Multiple myeloma (MM), the second most common hematologic cancer, is an indolent B-cell malignancy characterized by clonal expansion of terminally differentiated, immunoglobulin-producing, transformed plasma cells in the bone marrow.1 In spite of the substantial improvement in overall survival (OS) seen in in MM over the last decades, it accounts for approximately 20% of hematologic malignancy-related deaths and for 2% of all cancer deaths.42 Although causes of cancer-related deaths often include the underlying disease, infections and organ dysfunction, one essential complication in MM throughout the disease course are skeletal-related events (SRE). SRE, including pathological bone fractures, spinal cord compression, the need for radiation, and the need for surgical intervention on bones, are the leading symptom and feared complication in MM.65
At the time of MM diagnosis, the majority of patients present various skeletal abnormalities: osteolytic lesions, osteopenia and (secondary) osteoporosis, or a combination of these. Moreover, during the course of the disease, up to 90% of MM patients develop osteolytic lesions.7 The cause of bone disease lies in the interaction between malignant plasma cells and the bone microenvironment, which leads to osteoclastic bone destruction, reduced osteoblast function, and blocking of bone repair.8
Bisphosphonates are the current mainstay of treatment of bone disease in MM, as they reduce SRE and bone pain.129 Newer drugs, such as the anti-RANKL monoclonal antibody denosumab, have already been approved in MM.13 Bone anabolic agents such as romosozumab, licensed for the treatment of post-menopausal osteoporosis, are currently under investigation and may represent further promising tools in the treatment.14 However, even after appropriate treatment with anti-myeloma agents and osteoclast-targeting therapy with bisphosphonates, denosumab or others given at initial diagnosis, pathological bone fractures frequently occur during the course of the disease. Indeed, in a recent study, the authors found SRE in newly diagnosed MM patients who very frequently had osteolytic disease: two-thirds of patients had an SRE before study enrolment, an additional 44% had at least one on-study SRE, with 60% of all first SRE occurring within the first three months, and 81% occurring within the first six months.13
While pathological fractures can occur in almost every bone (but most commonly vertebras), the long bones (femur and humerus) and the ribs are often affected. However, their impact on patients’ mobility depends on their location, with fractures of the long bones along with vertebral fractures, especially in combination with spinal cord compression, being the most harmful. Figure 1 illustrates different manifestations and locations of osteolyses in MM patients, including operative treatment options.
As a consequence, the detection of bone lesions is crucial for the investigation and subsequent treatment of MM. SRE-prevention and treatment in MM is aimed at avoiding or minimizing such events. However, these are often present at initial diagnosis and upon relapse, and, therefore, often drive treatment decisions, i.e. of systemic and/or operative and radiation treatment, as well as of additional supportive measures.151110
In this issue of the journal, Thorsteinsdottir et al. report results of their large retrospective population-based study “Fractures and Survival in Multiple Myeloma”.16 They used data from 14,013 MM patients diagnosed in Sweden in the years 1990-2013, who had been identified by the Cancer Registry. Information on date of birth, MM diagnosis, fractures, and death were collected from central registries. Their aim was to compare survival in patients with and without fractures at MM diagnosis, including certain subtypes of fractures. Furthermore, the authors compared the effect of fractures on survival in MM before and after the introduction of novel agents that have generally improved OS in MM patients.
In their impressive study, the authors show that MM patients with a fracture at the time of diagnosis had an inferior survival rate compared to those without a fracture at diagnosis. Moreover, patients who developed a fracture during the course of the disease had a 2-fold risk of death compared to those that did not develop a fracture. This risk of death was significantly increased in nearly all subtypes of fractures except for ankle fractures: e.g. for vertebral fractures [hazard ratio (HR)=1.74; 95% confidence interval (CI): 1.61-1.87], hip fractures (1.99; 95%CI: 1.82-2.18), humerus fractures (2.57; 95%CI: 2.31-2.85) and femoral fractures (2.62; 95%CI: 2.32-2.98). Furthermore, the risk of death for elderly MM patients ≥70 years of age at the time of MM diagnosis with a fracture was significantly increased compared to those without.16 Results from other studies are in line with these and these authors observed that pathological fractures increase the risk of death by 20-40%.17
Underlying causes for the observations of Thorsteinsdottir et al. are plentiful, the most likely being that SRE may hamper intensified systemic anti-MM treatment and impair patient constitution/fitness levels.2 Moreover, cancer patients may indeed have a better outcome when impending pathological fractures are prevented (i.e. by surgical intervention) than patients with actual pathological fractures. Substantial differences were observed with less average blood loss, shorter hospital stays, greater likelihood of discharge, and greater likelihood of resuming support-free ambulation.19186
If pathological fractures do occur, they are mainly treated surgically to stabilize the fractured bones and to improve patients’ quality of life via pain relief and restoration of function and mobility.20 Palliation, not cure, is usually the surgical objective of treatment of MM-related bone disease.
The findings of Thorsteinsdottir et al. deserve the interest of interdisciplinary teams of MM experts. However, further investigations are needed to corroborate and better understand these findings, i.e. that the risk of death after suffering a fracture has not significantly decreased compared to patients who do not develop a fracture after the introduction of more effective treatment agents in MM. Moreover, subsequent analyses should study the risk of death after fracture in MM patients compared to patients without cancer. This is of particular importance since elderly patients in general have a higher morbidity and mortality after fractures.
As a consequence of Thorsteinsdottir et al.’s and previous findings, the early recognition of an impending fracture remains highly relevant in MM and other cancer patients. This includes taking a detailed general medical history, especially if aggravating or novel pain occurs or reoccurs. The following questions should be asked: “Is there any new onset of pain?” “Is there pain at night?” “Is pain independent of movement?” etc. In addition, radiographic imaging, such as low-dose whole-body computed tomography (WB-CT) is mandatory as part of the diagnostic process to detect possible osteolyses that may threaten stability. Moreover, during the course of the disease follow up, when symptoms occur or reoccur, imaging may be required to guide changes in therapy and disease management that may prevent or delay the onset of clinically significant morbidity and mortality as a result of SRE.15
Most importantly, optimal treatment strategies for fractures or impending fractures as part of SRE are achieved by discussion of patients’ history of disease and image scans in interdisciplinary tumor boards, taking into consideration the actual status of the disease, prognosis, and background of the individual patient.21 This interdisciplinary approach should involve a team of MM specialists in hematology-oncology, radiology, radiotherapy, orthopedics, pathology/molecular scientists, and other specialized disciplines if required (i.e. nephrologists, cardiologists, neurologists).22 We are happy and fortunate that a highly-skilled interdisciplinary team of this kind is well established at our institution.
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