Carfilzomib and dexamethasone maintenance following salvage ASCT in multiple myeloma: A randomised phase 2 trial by the Nordic Myeloma Study Group

Objective: We investigated the efficacy and safety of carfilzomib-containing induction before salvage high-dose melphalan with autologous stem-cell transplantation (salvage ASCT) and maintenance with carfilzomib and dexamethasone after salvage ASCT in multiple myeloma.Methods: This randomised, open-label, phase 2 trial included patients with first relapse of multiple myeloma after upfront ASCT who were re-induced with four cycles of carfilzomib, cyclophosphamide and dexamethasone. Two months after salvage, ASCT patients were randomised to either observation or maintenance therapy with iv carfilzomib 27 -> 56 mg/sqm and p.o. dexamethasone 20 mg every second week. The study enrolled 200 patients of which 168 were randomised to either maintenance with carfilzomib and dexamethasone (n = 82) or observation (n = 86).Results: Median time to progression (TTP) after randomisation was 25.1 months (22.5-NR) in the carfilzomib-dexamethasone maintenance group and 16.7 months (14.4-21.8) in the control group (HR 0.46, 95% CI 0.30-0.71; P = .0004). The most common adverse events during maintenance were thrombocytopenia, anaemia, hypertension, dyspnoea and bacterial infections.Conclusion: In summary, maintenance therapy with carfilzomib and dexamethasone after salvage ASCT prolonged TTP with 8 months. The maintenance treatment was in general well-tolerated with manageable toxicity.</p

Clinical and Population-based Studies in Multiple Myeloma and Monoclonal Gammopathy – Focus on Infections

Multiple myeloma is a haematological disorder of the bone marrow. It is preceded by the benign precursor monoclonal gammopathy of undetermined significance (MGUS). In multiple myeloma, a progression leading to expansion of malignant plasma cells occurs, causing skeletal lesions, anemia and renal insuffiency. Multiple myeloma is incurable, but the disease can be controlled with chemotherapy and other immunosuppressive drugs. It is known that both conditions have compromised immune responses, which lead to an increased risk of infections. However, there is no population-based data on the occurrence and type of infections in patients with plasma cell disorders compared to the normal population. Considering the cumulative immunodeficiency in patients with multiple myeloma, caused by multiple cytotoxic and immunomodulating therapies, there is a demand for less toxic treatments in the relapse setting, aiming to reduce morbidity and mortality in infections. Recent studies have suggested that immunomodulating treatment is beneficial even in smouldering multiple myeloma. There is a lack of population-based incidence data in smouldering multiple myeloma patients with high risk of progressing to multiple myeloma, and there is a need of identifying patients with smouldering multiple myeloma that could benefit from up-front treatment. In paper I we investigated the treatment with intermediate-dose melphalan (Mel 100) and stem cell support in multiple myeloma patients relapsing after high dose melphalan and autologous transplantation (ASCT) in 66 patients. With an overall response of 62%, limited toxicity and a progression-free survival of 8.5 months, we conclude that Mel 100 is a viable therapeutic option in relapsed patients and the best efficacy was seen in patients with longlasting response after ASCT. In paper II and III we studied the risk of infections in MGUS and multiple myeloma patients compared to matched controls. Using population-based data from Sweden, in paper II we estimated the risk of infections among 5 326 MGUS patients compared to 20 161 matched controls. We found that patients with MGUS had a 2-fold increased increased risk (hazard ratio (HR) 2.1; 95% confidence interval (CI) 2.0-2.3(p<0.05)) of developing any infection at 5- follow up, and at 10-year follow up the risk was very similar (HR=2.2; 95% CI 2.0-2.3). Patients with M-protein concentration over 2.5 mg/dl had the highest risk of infections. In paper III we compared the risk of infections in 9 253 multiple myeloma patients to 34 931 matched controls. Overall, multiple myeloma patients had a 7-fold (HR =7.1; 95% CI 6.8-7.4) risk of developing any infection compared to matched controls. The increased risk of developing a bacterial infection was 7-fold (7.1; 6.8-7.4), and for viral infections it was 10-fold (10.0; 8.9-11.4). Multiple myeloma patients diagnosed in the more recent calendar periods had significantly higher risk of infections compared to patients diagnosed earlier (p<0.001). We could show, that in patients who died within the first year of diagnosis, 22 % of deaths were infection-related. Our findings provide novel insights into the mechanisms behind infections in patients with plasma cell disorders, and may have clinical implications and could give support to preventive interventions. In paper IV we estimated the risk of progression to symptomatic multiple myeloma in a cohort of smouldering multiple myeloma patients with high-risk features using populationbased data from the Swedish Myeloma Registry. The 2-year risk of progressing was 56% and this cohort count for 29% of all smouldering multiple myeloma patients and should be considered for clinical early treatment trials

Rapidly changing myeloma epidemiology in the general population: increased incidence, older patients, and longer survival

The incidence of multiple myeloma is characterized by a steep increase with advancing age. Dramatic improvements in survival have been reported in clinical trials; however, elderly patients are generally underrepresented in these. The aims of this study are to review patterns of incidence and survival in multiple myeloma in the general population. We searched PubMed for population-based studies on trends in incidence and survival published between January 1, 2000 and June 30, 2017 and based on regional or national cancer registries and report the following results of the review. The age-adjusted incidence of multiple myeloma has increased during the second half of the 20th Century in some countries but remained stable in areas with high case ascertainment and access to universal medical care. The crude incidence is increasing globally due to an ageing population. Survival rates have improved and 5-year relative survival rates are now around 50% and over 60% in patients 65–70 years or younger. Preliminary data suggest a 3-fold increase in the prevalence of multiple myeloma. We conclude that the number of multiple myeloma patients is increasing in the general population due to (1) aging populations and (2) more patients living longer due to modern drugs

