In the Western world, the annual age-adjusted incidence for multiple myeloma is 4.8 to 8 per 100 000.1 The median age at diagnosis is approximately 70 years and is only occasionally diagnosed in persons aged below 40 years.2 In recent years, several new therapeutic agents with novel mechanisms of action have been approved by the FDA for multiple myeloma such as lenalidomide, pomalidomide, bortezomib and carfilzomib.3 According to randomized clinical trials, survival has improved with these drugs. Importantly, randomized clinical trials are inherently subject to selection bias owing to strict inclusion and exclusion criteria, often with omission of elderly patients.2, 4, 5 Population-based studies are effective to estimate survival changes over time in a non-selected group of persons.6
In 2007, using population-based data from Sweden on 14 381 multiple myeloma patients, we were the first to show that multiple myeloma survival has improved in the general population,2 which was later confirmed by other studies.2, 7, 8, 9, 10 In fact, several population-based studies in multiple myeloma have consistently shown that the improvements in survival over the last years are restricted to the younger multiple myeloma patents (below the age of 65–70 years) and that elderly patients have not benefitted from the introduction of the new drugs. This, in turn, suggests that high-dose melphalan therapy followed by autologous stem cell transplantation has been the main driver for the observed improvement in survival in population-based multiple myeloma studies.2, 8 However, the use of modern drugs among older patients is a relatively new phenomenon, and, until date, no population-based study with sufficient follow-up has been conducted to formally assess survival patterns in older multiple myeloma patients in the era of modern drugs.
In a recent follow-up study from the Mayo Clinic, based on 1038 multiple myeloma patients diagnosed during 2001–2010 at their single center, tertiary referral clinic, a continued improvement in survival was observed in recent years.11 More specifically, the Mayo Clinic study found their improved survival patterns to be driven by 540 patients older than 65 years at diagnosis. In their study, median survival in patients older than 65 years improved from 3.2 to 5 years in patients diagnosed during 2001–2005 and 2006–2010, respectively. No improvement was observed for younger patients over time. In addition, there was a significant improvement in early mortality between the two calendar periods.
To follow-up on these findings from a single center, tertiary referral center, we performed a population-based study on survival among more than 45 000 multiple myeloma patients (2/3 of the patients were 65 years or older) diagnosed during 1973–2009 analyzing short- and long-term survival. Information on all patients with multiple myeloma diagnosed from January 1973 through December 2009 was obtained using the NCI Surveillance Epidemiology and End Results 9 Registries Database (SEER 9, based on November 2011 submission).12 Multiple myeloma was defined using International Classification of Disease for Oncology, 3rd edition (ICD-O-3) topographic (C42.1) and morphologic (9732) codes.13 The NCI SEER 9 data included SEER’s original 9 Tumor Registries (Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, California, Seattle-Puget Sound, Washington and Utah), and covering approximately 10% of the US population.12
Survival was calculated for multiple myeloma as defined by ICD-8 to ICD-10 mortality codes. Data on the year of diagnosis, age and gender were available for each case. On the basis of advances in multiple myeloma diagnosis and treatment, myeloma patients were divided into four age groups (0–50, 51–65, 66–79 and 80 years) and four time-periods of diagnosis (1973–1979, 1980–1989, 1990–1999 and 2000–2009). Actuarial myeloma-specific survival rates with 95% confidence intervals were calculated using the Kaplan–Meier method. All statistical tests are two-sided, with P<0.05 considered statistically significant.
There were 45 595 persons with multiple myeloma diagnosed from 1973 through 2009. The number of patients diagnosed in the calendar periods 1973–1979, 1980–1989, 1990–1999 and 2000–2009 were n=5509, n=10 325, n=13 408, and n=16 253, respectively. The number of patients in the age groups of 0–50, 51–65, 66–79 and 80–106 years were 3783, 13 010, 19 370 and 9332, respectively. Overall, for all age groups, short-term (3 months) survival improved significantly over time (1973–2009) (P<0.05). Among patients under the age of 50 years (Figure 1), cumulative percent (%) five-year myeloma-specific survival improved statistically significantly (P<0.05) over time; ranging from 36% during 1973–1979, to 46% during 1980–1989, to 56% during 1990–1999, to 68% from 2000–2009. Similarly, there was a significant improvement in 5-year survival among patients in the age groups of 51–65 years (34, 38, 44 and 58%) and 66–79 years (26, 32, 32 and 41%), respectively.
