As discussed in a 2024 study, multiple myeloma accounts for approximately 1.8% of all malignancies, comprising approximately 23% of all hematologic malignancies.¹ The condition is diagnosed in more than 35,000 patients each year in the United States,¹ equating to an annual age-adjusted incidence of approximately 98 cases per million. Although the incidence has not significantly changed over recent decades, improvements in survival have increased the overall prevalence of myeloma over the past 20 years,² resulting in increasing prevalence. This disease has a slight predominance in men and is two to three times more common in men of African descent.³ The median age is approximately 70 years, although 37% of patients are older than 75 years and 37% are younger than 65 years at diagnosis, as discussed in a 2022 study.⁴

In the setting of a plasma cell lesion within a bone, the histologic appearance will include nodules or sheets of plasma cells that displace normal marrow elements. Most plasma cells may appear normal in histologic appearance—a basophilic round cell with a prominent perinuclear halo. Large, peripheral clumps of heterochromatin give the nucleus the appearance of a clock face or cartwheel. Despite the typical histologic appearance of most cells, flow cytometric analysis demonstrates that more than 90% will have a neoplastic phenotype.¹⁷ Other more atypical features may include dysplastic plasmablasts with large nucleoli, binucleation, or intracellular inclusions and Russell bodies. Cells with abundant immunoglobulin A production may exhibit a bright eosinophilic cytoplasmic staining, called a flame cell.

Despite its origination as a terminally differentiated B lymphocyte, the cells in plasmacytomas generally do not express the typical B-cell antigens CD19 and CD20, which help distinguish them from normal plasma cells. Expression of CD38, CD56, CD79, and CD138 are common in myeloma cells and may be used in flow cytometry or immunohistochemistry for diagnostic confirmation, particularly in bone marrow biopsies.¹⁷

Painful bony symptoms are one of the most common presenting symptoms for multiple myeloma (Figure 1). Given the overlap in age distribution, myeloma should be consistently included with metastatic carcinoma and lymphoma in the differential diagnosis for a lytic bone lesion of unknown origin, in patients older than 40 years. Routine testing of complete blood count, erythrocyte sedimentation rate, or bleeding time may provide the impetus for evaluation in asymptomatic patients. Patients with multiple myeloma will often have an elevated erythrocyte sedimentation rate, reflecting the increased light chain production and potential for rouleaux formation. Myeloma bone disease or spinal cord compression, however, is likely to direct a patient toward orthopaedic care, because osseous lesions develop in almost 80% of cases.¹⁸ It is important to recognize that the presenting clinical features can vary widely and include renal dysfunction, anemia, infection, hyperviscosity, bleeding, or hypercalcemia. The prompt recognition of these clinical features, particularly with regard to spinal cord compression, renal dysfunction, and hypercalcemia, may be critical, because emergent treatment can prevent severe or life-threatening complications.

Plasmacytoma (or plasma cell cytoma), MGUS, and SMM will not exhibit myeloma-related organ or tissue impairment, including identifiable bone changes (outside of the single plasmacytoma lesion). These lesions contain fewer than 10% plasma cells in the bone marrow. For symptomatic myeloma, no discrete numbers are used for the diagnosis, but rather for the presence of end-organ damage in the setting of histopathologically confirmed neoplastic plasma cells. Evaluation of a patient suspected of having myeloma, including adults with a lytic bone lesion of unknown etiology, should include a complete history and physical examination and a standard battery of screening studies before histologic analysis is attempted. Laboratory blood tests include complete blood count, erythrocyte sedimentation rate, coagulation times, and serum chemistries (blood urea nitrogen, creatinine, serum calcium, serum albumin). Serum protein electrophoresis and concentrated urine protein electrophoresis should be performed, with immunofixation for identification and typing of M protein.¹⁹ Additional quantification of M protein is determined by densitometry. In patients with strong clinical suspicion of myeloma or a diagnosis of solitary plasmacytoma, where routine serum protein electrophoresis and urine protein electrophoresis are negative, a serum free light chain assessment increases sensitivity for the detection of light chain-only myeloma.

In addition to detection of M protein, the diagnosis of myeloma requires histopathologic demonstration of monoclonal or abnormal plasma cells. This is usually evaluated with bone marrow aspiration, which is ideally performed using a 20-mm-long trephine biopsy. Alternatively, confirmation can be made by biopsy of a skeletal lesion, so radiographs of symptomatic lesions should ideally be obtained before bone marrow aspiration. Even in pathologically confirmed myeloma, there may be some prognostic benefit from marrow sampling as well as providing an additional means of following response to systemic treatment. Although it is rare for histologic features of a myeloma bone lesion to be equivocal, flow cytometry or immunohistochemical staining for CD138 may be useful in challenging cases. Conventional karyotyping and fluorescence in situ hybridization have become standard because of their demonstrated prognostic and potential therapeutic significance.²⁰ Next-generation whole genome sequencing at the time of myeloma diagnosis represents the most recent advance in the field, allowing for prognostic classification based
on mutational burden, recurrent translocations, and copy number abnormalities.²⁰

