Prior cancer and risk of monoclonal gammopathy of undetermined significance: a population-based study in Iceland and Sweden.

There is some evidence that a prior cancer is a risk factor for the development of multiple myeloma (MM). If this is true, prior cancer should be associated with higher prevalence or increased progression rate of monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM and related disorders. Those with a history of cancer might therefore present a target population for MGUS screening. This two-part study is the first study to evaluate the relationship of MGUS and prior cancers. First, we evaluated whether prior cancers were associated with having MGUS at the time of screening in the Iceland Screens Treats or Prevents Multiple Myeloma (iStopMM) study that includes 75,422 individuals screened for MGUS. Next, we evaluated the association of prior cancer and the progression of MGUS to MM and related disorders in a population-based cohort of 13,790 Swedish individuals with MGUS. A history of prior cancer was associated with a modest increase in the risk of MGUS (odds ratio (OR)= 1.10; 95% confidence interval (CI): 1.00-1.20). This excess risk was limited to prior cancers in the year preceding MGUS screening. A history of prior cancer associated with the progression of MGUS, except for myeloid malignancies which were associated with lower risk of progression (hazard ratio (HR)=0.37; 95%CI: 0.16-0.89; p=0.028). Our findings indicate that a prior cancer are not a significant aetiological factor in plasma cell disorders. The findings do not warrant MGUS screening or different management of MGUS in those with a prior cancer.

Use of Linked Nordic Registries for Population Studies in Hematologic Cancers: The Case of Multiple Myeloma.

Purpose: Linked health-care registries and high coverage in Nordic countries lend themselves well to epidemiologic research. Given its relatively high incidence in Western Europe, complexity in diagnosis, and challenges in registration, multiple myeloma (MM) was selected to compare registries in Denmark, Finland, and Sweden. Patients and Methods: Data were obtained from four archetypal registries in each country (spanning January 2005-October 2018): National Patient Registry (NPR), Prescribed Drug Registry (PDR), Cancer Registry (CR), and Cause of Death Registry. Patients newly diagnosed with MM who received MM-specific treatment were included. PDR/NPR treatment records were used to assess incident NPR cases. The registration quality of MM-specific drugs in the PDR of each country was also evaluated. Results: In Denmark, only 6% of patients in the NPR were not registered in the CR; in Sweden, it was 16.9%. No systematic differences were identified that could explain this discrepancy. In Denmark, lenalidomide and bortezomib were registered in the NPR with high coverage, but less expensive drugs typically given in combination with bortezomib were not covered in any of the registries. In Finland and Sweden, bortezomib records were not identified in the PDR, but some were in the NPR; other drugs had good coverage in the PDR. Conclusions: The registries evaluated in this study can be used to identify the MM population; however, given the gaps in MM registration in the Finnish and Swedish CRs, Danish registries provide the most comprehensive datasets for research on treatment patterns for MM.

Improved survival in myeloma patients-a nationwide registry study of 4,647 patients ≥75 years treated in Denmark and Sweden.

The prevalence of multiple myeloma (MM) is increasing in Nordic countries and the rest of the western world. Patients aged ≥75 years at diagnosis constitute an increasing proportion of all MM patients, but are underrepresented in randomized clinical trials. There is an urgent need for studies of the characteristics, treatment and outcome in this cohort. We present data from two nationwide population-based registries of all MM patients diagnosed in Denmark from January 1, 2005 until February 18, 2020, and in Sweden from January 1, 2008 until December 31, 2019, including treatment data for patients diagnosed until 2018 (Denmark) and 2019 (Sweden). In total 4,647 patients were ≥75 years at diagnosis, compared to 7,378 younger patients. Patients ≥75 years, accounting for approximately 40% of all MM patients, are a distinct cohort with more advanced disease at diagnosis, reflected by higher International Staging System (ISS) stage, and a higher proportion have renal failure and anemia. We found a more gradual introduction of modern medications in the older cohort than in the younger, despite simultaneous changes in guidelines. Compared to the cohorts in randomized controlled trials that guide the treatment of non-transplant eligible patients, we found a higher proportion of patients ≥75 years and presenting with ISS III in the real-world populations. Nevertheless, response rates and survival are increasing, indicating that modern treatment regimens are effective and well tolerated also in elderly MM patients in real-world populations.

