Exercise in newly diagnosed patients with multiple myeloma: A randomized controlled trial of effects on physical function, physical activity, lean body mass, bone mineral density, pain, and quality of life.

Reduced physical function caused by bone destruction, pain, anemia, infections, and weight loss is common in multiple myeloma (MM). Myeloma bone disease challenges physical exercise. Knowledge on the effects and safety of physical exercise in newly diagnosed patients with MM is limited. In a randomized, controlled trial, we studied the effect of a 10-week individualized physical exercise program on physical function, physical activity, lean body mass (LBM), bone mineral density (BMD), quality of life (QoL), and pain in patients newly diagnosed with MM. Lytic bone disease was assessed, and exercise was adjusted accordingly. Primary outcome: knee extension strength. Secondary outcomes: Six-Minute-Walk-Test, 30-s Sit-to-Stand-Test (SST), grip strength, level of physical activity, LBM, BMD, QoL, and pain. Measurements were conducted pre- and post-intervention, and after 6 and 12 months. We included 100 patients, 86 were evaluable; 44 in the intervention group (IG) and 42 in the control group (CG). No statistically significant differences between groups were observed. Knee extension strength declined in the IG (p = .02). SST, aerobic capacity, and global QoL improved in both groups. Pain decreased consistently in the IG regardless of pain outcome. No significant safety concerns of physical exercise in newly diagnosed patients with MM were observed.

Longitudinal minimal residual disease assessment in multiple myeloma patients in complete remission - results from the NMSG flow-MRD substudy within the EMN02/HO95 MM trial.

BACKGROUND: Multiple myeloma remains an incurable disease with multiple relapses due to residual myeloma cells in the bone marrow of patients after therapy. Presence of small number of cancer cells in the body after cancer treatment, called minimal residual disease, has been shown to be prognostic for progression-free and overall survival. However, for multiple myeloma, it is unclear whether patients attaining minimal residual disease negativity may be candidates for treatment discontinuation. We investigated, if longitudinal flow cytometry-based monitoring of minimal residual disease (flow-MRD) may predict disease progression earlier and with higher sensitivity compared to biochemical assessments. METHODS: Patients from the Nordic countries with newly diagnosed multiple myeloma enrolled in the European-Myeloma-Network-02/Hovon-95 (EMN02/HO95) trial and undergoing bone marrow aspiration confirmation of complete response, were eligible for this Nordic Myeloma Study Group (NMSG) substudy. Longitdudinal flow-MRD assessment of bone marrow samples was performed to identify and enumerate residual malignant plasma cells until observed clinical progression. RESULTS: Minimal residual disease dynamics were compared to biochemically assessed changes in serum free light chain and M-component. Among 20 patients, reaching complete response or stringent complete response during the observation period, and with ≥3 sequential flow-MRD assessments analysed over time, increasing levels of minimal residual disease in the bone marrow were observed in six cases, preceding biochemically assessed disease and clinical progression by 5.5 months and 12.6 months (mean values), respectively. Mean malignant plasma cells doubling time for the six patients was 1.8 months (95% CI, 1.4-2.3 months). Minimal malignant plasma cells detection limit was 4 × 10-5. CONCLUSIONS: Flow-MRD is a sensitive method for longitudinal monitoring of minimal residual disease dynamics in multiple myeloma patients in complete response. Increasing minimal residual disease levels precedes biochemically assessed changes and is an early indicator of subsequent clinical progression. TRIAL REGISTRATION: NCT01208766.

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 â†’ 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.

Physical function in patients newly diagnosed with multiple myeloma; a Danish cohort study.

BACKGROUND: Multiple myeloma is a cancer in the bone marrow causing bone destruction. Patients experience various symptoms related to the disease and/or treatment, such as pain and fatigue, leading to poorer quality of life. The symptom burden might affect physical function and physical activity levels, posing a risk of physical deterioration. The aim was to investigate whether physical function in newly diagnosed patients with multiple myeloma differs from the reference values of the normal population and other cancer patients. METHODS: The study is a cross sectional descriptive analysis of a prospective cohort of 100 patients newly diagnosed with multiple myeloma. Four physical function tests were carried out; Six-Minute-Walk-Test, Sit-to-Stand-Test, grip strength and knee extension strength. Age and gender specific results of physical function from the multiple myeloma population were compared to normative data and to data from other cancer populations. RESULTS: Of the 100 patients included, 73% had bone disease and 55% received pain relieving medicine. Mean age was 67.7 years (SD 10.3). Patients with multiple myeloma had significantly poorer physical function compared to normative data, both regarding aerobic capacity and muscle strength, although not grip strength. No differences in physical function were found between patients with multiple myeloma and other cancer populations. CONCLUSIONS: Physical function in newly diagnosed Danish patients with multiple myeloma is lower than in the normal population. Exercise intervention studies are warranted to explore the value of physical exercise on physical function. TRIAL REGISTRATION: ClinicalTrials.gov, ID NCT02439112, registered 8 May 2015.

