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.

Relationship between reasons for intermittent missing patient-reported outcomes data and missing data mechanisms.

PURPOSE: Non-response (NR) to patient-reported outcome (PRO) questionnaires may cause bias if not handled appropriately. Collecting reasons for NR is recommended, but how reasons for NR are related to missing data mechanisms remains unexplored. We aimed to explore this relationship for intermittent NRs. METHODS: Patients with multiple myeloma completed validated PRO questionnaires at enrolment and 12 follow-up time-points. NR was defined as non-completion of a follow-up assessment within seven days, which triggered contact with the patient, recording the reason for missingness and an invitation to complete the questionnaire (denoted "salvage response"). Mean differences between salvage and previous on-time scores were estimated for groups defined by reasons for NR using linear regression with clustered standard errors. Statistically significant mean differences larger than minimal important difference thresholds were interpreted as "missing not at random" (MNAR) mechanism (i.e. assumed to be related to declining health), and the remainder interpreted as aligned with "missing completely at random" (MCAR) mechanism (i.e. assumed unrelated to changes in health). RESULTS: Most (7228/7534 (96%)) follow-up questionnaires were completed; 11% (802/7534) were salvage responses. Mean salvage scores were compared to previous on-time scores by reason: those due to hospital admission, mental or physical reasons were worse in 10/22 PRO domains; those due to technical difficulties/procedural errors were no different in 21/22 PRO domains; and those due to overlooked/forgotten or other/unspecified reasons were no different in any domains. CONCLUSION: Intermittent NRs due to hospital admission, mental or physical reasons were aligned with MNAR mechanism for nearly half of PRO domains, while intermittent NRs due to technical difficulties/procedural errors or other/unspecified reasons generally were aligned with MCAR mechanism.

Geographical and ecological analyses of multiple myeloma in Denmark: Identification of potential hotspot areas and impact of urbanisation.

BACKGROUND: The aetiology of multiple myeloma (MM) is unknown but various environmental exposures are suspected as risk factors. We present the first paper analysing the geographical distribution of MM in Denmark at the municipal level to investigate variations that could be explained by environmental exposures. METHODS: Patients diagnosed with MM in Denmark during 2005-2020 were identified from nationwide registries and grouped into the 98 Danish municipalities based on residence. The age- and sex-standardised incidence rate (SIR) of each municipality was compared to the national incidence in a funnel plot with 95% control limits. Differences in SIRs of rural, suburban, and urban areas were evaluated with incidence rate ratios. RESULTS: In total, 5243 MM patients were included. Overall, we found a heterogeneous geographical distribution of MM and a potential hotspot in southern Denmark. This hotspot contains three municipalities with SIRs above the 95% control limit assuming considerably higher rate of MM compared to the national incidence rate. A significant higher SIR was found in rural areas compared to urban areas. CONCLUSION: The geographical distribution of MM in Denmark indicates that the risk of developing MM depends on place of residence probably due to environmental factors.

Polymorphisms within Autophagy-Related Genes as Susceptibility Biomarkers for Multiple Myeloma: A Meta-Analysis of Three Large Cohorts and Functional Characterization.

