1, 2

Epidemiology and Patient Demographics

• Multiple myeloma accounts for approximately 1.8% of all cancers and 10-15% of hematologic malignancies 1, 2
• The median age at diagnosis is 65-70 years, with most patients diagnosed between ages 65-74 years 1, 2
• In the United States, approximately 32,270 new cases are diagnosed annually with 12,830 deaths 2
• The incidence is 4.5-6.0 per 100,000 per year in Europe 1
• The 5-year survival rate has improved from 25% in 1975 to 34% in 2003 due to newer treatment options 1

Pathophysiology

The disease results from neoplastic plasma cell clones that accumulate in bone marrow, producing monoclonal immunoglobulin detectable in serum and/or urine. 2, 3

• Nearly all patients evolve from an asymptomatic pre-malignant stage called monoclonal gammopathy of undetermined significance (MGUS), which progresses to MM at 1% per year 1
• Some patients progress through an intermediate stage called smoldering multiple myeloma (SMM), which progresses at 10% per year for the first 5 years, then 3% per year for the next 5 years, then 1.5% per year thereafter 1
• The disease is heterogeneous with various cytogenetic abnormalities and mutations contributing to pathophysiology 1, 4

Clinical Presentation in Older Adults

Approximately 73% of patients present with anemia, 79% with osteolytic bone disease, and 19% with acute kidney injury. 3

CRAB Criteria (End-Organ Damage):

• Calcium elevation: Hypercalcemia >11.5 mg/dL 1
• Renal insufficiency: Creatinine >2 mg/dL 1
• Anemia: Hemoglobin <10 g/dL or 2 g/dL below normal 1
• Bone lesions: One or more osteolytic lesions on skeletal radiography, MRI, or PET-CT 1

Common Presenting Symptoms:

• Bone pain from lytic lesions and pathologic fractures 5
• Fatigue and weakness from anemia 3
• Recurrent infections from immune dysfunction 1
• Kidney dysfunction from light chain deposition and hypercalcemia 3

Diagnostic Criteria

The International Myeloma Working Group requires ≥10% clonal bone marrow plasma cells or biopsy-proven plasmacytoma PLUS either CRAB criteria OR specific myeloma-defining biomarkers. 1, 2, 6

Myeloma-Defining Biomarkers (Even Without CRAB Features):

• ≥60% clonal plasma cells in bone marrow 1, 2
• Involved/uninvolved free light chain ratio ≥100 (with involved FLC ≥100 mg/L) 1, 2
• More than one focal lesion on MRI (≥5 mm) 1, 2

Required Diagnostic Workup

Blood Tests:

• Complete blood count with differential and platelet counts 1, 2
• Comprehensive metabolic panel: BUN, creatinine, electrolytes, calcium, albumin 1, 2
• Lactate dehydrogenase (LDH) and beta-2 microglobulin for tumor burden assessment 1, 2
• Serum protein electrophoresis (SPEP) with immunofixation (SIFE) 1
• Quantitative immunoglobulins (IgG, IgA, IgM) 1
• Serum free light chain assay with kappa/lambda ratio 1, 2

Urine Tests:

• 24-hour urine collection for total protein 1
• Urine protein electrophoresis (UPEP) with immunofixation (UIFE) 1

Bone Marrow Evaluation:

• Bone marrow aspiration and biopsy with CD138 staining 2, 6
• Cytogenetic analysis and FISH studies for risk stratification 1, 2
• Plasma cell percentage quantification 1, 2

Imaging Studies:

• Skeletal bone survey (spine, pelvis, skull, humeri, femurs) as initial imaging 1
• MRI or CT scan for symptomatic areas negative on plain radiographs 1
• MRI is more sensitive than plain radiographs and recommended when spinal cord compression is suspected 1
• PET/CT scan is under evaluation but not routinely recommended 1

Disease Classification

Smoldering (Asymptomatic) Multiple Myeloma:

• Serum monoclonal protein (IgG or IgA) ≥30 g/L and/or clonal bone marrow plasma cells 10-60% 1, 2
• Absence of myeloma-defining events or amyloidosis 1
• No CRAB features present 2

Symptomatic (Active) Multiple Myeloma:

• ≥10% clonal plasma cells or biopsy-proven plasmacytoma 2, 6
• Presence of CRAB criteria OR myeloma-defining biomarkers 2, 6

High-Risk Multiple Myeloma:

• Specific cytogenetic abnormalities: t(4;14), t(14;16), t(14;20), del(17p), gain 1q, or p53 mutation 2, 6
• Hypodiploidy 2

Staging and Prognosis

International Staging System (ISS):

• Based on serum beta-2 microglobulin and albumin levels 6
• Stage I patients have median 5-year survival of 82% 3

Revised International Staging System (R-ISS):

• Incorporates ISS parameters plus high-risk cytogenetics and LDH levels 6
• Provides more accurate prognostic stratification 6

Bone Disease Complications

Approximately 50% of patients with bone disease will experience skeletal-related events (SREs) such as spinal cord compression and pathologic fractures, which increase mortality risk by 20-40%. 5

• Bone disease results from tumor-driven imbalance between osteoclast bone resorption and osteoblast bone formation 5
• Bisphosphonates (zoledronic acid) and RANKL inhibitors (denosumab) reduce SREs and delay bone complications 6, 5

Key Clinical Pitfalls

• Do not wait for CRAB features to appear in high-risk smoldering myeloma patients - the updated IMWG criteria allow treatment initiation based on biomarkers alone 1
• MRI and PET/CT are more sensitive than plain radiographs - use them when symptomatic areas show no abnormality on skeletal survey 1
• Serum free light chain assay is essential - it provides high sensitivity for screening and monitoring, especially in light chain-only disease 1
• Cytogenetic/FISH studies are mandatory - they identify high-risk disease requiring more aggressive treatment approaches 2, 6