Patterns of Survival in Multiple Myeloma: A Population-Based Study of Patients Diagnosed in Sweden From 1973 to 2003
Publication: Journal of Clinical Oncology
Abstract
Purpose
To define patterns of survival among all multiple myeloma (MM) patients diagnosed in Sweden during a 30-year period.
Patients and Methods
A total of 14,381 MM patients (7,643 males; 6,738 females) were diagnosed in Sweden from 1973 to 2003 (median age, 69.9 years; range 19 to 101 years). Patients were categorized into six age categories and four calendar periods (1973 to 1979, 1980 to 1986, 1987 to 1993, and 1994 to 2003). We computed relative survival ratios (RSRs) as measures of patient survival.
Results
One-year survival improved (P < .001) over time in all age groups and RSRs were 0.73, 0.78, 0.80, and 0.82 for the four calendar periods; however, improvement in 5-year (P < .001) and 10-year (P < .001) RSR was restricted to patients younger than 70 years and younger than 60 years, respectively. For the first time, in analyses restricted to MM patients diagnosed at age younger than 60 years, we found a 29% (P < .001) reduced 10-year mortality in the last calendar period (1994 to 2003) compared with the preceding calendar period (1987 to 1993). Females with MM had a 3% (P = .024) lower excess mortality than males.
Conclusion
One-year MM survival has increased for all age groups during the last decades; 5-year and 10-year MM survival has increased in younger patients (younger than 60 to 70 years). High-dose melphalan with subsequent autologous stem-cell transplantation, thalidomide, and a continuous improvement in supportive care measures are probably the most important factors contributing to this finding. New effective agents with a more favorable toxicity profile are needed to improve survival further, particularly in the elderly.
Introduction
Multiple myeloma (MM) is a chronic malignant B-cell disorder with an age-adjusted incidence rate of 2.5 to 7.2 per 100,000 in Western countries.1-3 The proliferation and accumulation of malignant plasma cells in the bone marrow, coupled with the overproduction of monoclonal proteins in the serum or urine cause the clinical manifestations of this disorder, which is characterized by bone lesions, anemia, hypercalcemia, and renal insufficiency.4 Before the introduction of alkylating agents in the management of MM, the median survival of symptomatic patients was less than 1 year.5 Melphalan-prednisone treatment has remained the mainstay of MM therapy. Since its introduction more than 30 years ago, there has been an increase in the median overall survival between 24 and 48 months.6-8 Interferon alfa (IFN-α) was introduced in the late 1970s.9 It has been used as a single agent, but is most commonly applied in combination with chemotherapy, both in induction and in maintenance treatment. In a meta-analysis, IFN-α was reported to increase survival by approximately 4 months.10 The next important contribution was the observation that dose-escalated melphalan could overcome primary resistance to conventional doses of chemotherapy.11
In the late 1980s, the vincristine, doxorubicin, and dexamethasone regimen was reported to induce high response rates in MM patients.12 Prolonged myelosuppression restricted the use of high-dose chemotherapy. Eventually, autologous stem-cell transplantation (ASCT) was introduced in MM therapy in the 1980s.13-15 Later, a double-transplantation procedure was also shown to prolong survival in certain subgroups.16 There are indications that ASCT treatment applied after induction therapy or at the time of relapse prolongs overall survival,13,14 although it is not curative. Others have found similar overall survival with ASCT and conventional treatment.17,18 The impact of allogeneic stem-cell transplantation remains restricted, given that only 5% to 10% of patients are candidates for this procedure because of age-related issues, comorbidity, toxicity, and donor availability.19-21
Clinical trials have reported thalidomide therapy to be associated with an increased MM survival.23,24 In Sweden, thalidomide was introduced in the medical treatment of relapsed and/or refractory MM in late 1998.22,23 Recently, bortezomib, a proteasome inhibitor, has been shown to be effective in previously untreated and in relapsed/refractory MM patients.25-27 In addition, lenalidomide, an analog of thalidomide, has significant antimyeloma activity.28 However, neither bortezomib nor lenalidomide was in routine clinical use during the study period.
These briefly summarized treatment options have undoubtedly improved prognosis and quality of life of many patients. However, clinical trials are associated to a certain degree with the selection of patients, especially in the elderly population. In addition, there is a lag phase in the broad introduction of newly identified treatments into the medical community. Thus, it remains unclear to what extent the developments in the management of MM patients have improved the survival in the entire MM population.