Multiple myeloma (MM) arises following malignant proliferation of plasma cells in the bone marrow, that secrete high amounts of specific monoclonal immunoglobulins or light chains, resulting in the massive production of unfolded or misfolded proteins. Autophagy can have a dual role in tumorigenesis, by eliminating these abnormal proteins to avoid cancer development, but also ensuring MM cell survival and promoting resistance to treatments. To date no studies have determined the impact of genetic variation in autophagy-related genes on MM risk. We performed meta-analysis of germline genetic data on 234 autophagy-related genes from three independent study populations including 13,387 subjects of European ancestry (6863 MM patients and 6524 controls) and examined correlations of statistically significant single nucleotide polymorphisms (SNPs; p < 1 × 10-9) with immune responses in whole blood, peripheral blood mononuclear cells (PBMCs), and monocyte-derived macrophages (MDM) from a large population of healthy donors from the Human Functional Genomic Project (HFGP). We identified SNPs in six loci, CD46, IKBKE, PARK2, ULK4, ATG5, and CDKN2A associated with MM risk (p = 4.47 × 10-4-5.79 × 10-14). Mechanistically, we found that the ULK4rs6599175 SNP correlated with circulating concentrations of vitamin D3 (p = 4.0 × 10-4), whereas the IKBKErs17433804 SNP correlated with the number of transitional CD24+CD38+ B cells (p = 4.8 × 10-4) and circulating serum concentrations of Monocyte Chemoattractant Protein (MCP)-2 (p = 3.6 × 10-4). We also found that the CD46rs1142469 SNP correlated with numbers of CD19+ B cells, CD19+CD3- B cells, CD5+IgD- cells, IgM- cells, IgD-IgM- cells, and CD4-CD8- PBMCs (p = 4.9 × 10-4-8.6 × 10-4) and circulating concentrations of interleukin (IL)-20 (p = 0.00082). Finally, we observed that the CDKN2Ars2811710 SNP correlated with levels of CD4+EMCD45RO+CD27- cells (p = 9.3 × 10-4). These results suggest that genetic variants within these six loci influence MM risk through the modulation of specific subsets of immune cells, as well as vitamin D3-, MCP-2-, and IL20-dependent pathways.

STAT3 is over-activated within CD163pos bone marrow macrophages in both Multiple Myeloma and the benign pre-condition MGUS.

Tumour-associated macrophages (TAMs) support cancer cell survival and suppress anti-tumour immunity. Tumour infiltration by CD163pos TAMs is associated with poor outcome in several human malignancies, including multiple myeloma (MM). Signal transducer and activator of transcription 3 (STAT3) is over-activated in human cancers, and specifically within TAMs activation of STAT3 may induce an immunosuppressive (M2-like) phenotype. Therefore, STAT3-inhibition in TAMs may be a future therapeutic strategy.We investigated TAM markers CD163, CD206, and activated STAT3 (pSTAT3) in patients with MGUS (n = 32) and MM (n = 45), as well as healthy controls (HCs, n = 13).Blood levels of the macrophage biomarkers sCD163 and sCD206, and circulating cytokines, as well as bone marrow mRNA expression of CD163 and CD206, were generally increased in MGUS and MM patients, compared to HCs, but to highly similar levels. By immunohistochemistry, bone marrow levels of pSTAT3 were increased specifically within CD163pos cells in both MGUS and MM patients.In conclusion, macrophage-related inflammatory changes, including activation of STAT3, were present already at the MGUS stage, at similar levels as in MM. Specific increase in pSTAT3 levels within CD163pos cells supports that the CD163 scavenger receptor may be a useful target for future delivery of STAT3-inhibitory drugs to TAMs in MM patients.

The role of E3 ubiquitin ligase in multiple myeloma: potential for cereblon E3 ligase modulators in the treatment of relapsed/refractory disease.

INTRODUCTION: Insights into the mechanisms of protein homeostasis and proteasomal degradation have led to new strategies of redirecting the ubiquitin-proteasome system (UPS) to reduce or eliminate proteins or survival factors key to malignant pathobiology, multiple myeloma (MM) in particular. These strategies have enabled researchers to target proteins that were previously considered difficult to modulate by pharmacological means. AREAS COVERED: This review provides a brief overview of UPS biology, particularly the role of the CRL4CRBN E3 ubiquitin ligase complex, and summarizes current strategies for co-opting the UPS, including CELMoD compounds, SNIPERs, PROTACs, and degronimids. A detailed discussion is provided on lead CELMoD compounds iberdomide and mezigdomide, which are currently being evaluated in clinical trials in patients with MM. EXPERT OPINION: Since a high proportion of patients develop drug resistance, it is vital to have novel therapeutic agents for treating relapsed patients with MM more effectively. It is encouraging that the expanding pathophysiological insight into cellular signaling pathways in MM increasingly translates into the development of novel therapeutic agents such as targeted protein degraders. This holds promise for improving outcomes in MM and beyond.

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.

