Multiple Myeloma
Multiple myeloma is a malignant neoplasm of plasma cells, characterized by the clonal proliferation of abnormal plasma cells within the bone marrow. These malignant cells produce a monoclonal immunoglobulin, commonly referred to as M-protein or paraprotein, which can be detected in the blood or urine. The pathogenesis of multiple myeloma involves a complex interplay of genetic abnormalities, such as translocations involving the immunoglobulin heavy chain locus, chromosomal deletions, and mutations that drive plasma cell proliferation and survival. The bone marrow microenvironment further promotes disease progression through cytokine production, angiogenesis, and evasion of immune surveillance. The resulting accumulation of malignant plasma cells disrupts normal hematopoiesis, leading to anemia, immunodeficiency, and thrombocytopenia. Additionally, the overproduction of monoclonal protein can cause renal impairment, and the activation of osteoclasts leads to bone resorption, resulting in bone pain, lytic lesions, and an increased risk of fractures. Multiple myeloma is a systemic disease with significant morbidity and mortality, impacting various organ systems through both direct tumor infiltration and the effects of secreted paraproteins.
IgG myeloma is the most common subtype of multiple myeloma, accounting for approximately half of all cases. It is characterized by the excessive production of immunoglobulin G (IgG) monoclonal protein by malignant plasma cells. Clinical manifestations are similar to other forms of the disease, including bone involvement, renal dysfunction, and susceptibility to infections. Laboratory findings typically reveal a prominent IgG spike on serum protein electrophoresis.
IgA myeloma constitutes about 20% of multiple myeloma cases and is defined by the overproduction of immunoglobulin A (IgA) monoclonal protein. Patients often present with higher rates of extramedullary disease and may exhibit more pronounced hyperviscosity symptoms due to the molecular characteristics of IgA. Diagnostic evaluation often reveals a distinct IgA band on immunofixation electrophoresis.
Light chain myeloma, also known as Bence Jones myeloma, involves the secretion of only immunoglobulin light chains (kappa or lambda) without associated heavy chains. These free light chains are filtered by the kidneys and can be detected in the urine as Bence Jones protein. This subtype is associated with an increased risk of renal impairment and may present with less prominent M-protein on serum electrophoresis.
Non-secretory myeloma is a rare form in which malignant plasma cells do not produce detectable levels of monoclonal immunoglobulin in the serum or urine. Diagnosis relies on bone marrow biopsy and immunohistochemical staining to confirm the presence of clonal plasma cell proliferation. Despite the absence of measurable M-protein, patients may still develop classic complications such as bone lesions and cytopenias.
IgD and IgE myeloma are exceedingly rare subtypes, together comprising less than 2% of cases. These forms are characterized by the production of immunoglobulin D or E, respectively. IgD myeloma often presents at a younger age and may have a more aggressive clinical course, whereas IgE myeloma is extremely uncommon and has limited data regarding its clinical features.
Multiple myeloma accounts for approximately 1% of all malignancies and about 10% of hematologic cancers worldwide. The annual incidence is estimated at 4 to 6 cases per 100,000 individuals, with higher rates observed in developed countries and among individuals of African descent. The median age at diagnosis is around 69 years, and the disease is slightly more prevalent in males than females. Risk factors include advanced age, male gender, African ancestry, family history of hematologic malignancies, and exposure to certain environmental agents such as ionizing radiation or pesticides. Survival outcomes have improved in recent decades due to advances in therapy, with a current median overall survival of approximately 5 to 7 years, although outcomes remain heterogeneous depending on patient and disease characteristics.
