What is multiple myeloma?

Multiple Myeloma: A Comprehensive Overview

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure, characterized by clonal plasma cell proliferation producing monoclonal immunoglobulins and causing end-organ damage. 1

Pathophysiology

Multiple myeloma originates from post-germinal center B-cells that have undergone somatic hypermutation and differentiated into plasma cells. These malignant plasma cells:

• Infiltrate the bone marrow, displacing normal hematopoietic cells
• Produce abnormal monoclonal immunoglobulins (M-proteins)
• Disrupt the balance between osteoblasts and osteoclasts, leading to bone destruction
• Cause various complications including hypercalcemia, renal insufficiency, anemia, and increased susceptibility to infections 2

Genetic Classification

Multiple myeloma can be classified into two major genetic subtypes:

1. Hyperdiploid Myeloma (40-50% of cases):

   • Characterized by trisomies of odd-numbered chromosomes
   • Generally associated with more indolent disease and better prognosis 2

2. Non-Hyperdiploid Myeloma (40-50% of cases):

   • Characterized primarily by IgH translocations
   • Generally associated with more aggressive disease features 2

Diagnostic Criteria

The diagnosis of multiple myeloma requires:

1. ≥10% clonal plasma cells on bone marrow examination or a biopsy-proven plasmacytoma 1

2. Evidence of end-organ damage (CRAB criteria) attributed to the plasma cell disorder:

   • C: Hypercalcemia (serum calcium >11.5 mg/dl)
   • R: Renal insufficiency (serum creatinine >1.73 μmol/l or >2 mg/dl or estimated creatinine clearance <40 ml/min)
   • A: Anemia (normochromic, normocytic with hemoglobin value ≥2 g/dl below the lower limit of normal or <10 g/dl)
   • B: Bone lesions (lytic lesions, severe osteopenia, or pathologic fractures) 1

Diagnostic Workup

The comprehensive diagnostic workup includes:

1. Blood tests:

   • Complete blood count with differential
   • Blood urea nitrogen, serum creatinine, and electrolytes
   • Serum calcium, albumin, LDH, and beta-2 microglobulin
   • Serum protein electrophoresis, immunofixation, and free light chain assay 1

2. Urine analysis:

   • 24-hour urine for total protein
   • Urine protein electrophoresis and immunofixation 1

3. Bone marrow assessment:

   • Bone marrow aspiration and/or biopsy
   • Cytogenetic/FISH studies
   • Immunophenotypic and molecular investigations 1

4. Imaging studies:

   • Skeletal survey (spine, pelvis, skull, humeri, and femurs)
   • MRI or CT scan for symptomatic sites
   • MRI for suspected spinal cord compression 1

Disease Spectrum

Multiple myeloma exists on a continuum of plasma cell disorders:

1. Monoclonal Gammopathy of Undetermined Significance (MGUS):

   • Serum monoclonal protein <3 g/dl
   • Clonal bone marrow plasma cells <10%
   • Absence of end-organ damage (CRAB criteria)
   • Progression to MM occurs at approximately 1% per year 3

2. Smoldering Multiple Myeloma (SMM):

   • Serum monoclonal protein ≥3 g/dl and/or clonal bone marrow plasma cells ≥10%
   • Absence of end-organ damage
   • Higher risk of progression to MM compared to MGUS 1

3. Symptomatic Multiple Myeloma:

   • Meets diagnostic criteria for MM with CRAB features
   • Requires immediate treatment 1

Complications

Bone Disease

• Malignant plasma cells disrupt the balance between osteoblasts and osteoclasts
• Results in increased osteoclast activity and decreased osteoblast function
• Leads to lytic bone lesions, pathologic fractures, bone pain, and hypercalcemia
• Approximately half of patients with bone disease will experience skeletal-related events (SREs), increasing mortality risk by 20-40% 4

Renal Insufficiency

• Caused by multiple mechanisms:
  • Cast nephropathy from excess light chains
  • Hypercalcemia
  • Direct tubular toxicity from light chains
  • Dehydration 2

Hematologic Complications

• Anemia due to bone marrow infiltration and decreased erythropoiesis
• Increased susceptibility to infections due to immunoglobulin suppression
• Thrombocytopenia and leukopenia 2

Treatment Approaches

Treatment should be initiated in all patients with active myeloma fulfilling the CRAB criteria or those symptomatic due to the underlying disease 1.

Elderly Patients (Non-transplant Setting)

Standard of care options include:

• Melphalan/prednisone/thalidomide (MPT)
• Bortezomib/melphalan/prednisone (VMP)
• Bendamustine plus prednisone (for patients with clinical neuropathy at diagnosis) 1

Novel Therapies

Multiple myeloma treatment has evolved significantly with:

• Proteasome inhibitors (bortezomib)
• Immunomodulatory drugs
• Monoclonal antibodies (daratumumab)
• CAR-T cell therapy for relapsed/refractory disease 5

Prognosis

• Multiple myeloma remains incurable in most cases
• Survival time range for newly diagnosed MM is 5-7 years 3
• Prognosis varies based on genetic subtypes, with hyperdiploid myeloma generally having better outcomes than non-hyperdiploid variants 2

Important Considerations

• Bisphosphonates are essential for minimizing skeletal morbidity in MM patients with lytic bone disease or severe osteoporosis 1
• Patients receiving novel therapies like daratumumab should be monitored for infusion-related reactions 6
• Regular monitoring for disease progression and treatment-related toxicities is crucial

Multiple myeloma management continues to evolve with emerging targeted therapies and immunotherapeutic approaches, offering hope for improved outcomes in this challenging malignancy.