Myeloma is somewhat distinct among malignancies, in that the diagnosis is defined clinically as well as histopathologically, as the disease is distinguished from SMM by the presence of myeloma-related organ or tissue damage. Historically, systemic treatment has been reserved only for patients with end-organ damage. However, with advances in systemic options and improved risk stratification, some patients may be indicated for treatment before progression to symptomatic myeloma.^21,22 On a rare occasion, the patient may have biopsy-proven clonal plasma cells and myeloma-related organ or tissue damage in the absence of detectable M protein in the serum or urine, a true nonsecretory multiple myeloma. End-organ damage is often remembered by the mnemonic, CRAB: hypercalcemia (serum calcium > 10.5 mg/dL), renal insufficiency (creatinine > 2 mg/dL), anemia (Hb < 10 g/dL), or bone lesions, although any other sign or symptom of organ dysfunction related to plasma cell proliferation or light chain production can qualify as a diagnostic criterion.²⁰ Amyloidosis, as can be found in bilateral compressive neuropathy, may represent an uncommon manifestation of end-organ involvement in myeloma as well, as discussed in a 2021 study.²³ In patients with clonal plasma cells comprising more than 60% of the marrow aspirate, as well as patients with high-risk SMM,^22,24 current recommendations would favor treatment with systemic therapy even in the absence of end-organ damage.²⁴

Once a diagnosis of multiple myeloma has been established, staging studies should be performed to assess tumor burden, prognosis, and myeloma-related organ and tissue impairment. Whole-body bone imaging, as outlined later, is indicated to assess the extent of osseous involvement, as well as determination of lesions at risk for pathologic fracture.²⁵ Similarly, markers of bone resorption (C-telopeptide, N-telopeptide, pyridinoline, deoxypyridinoline) and bone formation (alkaline phosphatase, osteocalcin) have been correlated with skeletal-related events (SREs), progression, and survival.²⁶ Other prognostic factors, such as M protein quantity and serum levels of hemoglobin, calcium, and creatinine, were included in the Durie-Salmon staging system for multiple myeloma.²⁷ Serum albumin and beta-2 microglobulinemia are additional independent prognostic indicators, which determine the widely used International Staging System (ISS)²⁸ (Table 1). The revised ISS (R-ISS) added cytogenetic factors as well as lactate dehydrogenase to improve prognostication, although more than 60% of patients remained in the intermediate risk group.²⁹ As discussed in a 2022 study, a second revision of the ISS (R2-ISS) provides better stratification of patient risk.³⁰

Among patients with symptomatic myeloma, the prognosis may vary widely, with duration of survival ranging from weeks to decades. Overall, the median survival for newly diagnosed multiple myeloma is approximately 5 years, as discussed in a 2022 study,³¹ reflecting an improvement over the prior decade with
advances in treatment options.³² Interestingly, the improvements in survival have been most pronounced in patients older than 65 years, in whom novel medication combinations have allowed more successful treatment in patients who were likely unable to tolerate older, more toxic regimens.³² In addition to age, the R2-ISS has improved prognostic significance in extensive analysis, with median survival ranging from 38 to 109 months, depending on the stage, with the lowest risk group not having met the median overall survival at the conclusion of the analysis.³⁰ Revisions of the ISS have incorporated lactate dehydrogenase and fluorescence in situ hybridization and conventional karyotyping for risk stratification, as well as risk-adapted therapeutic strategies.

Radiologically, the appearance of multiple myeloma is dictated by the pathophysiology responsible for the skeletal lesions. The disease primarily involves the red marrow, with subsequent trabecular bone resorption. As a result, the most common sites of disease are those areas rich in red marrow in the adult population: spine, skull, pelvis, ribs, proximal femur, and proximal humerus. With progression of disease and increasing marrow replacement, additional long bone involvement often follows. Also, in light of the biologic process of osteoclastic bone resorption, with a relative paucity of osteoblastic bone formation on histopathology, the initial radiographic findings are most often characterized by focal, osteolytic lesions without a sclerotic rim. These lesions generally begin centrally in the marrow, but with enlargement of the tumors, endosteal scalloping, cortical destruction, and fracture may develop, and a soft-tissue mass may form. Osteolytic foci are often well circumscribed, with a sharp zone of transition. In the skull, they are described as punched-out lesions. In some patients, myeloma may produce a more diffuse pattern of osteolysis, which can either mimic senile osteoporosis or take on a permeative destructive appearance. Following systemic treatment, however, these lesions will often develop a thin sclerotic rim, which can sometimes be helpful in determining chronicity, especially following antiresorptive therapy (Figure 2).