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Perspectives
er understanding and statistical evaluation: the relation- ship between the occurrence of skeletal-related events and progression-free survival-defining events needs to be defined. Furthermore, an assessment of cumulative inci- dence rates of skeletal-related events with death as a competing event will be helpful, as the slight overall sur- vival disadvantage in the zoledronic acid arm might have led to fewer skeletal-related events. Nevertheless, with full publication of the results16 and with EMA approval, denosumab will be used in Europe in MM patients.1–3
Given these insights and major advances in the under- standing of the disease, early MM diagnosis, especially of symptomatic patients, has been advocated. However, since MM is an insidiously developing malignancy and may appear with non-specific symptoms, e.g. bone pain, the diagnosis and therapeutic decisions can be complicat- ed. A German study group (DSMM) and EMN project addressed this aspect with the aim of optimizing the prompt diagnosis and further improving the quality of MM care.17 An initial retrospective analysis of 101 MM patients was followed by a prospective study of 176 patients using a structured MM-specific questionnaire. The median time from the patients' first symptoms to the final MM diagnosis was 4 months (range, 0.5-120) in the retrospectively studied cohort and very similar to the 6 months (range, 0.5-60) in the prospective cohort. Of inter- est, the time from onset of symptoms to diagnosis of MM was ≥12 months in 20% of the patients in the retrospec- tive analysis and 35% in the prospective study (Figure 1A). The frequencies of MM-related bone fractures, renal complications and infections occurring before the diagno- sis of MM was made were 41%, 35% and 16%, respec- tively. Moreover, 43% had one, 20% had two and 3% had three of these complications. The most frequent symptom was bone pain, which occurred in 73% of MM patients before the final MM diagnosis was made. In 6% of patients, MM was first suspected by orthopedists, whereas the clinical suspicion was raised by nephrolo- gists in 16% of cases, even though renal impairment was less frequent (Figure 1B). Of interest, 61% of patients were completely or fairly satisfied with the diagnostic process, whereas 39% were less satisfied (Figure 1C). Fifty-eight percent of the patients believed that their dis- ease could have been diagnosed more expeditiously (Figure 1D). Patients, who criticized the slow diagnostic process had a much longer median time interval from symptom onset to their final MM diagnosis compared to those who were less critical (9 versus 3 months, respec- tively). These results demonstrate that there is still con- siderable latency in the diagnosis of MM. However, even with early diagnosis and treatment with novel agents, skeletal-related events continue to occur, in part due to MM responses ("melting-down MM") and relapses, reminding us that progress in MM involves understand- ing how best to avoid skeletal-related events before the diagnosis of the disease is made and with antimyeloma treatment, because this substantially influences patients' coping and their approval of our MM care.2,3,17 The notion that treatment based on novel agents promotes bone- healing - apart from osteoprotective supportive agents such as bisphosphonates and denosumab - has recently led to the demanding discussion18,19 of whether bone-
seeking agents are currently needed. Since skeletal-related events continue to occur in the first months of treatment and with relapse (despite the use of novel agents and osteoprotection1–3), effective prevention and reduction of destructive skeletal-related events remain fundamental.1,20 Recent data from the national registry, Hospital Episode Statistics determined fracture rates and the effect on over- all survival in MM patients between 2001 and 2015: expectedly, fracture rates were 18 times higher with MM in the first year after admission than in the general popu- lation, and remained elevated for up to 10 years. In line with the data on early diagnosis in MM,2,3,17 the increased fracture risk preceded the first admission with MM and conversely the incidence of MM increased after admis- sion with one or more fractures. Fractures were associat- ed with poorer outcome (HR for overall survival: 1.2), indicating the need for regular use of bone supportive drugs despite novel agent-based treatment.21 In addition, cost analyses in 1028 MM patients (596 with ≥1 skeletal- related events and 432 without skeletal-related events) demonstrated that a higher frequency of skeletal-related events was associated with greater utilization of health- care resources, suggesting that bone supportive drugs need to be used diligently to avoid higher healthcare costs due to skeletal complications and patients’ discontent.22 Since bisphosphonates in symptomatic MM have been suggested, but beyond 2 years and with stable MM are left to the discretion of the treating physician, a random- ized trial assessed 170 untreated, symptomatic patients using zolendronic acid for 4 versus 2 years.23 All patients were treated with the same induction therapy and stem- cell transplantation. The group treated for 4 years had substantially fewer skeletal-related events than the group treated for 2 years (21 versus 43%, respectively; P<0.001). Actuarial curves at 5 years showed that progression-free survival was 75% (95% CI: 64%-82%) and overall sur- vival 68% (95% CI, 60%-76%) in the group treated for 4 years; these rates were not significantly different from those of the control group treated for 2 years with zole- dronic acid (P=0.67); but this trial was underpowered to show differences in survival. The trial did, however, con- firm that the continued use of zoledronic acid was useful to reduce skeletal-related events and to preserve a better quality of life.23
With bisphosphonates and denosumab being potent options in MM, Goldstein, in this issue of the Journal, comments on both costs and the fact that novel patent- protected drugs will induce greater expenditure than generically available alternatives.24 While there is an unequivocal need to thoroughly evaluate and measure "real" advances with new drugs, shortcomings of this commentary are the "generalization" regarding patent versus generic medications, the understatement of pro- gression-free survival differences, convenience of subcu- taneous versus i.v. medication, and the decreased renal impairment and safer use of denosumab in patients with renal impairment. Moreover, Goldstein’s conclusions only apply to the health system in the USA, whereas reimbursement of medication providers and financial incentives to physicians to prescribe more expensive drugs are different in Europe (Table 1).24 The rising cost of patented cancer medicines in the USA is a known phe-
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