Regional differences in treatment and outcome for myeloma patients in Sweden: A population based Swedish myeloma register study.

BACKGROUND: We wanted to evaluate if health care for multiple myeloma (MM) patients is equal in different regions of Sweden. AIM: To study differences in survival for MM depending on health care region and early use of modern treatment. METHODS AND RESULTS: Data from the Swedish Myeloma Register from patients diagnosed between 2008 and 2017 was used. Cohorts were defined by the six healthcare regions (labeled A-F) in Sweden and modern initial treatment was defined as including certain drug combinations. To adjust for time to treatment bias, survival analyses were performed also for patients alive 6 months after diagnosis. In all treated MM patients (n = 5326), we observed a superior overall survival (OS) for region A compared to all other regions (p < .01 for all respectively). After adjusting for time to treatment there was also a superior survival in the region with highest use of modern initial treatment (region A) compared to the regions defined in the study as having intermediate and low use (p < .01 for both). In patients receiving autologous stem cell transplantation (ASCT) a superior survival was observed for region A compared to all regions besides region B. Similar results were seen when adjusting for a time to treatment bias. In patients not receiving ASCT, 75 years or older and adjusted for time to treatment bias, a difference was noted only between region A and E (log rank p = .04, HR 1.2, CI 1.00-1.44, p = .06). In multivariate analyses including age, international staging system stage and time period of diagnosis, differences in survival remained for patients receiving ASCT between region A versus C, D, E and F (p = .01, p < .01, p < .01, p = .03). CONCLUSION: We observed a superior survival in region A for patients receiving ASCT. Explanations may be higher usage of modern initial treatment or regional residual confounding. For patients not receiving ASCT, 75 years or older, differences in survival could be adjusted for.

Outcome data from >10 000 multiple myeloma patients in the Danish and Swedish national registries.

OBJECTIVE: We describe real-world evidence (RWE) from the nationwide Swedish and Danish registries that provide important information on incidence and outcome in multiple myeloma (MM). METHOD: First line treatment data on more than 10.000 MM patients from Denmark and Sweden between 2005-2018 are presented. Key results from research conducted within the Swedish and Danish myeloma registries are summarized, describing subgroups of patients with comorbidity, myeloma complications, and early relapse. RESULTS: We show that national guidelines, generated on results from randomized clinical trials (RCTs) are rapidly implemented and improve overall survival (OS). We find that both the incidence of MM and the median age at diagnosis is higher in national registries compared to results from referral centres, indicating a more complete coverage. This highlights the need of validation of prognostic scoring systems and indices in e.g., SMM and high-risk MM in a real- world-population. We show that these subgroups are unlikely to be captured in RCTs with narrow inclusion and exclusion criteria, that they have worse survival, and are in need of new treatment approaches. CONCLUSION: National registries that include all MM patients are an important source of knowledge on epidemiology, treatment and outcome with implications for the planning of MM care. Despite the introduction of new and better treatments, rapidly implemented in our countries, our registries uncover subgroups of patients that still have inferior outcome. Our RWE can help to identify important research questions to be studied in further clinical trials also in patients currently not included in RCTs.

Cumulative exposure to melphalan chemotherapy and subsequent risk of developing acute myeloid leukemia and myelodysplastic syndromes in patients with multiple myeloma.