Outcome and survival of myeloma patients diagnosed 2008-2015. Real-world data on 4904 patients from the Swedish Myeloma Registry

Epidemiology and outcome of myeloma are mainly reported from large university centers and collaborative groups, and do not represent real-world patients. The Swedish Myeloma Registry is a prospective population-based registry documenting characteristics, treatment and outcome in newly diagnosed myeloma, including asymptomatic and localized forms, with the purpose of improving disease management and outcome. This report presents information on patients diagnosed between 2008 and 2015, including data on first-line treatment in patients diagnosed up to 2014, with a follow up until December 2016. We present age-adjusted incidence, patients characteristics at baseline, treatment, response, and survival. Baseline data were available with a 97% coverage in 4904 patients (median age 71 years, males 70 years, females 73 years; 72% were 65 years or older), and at 1-year follow up in 3558 patients with symptomatic disease (92% of patients initially reported). The age-adjusted incidence was 6.8 myeloma cases per 100,000 inhabi-ants per year. Among initially symptomatic patients (n= 3988), 77% had osteolytic lesions or compression fractures, 49% had anemia, 18% impaired kidney function, and 13% hypercalcemia. High-dose therapy with autologous stem cell transplantation was given to 77% of patients aged up to 66 years, and to 22% of patients aged 66-70 years. In the study period, 68% received bortezomib, thalidomide, and/or lenalidomide as part of the first-line treatment, rising from 31% in 2008 to 81% in 2014. In active myeloma, the median relative survival of patients aged 65 years or under was 7.7 years, and 3.4 years in patients aged 66 years and over. Patients diagnosed with myeloma in more recent years were associated with significantly higher rates of complete or very good partial remission (Pamp;lt;0.05), and with a significantly higher survival, with a Hazard Ratio (HR) of 0.84 (95% CI: 0.77-0.92; Pamp;lt;0.05). There was a small, but significant survival benefit in patients treated at university hospitals (HR 0.93; 95% CI: 0.87-0.99; Pamp;lt;0.05). We report here on a near complete real-world population of myeloma patients during an 8-year period; a period in which newer drugs were implemented into standard practice. The overall incidence and median age were both higher than in most previous studies, indicating a more complete coverage of older patients. Myeloma survival in Sweden is comparable to other large registry studies, and responses and survival improved during the study period

Outcome and characteristics of non-measurable myeloma : A cohort study with population-based data from the Swedish Myeloma Registry

Objective: We describe survival in patients with oligo- and non-secretory multiple myeloma (MM). We refer to the whole group as non-measurable MM and compare it with secretory MM. Methods: Oligo-secretory MM was defined as M protein in serum <10 g/L and M protein in urine <200 measured as mg/day, mg/liter or mg/mmol creatinine. If patients had no M protein, they were defined as non-secretory. The groups were also subdivided by Free Light Chains (SFLC) level and ratio. Results: Out of 4325 patients with symptomatic MM in the Swedish Myeloma Registry during 2008-2016 eligible for the study, 389 patients (9%) had non-measurable MM. Out of these, 253 patients (6%) had oligo-secretory and 136 (3%) had non-secretory MM. Median survival for secretory MM was 42.7 months, non-measurable MM 40.2 months, oligo-secretory MM 38.6 months, and non-secretory MM 44.6 months. Difference in overall observed survival was non-significant for all groups when compared with secretory MM. Within non-secretory MM, stem cell transplantation (SCT), 95% being auto-SCT, was significant for superior survival in multivariate analysis (HR 0.048. P =.0015). Conclusion: In this population-based study, we found no difference in survival between oligo- or non-secretory MM when compared with secretory MM. SCT appears to be important also for patients with non-secretory disease

Measurable Residual Disease Testing in Multiple Myeloma Routine Clinical Practice: A Modified Delphi Study

We used a modified Delphi approach to establish areas of consensus and nonconsensus regarding the utility of determining measurable residual disease (MRD) to assess multiple myeloma (MM) treatment response, which may inform disease management and design of future clinical trials. This modified Delphi study incorporated 2 iterative rounds of surveys to evaluate the opinions of an expert panel of 61 practicing hematological oncologists from across 14 countries in Europe concerning the use of MRD testing in MM management. Survey 1 assessed experts’ opinions on MRD testing in different clinical situations and associated challenges. Survey 2 focused on the lack of consensus areas identified in survey 1. Consensus to an individual question was defined a priori as 75% agreement or disagreement by the panel. From the 2 rounds of surveys, the experts reached consensus agreement that MRD testing should be performed in newly diagnosed or relapsed patients who achieved complete response (CR) or better after transplantation. In transplant-ineligible patients, experts recommended MRD testing in those who are ≤70 years old and in CR. If a patient was previously positive on positron-emission tomography and computed tomography (PET/CT), both MRD and PET/CT should be assessed at CR. MRD testing should be performed ≤6 months after transplantation and every 6–12 months in continuously treated patients in CR. There was no consensus on making treatment decisions based on MRD status. MRD testing is an important component of clinical management in MM. Additional data will further clarify the role of MRD in guiding treatment decisions

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

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

To access publisher's full text version of this article click on the hyperlink belowHigh 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. Keywords: comorbidities; multiple myeloma; survival.Research Fund of Landspitali, University Hospital of Iceland, The Nordic Cancer Union Icelandic Centre for Researc