Multiple myeloma

Multiple myeloma is a malignant hematologic neoplasm characterized by clonal proliferation of post-germinal center plasma cells, primarily within the bone marrow.[1][2] The disease produces monoclonal immunoglobulin (M protein) and drives osteoclast-mediated bone destruction through overactivation of the RANK/RANKL pathway.[1][3] Approximately 80–90% of patients develop osteolytic bone disease, and the jaws—particularly the mandible—are a recognized site of involvement.[3][4] The characteristic imaging pattern consists of well-defined, "punched-out" radiolucencies without sclerotic margins.[5] Management is systemic, coordinated by hematology-oncology, with dental specialists playing a critical role in early recognition of jaw lesions and in mitigating medication-related osteonecrosis of the jaw (MRONJ).[6][7]

The 2022 International Consensus Classification (ICC) formally adopted the term multiple myeloma, replacing "plasma cell myeloma" used in the 2016 WHO classification.[8] Multiple myeloma is further subdivided into cytogenetic groups: MM with CCND family translocations, MM with MAF family translocations, MM with NSD2 translocation, MM with hyperdiploidy, and MM, NOS.[8] The disease belongs to the spectrum of plasma cell neoplasms, which includes monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma, solitary plasmacytoma (osseous and extraosseous), and plasma cell leukemia.[9][10] The older Durie-Salmon staging system has been largely supplanted by the Revised International Staging System (R-ISS) for prognostic classification.[10] When a single clonal plasma cell mass arises in bone or soft tissue without systemic disease, the correct designation is solitary plasmacytoma, a distinct entity with different treatment and prognosis.[8][9]

• Multiple myeloma is the second most common hematologic malignancy, with an increasing global incidence; approximately 34,920 new cases are diagnosed annually in the United States.[1][2]
• Median age at diagnosis exceeds 65 years; the disease is uncommon before age 40.[1][11]
• A slight male predominance exists, and incidence is approximately twice as high in Black/African American populations compared with White populations.[2]
• Jaw involvement is reported in approximately 15–35% of patients at diagnosis, with the mandible affected more often than the maxilla. Jaw lesions and skull lesions frequently coexist; isolated jaw involvement without concurrent skull or skeletal disease is uncommon.[4][12][13]
• Jaw lesions may be the first clinical evidence of disease in a small proportion of patients.[12][14]

Systemic presentation

The hallmark features are summarized by the CRAB acronym: hypercalcemia, renal insufficiency, anemia, and lytic bone lesions.[3][10] Bone pain is the most common presenting symptom, followed by fatigue, weight loss, and recurrent infections.[2][15]

Oral and maxillofacial findings

• Jaw pain and swelling are the most common oral complaints, though jaw lesions are frequently asymptomatic and discovered incidentally on dental radiographs.[4][6]
• Tooth mobility and spontaneous tooth loosening may occur when alveolar bone is infiltrated.[6]
• Soft-tissue masses (epulis-like gingival swellings) occasionally develop over areas of bony involvement, and malignant plasma cells may be found at sites of gingival inflammation, periapical regions, or extraction sockets.[6][14]
• Numb chin syndrome (mental nerve neuropathy) is an occasional presenting feature and should raise suspicion for malignant marrow infiltration of the mandible.[16]
• Pathologic fracture of the mandible is rare but reported.
• In patients receiving intravenous bisphosphonates or denosumab, MRONJ is a significant complication, with reported rates of approximately 17% in long-term follow-up; exposed bone, nonhealing extraction sockets, and jaw sequestration may develop.[7][12]

Location and distribution

• Jaw lesions favor the posterior mandible, particularly the molar and premolar regions, corresponding to areas of persistent red marrow.[4][12]
• The mandibular body and ramus are more commonly affected than the maxilla.[12][13]
• Lesions are typically multifocal; when present in the jaws, concurrent lesions in the calvarium and remainder of the skeleton are common.[13]
• Isolated maxillary involvement is uncommon.

Periphery and shape

• The characteristic lesion is a sharply defined, round or ovoid radiolucency with a non-corticated ("punched-out") margin and no surrounding sclerotic rim.[4][5]
• Borders are typically well demarcated but lack the corticated rim seen in odontogenic cysts.
• Larger lesions may become irregular or confluent.

Internal architecture

• Lesions are purely radiolucent with no internal mineralization, septation, or trabeculation.[5][17]
• A generalized mottled or "rarefied" pattern of the affected bone may be seen when diffuse marrow infiltration is present rather than discrete focal lesions.[5]
• Diffuse osteopenia of the jaws without discrete lesions is an occasional pattern and may be the only radiographic manifestation.

Effects on teeth and adjacent structures

• Teeth within or adjacent to lesions commonly remain vital.
• Displacement of teeth and loss of the lamina dura are common findings.[18]
• Root resorption is rare but documented; when present, it tends to involve mandibular premolars and molars in the setting of extensive jaw infiltration.[19]
• Widening of the periodontal ligament space may be observed.