OBJECTIVES: The aim of this study was to determine risk factors for development of acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) in patients with multiple myeloma (MM). METHODS: We identified all patients diagnosed with MM in Sweden from January 1st, 1958 to December 31, 2011. A total of 26 627 patients were diagnosed with MM with during the study period. Of these, 124 patients (0.5%) developed subsequent AML/MDS. For each patient with MM and a subsequent AML/MDS diagnosis, we randomly selected a matched (age, sex, and date of MM diagnosis) MM patient without a subsequent second malignancy diagnosis. RESULTS: The cumulative melphalan exposure was significantly higher (OR = 2.8, 95% CI 1.7-5.2; P < .001) among cases (median 988 mg; IQR 644-1640) compared with controls (median 578 mg; IQR 360-967). Median time to AML/MDS development was 3.8 years (IQR 2.8-5.8). Risk of AML/MDS was not statistically altered by M protein isotype, anemia, renal failure, hypercalcemia, lytic bone lesions, or radiation therapy. CONCLUSION: In this nationwide population-based study, we show that increased cumulative doses of alkylating therapy with melphalan increases the subsequent risk of developing AML/MDS in patients with MM. Given improved survival in MM patients over the last decade future studies will be important to better define long-term risks.

Untangling fracture risk in monoclonal gammopathy of undetermined significance: A population-based cohort study.

OBJECTIVE: Monoclonal gammopathy of undetermined significance (MGUS) is the asymptomatic precursor of multiple myeloma (MM). Lytic bone lesions and fractures are hallmarks of MM and although there are no lytic lesions in MGUS, it has also been associated with fractures. The causes of fractures in MGUS are currently unclear but potential causes include inherent MGUS bone disease, undiagnosed MM, and peripheral neuropathy (PN). We therefore conducted a large population-based study including 8395 individuals with MGUS and 30 851 matched controls from Sweden. METHODS: Data on fractures, PN, and confounders were acquired from high-quality registers in Sweden. RESULTS: Monoclonal gammopathy of undetermined significance and PN were independently associated with fractures (hazard ratio [HR]: 1.29; 95% confidence interval [95% CI]: 1.21-1.37; P < .001 and HR: 1.34; 95% CI: 1.16-1.55; P < .001). Imminent MGUS progression increased the risk of fractures (odds ratio: 1.66; 95% CI: 1.27-2.16; P < .001). Fractures were not associated with long-term risk of MGUS progression (HR: 1.08; 95% CI: 0.77-1.53; P = .64). DISCUSSION: Based on these findings, we speculate that MGUS leads to fractures through at least 3 independent mechanisms: undetected MGUS progression to MM, MGUS inherent bone disease, and PN through falls. These findings highlight the need for further study of MGUS inherent bone disease and can inform further research into fracture prevention in MGUS.

Germline variants at SOHLH2 influence multiple myeloma risk.

Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10-14). This gene encodes a transcription factor involved in gametogenesis that is normally only weakly expressed in plasma cells. The association is represented by 14 variants in linkage disequilibrium. Among these, rs75712673 maps to a genomic region with open chromatin in plasma cells, and upregulates SOHLH2 in this cell type. Moreover, rs75712673 influences transcriptional activity in luciferase assays, and shows a chromatin looping interaction with the SOHLH2 promoter. Our work provides novel insight into MM susceptibility.

Comorbidities in multiple myeloma and implications on survival: A population-based study.

High proportion of patients with multiple myeloma suffer from comorbidities which may alter clinical management. Therefore, our aims were to evaluate the prevalence of comorbidities and their impact on survival. We included patients diagnosed with multiple myeloma 1990-2013 in Sweden and all diagnoses from each patient from 1985. A total of 13 656 patients with multiple myeloma were included in the study, thereof 7404 (54%) had comorbidity at diagnosis. The risk of death was increased for those with one comorbidity at diagnosis compared to those without any comorbidity (hazard ratio = 1.19; 95% confidence interval:1.14-1.25); this risk was higher for those with two (1.38; 1.30-1.47) and three or more comorbidities (1.72; 1.62-1.83). Furthermore, the risk of death was increased in patients with prior history of cancer, arrhythmia, heart failure, diabetes mellitus, cerebrovascular disease, chronic lung disease, psychological disease, peptic ulcer, neurological disease, peripheral vascular disease, chronic kidney disease, dementia, and inflammatory bowel disease. This large study shows that over 50% of multiple myeloma patients have a comorbidity at diagnosis and survival decreased with increasing numbers of comorbidities. This emphasizes the importance of comorbidities when evaluating patients and deciding on treatment strategies for individuals with multiple myeloma.