A prospective study of Skeletal survey versus Low-dose whole-body CT for Osteolytic lesions in Multiple Myeloma.

Whole-body low-dose CT (WBLDCT) is recommended over classical skeletal surveys (CSS) for investigating bone disease in multiple myeloma (MM) based on retrospective studies. No prospective studies with serial follow-up scans exist. OBJECTIVE: To compare WBLDCT to CSS for identifying progressive bone disease in MM in a prospective setting. METHODS: Ninety-six patients with MM at Odense University Hospital and Stavanger Hospital were followed for up to four years. Patients were scanned with WBLDCT and CSS every year for the first two years and every six months thereafter or at suspicion of progression. RESULTS: Nineteen cases of progressive bone disease were found using WBLDCT vs eight cases using CSS (p < 0.001). All cases of progressive bone disease using CSS were also identified by WBLDCT. Progression not found by CSS was primarily in the spine, sternum, and pelvis. Of the 19 cases, five patients had progressive bone disease only without other criteria for clinical progression. WBLDCT consistently identified more bone lesions per patient, 8.2 CI(6.8;9.6) vs CSS, 3.6 CI(2.7;4.5). CONCLUSION: WBLDCT outperformed CSS for finding progressive bone disease and osteolytic lesions. More new lesions were found during follow-up by WBLDCT than CSS. Using CSS for lytic lesions will underestimate progression rates. Our data offer prospective evidence for the current recommendation using WBLDCT for skeletal evaluations in patients with multiple myeloma.

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.

Comparative evaluation of the heterozygous variant standard deviation as a quality measure for next-generation sequencing.

Next-generation sequencing holds unprecedented throughput in terms of informational content to cost. The technology has entered the scene in laboratory diagnostics and offers flexible workflows in biomedical research. However, the rapid acquisition of genomic data also gives rise to a substantial fraction of sequencing artifacts, causing the detection of false-positive germline variants or erroneous somatic mutations. Consequently, there is a pressing need for efficient and practical quality assessment in sequencing projects. In this study, we investigate using heterozygous variant allele frequency (VAF) standard deviation (σ) for supplementary quality control. Whereas several proposed quality metrics are based on empirical assessments, the dispersion of the allele frequencies reflects a direct approximation of the inherent and discrete features of a diploid genome. Consequently, homologous chromosomes display heterozygous VAF of approximately 1/2. Based on the meta-analysis of 152 whole-exome sequencing data sets, we found that σ reflects both sequencing coverage and noise and can be effectively modeled. It is concluded that the relative comparison of heterozygous VAF σ provides a practical handle for quality assessment, even for samples afflicted with copy-number alterations. The approach can be implemented when performing whole-exome, whole-genome, or targeted panel sequencing and helps identify problematic samples, such as those retrieved from archived formalin-fixed paraffin-embedded tissue.

Treatment of multiple myeloma-related bone disease: recommendations from the Bone Working Group of the International Myeloma Working Group.

In this Policy Review, the Bone Working Group of the International Myeloma Working Group updates its clinical practice recommendations for the management of multiple myeloma-related bone disease. After assessing the available literature and grading recommendations using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) method, experts from the working group recommend zoledronic acid as the preferred bone-targeted agent for patients with newly diagnosed multiple myeloma, with or without multiple myeloma-related bone disease. Once patients achieve a very good partial response or better, after receiving monthly zoledronic acid for at least 12 months, the treating physician can consider decreasing the frequency of or discontinuing zoledronic acid treatment. Denosumab can also be considered for the treatment of multiple myeloma-related bone disease, particularly in patients with renal impairment. Denosumab might prolong progression-free survival in patients with newly diagnosed multiple myeloma who have multiple myeloma-related bone disease and who are eligible for autologous stem-cell transplantation. Denosumab discontinuation is challenging due to the rebound effect. The Bone Working Group of the International Myeloma Working Group also found cement augmentation to be effective for painful vertebral compression fractures. Radiotherapy is recommended for uncontrolled pain, impeding or symptomatic spinal cord compression, or pathological fractures. Surgery should be used for the prevention and restoration of long-bone pathological fractures, vertebral column instability, and spinal cord compression with bone fragments within the spinal route.

Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients.

Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10-7 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04-1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.

Validation of the UK myeloma research alliance risk profile, a new clinical prediction model for outcome in patients with newly diagnosed multiple myeloma not eligible for autologous stem cell transplantation; a population-based study from the Danish national multiple myeloma registry.

In 2019 the UK Myeloma Research Alliance introduced the Myeloma Risk Profile (MRP) for prediction of outcome in patients with newly diagnosed multiple myeloma (MM), ineligible for autologous stem cell transplantation. To validate the MRP in a population-based setting we performed a study of the entire cohort of transplant ineligible MM patients above 65 years in the Danish National MM Registry. Our data confirmed the value of the MRP. In a cohort of 1,377 patients, the MRP score separated patients into three distinct risk-groups with an observed hazard ratio of 2.91 for early death in high-risk versus low-risk patients.

The impact of changed treatment patterns in multiple myeloma on health-care utilisation and costs, myeloma complications, and survival: A population-based comparison between two time periods in Denmark.

OBJECTIVES: To evaluate health-care utilisation and costs, myeloma complications and survival in Danish patients with multiple myeloma (MM) before and after implementation of new early-line treatments in 2009. METHODS: Based on data from the Danish National Health Registers, 3518 patients diagnosed with MM during 2002-2005 or 2010-2013 and randomly matched control individuals were identified, and health-care utilisation and costs were estimated. RESULTS: Health-care utilisation showed a marked shift from inpatient admissions towards outpatient visits. From early to late period, the mean annual number of outpatient visits increased by 22% and 28% in patients <65 years and ≥65 years, respectively. Additionally, the mean annual outpatient service costs increased correspondingly from 17 001€ to 23 643€ in younger patients and from 11 317€ to 16 144€ in the elderly. Increasing outpatient costs were outbalanced by lower inpatient admission costs and the adjusted total mean annual costs decreased in younger patients, probably partly due to fewer myeloma complications. The five-year survival rates increased markedly in both younger (HR = 0.51) and elderly (HR = 0.69) patients. CONCLUSION: Despite the introduction of new expensive early-line MM treatments in 2009, health-care costs remained stable due to a shift in health-care utilisation towards outpatient clinic care and fewer complications.

Assessment of atherosclerosis in multiple myeloma and smoldering myeloma patients using 18F- sodium fluoride PET/CT.

BACKGROUND: To compare the NaF uptake in the thoracic aorta and whole heart, as an early indicator of atherosclerosis, in multiple myeloma (MM) and smoldering multiple myeloma (SMM) patients with a healthy control (HC) group. METHODS: Forty-four untreated myeloma patients (35 MM and nine SMM) and twenty-six age and gender-matched HC subjects were collected. Each individual's NaF uptake in three parts of the aorta (AA: ascending aorta, AR: aortic arch, DA: descending aorta) and the whole heart was segmented. Average global standardized uptake value means were derived by sum of the product of each slice area divided by the sum of those slice areas. Results were reported as target to background ratio (TBR). RESULTS: There was a significant difference between the NaF uptake in the thoracic aorta of myeloma and HC groups [AA (myeloma = 1.82 ± 0.21, HC = 1.24 ± 0.02), AR (myeloma = 1.71 ± 0.19, HC = 1.28 ± 0.03) and DA (myeloma = 1.96 ± 0.28, HC = 1.38 ± 0.03); P-values < 0.001]. The difference in the whole heart NaF uptake between two groups was also significant (P < 0.001). CONCLUSIONS: We observed a higher uptake of NaF in the thoracic aorta and whole heart of myeloma patients in comparison to the matched control group.

Use of bisphosphonates in multiple myeloma patients in Denmark, 2005-2015.