Clarithromycin added to bortezomib-cyclophosphamide-dexamethasone impairs health-related quality of life in multiple myeloma patients.

OBJECTIVES: The Danish Myeloma Study Group initiated a randomized, placebo-controlled, double-blinded phase II study to investigate the efficacy of adding clarithromycin to cyclophosphamide-bortezomib-dexamethasone (VCD) induction therapy in transplant eligible, newly diagnosed multiple myeloma patients. The study was prematurely terminated due to severe complications, and no effect of adding clarithromycin was found. The aim of this study was to compare health-related quality of life (HRQoL) between the two groups and to explore the coherence hereof with adverse event (AE) registration by clinicians. METHODS: Patients completed three validated HRQoL questionnaires at inclusion, before cyclophosphamide priming, and two months after high-dose therapy (HDT). The mean score difference was interpreted by clinically relevant differences between groups. Spearman's correlation analysis was used to compare patient-reported toxicities with AEs. RESULTS: Of 58 included patients, 55 participated in the HRQoL reporting. Before cyclophosphamide priming, patients in the clarithromycin group reported clinically relevant reduced HRQoL for eleven domains with persistent reduction in four domains two months after HDT. Poor correlation between patient-reported toxicities and clinician-reported AEs was observed. CONCLUSIONS: Despite the premature study termination, our data demonstrate impaired HRQoL when clarithromycin was added to the VCD regimen. We found clear underreporting of toxicities by clinicians. ClinicalTrials.gov number NCT02573935.

Smoldering multiple myeloma risk factors for progression: a Danish population-based cohort study.

Several risk scores for disease progression in patients with smoldering multiple myeloma (SMM) have been proposed; however, all have been developed using single-center registries. To examine risk factors for time to progression (TTP) to multiple myeloma (MM) for SMM, we analyzed a nationwide population-based cohort of 321 patients with newly diagnosed SMM registered within the Danish Multiple Myeloma Registry between 2005 and 2014. Significant univariable risk factors for TTP were selected for multivariable Cox regression analyses. We found that both an M-protein ≥30 g/L and immunoparesis significantly influenced TTP (HR 2.7, 95%CI (1.5;4.7), P = 0.001, and HR 3.3, 95%CI (1.4;7.8), P = 0.002, respectively). High free light chain (FLC) ratio did not significantly influence TTP in our cohort. Therefore, our data do not support recent IMWG proposal of identifying patients with FLC ratio above 100 as having ultra high-risk of transformation to MM. Using only immunoparesis and M-protein ≥30 g/L, we created a scoring system to identify low-, intermediate-, and high-risk SMM. This first population-based study of patients with SMM confirms that an M-protein ≥30 g/L and immunoparesis remain important risk factors for progression to MM.

Nationwide implementation of lenalidomide maintenance in multiple myeloma: A retrospective, real-world study.

Lenalidomide maintenance (LM) has shown benefit in progression-free survival (PFS) and overall survival (OS) in clinical trials. LM is the recommended standard of care in patients with newly diagnosed multiple myeloma (MM) after high-dose melphalan and autologous stem cell transplantation (HDM-ASCT). In Denmark, LM has been approved and publicly funded for all patients treated with HDM-ASCT since June 2019. Patients with newly diagnosed MM treated with their first HDM-ASCT between June 2019 and March 2022 were included and followed until data cut-off in June 2023. To compare outcomes, a historical pre-LM cohort from the Danish MM Registry, consisting of 364 MM patients treated with HDM-ASCT between June 2015 and June 2019, was used. Among 364 patients treated with HDM-ASCT after June 2019, 22.3% received consolidation therapy and 3.7% underwent tandem HDM-ASCT. During follow-up, 297 patients (81.6%) initiated maintenance therapy, with 277 (76.1%) receiving LM. Overall, 145 patients (52.3%) discontinued LM most commonly due to toxicity 75 (51.7%), with fatigue (30.7%), cytopenia (25.3%), and neuropathy (17.3%) being the main reasons. In a 6-month landmark analysis, early discontinuation did not negatively impact PFS or OS. The LM cohort had similar PFS, and OS compared to the pre-LM cohort. The 3-year PFS and OS rates in the LM cohort were 61% and 86%, respectively, while the pre-LM cohort had a 3-year PFS of 55% and a 3-year OS of 89%. In conclusion, the introduction of LM as a nationwide treatment option in Denmark did not lead to improved clinical outcomes.