We have conducted a large population-based cohort study including 14,381 MM patients diagnosed in Sweden 1973 to 2003, who survived at least 1 month after diagnosis. The aim of the study was to define variations in patterns of survival among all MM patients diagnosed in Sweden during a 30-year period.
Patients and Methods
Central Registers
Information regarding every patient diagnosed with a malignant disorder in Sweden is reported to a centralized nationwide Swedish Cancer Register, established in 1958. The register contains information on diagnosis, sex, date of birth, date of diagnosis, and hospital where the diagnosis was made.2,29 Every physician and pathologist/cytologist is obliged by law to report each occurrence of cancer to the registry. Each individual in Sweden is given a unique national registration number. For each individual, the date of death is centrally registered. Stem-cell transplantations performed in Sweden are reported to the European Group for Blood and Marrow Transplantation (EBMT) register, which was established in 1974. Information on the number of stem-cell transplantations in MM patients reported from Swedish centers during the study period was obtained from the EBMT register.
Patient Cohort
Patients diagnosed with MM between January 1, 1973, and December 31, 2003, were identified from the Swedish Cancer Register and observed up to December 31, 2004. Only patients who survived at least 1 month after diagnosis were included. The choice to include patients from 1973 was based on the facts that by then, the Swedish Cancer Register had reached a high coverage, and the melphalan-prednisone regimen had been introduced as standard treatment for most patients receiving active treatment.6,7 Thereby, information was gathered for sex, date of birth, date of diagnosis, date of death, and hospital where the patient was diagnosed. The following hospital categories were used: small local hospitals serving 30,000 to 100,000 inhabitants; large local hospitals with greater catchment areas sometimes comprising more than 100,000 inhabitants; county hospitals, which offer all of the major specialties for the entire county in addition to their own primary catchment areas; university/regional hospitals, which offer all in-hospital care to a defined primary catchment area population (typically 100,000 to 150,000 inhabitants), in addition to being the ultimate referral center for an entire health care region (n = 10).
No data on clinical details such as MM subtype, clinical stage, or laboratory results were available for the cohort. Approval was obtained from the Karolinska Institutional Review Board for this study. Informed consent was waived because we had no contact with study patients.
Survival Analyses
Relative survival ratios (RSRs) were computed as measures of MM survival.30,31 An important advantage of RSR is that it does not rely on the accurate classification of cause of death. Instead, RSR provides a measure of total excess mortality associated with a diagnosis of MM irrespective of whether the excess mortality was directly or indirectly associated with MM. One-, 5-, and 10-year RSRs can be interpreted as the proportion of MM patients who survived their malignancy at 1, 5, and 10 years, respectively. RSR is defined as the observed survival in the patient group (where all deaths are considered events) divided by the expected survival of a comparable group from the general population, which is assumed to be free of the cancer in question. Expected survival was estimated using the Hakulinen method32 from Swedish population life-tables stratified by age, sex, and calendar time. One-, 5-, and 10-year RSRs were calculated for four calendar periods: 1973 to 1979, 1980 to 1986, 1987 to 1993, and 1994 to 2003, and six age categories (0 to 40, 41 to 50, 51 to 60, 61 to 70, 71 to 80, and > 80 years). We constructed regression models with the goal of estimating the effect of the target factors previously defined in this article, while controlling for potential confounding factors. Poisson regression was used to model excess mortality.33 The estimates from this model are interpreted as excess mortality ratios; an excess mortality ratio of 1.5, for example, for males/females indicates that males experience 50% higher excess mortality than females. All calculations were performed using SAS version 9 (SAS Institute, Cary, NC).
Results
A total of 14,381 MM patients (7,643 males and 6,738 females; median age, 69.9 years; range, 19 to 101 years), who survived more than 1 month from diagnosis, were recorded between January 1, 1973, and December 31, 2003 (Table 1). Throughout the study period, there was a significant and consistent male predominance (Table 1). Thirty-two percent of the patients were diagnosed at university/regional hospitals. A total of 1,285 stem-cell transplantations in MM patients were reported to the EBMT register during the study period. Of these, more than 90% were carried out during the last calendar period (Table 1).
