What is Multiple Myeloma?
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
Definition and Origin
Multiple myeloma originates from post-germinal center B-cells that have undergone somatic hypermutation and differentiated into plasma cells. These malignant plasma cells:
- Accumulate in the bone marrow
- Displace normal hematopoietic cells
- Cause bone destruction and marrow failure
- Produce abnormal monoclonal immunoglobulins (M-protein) 1
Diagnostic Criteria
The diagnosis of multiple myeloma requires:
- ≥10% clonal plasma cells on bone marrow examination or a biopsy-proven plasmacytoma
- Evidence of end-organ damage (CRAB criteria) attributed to the plasma cell disorder:
- C: Hypercalcemia
- R: Renal insufficiency
- A: Anemia
- B: Bone lesions 1
Additional biomarkers that define multiple myeloma even without CRAB features include:
- ≥60% clonal plasma cells in bone marrow
- Involved/uninvolved serum free light chain ratio ≥100
1 focal lesion on MRI (≥5 mm in size) 1
Disease Progression
Multiple myeloma typically evolves through a multi-step process:
- Monoclonal Gammopathy of Undetermined Significance (MGUS): A premalignant condition with abnormal immunoglobulin production
- Smoldering Multiple Myeloma (SMM): Higher levels of abnormal immunoglobulins and more plasma cells in bone marrow
- Symptomatic Multiple Myeloma: Meets diagnostic criteria with CRAB features 1, 2
MGUS progresses to MM at a rate of approximately 1% per year, while most cases of SMM progress to MM over 15 years 2.
Pathophysiology
The disease causes several pathological changes:
- Bone damage: Malignant plasma cells disrupt the balance between osteoblasts and osteoclasts, leading to increased osteoclast activity and decreased osteoblast function, resulting in lytic bone lesions, pathologic fractures, bone pain, and hypercalcemia 1
- Hematologic abnormalities: Bone marrow infiltration results in anemia, thrombocytopenia, and leukopenia 1
- Renal damage: Caused by cast nephropathy from excess light chains, hypercalcemia, amyloidosis, direct tubular toxicity from light chains, and dehydration 1
- Immune dysfunction: Suppression of normal immunoglobulin production, functional defects in various immune cells, and increased susceptibility to infections 1
Genetic Classification
Multiple myeloma can be classified into two major genetic subtypes:
Hyperdiploid Myeloma (40-50% of cases):
- Characterized by trisomies of odd-numbered chromosomes
- Generally associated with a more indolent disease course and better prognosis 1
Non-Hyperdiploid Myeloma (40-50% of cases):
- Primarily characterized by IgH translocations
- Generally associated with more aggressive disease features 1
Treatment Approaches
Treatment is initiated in patients with active myeloma fulfilling the CRAB criteria or those symptomatic due to the underlying disease. Standard treatment options include:
- Combination therapies such as:
- Melphalan/prednisone/thalidomide (MPT)
- Bortezomib/melphalan/prednisone (VMP)
- Bendamustine plus prednisone 1
- Newer agents like daratumumab (monoclonal antibody) 3
- Proteasome inhibitors like bortezomib 4
- Autologous stem cell transplantation for eligible patients 5
- Bisphosphonates for skeletal-related complications 1
Prognosis
Multiple myeloma is currently considered incurable. The survival time range for patients with newly diagnosed MM is typically 5-7 years 2. However, with modern treatments including combination therapies and stem cell transplantation, survival outcomes have improved significantly, with some patients achieving long-term disease control.
Common Complications
- Recurrent infections due to immunodeficiency
- Bone pain and pathological fractures
- Renal insufficiency or failure
- Hypercalcemia
- Anemia
- Hyperviscosity syndrome
- Thromboembolic events 2