Supervised and home-based physical exercise in patients newly diagnosed with multiple myeloma-a randomized controlled feasibility study.

BACKGROUND: The study evaluated the feasibility and safety of the exercise intervention and physical test procedures of our ongoing randomized controlled trial, examining the effect of physical exercise in newly diagnosed patients with multiple myeloma. METHODS: Patients are randomized 1:1 to a control group (usual care) or an intervention group (usual care and exercise) by block randomization with stratification of planned treatment, WHO performance status, and study site. The exercise intervention consists of eight supervised exercise sessions combined with home-based exercise over a 10-week period. Bone disease is systematically evaluated to determine limitations regarding physical testing and/or exercise. Feasibility outcome measures were study eligibility, acceptance, and attrition, and furthermore attendance, adherence, tolerability, and safety to the exercise intervention. Additionally, test completion, pain, and adverse events during the physical test procedures were evaluated. Outcome assessors were blinded to allocation. RESULTS: Of 49 patients screened, 30 were included. The median age was 69 years, range 38-90, 77% were males, and 67% had bone disease. Study eligibility was 82%, acceptance 75%, and attrition 20%. Attendance at supervised exercise sessions was 92%, and adherence to supervised exercise sessions and home-based exercise sessions was 99% and 89%, respectively. No serious adverse events attributed to exercise or physical tests were reported. All patients completed the physical tests, except for two patients, where physical test procedures were modified due to bone disease. DISCUSSION: The exercise intervention and physical test procedures were feasible and safe in patients with multiple myeloma, even in older patients with multiple myeloma and in patients with myeloma bone disease. TRIAL REGISTRATION: ClinicalTrials.gov. ID NCT02439112. Registered on May 7, 2015.

A randomized placebo-controlled phase II study of clarithromycin or placebo combined with VCD induction therapy prior to high-dose melphalan with stem cell support in patients with newly diagnosed multiple myeloma.

BACKGROUND: The objective of this randomized placebo-controlled study was to investigate the efficacy and safety of clarithromycin in combination with bortezomib-cyclophosphamide-dexamethasone (VCD) in patients with newly diagnosed multiple myeloma eligible for high-dose therapy. METHODS: Patients were randomized to receive tablet clarithromycin 500 mg or matching placebo tablet twice daily during the first 3 cycles of VCD induction therapy. Primary endpoint was to compare the rate of very good partial response (VGPR) or better response after three cycles of VCD combined with clarithromycin or placebo. RESULTS: The study was prematurely stopped for safety reasons after the inclusion of 58 patients (36% of the planned study population). The patients were randomly assigned to clarithromycin (n = 27) or placebo (n = 31). VGPR or better response after the VCD induction therapy was obtained in 12 patients (44.4%, 95% CI 25.5-64.7) and in 16 patients (51.6%, 33.1-69.8) (p = 0.59) in the clarithromycin group and the placebo group, respectively. Seven patients (25.9%) in the clarithromycin group developed severe gastrointestinal complications (≥ grade 3) comprising pain, neutropenic enterocolitis, paralytic ileus or peptic ulcer. These complications occurred in only one patient in the placebo group. Septicemia with Gram negative bacteria was observed in 5 patients in the clarithromycin group in contrast to one case of pneumococcal septicemia in the placebo group. Patient-reported QoL were negatively affected in the clarithromycin group compared to the placebo group. CONCLUSION: The study was prematurely stopped due to serious adverse events, in particular serious gastrointestinal complications and septicemia. The response data do not suggest any effect of clarithromycin when added to the VCD regimen. The combination of clarithromycin and bortezomib containing regimens is toxic and do not seem to offer extra anti-myeloma efficacy.Trial registration EudraCT (no. 2014-002187-32, registered 7 October 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002187-32/DK) and ClinicalTrials.gov (no NCT02573935, retrospectively registered 12 October 2015, https://www.clinicaltrials.gov/ct2/show/NCT02573935?term=Gregersen&cntry=DK&rank=9).