Serum metabolomic profiling correlated with ISS and clinical outcome for multiple myeloma patients treated with high-dose melphalan and autologous stem cell transplantation.

The metabolome, which is the final down-stream global product of metabolic processes in organisms, is not sufficiently described in multiple myeloma (MM) patients. The aim of this study was, therefore, to study the serum metabolomic profile using proton nuclear magnetic resonance (1H-NMR) spectroscopy, and its relationship to clinical characteristics and patient outcome. Serum samples, which were taken at diagnosis, from 201 MM patients who underwent high-dose melphalan followed by autologous stem cell transplantation as the first-line therapy, were analyzed. We found that the metabolomic profile differed between patients with different MM International Staging System (ISS) stages. The profile revealed increased levels of cholesterol, phospholipids, high-density lipoprotein, low-density lipoprotein, apolipoproteins A1 and A2, valine, and leucine in ISS I patients compared with ISS III patients. The metabolomic profile also differed between patients with IgA and IgG paraproteins, predominantly because of higher levels of high- and low-density lipoprotein subfractions in IgA patients. The exact pathway of metabolism leading to accumulation of these metabolites is still elusive, but this study indicates an area of interest for further investigation in the search for new therapy targets and prognostic markers for this disease.

Autoimmune disease is associated with a lower risk of progression in monoclonal gammopathy of undetermined significance.

OBJECTIVES AND METHODS: We conducted a population-based study including 19 303 individuals diagnosed with MGUS in Sweden from 1985 to 2013, with the aim to determine whether a prior history of autoimmune disease, a well-described risk factor for MGUS is a risk factor for progression of MGUS to multiple myeloma (MM) or lymphoproliferative diseases (LPs). Using the nationwide Swedish Patient registry, we identified MGUS cases with versus without an autoimmune disease present at the time of MGUS diagnosis and estimated their risk of progression. RESULTS: A total of 5612 (29.1%) MGUS cases had preceding autoimmune diseases. Using Cox proportional hazards models, we found the risk of progression from MGUS to MM (HR = 0.83, 95% CI 0.73-0.94) and LPs (HR = 0.84, 95% CI 0.75-0.94) to be significantly lower in MGUS cases with prior autoimmune disease (compared to MGUS cases without). CONCLUSIONS: In this large population-based study, a history of autoimmune disease was associated with a reduced risk of progression from MGUS to MM/other LPs. Potential underlying reason is that MGUS caused by chronic antigen stimulation is biologically less likely to undergo the genetic events that trigger progression. Our results may have implications in clinical counseling for patients with MGUS and underlying autoimmune disease.

A nationwide study on inpatient opportunistic infections in patients with chronic lymphocytic leukemia in the pre-ibrutinib era.

OBJECTIVE: Opportunistic infections in chronic lymphocytic leukemia (CLL) have been described in clinical trials, single-center studies, and case reports. We performed a nationwide study to estimate the incidence and impact of inpatient opportunistic infections. METHODS: The incidence rate (IR) and incidence rate ratio (IRR) for Swedish CLL patients diagnosed 1994-2013, and matched controls were calculated, as well as the case-fatality ratio (CFR). RESULTS: Among 8989 CLL patients, a total of 829 opportunistic infections were registered (IR 16.6 per 1000 person-years) compared with 252 opportunistic infections in 34 283 matched controls (IR 0.99). The highest incidence in the CLL cohort was for Pneumocystis pneumonia (200 infections, IR 4.03); Herpes zoster (146 infections, IR 2.94), and Pseudomonas (83 infections, IR 1.66) infections. The highest risk relative to matched controls was observed for Pneumocystis pneumonia (IRR 114, 95% confidence interval 58.7-252). The 60-day CFR for CLL patients with opportunistic infections was 23% (188/821), highest for progressive multifocal encephalopathy (5/7, 71%) and aspergillosis (25/60, 42%). CONCLUSION: We have uniquely depicted the incidence of rare and serious infections in CLL patients and found a relatively high incidence of Pneumocystis pneumonia. Of the most common opportunistic infections, CLL patients with aspergillosis had the poorest prognosis.

