The results from this population-based study show that over the past twenty years, age-standardised 5-year relative survival of patients with MM under the age of eighty remarkably increased from 36.7% to 62.4%. While survival probabilities remained strongly dependent on age, we showed that survival improvement over time occurred in both age categories 15-69 years and 70-79 years.
Data from other population-based studies have shown that survival in MM has improved substantially over the last two decades. Turesson et al. have reviewed the available evidence coming from registry studies including data until the year of 2014 [4]. Pulte et al. examined trends in survival from 2002 to 2010 in a cohort from twelve regional cancer registries in Germany aged 15-74 years and reported an increase of 5-year RS from 47.3% to 53.8% [21]. Studies from the Netherlands and from New Zealand included patients diagnosed between 1989-2018 and 1990-2016, respectively, reporting that the main improvement of survival was achieved from 1999 onwards, that is, in the period covered by our analysis [5,22]. Our 5-year RS estimates from the most recent period are overall comparable to data from other cancer registries, apart from differences in the age groups included [5,23,24].
The number and the efficacy of therapeutic substances for MM has increased dramatically. The introduction of the proteasome inhibitor bortezomib as well as immunomodulatory drugs thalidomide and lenalidomide and their European Medicines Agency approvals in the years 2004-2009 has changed treatment paradigms in MM. Since then, results from RCTs have shown that the use of novel agents, targeted therapies, and multidrug regimens in patients with MM has led to improvements of overall survival [25–29]. These improvements are consistent with the ongoing increase of RS since the years 2000-2004 shown in the data presented here.
Importantly, we observed improvement of survival estimates in the age group 70-79 years from 2000-2004 to 2010-2014, a subgroup which is often not well represented in clinical trials [30]. This is consistent with findings from other studies, reporting survival improvements in advanced age groups during the past 15-20 years [5,23,31]. From 2010-2014 to 2015-2019, we observed stagnation of survival estimates in this subgroup, although statistical precision is limited due to small numbers. A reason for this stagnation might be more rapid “real-world” dissemination of newly approved substances in younger patients as compared to elderly patients [30,31]. Our findings should be verified in a larger dataset and in a more recent period.
Alternative or additional reasons for survival improvements may include novel diagnostic techniques and new diagnostic criteria released by the International Myeloma Working Group (IMWG) in 2014 that might have led to earlier diagnosis and thereby might have influenced survival time [32]. However, we did not observe major changes in the annual incidence rates following the publication of the new diagnostic criteria in our data. In the absence of population-based studies assessing the epidemiological impact of the IMWG update, we assume that the proportion of MM cases in whom the new diagnostic criteria has brought forward the time of diagnosis without therapeutic benefit (lead time bias) is small.
To our knowledge, this is the first study reporting estimates of conditional RS in MM in the era of effective multidrug therapies. We could to show that, for patients from the NRW cohort, conditional 5-year RS slightly increased from 60.6% to 67.0% after five years already survived compared to diagnosis. Accordingly, previous population-based analyses have shown that conditional RS slightly increased over 5 years [33,34], whereas results from a clinical study suggest that conditional overall survival remained stable after one, three, and five years survived [35]. Overall, the results are in line with registry-based studies investigating long-term survival, showing that the evolution of MM is not precluded after 5 years, but late mortality is an ongoing issue [24]. Through dynamic assessment of cause-specific survival we provide valuable information for patients and clinicians on how prognosis develops over the course of the disease.
As MM survivorship increases following the introduction of novel therapies, mortality from SPM and late side effects of treatment as well as from fatal age-related diseases becomes an issue. In our analysis, MM patients were more likely to die from cardiovascular diseases or from non-myeloma malignancies (including SPM) compared to the general population. While in earlier studies the overall risk of SPM was not increased in MM patients [36], population-based studies have shown an increase in the incidence of SPM in recent years due to longer survival and possibly linked to the administration of lenalidomide and melphalan [12,37]. Consistent with our findings, an analysis of data from the Surveillance, Epidemiology, and End Results (SEER) Program found a proportion of non-myeloma cancer deaths in MM patients of 5.4% and showed a more than twofold increase in the risk of death from cardiovascular diseases in MM patients compared to the general population [11]. Our findings raise awareness of long-term risks and toxicities, highlighting the particular role of intensified monitoring and screening as well as prevention measures in this patient collective.
The strength of this study is the use of population-based data from one of Europe’s largest cancer registries, providing survival data of patients treated in Germany, where 90% of patients belong to one of the statutory health insurances, which in principle ensures equal access to cancer therapy. Using the relative survival approach, we were able to generate evidence about cancer-specific survival in addition to overall survival. In an aging patient population, comorbidities increasingly contribute to mortality and relying on overall survival only might underestimate benefits of therapy. Moreover, due to comprehensive mortality follow-up in the Cancer Registry of NRW, we were able to provide a detailed analysis of causes of death.
We recognise that our work has some limitations. First, for periods back into the past, we had to rely on data from a subset of the cancer registry only, and survival estimates were based on limited numbers of patients, especially when age stratification was applied. Second, as information about stage at diagnosis, prognostic factors, and therapy is incomplete in the registry dataset, evidence about the impact of new therapies on survival is merely indirect [38]. Third, a substantial proportion of incident cases were death certificate only (DCO) notified and had to be excluded from our survival analysis. As DCO cases tend to be older and have a worse prognosis than cases notified at lifetime, exclusion of DCO cases might lead to overestimation of survival [39]. Furthermore, due to particularly high percentage of DCO-cases in older age groups, we only included patients up to the age of 79 years. Consequently, our survival estimates cannot be applied to the age group 80+, which is in fact a substantial proportion of patients in a disease with an average age at onset of 70-75 years [4]. Nonetheless, in our age-restricted survival analysis, the median age at diagnosis of 67-69 years is still relatively high as compared to clinical study populations [35].
Regarding causes of death, there might be cases of misclassification. Renal failure (50 cases of death in our analysis) was formally assigned to ICD-10 chapter N, “Diseases of the genitourinary system”, but might instead be a consequence of active MM disease as the underlying cause of death. Death from amyloidosis (15 cases of death) was formally assigned to ICD-10 chapter E, “Endocrine, metabolic and nutritional diseases”. In the context of known underlying MM, most of these cases might have been instances of systemic light chain (AL) amyloidosis, for whom redistribution to MM as the underlying cause of death might have been correct.