The impact of comorbidity on mortality in multiple myeloma: a Danish nationwide population-based study.

To describe the prevalence of comorbidity and its impact on survival in newly diagnosed multiple myeloma patients compared with population controls. Cases of newly diagnosed symptomatic multiple myeloma during the 2005-2012 period were identified in the Danish National Multiple Myeloma Registry. For each myeloma patient, 10 members of the general population matched by age and sex were chosen from the national Civil Registration System. Data on comorbidity in the myeloma patients and the general population comparison cohort were collected by linkage to the Danish National Patient Registry (DNPR). Cox proportional hazards regression models were used to evaluate the prognostic significance of comorbidity. The study included 2190 cases of multiple myeloma and 21,900 population controls. The comorbidity was increased in multiple myeloma patients compared with population controls, odds ratio (OR) 1.4 (1.1-1.7). The registration of comorbidity was highly increased within the year preceding diagnosis of multiple myeloma (OR 3.0 [2.5-3.5]), which was attributable to an increased registration of various diseases, in particular, renal disease with OR 11.0 (8.1-14.9). The median follow-up time from diagnosis of multiple myeloma for patients alive was 4.3 years (interquartile range 2.4-6.3). Patients with registered comorbidity had increased mortality compared with patients without comorbidity, hazard ratio 1.6 (1.5-1.8). Multiple myeloma patients have increased comorbidity compared with the background population, in particular during the year preceding the diagnosis of myeloma.

Immunoparesis in newly diagnosed Multiple Myeloma patients: Effects on overall survival and progression free survival in the Danish population.

Immunoparesis (hypogammaglobulinemia) is associated to an unfavorable prognosis in newly diagnosed Multiple myeloma (MM) patients. However, this finding has not been validated in an unselected population-based cohort. We analyzed 2558 newly diagnosed MM patients in the Danish Multiple Myeloma Registry representing the entire MM population in Denmark from 2005-2013. Two-thousand two hundred and fifty three patients (90%) presented with reduction below lower normal levels of at least one uninvolved immunoglobulin. Using multivariable Cox regression we found that high age, high ISS score, high LDH and IgA MM were associated to both shorter overall survival and progression free survival. Furthermore, bone marrow plasma cell % was associated to short progression free survival. Immunoparesis had no independent significant effect on OS (HR 0.9 (95%CI: 0.7;1.0; p = 0.12)). Likewise, the number of suppressed immunoglobulins or the relative degree of suppressed uninvolved immunoglobulins from lower normal level (quantitative immunoparesis) was not associated to OS in the multivariable analysis. However, quantitative immunoparesis with at least 25% reduction (from lower normal level) of uninvolved immunoglobulins was associated to shorter PFS for the entire population. The impact of quantitative immunoparesis on PFS was present irrespective of calendar periods 2005-2008 and 2009-2013. Our population-based study does not confirm that immunoparesis at diagnosis is an independent prognostic factor regarding OS. However, quantitative immunoparesis is associated to a shorter PFS.

[Indications for radioimmunotherapy for patients with non-Hodgkin's lymphoma]. / Indikationer for radioimmunterapi til patienter med non-Hodgkins lymfom.

Radioimmunotherapy is a well-known treatment for non-Hodgkin's lymphoma. (90)yttrium (Y)-ibritumomab-tiuxetan consists of a radioisotope conjugated to a monoclonal anti-cluster of differentiation 20 antibody, which is targeted against B-lymphocytes. Initially the treatment indication was relapse of low-grade non-Hodgkin's lymphoma. However, (90)Y-ibritumomab-tiuxetan has later been used in clinical trials in the treatment of other types of non-Hodgkin's lymphoma and prior to stem cell transplantation. Based on the literature this systematic review aims to throw light on the future possibilities of radioimmunotherapy.

[Burkitt lymphoma is a highly malign tumour with a doubling time of twenty-four hours]. / Burkitts lymfom er en højmalign tumor med en fordoblingstid på et døgn.

The treatment results for patients with Burkitt lymphoma have improved markedly over the past 20 years. Focus on the rapid doubling time of the lymphoma, and the frequent involvement of the central nervous system, have led to effective intensive chemotherapy regimens, where several of the drugs cross the blood-brain barrier. The overall survival is now 65-80% even when patients have advanced disease at the time of diagnosis. However, the condition and its complications such as tumour lysis syndrome are acute life threatening, and a quick diagnosis and proper management of complications are essential for the prognosis.