A population-based study on serious inpatient bacterial infections in patients with chronic lymphocytic leukemia and their impact on survival.

OBJECTIVE: Infections in chronic lymphocytic leukemia (CLL) have been thoroughly investigated in the setting of clinical trials and single-center studies. However, large cohort studies on real-world data and studies on temporal trends are lacking. We performed a nationwide study on serious bacterial infections in CLL. METHODS: Using high-quality Swedish government-based registries, 13 009 CLL patients diagnosed in 1982-2013 and their 49 380 matched controls were included. RESULTS: Overall, CLL patients had an increased risk of serious inpatient bacterial infections with a hazard ratio (HR) 5.32 and 95% confidence interval (95% CI) 5.11-5.53, and the highest risk was observed for septicemia (HR 6.91, 95% CI 6.46-7.39) and lung infections (5.91, 5.64-6.18). The risk of serious inpatient bacterial infections decreased overtime with HR 0.87 (0.81-0.94) and HR 0.76 (0.70-0.82) in 1993-2002 and 2003-2013, respectively, compared to 1982-1992. CLL patients had an increased risk of death following a serious inpatient bacterial infection compared to matched CLL patients, and the risk was highest in the first 12 months after the infection (HR 5.48, 95% CI 5.11-5.90). CONCLUSION: We have, in this nationwide study, characterized the risk of serious bacterial infections in CLL patients and, importantly, depicted that the risk has decreased overtime.

Second malignancies in multiple myeloma; emerging patterns and future directions.

The changing landscape of treatment options for multiple myeloma has led to a higher proportion of patients achieving deep, long-lasting responses to therapy. With the associated improvement in overall survival, the development of subsequent second malignancies has become of increased significance. The risk of second malignancy after multiple myeloma is affected by a combination of patient-, disease- and therapy-related risk factors. This review discusses recent data refining our knowledge of these contributing factors, including current treatment modalities which increase risk (i.e. high-dose melphalan with autologous stem cell transplant and lenalidomide maintenance therapy). We highlight emerging data towards individualized risk- and response-adapted treatment strategies and discuss key areas requiring future research.

Fractures and survival in multiple myeloma: results from a population-based study.

Multiple myeloma causes lytic bone lesions and fractures. The impact of fractures on multiple myeloma (MM) survival is unclear. The aim of this study was to evaluate the effect of fractures on survival in MM using data from MM patients diagnosed in Sweden in the years 1990-2013, identified from the Swedish Cancer Registry. Information on date of birth, MM diagnosis, fractures, and death was collected from central registries. A Cox regression model was used to compare survival in patients with and without a fracture at MM diagnosis and another Cox model was used with fracture as a time-dependent variable to assess the effect of fracture on survival after MM diagnosis. Results were adjusted for age, sex, year of diagnosis, and previous fractures. A total of 14,013 patients were diagnosed with MM during the study, of whom 1,213 (8.7%) were diagnosed with a fracture at MM diagnosis, and 3,235 (23.1%) after diagnosis. Patients with a fracture at diagnosis were at a significantly increased risk of death (hazard ratio=1.28; 95% confidence interval: 1.19-1.37). The risk of death was significantly increased in patients with a fracture after MM diagnosis (2.00; 1.90-2.10). The impact of fractures on survival did not change significantly between the two calendar periods 1990-1999 and 2000-2013 (0.98; 0.89-1.08). Our large study shows that MM patients with fractures are at a significantly increased risk of dying compared to those without fractures, which stresses the importance of preventing bone disease in MM.