ABSTRACT: Multiple myeloma is a uniformly fatal hematologic malignancy that results from the clonal expansion of plasma cells within the bone marrow. Skeletal-related complications affect nearly all patients with multiple myeloma and have a major impact on both patient morbidity and mortality. These complications most frequently include the development of osteolytic lesions that lead to severe bone pain, hypercalcemia, and pathologic fractures. Comprehensive skeletal imaging, using first plain radiographs and then more advanced modalities if necessary, is critical both at the time of diagnosis and throughout the course of therapy to assess the skeletal impact of the disease. The widespread use of intravenous bisphosphonate therapy has significantly improved the quality of life of myeloma patients by limiting the amount of osteolytic destruction that occurs. Bisphosphonate treatment, however, does not lead to repair of bone damage that has already occurred. The recent identification of multiple molecular targets with key roles in the osteolytic process has illuminated our understanding of myeloma bone disease, and may transform our future approaches to providing multiple myeloma patients with optimal skeletal care.
Despite the significant progress that has occurred in recent decades in the treatment of many advanced malignancies, skeletal morbidity remains a major problem for patients affected by cancers that metastasize to or grow primarily within bone. Thus as patients with a variety of malignancies survive longer, therapies to limit cancer-associated as well as treatment-associated skeletal complications have become increasingly important for the provision of optimal patient care.
Multiple Myeloma Bone Disease: The Nature of the Problem
Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal expansion of malignant plasma cells within the bone marrow. In the United States, nearly 20,000 patients are diagnosed with MM each year, with roughly 11,000 cancer-related deaths occurring annually. Although median survival of MM patients is only 3 to 4 years from the time of diagnosis, the recent development of novel chemotherapeutic agents has resulted in an increasing proportion of patients who achieve prolonged periods of survival, including some with survival of greater than 10 years.[3,4] Accordingly, improving quality of life by limiting disease-associated complications is an important aspect of caring for all patients with MM.
For many patients, a pathologic fracture or severe bone pain resulting from the lytic destruction of bone within the marrow cavity is the sentinel event that precipitates a diagnosis of MM. Indeed in the year preceding diagnosis, MM is associated with a 16-fold increased risk for fracture. Bone pain (which is usually worsened by movement and improved by rest) is present in approximately 60% of patients at the time of MM diagnosis. Roughly 90% of MM patients will ultimately suffer from osteolytic lesions and approximately 60% will develop a fracture at some point during the course of their disease.
Further, the presence of a pathologic fracture in MM patients is associated with at least a 20% increased risk of death. Skeletal-related complications cause significant morbidity and mortality in affected patients. Although osteolytic lesions may occur at any skeletal site, those most commonly affected include the central skeleton (spine, ribs, and pelvis), skull, and proximal long bones (humeri and femora). Frequent skeletal-associated complications include pathologic fractures (particularly vertebral), intractable bone pain, hypercalcemia of malignancy, and spinal cord compression. Importantly, even a significant MM cell response to chemotherapy may not prevent the progression of skeletal disease, and patients in complete remission generally do not demonstrate any radiographic evidence of bone lesion healing.