The 1-, 5-, and 10-year RSRs in the four calendar periods are shown in Figures 1 to 4. The 1-year RSRs improved significantly during the four calendar periods: 0.73, 0.78, 0.80, and 0.82, respectively (P < .001). The same was true for 5-year RSRs, which were 0.31, 0.32, 0.34, and 0.36, respectively (P < .001). Ten-year RSRs improved slightly in the last two calendar periods consistent with the improvement during the first 5 years (P < .001). Thus, the 10-year RSRs were 0.12, 0.11, 0.14, and 0.14 during the calendar periods. One-year RSRs improved with calendar period in all age categories (P < .001; Fig 2), whereas improvement in 5-year RSRs was confined to patients younger than 70 years at MM diagnosis (P < .001; Fig 3). Ten-year RSRs stratified by age categories are shown in Figure 4. Ten-year RSRs improved significantly (P < .001) in patients younger than 60 years at diagnosis. This was reflected further in a 29% lower 10-year excess mortality among MM patients diagnosed from 1994 to 2003 compared with those diagnosed from 1987 to 1993; however, in individuals older than 60 years at diagnosis, there was no difference. On the basis of small numbers (n = 27), a high 10-year RSR was observed among young patients in the first calendar period. Survival decreased with increasing age at diagnosis during all calendar periods (Figs 2 to 4).
Discussion
Based on the analysis of this large national cohort of 14,381 MM patients, it is undisputable that the prognosis of patients with MM has improved significantly during the last three decades. The better outcome was reflected essentially as increasing 1- and 5-year MM survival. For the first time, in an analysis restricted to patients diagnosed with MM at the age of 60 years or younger, we found evidence of an improved 10-year MM survival over time, despite the so-far chronic and incurable character of the disease. It is important to note that 1-year survival among MM patients increased across all age categories, whereas the improvement in 5-year MM survival was confined to patients younger than 70 years of age, and was most prominent in the younger (younger than 60 years) patient population. In addition, this increase was most marked in patients diagnosed during the last calendar period. Thus, age remains an important predictor of prognosis, confirming results of many therapeutic trials.34
The most likely explanation for the observed improvement in outcome in recent years is the introduction of high-dose melphalan supported by ASCT.15,16,35 The popularity of this approach in patients mainly younger than 60 to 65 years is reflected in the number of ASCTs performed during the last calendar period (Table 1). The prognostic impact of allogeneic stem-cell transplantations appears to be restricted due to their limited number (Table 1). Given that IFN-α was used alone and in different combinations during the last three calendar periods, it is not possible to define its effect on survival in our study. Thalidomide was introduced in the therapeutic armamentarium in MM at the turn of the century,23 and it has been used in Sweden since late 1998.22 In this study, we had no access to clinical information on individual patients. However, according to data from the Swedish Medical Products Agency (www.mpa.se), a total of 1,232 MM patients were prescribed thalidomide between late 1998 and December 31, 2003. Probably a vast majority of these individuals had relapsed/refractory MM at that time point and therefore received thalidomide. Based on clinical experience, we assumed the median time from MM diagnosis to thalidomide exposure to be approximately 3 years during the actual time period. Between January 1, 1999, and December 31, 2003, we identified a total of 1,369 MM patients who were alive and had survived 3 years or more after diagnosis. On the basis of these conjectures, we believe that it is reasonable to propose that thalidomide has contributed to the improved MM survival observed in the latter calendar period of this study. Bortezomib was only prescribed to four MM patients in the total cohort, and lenalidomide was not yet introduced.
During the 30-year study period, a number of clinical studies have been performed in Swedish MM patients, which together with the already cited pivotal trials, have influenced treatment strategies.36-44 We have estimated that approximately 1,000 patients, or approximately 7% of the cohort, were included in clinical trials during the study period. In parallel, important developments in supportive measures for anemia, renal disease, and infectious and skeletal complications have been introduced in the management of patients with MM.1
Clinical studies have shown age to be an important predictor of prognosis, with younger patients having a better survival.45 Among elderly MM patients, the observed improved 1-year survival probably reflects a complex contribution of several factors, such as the acquisition of a more active treatment attitude and improved supportive care. The underlying causes of the absent improvement in long-term survival among elderly patients remain unclear. Early mortality has been reported to be higher among elderly patients.46 In addition to the fact that elderly patients do not tolerate aggressive treatment such as high-dose therapy, it has also been proposed that elderly patients present with a more advanced disease at diagnosis.35,47
Consistent with the literature, there was a male predominance in the cohort. In addition, in accordance with survival data from five continents released by the International Agency for Research on Cancer,48 we found a consistently better survival for women when adjusted for age and calendar period. Similar observations have been made in other hematologic and nonhematologic malignancies,49,50 but the underlying mechanisms are unknown. Possible explanations to this finding are different clinical stage at diagnosis, comorbidity, and different distribution of prognostic factors among males and females. Interestingly, estrogen medication has recently been found to reduce the risk of developing MM among women,51 potentially via blocking effects on interleukin-6–mediated MM cell proliferation.52
Management in specialized/referral hematology and oncology units has been reported to improve outcome in patients with certain solid tumors and acute lymphoblastic leukemia.53-56 This aspect has not been studied in MM to date. However, in a study involving 21 centers in the United States, the survival of MM patients improved with increasing distance from the treatment center.57 In a Nordic study, treatment strategies did not differ between large and small centers.58 In our study, we observed significantly higher 5- and 10-year mortality in MM patients diagnosed at nonuniversity/regional compared with university/regional hospitals. However, because of the lack of detailed clinical information on individual patients, one has to interpret these findings with caution. Potentially, it might reflect underlying variation with regard to diagnostic procedures, supportive care, and mechanisms involving referral bias.
