Multiple Myeloma

Multiple myeloma is the most common primary malignancy of bone, although it is not a tumor of bone cells. Multiple myeloma involves the proliferation of neoplastic monoclonal plasma cells that form a solitary or multiple plasmacytomas within the bone. These neoplasms replace the bone marrow and create lytic lesions, which are visible on x-ray. The term “multiple myeloma” highlights the presence of many lesions across different bones, distinguishing it from “solitary plasmacytoma,” a similar disease albeit with a single lesion that does not involve other areas of the bone marrow and has a decreased potential for systemic involvement. Multiple myeloma is associated with a constellation of findings denoted by the acronym “CRAB”: hyperCalcemia, Renal insufficiency, Anemia, and Bone pain. Patients with hypercalcemia may exhibit lethargy, mental status changes, cardiac conduction abnormalities, neuropathy, gastrointestinal upset, and constipation.

Epidemiology

Multiple myeloma is the most common primary malignancy of bone, with an annual incidence of 3 to 4 cases per 100,000 people. The disease predominantly affects individuals over 50 years old, with a mean age at presentation of 62 years. Males are affected twice as often as females. Notably, African Americans have at least twice the risk of developing multiple myeloma compared to Caucasians, and they also experience a mortality rate that is twice as high. Multiple myeloma typically arises in marrow-producing bones, with the vertebrae being the most common site of initial involvement.

Clinical Features

The most common symptom of multiple myeloma is bone pain, though other symptoms may include renal insufficiency, hypercalcemia, anemia, predisposition to infections, cardiac arrythmia, pathologic fractures, and an elevated erythrocyte sedimentation rate. These clinical findings are largely attributed to widespread bone lysis, marrow crowding, and elevated serum levels of monoclonal antibodies. A monoclonal spike on serum protein electrophoresis is diagnostic of a plasma cell neoplasm, as the neoplastic plasma cells all originate from the same lineage and so they produce identical antibodies. As these antibodies circulate through the kidneys, the light chains are excreted in the urine as Bence-Jones proteins, while the heavy chains remain in the serum (Figure 1). Over time, this antibody overload in the kidneys can lead to renal dysfunction.

Figure 1: Schematic diagram of an antibody demonstrating the heavy and light chains. (Image courtesy of Kunal P. Shah)

Multiple myeloma encompasses a spectrum of related diseases, each with distinct diagnostic criteria, treatment options, and prognoses. Symptomatic myeloma is diagnosed when the following criteria are met: (1) more than 10% clonal plasma cell infiltration is observed on a bone marrow biopsy, (2) a monoclonal spike is detected on serum protein electrophoresis, and (3) there is evidence of end-organ damage (e.g., CRAB symptoms, more than two severe infections per year, amyloidosis, or hyperviscosity syndrome). Asymptomatic or “smoldering” myeloma is diagnosed similarly to symptomatic myeloma, with the key difference being the absence of end-organ damage. Non-secretory myeloma is also diagnosed similarly to symptomatic myeloma, except that no monoclonal spike is observed. Monoclonal gammopathy of undetermined significance (MGUS) is a benign form of plasma cell dyscrasia which is diagnosed when less than 10% clonal plasma cell infiltration is observed on bone marrow biopsy. Patients with MGUS have a yearly risk of transformation to myeloma of 1%. Finally, solitary plasmacytoma is diagnosed when a single plasmacytoma is present without further bone marrow involvement.

Radiologic Features

Multiple myeloma typically presents as purely lytic, “punched out” lesions with geographic margins without surrounding sclerosis, cortical thinning, and occasionally frank cortical destruction. These lesions commonly arise in the long bones, skull, and vertebrae and are frequently associated with pathologic fractures but usually not periosteal reactions (Figures 2-4). When the lesions are less discrete, they can mimic diffuse osteopenia or osteoporosis.

Figure 2: X-ray of a myelomatous lesion in left distal femur, demonstrating a “punched out” appearance and cortical thinning. A minimally-displaced pathologic fracture exists.

Figure 3: X-ray of a myeloma with an associated pathologic fracture in the left distal humerus. The moth-eaten/permeative appearance of the lesion suggests advanced disease.

Figure 4: X-ray of “punched out” lytic lesions in the calvarium.

A skeletal survey – a series of x-rays taken of the entire skeleton – is preferred over a bone scan in the imaging workup for multiple myeloma. This is because bone scans measure the osteoblastic uptake of radiolabeled diphosphate, whereas the lytic lesions in multiple myeloma are osteoclast-mediated. Computed tomography (CT) is utilized to assess cortical integrity, which can be crucial for surgical decision-making. Magnetic resonance imaging (MRI) is employed to evaluate the marrow extent of myeloma bone lesions and any soft-tissue masses, which are often painful and inflammatory. MRI findings can support decisions for resection of the involved bone and endoprosthetic replacement over intramedullary stabilization. On MRI, multiple myeloma appears isointense to muscle on T1 sequences, hyperintense on short tau inversion recovery (STIR) sequences, and shows internal enhancement on post-contrast sequences (Figure 5). Marrow replacement can also be visualized on T1 sequences.