PURPOSE: To describe use of bisphosphonates in newly diagnosed multiple myeloma patients in Denmark. METHODS: Using data from the Danish National Multiple Myeloma Registry, we conducted a population-based cohort study. Among patients newly diagnosed with multiple myeloma from 2005 to 2015, we examined use of bisphosphonates at first- and at progression/second-line anti-myeloma treatment overall, by patient characteristics, and myeloma complications. RESULTS: Of 2947 patients starting first-line anti-myeloma treatment, 2207 patients (74.9%) received bisphosphonates. During a median follow-up of 27.6 (quartiles, 10.6-52.5) months, disease progression post-first-line treatment was recorded in 1546 patients, of whom 1065 (68.9%) were treated with bisphosphonates. Altogether, 80.9% of patients with and 37.6% of patients without myeloma bone disease were treated with bisphosphonates at first line and 73.0% and 42.7%, respectively, at progression/second line. Moreover, the proportion of patients treated with bisphosphonates decreased with increasing severity of renal impairment at first and at progression/second-line treatment. CONCLUSION: The proportion of patients treated with bisphosphonates as part of first- and second-line anti-myeloma treatment increased with presence of myeloma bone disease and decreased by presence and severity of renal impairment. Overall, 25% of newly diagnosed multiple myeloma patients had no record of bisphosphonate treatment, potentially indicating an unmet need.

Classification of Amyloidosis by Model-Assisted Mass Spectrometry-Based Proteomics.

Amyloidosis is a rare disease caused by the misfolding and extracellular aggregation of proteins as insoluble fibrillary deposits localized either in specific organs or systemically throughout the body. The organ targeted and the disease progression and outcome is highly dependent on the specific fibril-forming protein, and its accurate identification is essential to the choice of treatment. Mass spectrometry-based proteomics has become the method of choice for the identification of the amyloidogenic protein. Regrettably, this identification relies on manual and subjective interpretation of mass spectrometry data by an expert, which is undesirable and may bias diagnosis. To circumvent this, we developed a statistical model-assisted method for the unbiased identification of amyloid-containing biopsies and amyloidosis subtyping. Based on data from mass spectrometric analysis of amyloid-containing biopsies and corresponding controls. A Boruta method applied on a random forest classifier was applied to proteomics data obtained from the mass spectrometric analysis of 75 laser dissected Congo Red positive amyloid-containing biopsies and 78 Congo Red negative biopsies to identify novel "amyloid signature" proteins that included clusterin, fibulin-1, vitronectin complement component C9 and also three collagen proteins, as well as the well-known amyloid signature proteins apolipoprotein E, apolipoprotein A4, and serum amyloid P. A SVM learning algorithm were trained on the mass spectrometry data from the analysis of the 75 amyloid-containing biopsies and 78 amyloid-negative control biopsies. The trained algorithm performed superior in the discrimination of amyloid-containing biopsies from controls, with an accuracy of 1.0 when applied to a blinded mass spectrometry validation data set of 103 prospectively collected amyloid-containing biopsies. Moreover, our method successfully classified amyloidosis patients according to the subtype in 102 out of 103 blinded cases. Collectively, our model-assisted approach identified novel amyloid-associated proteins and demonstrated the use of mass spectrometry-based data in clinical diagnostics of disease by the unbiased and reliable model-assisted classification of amyloid deposits and of the specific amyloid subtype.

Combined Subcutaneous Fat Aspirate and Skin Tru-Cut Biopsy for Amyloid Screening in Patients with Suspected Systemic Amyloidosis.

Screening for systemic amyloidosis is typically carried out with abdominal fat aspirates with varying reported sensitivities. Fat aspirates are preferred for use in primary screening instead of organ biopsies as they are less invasive and thereby minimize the potential risk of complications. At Odense Amyloidosis Center, we performed a prospective study on whether the combined use of fat aspirate and tru-cut skin biopsy could increase the diagnostic sensitivity. Both fat aspirates and skin biopsies were screened with Congo Red staining, and positive biopsies were subsequently subtyped using immunoelectron microscopy and mass spectrometry. Seventy-six patients were included. In total, 24 patients had systemic amyloidosis (11 AL, 12 wtATTR, 1 AA), and 6 patients had localized amyloidosis. Combined fat aspirate and skin biopsy were Congo Red-positive in 15 patients (overall sensitivity (OS) 62.5%). Fat aspirates were positive in 14 patients (OS 58.3%), and the skin biopsy was positive in 5 patients (OS 20.8%). In only one patient did the skin biopsy add extra diagnostic information. The sensitivity differed between AL and ATTR amyloidosis-81.8% and 41.7%, respectively. Using skin biopsy as the only screening method is not recommended.

