Page 17 - Haematologica April 2020

Editorials
Prevention of bone disease and early detection of impending fractures in multiple myeloma patients can reduce morbidity and mortality: the necessity of interdisciplinary state-of-the-art treatment
Georg W. Herget,1,2 Ralph Wäsch,2,3 Lukas Klein,1,2 Hagen Schmal,1,2 Evangelos Terpos4 and Monika Engelhardt2,3
1Department of Orthopaedics and Trauma Surgery, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany; 2Comprehensive Cancer Center Freiburg (CCCF), Medical Center University of Freiburg, Freiburg, Germany; 3Department of Medicine I Hematology and Oncology, Medical Center, University of Freiburg, Faculty of Medicine, Freiburg, Germany and 4Department of Clinical Therapeutics, University of Athens School of Medicine, Alexandra General Hospital, Athens, Greece
E-mail: GEORG W. HERGET - georg.herget@uniklinik-freiburg.de doi:10.3324/haematol.2019.245423
Multiple myeloma (MM), the second most com- mon 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 approxi- mately 20% of hematologic malignancy-related deaths and for 2% of all cancer deaths.2-4 Although causes of can- cer-related deaths often include the underlying disease, infections and organ dysfunction, one essential complica- tion 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.5,6
At the time of MM diagnosis, the majority of patients present various skeletal abnormalities: osteolytic lesions, osteopenia and (secondary) osteoporosis, or a combina- tion 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.9-12 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 osteoporo- sis, 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, deno- sumab 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 illus- trates different manifestations and locations of osteolyses in MM patients, including operative treatment options.
As a consequence, the detection of bone lesions is cru- cial 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.10,11,15
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 diag- nosis, fractures, and death were collected from central reg- istries. 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 sub- types of fractures except for ankle fractures: e.g. for verte- bral 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 signifi- cantly 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 treat- ment and impair patient constitution/fitness levels.2 Moreover, cancer patients may indeed have a better out- come when impending pathological fractures are prevent-
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