Intestinal involvement in amyloidosis is a sequential process den Braber‐Ymker, Marjanne; Heijker, Sanneke; Lammens, Martin ...
Neurogastroenterology & motility/Neurogastroenterology and motility,
December 2018, 2018-12-00, 20181201, Volume:
30, Issue:
12
Journal Article
Peer reviewed
Open access
Background
Gastrointestinal amyloidosis causes dysmotility. A comprehensive histological analysis to explain these symptoms is lacking. Therefore, we systematically examined histological features of ...intestinal dysmotility in patients with AL and AA amyloidosis, compared to controls.
Methods
Autopsy tissue material from small bowel and colon was used for histological (semiquantitative) evaluation of the mucosa, blood vessels, muscular layers, enteric nervous system (ENS) and the interstitial cells of Cajal (ICC), using hematoxylin and eosin, periodic acid Schiff, Elastic von Gieson and Congo red staining, and immunohistochemistry with α‐smooth muscle actin, HuC/D, S100 and CD117 antibodies, according to guidelines of the Gastro 2009 International Working Group.
Key Results
Amyloid deposits were present in the vascular walls of all amyloidosis patients. In the mucosa, amyloid was found in 67% of AA patients. The muscular layers were involved in 64% of amyloidosis patients, most prominent in AA patients, associated with the presence of polyglucosan inclusion bodies, but not with either abnormal α‐actin patterns or fibrosis. Amyloid in the muscularis propria surrounding the myenteric plexus was found, but not inside the myenteric plexus. These deposits might be related to loss of the ICC network, but there was no association with decreased neuronal or nerve fiber density.
Conclusions & Inferences
We hypothesize that intestinal dysmotility in amyloidosis patients is a sequential process: amyloid deposition starts in the vasculature, followed by involvement of the muscular layers, ICC loss, and potentially affect the myenteric plexus. This final stage may be accompanied by clinical symptoms of severe intestinal dysmotility.
We performed a comprehensive and systematic histological analysis to explain intestinal symptoms of dysmotility in amyloidosis patients, since this is currently lacking. Amyloid deposits were found in blood vessels (all patients with AL and AA), the mucosa (AA), and in the muscular layers (AL and AA) around the myenteric plexus, probably related to loss of interstitial cells of Cajal. We hypothesize that intestinal dysmotility in amyloidosis patients is a sequential process.
It is unknown whether the route of administration influences dendritic cell (DC)-based immunotherapy. We compared the effect of intradermal versus intranodal administration of a DC vaccine on ...induction of immunologic responses in melanoma patients and examined whether concomitant administration of interleukin (IL)-2 increases the efficacy of the DC vaccine.
HLA-A2.1(+) melanoma patients scheduled for regional lymph node dissection were vaccinated four times biweekly via intradermal or intranodal injection with 12 × 10⁶ to 17 × 10⁶ mature DCs loaded with tyrosinase and gp100 peptides together with keyhole limpet hemocyanin (KLH). Half of the patients also received low-dose IL-2 (9 MIU daily for 7 days starting 3 days after each vaccination). KLH-specific B- and T-cell responses were monitored in blood. gp100- and tyrosinase-specific T-cell responses were monitored in blood by tetramer analysis and in biopsies from delayed-type hypersensitivity (DTH) skin tests by tetramer and functional analyses with (51)Cr release assays or IFNγ release, following coculture with peptide-pulsed T2 cells or gp100- or tyrosinase-expressing tumor cells.
In 19 of 43 vaccinated patients, functional tumor antigen-specific T cells could be detected. Although significantly more DCs migrated to adjacent lymph nodes upon intranodal vaccination, this was also highly variable with a complete absence of migration in 7 of 24 intranodally vaccinated patients. Intradermal vaccinations proved superior in inducing functional tumor antigen-specific T cells. Coadministration of IL-2 did not further augment the antigen-specific T-cell response but did result in higher regulatory T-cell frequencies.
Intradermal vaccination resulted in superior antitumor T-cell induction when compared with intranodal vaccination. No advantage of additional IL-2 treatment could be shown.
Introduction and background
The treatment of patients with Multiple Myeloma (MM) with relapse or progressive disease after bortezomib, lenalidomide and high-dose therapy represents an important ...challenge. In the EMN02 collaborative trial newly diagnosed patients with symptomatic MM were randomized to receive VCD induction followed by HDM/ASCT or VMP, followed by a second randomization for VRD consolidation or no consolidation, followed by lenalidomide maintenance until progression (Cavo et al, ASH2017, abstract #397; Sonneveld et al, EHA2018, abstract #108). The present Phase 2 trial was designed for patients with refractory disease or first progression after inclusion in EMN02 in order to evaluate a salvage treatment with next generation proteasome inhibition and IMId, i.e., Carfilzomib, Pomalidomide and Dexamethasone. The primary endpoints were response and progression-free survival (PFS). This trial is registered at www.trialregister.nl as NTR5349 and EudraCT 2013-003265-34.