Within the adult skeleton, there is normally a balanced bone-remodeling sequence as osteoclast-mediated resorption of fatigued or damaged bone is followed both spatially and temporally by osteoblast-mediated new bone formation. Disruption of this balance leads to bone loss, impaired bone structural integrity, and the potential for skeletal complications. It is now clear that MM bone disease results from both an increase in osteoclast-mediated bone resorption and a reduction in osteoblast-mediated new bone formation. Together, this imbalance of bone cell activity results in the development of lytic bone lesions, and also likely contributes to the systemic bone loss and approximately twofold increased risk of osteoporotic fractures found in MM patients.[6,14]
In recent years, our understanding of the altered osteoclast and osteoblast activity that underlies MM bone disease has increased markedly, due to the identification of factors made by MM cells or within the local bone marrow microenvironment that affect bone cell function. Localization of MM cells adjacent to sites of lytic bone destruction suggests that locally produced factors play an important role in the development of osteolytic lesions, whereas the generalized bone loss that also occurs suggests that systemic factors are also likely important. Increases in osteoclast activity appear to result at least in part from increased levels of factors such as RANK ligand and macrophage inflammatory protein (MIP)-1alpha.[16,17] Likewise, the most prominent osteoblast inhibitory factor identified to date in subjects with osteolytic MM is dickkopf 1 (DKK1), with increases in DKK1 levels correlating with the extent of MM bone disease. Clinical trials are currently underway to evaluate the effects of modulating each of these molecules, as well as other identified molecular targets, and may yield important approaches to the future treatment of MM bone disease. Finally, it is important to note that several recently approved agents used for the treatment of MM also appear to affect bone cell function. Thus, an immunomodulatory drug has recently been shown to inhibit osteoclast formation, while a proteasome inhibitor has been shown to both induce osteoblast differentiation and suppress osteoclast function.[20,21] Thus, it will be important that future studies assessing therapies for MM bone disease be evaluated in the setting of these bone-active molecules now widely used as chemotherapeutic agents for the treatment of multiple myeloma.
As noted above, bone disease in MM reflects both regions of localized osteolytic destruction as well as generalized bone loss resulting in osteopenia/osteoporosis. Indeed, the identification of osteolytic lesions is one of the criteria used to diagnose MM. As such, skeletal imaging is an essential component in the evaluation of any patient either suspected or confirmed to have MM.
As recently articulated in guidelines developed by the International Myeloma Working Group (IMWG), a metastatic bone survey with plain radiographs is the initial imaging modality of choice at the time of diagnosis. This survey should provide images of all areas of possible myeloma involvement including the entire spine, skull, chest, pelvis, humeri, and femora.[7,22] However, it is important to recognize that plain radiographs do have limitations, including the ability to detect osteolytic lesions only after the loss of at least 30% of trabecular bone, and the inability to differentiate between malignant and nonmalignant (corticosteroid-associated or senile) causes of generalized bone loss. Despite these limitations, however, conventional skeletal surveys demonstrate some form of skeletal involvement (lytic lesions, fractures, or diffuse bone loss) in nearly 80% of patients. The most commonly affected sites are those with active hematopoiesis, and include the vertebral bodies, ribs, skull, shoulders, pelvis, and proximal humeri and femora. Notably, the IMWG recommends that even in the absence of skeletal symptoms, radiographic identification of lytic bone disease categorizes MM patients as “symptomatic” and warrants the initiation of MM therapy.
Despite the high rate at which skeletal lesions are identified by plain radiographs, approximately 10% to 20% of patients with complete skeletal surveys do not reveal any evidence of skeletal disease. Particularly in subjects with bone pain but no radiographic correlate identified on plain films, the use of alternative imaging methods, such as magnetic resonance imaging (MRI), can be very helpful for the detection of bone involvement. As recently reported, MRI permits the detection of both diffuse and focal bone marrow infiltration even in the absence of bone loss or local osteolysis on standard skeletal surveys, and detected focal lesions (in the spine, pelvis, and sternum) with a higher frequency than found by plain radiographs. Importantly, however, the same study demonstrated that standard metastatic bone surveys were able to detect some focal lesions (particularly in the ribs and proximal long bones) at a higher frequency than found by MRI. As such, the clinical utility of routinely using MRI to evaluate for skeletal involvement in subjects with myeloma remains to be determined.
However, as recommended by the recent IMWG guidelines, patients with an apparent solitary plasmacytoma should receive an MRI of the entire spine in addition to a standard skeletal survey. Finally, MRI is the method of choice for evaluating suspected spinal cord and/or nerve compression, although computed tomography (CT) can be used in situations in which MRI is not available.
Lastly, because bone scans assess new bone formation by osteoblasts (whose activity is severely suppressed in MM patients), bone scans frequently underestimate the extent of MM bone disease and are of little clinical use for either the initial diagnostic evaluation or in following MM patients longitudinally. Likewise, the routine use of positron emission tomography (PET) imaging is not recommended at this time, although trials assess the utility of PET-based techniques are currently underway.