Figure 5: STIR axial MRI of the right shoulder, demonstrating a hyperintense signal associated with a myeloma in the glenoid with soft tissue extension posteriorly.

Pathology

Grossly, multiple myeloma appears as a red or purple gelatinous tumor. Microscopically, closely packed plasma cells are observed which are morphologically atypical and can be either monomorphic or pleomorphic. These cells stain positively for CD138, a marker for plasma cells. The characteristic features of these cells include “clockface chromatin,” which refers to clumps of chromatin around the periphery of the nucleus, and a “perinuclear huff,” a pale area of cytoplasm adjacent to the nucleus (Figure 6). The perinuclear huff represents the Golgi apparatus actively synthesizing an abundance of monoclonal antibodies.

Figure 6: Intermediate-power H&E stain of a malignant plasma cell neoplasm demonstrating clockface chromatin within the nuclei of the plasma cells, and perinuclear clearing (“perinuclear huff”). (Image courtesy OrthopedicsOne- The Orthopaedic Knowledge Network. Accessed 2/15/22)

Differential Diagnosis

The differential diagnosis for symptomatic multiple myeloma is broad and depends on the presenting symptoms and affected sites. This list includes other plasma cell disorders such as plasma cell leukemia, plasma cell dyscrasias like Waldenstrom’s macroglobulinemia, monoclonal gammopathy of undetermined significance (MGUS), and solitary plasmacytoma. Lymphoma and leukemia must also be considered, as they can involve the bone marrow and present with similar symptoms. Additionally, metastatic carcinomas (e.g., breast, prostate and lung cancers that commonly metastasize to bone) and primary bone sarcomas (such as osteosarcoma and chondrosarcoma) are important diagnostic possibilities. Benign bone conditions like fibrous dysplasia and metabolic bone diseases (e.g., osteoporosis, hyperparathyroidism, Paget’s disease of bone) can mimic multiple myeloma radiologically and clinically. Systemic diseases affecting bone, such as sarcoidosis and amyloidosis (which can be associated with plasma cell disorders), also fall within the differential. Imaging studies and laboratory tests as well as biopsy confirmation are crucial in distinguishing multiple myeloma from these other conditions. For instance, the presence of a monoclonal spike on serum protein electrophoresis, elevated calcium levels, and characteristic lytic lesions on skeletal survey are key diagnostic features of multiple myeloma that help differentiate it from other diseases.

Disease Course: Treatment and Prognosis

Upon diagnosis, multiple myeloma is typically staged using the International Staging System, which relies on serum levels of beta-2 microglobulin, albumin, high-risk chromosomal abnormalities and LDH. The Durie-Salmon Staging System also exists, which includes additional criteria such as hemoglobin, serum calcium, presence of bone lesions, and others. Although chemotherapy can induce temporary remission, the majority of patients with symptomatic myeloma eventually relapse and succumb to the disease with an overall survival of approximately 55-60% at 5 years. Bone marrow transplantation is a treatment option for some patients and can prolong life by several years.

In addition to chemotherapy, treatment often involves a combination of palliative radiation and surgery, particularly with the goal of achieving solid, immediate weight-bearing on the affected limb. Surgery is generally indicated for pain that is refractory to radiation or for impending or completed pathologic fractures. Surgical interventions may include intralesional excision and cement packing, internal fixation, or en bloc excision and endoprosthetic reconstruction (Figures 7-9). To reduce the risk of future skeletal-related events, antiresorptive medications such as bisphosphonates or denosumab are routinely administered to all patients.

Figure 7: AP x-rays demonstrating pathologic fracture of the left distal femur in patient with multiple myeloma, with subsequent treatment involving curettage, cementation, and ORIF with combination of retrograde nail and plating.

Figure 8: AP x-rays demonstrating pathologic midshaft left femur fracture in a patient with multiple myeloma, with subsequent curettage, cementation, and IM nailing.

Figure 9: Reverse shoulder arthroplasty with right proximal humeral replacement for a pathologic fracture associated with solitary plasmacytoma.

In cases with painful spine lesions, kyphoplasty and vertebroplasty may be very beneficial and prevent the need for more invasive spinal surgery.

For patients diagnosed with solitary plasmacytoma, about half will eventually progress to widespread systemic disease and be re-diagnosed as multiple myeloma. The remaining cases may be cured with ablative radiation or en bloc resection of the plasmacytoma.

Key Test Topics

Characteristic punched out lytic lesions are formed by osteoclasts via the RANK-RANKL pathway
Monoclonal spike is seen on serum protein electrophoresis, diagnosis is confirmed with biopsy demonstrating >10% clonal plasma cell population
Associated with CRAB symptoms (hypercalcemia, renal insufficiency, anemia, and bone pain)
Identified by CD138-positive plasma cells on histopathology that demonstrate clock face nuclei and a perinuclear huff
Treatment is chemotherapy, radiation, stabilization of impending or completed pathologic fractures and sometimes a bone marrow transplant.