The last calendar period was chosen to be 2 years longer than the first three calendar periods. This was done to provide a more accurate long-term survival with more patients attributing to the estimates in this latter period. In addition, ASCT was not considered standard practice in the treatment of MM in Sweden in the preceding calendar periods (Table 1). Finally, on the basis of small numbers (n = 27), we computed a high 10-year RSR estimate in the youngest age category during the first calendar period (Fig 4). Recently, we conducted a population-based validation study of MM patients diagnosed in Sweden from 1964 to 2003 (unpublished data). In that study, more than 95% of included patients fulfilled up-to-date MM diagnostic criteria. Although that was true for all calendar periods in the validation study, we have speculated that the current skewed RSR estimate based on few cases is probably biased by some early diagnostic misclassification. Therefore, we do not find this RSR estimate meaningful.
In our study, we used a register-based cohort design, which ensured a population-based setting and generalization of our findings. By including all MM patients diagnosed in Sweden during a 30-year period, we were able to conduct the largest study to date with the goal of defining the impact of global management developments in MM. Swedish Cancer Register has a validity of more than 90% in routinely diagnosed hematologic malignancies.2,29 Therefore, under-reporting and diagnostic misclassifications may only marginally bias the results of our study. In this study, we computed RSR estimates as measures of MM survival. As mentioned, an RSR estimate reflects the ratio of the observed survival divided by the expected survival of a cohort of the general population, possessing similar characteristics with respect to age, sex, and era of diagnosis. Other major advantages of working with RSR estimates include the fact that data on cause of death are not required, which circumvents difficulties with inaccuracy or lack of death certificates. The crucial assumption in working with RSR estimates is that we can accurately estimate expected survival. For most cancers (including MM), patients diagnosed with cancer are representative of the general population, so their expected survival can be estimated using general population survival rates.
Limitations include lack of clinical data for individual patients and possible changes in diagnostic practices over time. It cannot be ruled out that the observed improved survival is influenced by an increased access to healthcare and earlier detection of the disease over time (ie, lead-time bias). However, because the incidence as well as the median age at diagnosis of MM is stable in the second, third, and fourth calendar periods, respectively, and MM survival was observed to be improved particularly in the most recent calendar periods, we feel comfortable with our interpretation of the results.
