Multiple Myeloma

Detailed Overview

The disease is driven by genetic mutations in post-germinal center B cells. It causes lytic bone lesions, hypercalcemia, renal failure, and anemia, collectively known as the CRAB criteria. The overproduction of monoclonal proteins (paraproteins) can cause cast nephropathy, while bone marrow infiltration suppresses normal hematopoiesis, leading to immunosuppression and cytopenias. Despite therapeutic advances, it remains largely incurable.

Epidemiology & Demographics

Incidence is approximately 7 per 100,000 annually in the US. The median age at diagnosis is 69 years. It is more common in men than women (1.4:1 ratio) and twice as common in individuals of African descent compared to those of European descent.

Etiological Mechanism

The exact cause is unknown, but it consistently evolves from an asymptomatic premalignant stage called monoclonal gammopathy of undetermined significance (MGUS). Specific cytogenetic abnormalities, such as t(11;14) or del(17p), play a crucial role in pathogenesis.

Primary Causes

Primary driver is the acquisition of genetic translocations (IgH locus on chromosome 14) or hyperdiploidy. Secondary factors include environmental exposures (radiation, benzene) and chronic immune stimulation.

• Age: Risk increases significantly with age; rarely diagnosed before 40.
• Race: African Americans have a 2- to 3-fold higher risk.
• MGUS: Prior diagnosis of Monoclonal Gammopathy of Undetermined Significance (1% progression per year).

Malignant plasma cells adhere to bone marrow stromal cells, triggering the release of cytokines like IL-6, which promotes myeloma cell growth and survival. These cells stimulate osteoclasts via the RANKL pathway and inhibit osteoblasts via DKK1, leading to osteolytic bone lesions and hypercalcemia. Monoclonal light chains are filtered by the glomerulus but precipitate in the renal tubules (combining with Tamm-Horsfall protein), causing light chain cast nephropathy.

Characteristic Clinical Presentation

• Bone pain: Often in the back or ribs, worsened by movement, caused by lytic lesions.
• Fatigue: Profound tiredness resulting from normocytic normochromic anemia.
• Recurrent infections: Frequent respiratory or urinary infections due to hypogammaglobulinemia.
• Polyuria and polydipsia: Symptoms of hypercalcemia secondary to bone resorption.

Physical Examination Signs

• Pallor from anemia.
• Bone tenderness on palpation (especially spine/ribs).
• Neurologic deficits if spinal cord compression is present.

• Spinal cord compression: From vertebral compression fractures or plasmacytoma, causing paraparesis.
• Hyperviscosity syndrome: Due to high levels of M-protein, causing mucosal bleeding, visual changes, and confusion.
• Renal failure: Cast nephropathy necessitating dialysis.

Diagnostic Criteria & Guidelines

Requires >= 10% clonal bone marrow plasma cells or biopsy-proven bony/extramedullary plasmacytoma PLUS one or more myeloma defining events: CRAB features (HyperCalcemia > 11 mg/dL, Renal insufficiency CrCl < 40 mL/min or serum Cr > 2 mg/dL, Anemia Hb < 10 g/dL, Bone lesions >= 1) OR biomarkers of malignancy (>= 60% clonal BM plasma cells, involved/uninvolved serum free light chain ratio >= 100, or >1 focal lesion on MRI).

Differential Diagnosis

• MGUS
• Smoldering Multiple Myeloma (SMM)
• Waldenström Macroglobulinemia
• AL Amyloidosis

Laboratory Tests & Biomarkers

• Serum Protein Electrophoresis (SPEP): Monoclonal spike (M-spike), typically IgG or IgA.
• Complete Blood Count (CBC): Normocytic, normochromic anemia (Hb < 10 g/dL); possible thrombocytopenia.
• Comprehensive Metabolic Panel (CMP): Elevated total protein with normal/low albumin; Calcium > 11 mg/dL; Creatinine > 2 mg/dL.

Imaging Modalities & Findings

• Whole-body low-dose CT (WBLDCT):
• MRI Spine/Pelvis:

• ISS Stage I
  Serum beta-2 microglobulin < 3.5 mg/L and serum albumin >= 3.5 g/dL. Better prognosis.
• ISS Stage II
  Neither Stage I nor Stage III.
• ISS Stage III
  Serum beta-2 microglobulin >= 5.5 mg/L. Indicates high tumor burden and poorer prognosis.

Second-Line & Adjunctive Therapy

Carfilzomib, Pomalidomide, and Dexamethasone (KPd) or bispecific T-cell engagers (e.g., Teclistamab) for relapsed/refractory disease. CAR-T cell therapy (Idecabtagene vicleucel) for patients with >= 4 prior lines of therapy.

Surgical & Procedural Management

Kyphoplasty or vertebroplasty for painful vertebral compression fractures. Orthopedic stabilization for impending pathologic fractures in long bones.

Recommended Lifestyle Changes

• Maintain high fluid intake (2-3 L/day) to prevent renal complications.
• Engage in weight-bearing exercise cautiously to maintain bone density.
• Avoid NSAIDs due to the risk of exacerbating renal impairment.

Patient Counseling & Advice

Educate on the signs of infection and the importance of prompt reporting, as infections are a leading cause of morbidity. Counsel on the teratogenic risks of lenalidomide (requires REMS program enrollment).

Follow-Up & Monitoring Schedule

Monthly evaluation of complete blood count, comprehensive metabolic panel, serum free light chains, SPEP, and UPEP during active treatment. Bone density scans (DEXA) annually.

Preventive Strategies

No primary prevention exists. Secondary prevention of bone events utilizes bisphosphonates (Zoledronic acid 4 mg IV monthly) or RANKL inhibitors (Denosumab 120 mg SQ monthly).

Median survival has improved to 5-7 years with novel agents. High-risk cytogenetics [del(17p), t(4;14), t(14;16)] reduce median overall survival to < 3 years.