Ten-year survival improved statistically significantly over time in patients under the age of 50 years at the time of multiple myeloma diagnosis: that is, 20, 26 and 41% during the calendar periods 1973–1979, 1980–1989 and 1990–1999, respectively (P<0.05; Figure 1). Similarly, there was a statistically significant improvement in 10-year survival among persons in the age groups of 51–65 years (15, 17 and 25%) and 66–79 years (12, 12 and 15%) at the time of multiple myeloma diagnosis. In contrast, no statistically significant improvement in long-term survival was observed for multiple myeloma among persons of age 80 years or older at diagnosis (Figure 1).
Three-month survival improved significantly over time (1973–2009) in all age groups (P<0.05). Between 1973–1979 and 2000–2009, patients diagnosed under the age of 50 years improved their cumulative survival at 3 months from 94 to 98%, patients aged 51–65 years from 92 to 96%, patients aged 66–79 years from 86 to 91%, and patients aged 80 years or older improved their cumulative percent survival at 3 months from 74 to 81%. Furthermore, between 1973–1979 and 2000–2009, patients diagnosed at the age of 80 years or older improved their 1-year cumulative survival from 52 to 61%.
In this large population-based study, based on more than 45 000 persons with multiple myeloma diagnosed over a period of three decades, we show that long-term survival has improved in multiple myeloma persons up to 80 years of age. These findings are important as they show that the modern drugs that are used worldwide in the treatment of multiple myeloma likely contributed to a major shift in survival in this disease.
During the last 15 years, there has been a great increase in the arsenal of drugs available for patients with multiple myeloma and several new agents are under way.3 Since the 1960s, oral melphalan and prednisone (MP) has been the standard of therapy for patients not eligible for autologous stem cell transplantation. Until recently, MP was considered the standard of care for symptomatic patients older than 65–70 years. On the basis of several clinical trials, the overall response rate with MP is relatively low and complete remissions (CR) are rare. This is reflected in a median overall survival of 24 to 48 months.14 Consequently, through the years, many clinical trials have been conducted to develop treatment regimens with higher response rates and improved overall survival compared with those of MP. Eventually, among younger patients who were able to tolerate therapy, autologous stem cell transplantation was introduced in multiple myeloma therapy in the 1980s. The introduction of modern drugs, including lenalidomide, pomalidomide, bortezomib and carfilzomib has changed the paradigm of anti-myeloma therapy. Combinations of modern agents with steroids, alkylating agents or anthracyclines have significantly improved response rates, depths of responses, progression free survival and overall survival in multiple myeloma.14
There have been concerns regarding early mortality due to complications associated with modern drugs, such as thrombosis and infections. No population-based study has systematically evaluated changes in early deaths (within 3 months) over time. The observed improvement in short-term survival (3 months) is probably a reflection of the superiority of modern drugs and improvement in supportive care leading to reduced complications at diagnosis (such as renal failure, thrombosis and infections).
The strengths of our study include the population-based design, very large sample size, and geographic, socioeconomic and racial diversity present in the SEER 9 registry. Our study is limited by the lack of specific clinical data regarding diagnosis and treatment. In addition, the inaccessibility of tumor tissue and serum samples in patients included in our study precludes an analysis of prognostic markers.15
In summary, based on more than 45 000 multiple myeloma patients, the majority diagnosed at the age of 65 years or older, we found that long-term survival has improved significantly after the introduction of modern drugs. An important observation is that overall survival has improved in multiple myeloma patients up to 80 years of age supporting the use of modern anti-myeloma therapy independent of age.16, 17