In summary, we found that MM patients younger than 70 years have gained significantly from the introduction of new management strategies, especially during the last 10 to 15 years. High-dose melphalan with subsequent ASCT, thalidomide, and a continuous improvement in supportive care measures are probably the most important factors contributing to this finding. Innovative agents and procedures suitable for the older patient (older than 70 years), coupled with better prognostic markers used to guide treatment and more individualized management in MM, are greatly needed.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Author Contributions
Conception and design: Sigurdur Yngvi Kristinsson, Ola Landgren, Paul W. Dickman, Asa Rangert Derolf, Magnus Björkholm
Administrative support: Sigurdur Yngvi Kristinsson, Ola Landgren, Magnus Björkholm
Provision of study materials or patients: Ola Landgren, Magnus Björkholm
Collection and assembly of data: Sigurdur Yngvi Kristinsson, Ola Landgren, Paul W. Dickman, Magnus Björkholm
Data analysis and interpretation: Sigurdur Yngvi Kristinsson, Ola Landgren, Paul W. Dickman, Åsa Rangert Derolf, Magnus Björkholm
Manuscript writing: Sigurdur Yngvi Kristinsson, Ola Landgren, Magnus Björkholm
Final approval of manuscript: Sigurdur Yngvi Kristinsson, Ola Landgren, Paul W. Dickman, Åsa Rangert Derolf, Magnus Björkholm
| Variable | 1973-1979 | 1980-1986 | 1987-1993 | 1994-2003 | Total 1973-2003 |
|---|---|---|---|---|---|
| Total No. of patients | 2,777 | 3,217 | 3,473 | 4,914 | 14,381 |
| Age, years | |||||
| 0-40 | 27 | 36 | 37 | 44 | 144 |
| 41-50 | 127 | 114 | 156 | 235 | 632 |
| 51-60 | 443 | 456 | 407 | 679 | 1,985 |
| 61-70 | 936 | 977 | 963 | 1,235 | 4,111 |
| 71-80 | 896 | 1,199 | 1,343 | 1,779 | 5,217 |
| 81+ | 348 | 435 | 567 | 942 | 2,292 |
| Age-adjusted incidence, per 100,000 person-years* | |||||
| Males | 5.6 | 7.2 | 8.0 | 7.6 | 7.1 |
| Females | 4.0 | 4.8 | 5.0 | 5.1 | 4.8 |
| Male/female ratio, % | 53/47 | 53/47 | 54/46 | 53/47 | 53/47 |
| Median age at MM diagnosis, years | 68.5 | 69.6 | 70.4 | 70.5 | 69.9 |
| No. of stem-cell transplantations | |||||
| Allogeneic | 0 | 6 | 13 | 65 | 84 |
| ASCT | 0 | 0 | 77 | 1,124 | 1,201 |
| Patients diagnosed at university/regional hospitals | |||||
| No. | 796 | 1,039 | 1,106 | 1,729 | 4,670 |
| % | 29 | 32 | 32 | 35 | 32 |
Abbreviations: MM, multiple myeloma; ASCT, autologous stem-cell transplantation.
*
Standardized to the Swedish year 2000 population.
| Variable* | Excess Mortality Ratio | 95% CI |
|---|---|---|
| Calendar period of MM diagnosis | ||
| 1973-1979 | 1.00 (reference) | |
| 1980-1986 | 0.92 | 0.86 to 0.99 |
| 1987-1993 | 0.85 | 0.79 to 0.91 |
| 1994-2003 | 0.78 | 0.73 to 0.83 |
| Sex | ||
| Male | 1.00 (reference) | |
| Female | 0.97 | 0.89 to 0.98 |
| Age at MM diagnosis, years | ||
| 0-40 | 1.00 (reference) | |
| 41-50 | 1.27 | 0.94 to 1.70 |
| 51-60 | 1.50 | 1.14 to 1.98 |
| 61-70 | 1.96 | 1.49 to 2.58 |
| 71-80 | 2.42 | 1.84 to 3.17 |
| 81+ | 3.40 | 2.57 to 4.48 |
| Hospital category | ||
| University/regional | 1.00 (reference) | |
| Large local | 1.12 | 1.04 to 1.21 |
| Small local | 1.08 | 1.01 to 1.15 |
| County | 1.12 | 1.06 to 1.19 |
Abbreviation: MM, multiple myeloma.
*
All variables are simultaneously adjusted for all other variables in the table.
Acknowledgments
This research was supported by grants from the Swedish Cancer Society, Stockholm County Council, and the Karolinska Institute Foundations. We thank Fereshte Ebrahim, The National Board of Health and Welfare, Stockholm, Sweden, for important efforts in setting up this database; Medical Products Agency, Uppsala, Sweden; Dalsu Baris, MD, PhD, for advice, and Lewis Edgel for critical linguistic review of the manuscript.
published online ahead of print at www.jco.org on April 9, 2007.
Supported by grants from the Swedish Cancer Society, Stockholm County Council, and the Karolinska Institutet Foundations.
Presented in part at the 46th Annual Meeting of the American Society of Hematology, December 4-7, 2004, San Diego, CA; and the 9th Annual Congress of the European Hematology Association, June 10-13, 2004, Geneva, Switzerland.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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© 2007 by American Society of Clinical Oncology.
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Published in print: May 20, 2007
Published online: September 21, 2016
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Patterns of Survival in Multiple Myeloma: A Population-Based Study of Patients Diagnosed in Sweden From 1973 to 2003. JCO 25, 1993-1999(2007).
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Journal of Clinical Oncology 2007 25:15, 1993-1999
Journal of Clinical Oncology 2007 25:15, 1993-1999
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