Cortical involvement and extent

• Cortical thinning, expansion, and erosion are common, particularly along the inferior border of the mandible and the walls of the maxillary sinus.[4]
• Perforation of the buccal or lingual cortex may occur with larger lesions, sometimes producing a palpable soft-tissue mass.
• The inferior alveolar canal may be destroyed or displaced, correlating with numb chin syndrome.[16]

Recognized variants and patterns

• Multiple discrete punched-out lesions: the classic and most recognizable pattern.
• Diffuse osteoporotic pattern: generalized rarefaction without discrete focal lesions; may mimic osteoporosis or hyperparathyroidism.
• Solitary expansile lesion: a single destructive radiolucency, indistinguishable from solitary plasmacytoma or metastatic disease on imaging alone.
• In patients treated with intravenous bisphosphonates, the radiographic pattern may change: solitary osteolytic lesions become less frequent, while lamina dura abnormalities, nonhealing alveolar sockets, diffuse sclerosis, and bone sequestration become more prevalent.[18]

Medical CT

Whole-body low-dose CT is the first-choice modality for detecting and quantifying osteolytic bone disease in multiple myeloma, with substantially higher sensitivity than conventional radiography.[2][3] On CT, myeloma lesions appear as well-circumscribed lytic defects with non-sclerotic margins and internal soft-tissue attenuation; expansile lytic lesions and, rarely, osteosclerotic lesions may also be seen.[5] CT is superior to panoramic radiography for detecting lesions in the spine and pelvis, though the two modalities perform comparably in the skull and long bones.[3]

FDG-PET/CT

FDG-PET/CT is the preferred initial imaging modality per NCCN guidelines and evaluates both the presence and metabolic activity of osseous and extraosseous disease.[9] More than three focal lesions or extramedullary disease on PET/CT at diagnosis carries adverse prognostic significance.[3] PET/CT is also the reference standard for detecting extramedullary plasmacytomas and for post-treatment response assessment.[20][21]

MRI

MRI is the most sensitive modality for detecting bone marrow infiltration, including diffuse and micronodular patterns that may be occult on CT and PET/CT.[21][22] More than one focal marrow lesion on MRI constitutes a myeloma-defining event per IMWG criteria.[10][23] Five recognized MRI patterns of marrow involvement include normal, focal, diffuse, combined focal-and-diffuse, and variegated ("salt-and-pepper").[5] Whole-body MRI with diffusion-weighted imaging is recommended when CT and PET/CT are negative in patients with suspected smoldering-to-active myeloma transition.[3][9]

The differential for multiple punched-out radiolucencies of the jaws without sclerotic margins centers on other processes that produce multifocal osteolysis in a patient typically older than 50 years.

The highest-risk diagnostic pitfall is misinterpreting multifocal jaw radiolucencies as odontogenic pathology (e.g., periapical lesions or cysts), delaying systemic workup. When multiple non-corticated lytic lesions are identified in the jaws of an older adult—particularly when teeth are vital and lesions do not conform to a periapical distribution—serum protein electrophoresis, serum free light chains, and complete blood count should be obtained promptly, with referral for bone marrow biopsy and whole-body imaging.[14][16]

Microscopic features

• Sheets or nodules of monomorphous, small to medium-sized plasma cells with eccentric nuclei, "clock-face" (peripherally clumped) chromatin, prominent perinuclear hof, and dense eosinophilic cytoplasm.[25][26]
• Interspersed larger atypical cells with plasmablastic (anaplastic) features—nuclear enlargement, hyperchromasia, high nuclear-to-cytoplasmic ratio, and occasional binucleation—may be present; when these constitute more than 50% of the population, the designation anaplastic plasma cell neoplasm applies.[25]
• Russell bodies (intracytoplasmic immunoglobulin inclusions) are characteristic.
• Amyloid deposits are identified in a subset of cases.[25]
• Osteoclastic resorption surfaces are increased in areas of plasma cell infiltration, reflecting the pathologic uncoupling of bone remodeling.[27]

Immunophenotype and clonality

• Neoplastic plasma cells express CD138 (syndecan-1) and CD38, which are used for identification and quantification on bone marrow biopsy.[2][28]
• Aberrant expression of CD56 is common in myeloma cells and absent in normal plasma cells; additional aberrant markers include CD28, CD33, CD117, and CD200.[28][29]
• Loss of CD19 and CD27 distinguishes myeloma cells from normal plasma cells.[28][30]
• Clonality is confirmed by demonstration of κ or λ light-chain restriction on immunohistochemistry, immunofluorescence, or flow cytometry.[14][31]
• Cyclin D1 expression is present in approximately 40% of cases and correlates with CCND1 translocation.[32]

Cytogenetic classification

The 2022 ICC subdivides myeloma into mutually exclusive cytogenetic groups based on primary genetic events: hyperdiploidy (trisomies) versus non-hyperdiploid subtypes harboring IgH translocations—t(11;14)/CCND1, t(4;14)/NSD2, t(14;16) or t(14;20)/MAF family.[8][33] Secondary abnormalities including del(17p), gain(1q), and del(1p) confer high-risk biology and are assessed by FISH on CD138-selected marrow samples.[9][10]

Dental role and initial workup

When jaw lesions suspicious for myeloma are identified on dental imaging, prompt referral to hematology-oncology is essential. Initial laboratory evaluation includes serum and urine protein electrophoresis with immunofixation, serum free light chain assay, complete blood count, serum calcium, creatinine, and β2-microglobulin.[2][9] Bone marrow aspirate and biopsy with immunohistochemistry, flow cytometry, and FISH panel are required for definitive diagnosis.[9][10] Whole-body FDG-PET/CT (preferred) or low-dose CT is recommended for skeletal staging.[9]

Systemic treatment

• Transplant-eligible patients receive induction therapy—typically a proteasome inhibitor,