The diagnosis of multiple myeloma is established through a combination of clinical, laboratory, and histopathological criteria. Initial evaluation includes a thorough history and physical examination, focusing on symptoms such as bone pain, fatigue, infections, and signs of hypercalcemia or renal impairment. Laboratory studies typically reveal anemia, elevated serum total protein, and the presence of a monoclonal protein (M-protein) detected by serum protein electrophoresis (SPEP), urine protein electrophoresis (UPEP), and immunofixation. Measurement of serum free light chains is particularly important in light chain and non-secretory subtypes. Bone marrow aspiration and biopsy are required to confirm clonal plasma cell infiltration, with diagnostic criteria typically requiring 10% or more clonal plasma cells in the marrow or biopsy-proven plasmacytoma. Additional diagnostic workup includes skeletal imaging, such as low-dose whole-body CT, MRI, or PET-CT, to assess for lytic bone lesions. The International Myeloma Working Group (IMWG) criteria define multiple myeloma by the presence of clonal bone marrow plasma cells ≥10% or biopsy-proven plasmacytoma, plus evidence of end-organ damage attributable to the plasma cell disorder (hypercalcemia, renal insufficiency, anemia, or bone lesions – the CRAB criteria), or biomarkers of malignancy such as ≥60% clonal plasma cells in marrow, involved/uninvolved serum free light chain ratio ≥100, or more than one focal lesion on MRI. Additional laboratory tests, including beta-2 microglobulin, lactate dehydrogenase, albumin, and cytogenetic studies, are used for risk stratification and staging.
Zevorcabtagene autoleucel is a cell-based gene therapy product designed to target and eliminate malignant plasma cells in patients with multiple myeloma. Equecabtagene autoleucel is another autologous CAR-T cell therapy that directs engineered T cells against specific antigens expressed on myeloma cells. Talquetamab, also known as talquetamab-tgvs, is a bispecific antibody that binds to both the GPRC5D antigen on myeloma cells and CD3 on T cells, thereby redirecting T cell cytotoxicity toward the malignant plasma cells. Elranatamab, referred to as elranatamab-bcmm, is a bispecific antibody targeting B-cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells, facilitating immune-mediated cell killing. Motixafortide is a CXCR4 antagonist that mobilizes hematopoietic stem cells and may be used to enhance stem cell collection and transplantation in the management of multiple myeloma. Teclistamab, or teclistamab-cqyv, is a bispecific antibody that engages BCMA on myeloma cells and CD3 on T cells, promoting T cell-mediated cytolysis of malignant cells. Ciltacabtagene autoleucel is an autologous CAR-T cell therapy engineered to recognize and eradicate BCMA-expressing plasma cells. Melflufen hydrochloride, also known as melphalan flufenamide hydrochloride, is a peptide–drug conjugate that delivers alkylating activity selectively to myeloma cells, resulting in targeted cytotoxicity. Idecabtagene vicleucel is a CAR-T cell therapy that targets BCMA and is indicated for the treatment of relapsed or refractory multiple myeloma. Daratumumab SC, available as daratumumab/hyaluronidase-fihj or daratumumab/vorhyaluronidase alfa, is a subcutaneous formulation of the anti-CD38 monoclonal antibody daratumumab, used to induce direct cytotoxicity and immune-mediated clearance of myeloma cells.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
| zevorcabtagene autoleucel (Rec INN; USAN) | ||||
| equecabtagene autoleucel (Rec INN) | ||||
| talquetamab (Rec INN; USAN); talquetamab-tgvs | 2226212-40-2 | |||
| elranatamab (Rec INN; USAN); elranatamab-bcmm | 2408850-14-4 | |||
 | motixafortide (Rec INN; USAN) | 664334-36-5 | C97 H144 F N33 O19 S2 | 2159.519 |
| teclistamab (Rec INN; USAN); teclistamab-cqyv | 2119595-80-9 | |||
| ciltacabtagene autoleucel (Rec INN; USAN) | 2641066-71-7 | |||
 | melflufen hydrochloride; melphalan flufenamide hydrochloride (Prop INNM; USAN) | 380449-54-7 | C24 H30 Cl2 F N3 O3 . Cl H | 534.879 |
| idecabtagene vicleucel (Rec INN; USAN) | 2306267-75-2 | |||
| daratumumab SC; daratumumab/hyaluronidase-fihj; daratumumab/vorhyaluronidase alfa |
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