Methods
Patients who were included received four 28-days re-induction cycles of KPd, i.e. Carfilzomib (20/36mg/m2, days 1,2,8,9,15,16) with Pomalidomide (4 mg days 1-21) and Dexamethasone (20mg days 1,2,8,9,15,16). In patients who had not previously received HDM/ASCT, HDM(200 mg/m2) was administered followed by autologous stem cell transplantation with stem cells harvested during after induction therapy in the EMN02 trial. Consolidation consisted of 4 additional cycles of KPd, identical to the induction cycles. Patients with stable disease or better received Pomalidomide 4mg w/o Dexamethasone in 28 days cycles until progression.
Results
At the time of this first planned interim analysis 82 patients were registered and this analysis was performed in the first 60 patients. 48% were randomized prior HDM/ASCT and 42% VMP, and 10% were not randomized. Prior best responses in the EMN02 trial were 35% CR/sCR , 75% ≥VGPR, 97% ≥PR. The median follow-up from inclusion in EMN02 was 43 months (range 21 - 62 months). In 44 patients cytogenetic risk were known, 15 (34%) of them had high-risk FISH (del17p, t(14;16) or t(4;14)). 57 fifty-seven (95%) of patients had progressed during lenalidomide maintenance, 3 patient's data are not yet available. In the present trial 38 (63%) of patients achieved normal completion of treatment according to of the protocol. Twenty patients received their first HDM plus ASCT. Median time on therapy was 14 months. Full dose re-induction treatment according to protocol could be administered in 68% (for Carfilzomib) and 64% (for Pomalidomide) of patients respectively, while for consolidation this was 62% for both Carfilzomib and Best response on protocol was 31% CR/sCR, 65% ≥VGPR, 87% ≥PR, respectively, with no difference according to response on initial treatments. Median time to response (≥PR) was 2 months. At a median follow-up of 16.3 months (range 3 - 32 months) median PFS was 18 months with better outcome in standard risk cytogenetics (HR=0.27 (0.09, 0.83) 95% CIs vs NR) and in patients with prior VMP treatment (HR=0.49 (0.21, 1.16) 95% CIs vs NR). 48 (80%) of patients are alive and in follow-up. KPd-emerging non-hematologic grade 3 and 4 adverse events included cardiovascular (5%), respiratory (5%), infections (20%) and neuropathy (3%). There were 3 fatal SAEs not related to progression (1 patient cardiac failure, 2 patients pneumonia). KPd-emerging hematological toxicity grade 3 and 4 occurred in 30% of patients.
Discussion
This Phase 2 clinical trial demonstrates that KPd is a feasible, effective and safe triple drug regimen in RRMM patients who have been previously treated and/or are refractory to bortezomib and refractory to lenalidomide. A 87% overall response rate including 31% CR/sCR is clinically relevant in this population. Since median OS has not been reached, longer follow-up is needed.
Acknowledgments
This trial was conducted as an investigator sponsored trial in EMN and supported by independent grants and drug supply from Amgen and Celgene.
Sonneveld:BMS: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corp.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavo:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Corradini:Roche: Honoraria, Other: Advisory Board & Lecturer; Gilead: Honoraria, Other: Advisory Board & Lecturer; Takeda: Honoraria, Other: Advisory Board & Lecturer; Novartis: Honoraria, Other: Advisory Board & Lecturer; Sandoz: Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board & Lecturer; Abbvie: Honoraria, Other: Advisory Board & Lecturer; Janssen: Honoraria, Other: Lecturer; Sanofi: Honoraria, Other: Advisory Board & Lecturer; Celgene: Honoraria, Other: Advisory Board & Lecturer. Patriarca:Janssen: Other: Advisory role; Celgene: Other: Advisory Role; Travel, accommodations, expenses; Jazz: Other: Travel, accommodations, expenses; MSD Italy: Other: Advisory Role; Medac: Other: Travel, accommodations, expenses. Minnema:Celgene: Consultancy, Research Funding; Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Servier: Consultancy. Costa:celgene: Employment. Iskander:amgen: Employment. Boccadoro:Mundipharma: Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding.
Abstract The HOVON 104 studied bortezomib‐dexamethasone induction therapy and autologous stem cell transplantation in 50 patients, of whom 35 received an autologous stem cell transplantation (ASCT). ...We demonstrate a 5‐year overall survival (OS) of 73% and progression‐free survival (PFS) of 52% for all 50 patients with a median follow‐up of 61.3 months. For the 35 transplanted patients, calculated from the date of ASCT, the 5‐year OS and PFS were 91% and 68%, respectively. After ASCT, the rate of organ response improved over time but stabilized around 3 years. A complete cardiac response was seen in around 60% of patients and remained stable from 2 years onward. Reaching complete renal response was slower over time and achieved by 61% of the renal‐affected patients at 5 years. We confirm the excellent outcomes after ASCT and demonstrate a 60% complete organ response with longer follow‐up.
