Review
Multiple myeloma—A painful disease of the bone marrow

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Abstract

Multiple myeloma is a bone marrow neoplasia with an incidence of 6/100,000/year in Europe. While the disease remains incurable, the development of novel treatments such as autologous stem cell transplantation, proteasome inhibitors and monoclonal antibodies has led to an increasing subset of patients living with long-term myeloma. However, more than two thirds of patients suffer from bone pain, often described as severe, and knowledge on the pain mechanisms and its effect on their health-related quality of life (HRQoL) is limited. In this review, we discuss the mechanisms of myeloma bone disease, the currently available anti-myeloma treatments and the lessons learnt from clinical studies regarding HRQoL in myeloma patients. Moreover, we discuss the mechanisms of cancer-induced bone pain and the knowledge that animal models of myeloma-induced bone pain can provide to identify novel analgesic targets. To date, information regarding bone pain and HRQoL in myeloma patients is still scarce and an effort should be made to use standardised questionnaires to assess patient-reported outcomes that allow inter-study comparisons of the available clinical data.

Introduction

Multiple myeloma (MM) is a haematological condition characterised by the abnormal proliferation of clonal, terminally differentiated B lymphocytes in the bone marrow. The estimated worldwide incidence of MM is 2 per 100,000 people [1] and up to 6 per 100,000 in Europe [2], [3].

While the aetiology of the disease remains unknown, a genetic component is suspected, as an increased risk among first-degree relatives of myeloma patients has been identified [4], [5], [6]. Whether the spike in prevalence among relatives has an underlying genetic cause or is a consequence of shared environmental factors, such as exposure to toxic chemicals, remains unclear. Several reports have suggested that exposure to pesticides is correlated with higher risk of myeloma development [7], [8], [9], [10], [11]. Similarly, it has been reported that clean-up workers of the Chernobyl disaster [12] and survivors of the Nagasaki atomic bomb [13] present a higher incidence of the disease than the general population, suggesting a role for ionising radiation in myelomagenesis.

Age is an important risk factor for disease development. In a 2012 study on myeloma prevalence, data from over 40,000 patients from the US National Cancer Institute register were analysed, demonstrating that myeloma is a disease of the elderly, with the mean patient age at diagnosis being almost 70 years [14]. These data are in line with other European multicentre studies showing mean age at diagnosis between 60 and 80 years [15], [16], [17], [18]. While survival expectancy is lower in patients above 65 years of age [14], autologous stem cell transplantation, a common treatment approach among developed nations e.g. European countries, Australia or North America [1], has shown encouraging results even in patients above 75 years of age [19].

Formal diagnosis of MM requires the detection of elevated monoclonal paraprotein (also known as monoclonal M protein) in serum or urine, the presence of at least 10% myeloma cells in the bone marrow, and the display of end-organ damage, often referred to as the CRAB criteria: hypercalcemia, renal failure, anaemia, and bone lesions [20], [21]. The clinical presentation of the disease comprises a constellation of symptoms, with bone pain, fatigue and infections being the main cause of initial physician consultation [22].

Interestingly, MM is preceded in virtually all patients by monoclonal gammopathy of undetermined significance (MGUS) [23], an asymptomatic disorder characterised by paraprotein levels > 3 g/dL and less than 10% clonal myeloma cells in the bone marrow without end-organ damage features [20]. In a prospective study, Landgren et al. [24] screened a population of almost 78,000 people and identified a total of 71 patients who developed MM during the course of the study. By measuring paraprotein levels in serum samples collected annually from 8 to 2 years before MM diagnosis, they found that all myeloma patients had previously developed MGUS. The estimated risk of MGUS evolving to MM or related disorders is approximately 1% per year, and remains stable over time [25], [26]. Several reports have indicated that the prevalence of MGUS ranges from 2% to 4% in the general population over 50 years of age, with men presenting a slightly higher prevalence than women, and ethnical heterogeneity, with Black and Hispanic men presenting higher prevalence of the disorder [26], [27], [28].

Section snippets

Myeloma-induced bone disease

Myeloma-induced bone disease, which is one of the main complications of MM, is characterised by severe bone loss and the development of osteolytic lesions, which frequently result in fracture in myeloma patients. Myeloma-induced bone disease occurs via several mechanisms, leading to an imbalance in normal bone remodelling, where bone resorption is dramatically increased and bone formation is suppressed (Fig. 1). Myeloma cells can induce these changes to bone remodelling by the secretion of

Current treatments for MM patients

Over the last twenty years major advances have been made in the treatment of MM, leading to improved overall survival. Typically, myeloma patients undergo a cycle of induction chemotherapy followed by autologous stem cell transplantation, which induces a remission phase of variable duration. In most cases, this phase is followed by disease relapse, leading to the use of second line therapy and the consequent treatment-free remission phase. This cycle generally continues, with each remission

Quality of life (QoL) in MM patients

MM patients have been shown to report more problems and symptoms than patients suffering from other haematological malignancies, such as leukaemia or lymphoma [90], with more than two thirds of patients being symptomatic at time of diagnosis [91]. Among the symptoms that impair the patient's health-related QoL (HRQoL), bone pain and fatigue are the commonest, with pain affecting 51–61% of patients [22], [79], [92], [93], followed by sleepiness, hypo- or paraesthesia, muscle cramps,

Pain in myeloma patients

Pain and fatigue are the main symptoms reported by myeloma patients, with the lower back and the arm/shoulder being the commonest sites of pain reported by patients (Table 1); interestingly, average pain intensity seems to be maintained at the different phases of disease progression and treatment. Myeloma pain can be classified into bone pain as a consequence of myeloma-induced bone disease (including skeletal-related events such as pathological fractures), procedural pain (as patients are

Conclusion

Multiple myeloma is a highly heterogeneous disease that causes bone pain in the majority of patients. While current advances in the field have led to increased survival, further research is needed to understand the aetiology of the disease and its symptoms, especially in regards to bone pain. Animal models of MM and myeloma-induced bone pain can be a useful tool to identify the underlying mechanisms of bone pain and potential novel targets for its treatment.

Conflicts of interest

The authors report no conflicts of interest.

Acknowledgements

This work was supported by the IMK Fonden. The funding source was not involved in planning, writing or submitting this manuscript.

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