Health-related quality of life in transplant ineligible newly diagnosed multiple myeloma patients treated with either thalidomide or lenalidomide-based regimen until progression: a prospective, open-label, multicenter, randomized, phase 3 study.

Data on the impact of long term treatment with immunomodulatory drugs (IMiD) on health-related quality of life (HRQoL) is limited. The HOVON-87/NMSG18 study was a randomized, phase 3 study in newly diagnosed transplant ineligible patients with multiple myeloma, comparing melphalan-prednisolone in combination with thalidomide or lenalidomide, followed by maintenance therapy until progression (MPT-T or MPR-R). The EORTC QLQ-C30 and MY20 questionnaires were completed at baseline, after three and nine induction cycles and six and 12 months of maintenance therapy. Linear mixed models and minimal important differences were used for evaluation. 596 patients participated in HRQoL reporting. Patients reported clinically relevant improvement in global quality of life (QoL), future perspective and role and emotional functioning, and less fatigue and pain in both arms. The latter being of large effect size. In general, improvement occurred after 6-12 months of maintenance only and was independent of the World Health Organisation performance at baseline. Patients treated with MPR-R reported clinically relevant worsening of diarrhea, and patients treated with MPT-T reported a higher incidence of neuropathy. Patients who remained on lenalidomide maintenance therapy for at least three months reported clinically meaningful improvement in global QoL and role functioning at six months, remaining stable thereafter. There were no clinically meaningful deteriorations, but patients on thalidomide reported clinically relevant worsening in neuropathy. In general, HRQoL improves both during induction and maintenance therapy with immunomodulatory drugs. The side effect profile of treatment did not negatively affect global QoL, but it was, however, clinically relevant for the patients. (Clinicaltrials.gov identifier: NTR1630).

Comparison of 18F-sodium fluoride uptake in the whole bone, pelvis, and femoral neck of multiple myeloma patients before and after high-dose therapy and conventional-dose chemotherapy.

AIM: To compare the effects of high-dose therapy (HDT consisting of high-dose chemotherapy followed by autologous stem cell transplantation) and conventional-dose chemotherapy (non-HDT) on the uptake of 18F-sodium fluoride (NaF) in the whole bone, pelvis, and femoral neck of multiple myeloma (MM) patients. METHOD: The data of 19 MM patients who received HDT (61.5 (SD 5.6) years) and 11 MM patients who received conventional-dose chemotherapy (70.9 (SD 7.2) years) were collected in a prospective study. NaF PET/CT imaging was performed at baseline, and 8 weeks and 2 weeks after treatment for the HDT group and the non-HDT group, respectively. A CT-based algorithm was applied to segment the bones, and the global mean SUV (GSUVmean) of the whole bone and pelvis was calculated (OsiriX MD v.9.0, Pixmeo SARL; Bernex, Switzerland). In addition, regions of interest for the whole, medial, and lateral femoral neck were delineated bilaterally. Whole bone and pelvis measurements were replicated by two observers. RESULTS: The average GSUVmean in the whole bone and pelvis of the patients who underwent HDT significantly decreased from before to after treatment (- 16.27%, p = 0.02 and - 16.54%, p = 0.01, respectively). A significant decrease in the whole and lateral femoral neck was also observed bilaterally in the HDT group. No significant decrease in average GSUVmean was observed in the non-HDT group. A high level of inter-observer reliability was found in intra-class correlation (ICC for pre-treatment whole bone 0.983, post-treatment whole bone 0.989, pre-treatment whole pelvis 0.998, post-treatment whole pelvis 0.996). CONCLUSION: NaF uptake significantly decreased after treatment in patients who received high-dose therapy. A high level of agreement was observed between two operators for whole bone and pelvis measurements.