Multiple myeloma (MM) is a neoplasm that exhibits a broad heterogeneity in both biological behavior and clinical presentation. Specific copy number abnormalities (CNAs) such as hyperdiploidy, 1p ...loss, 1q gain, 13q loss and 17p loss (including the TP53 gene), and IGH translocations, such as t(4;14)(p16;q32) and t(14;16)(q32;q23), provide important information regarding prognosis and treatment response.
Interphase fluorescence in situ hybridization (FISH) on enriched plasma cells, currently used in clinical diagnostics of MM, is a targeted test aimed at specific genomic loci. However, it is laborious and provides only genetic information of the probe targets. Microarray-based genomic profiling is a high-resolution tool that enables genome-wide analyses for copy number alterations (CNA), including focal CNA (<5 Mb) and regions of copy neutral loss of heterozogosity (CNLOH) that cannot be identified by FISH. A limitation of SNP-based array is its inability to identify balanced translocations.
The aim of this study was to compare FISH with SNP-based genomic arrays with respect to the detection yield for prognostic relevant genetic copy number abnormalities in enriched plasma cell samples from MM patients. In addition we have set up a diagnostic work flow in which on one sample of enriched plasma cells interphase FISH for (balanced) IGH translocations as well as SNP-based array for identification of CNA can be performed.
SNP-based genomic array profiling and FISH were performed in 37 MM patients. After enrichment of CD138 plasma cells half of each sample was treated with 0.075M KCl and, subsequently, fixed with 3:1 methanol/acetic acid and transferred to a microscopic slide for subsequent FISH. From the remaining part of the CD138-enriched plasma cell fraction DNA was extracted to perform SNP-based genomic array. Interphase FISH was performed according to standard methods using the following probes D5S23/D5S721/CEP9/CEP15, LSI13 (13q14), LSI TP53 (17p13.1) (all from Abbott Molecular, USA), and CDKN2C/CKS1B (from Cytocell, UK). 200 nuclei were analyzed by two different investigators and the detection limit was set at 20% as proposed by the EMN (Ross et al 2012; Haematologica 97:1272-1277). SNP-based array was performed using the CytoScan HD array platform (Affymetrix, USA), using the interpretation criteria as proposed by Schoumans (Schoumans et al 2016; Genes Chromosomes Cancer 55:480-491). Data regarding FISH and SNP-based array were obtained in a fully blinded fashion.
All prognostic relevant CNA as observed by FISH were also identified when only SNP-based genomic arrays would have been performed, including 4 cases with loss of 1p, 19 cases with gain of 1q, 14 cases with loss of 13q, 4 cases with loss of 17p, and 20 cases with a hyperdiploid karyotype. However, SNP-based arrays identified 20 additional prognostic relevant abnormalities which were not observed by interphase FISH for several reasons. Due to a higher detection limit of the applied SNP-based array platform, 2 cases with loss of 17p (abnormality present in 15-20% of the cells) and 1 case with loss of 13q and a hyperdiploid karyotype (present in 15% of the cells) were observed by SNP-array only. Four cases showed a 1p21 or 1p16 loss, which were not observed by FISH since these deleted regions were outside the 1p32 probe target region. In 3 cases tumor-associated regions of CNLOH were observed involving the regions 13q and 17p. Finally, in 4 cases in which FISH was suggestive for a hyperdiploid karyotype, the SNP-based array information regarding whole genome analysis and allele frequencies demonstrated that these 4 cases appeared to have a doubled up DNA content in their plasma cells, and therefore the losses of 1p, 13q and 17p were not observed by interphase FISH.
In conclusion, we demonstrate that SNP-based arrays are superior in the identification of prognostic relevant CNA in MM. SNP-based array do identify all CNA as observed by FISH, and in addition, identifies additional prognostic relevant abnormalities, such as loss of 1p, 13q, and 17p, that escaped the detection by FISH. The prognostic relevance of the CNLOH and the loss of 1p21 and 1p16 regions requires further evaluation in prospective clinical trials.
Zweegman:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding.
Background:
Novel agents such as IMIDs and proteasome inhibitors have substantially changed the therapeutic landscape in the first line treatment of multiple myeloma (MM). Better response rates and ...prolonged progression-free survival have lead to an improvement in overall survival (OS) with median values well beyond 5 years. Therefore to assess whether first line therapy strategies have an impact on the prognosis for patients with MM, long-term results of clinical trials with follow up covering >10 years are necessary.
Methods:
The HOVON-65/GMMG-HD4 study is a prospective randomized trial testing bortezomib+adriamycin+dexamethasone (PAD) for 3 cycles as induction prior to high-dose chemotherapy (HDT) and autologous stem cell transplantation compared to vincristine+adriamycin+dexamethasone (VAD) in the control arm. After one (HOVON) or two (GMMG) HDT maintenance was given for 2 years consisting of bortezomib every 2 weeks in the PAD arm and thalidomide 50 mg daily in the VAD arm. The study results were initially reported in 2012 (1) and with a median follow up of 91 months in 2018 (2). In this analysis we present OS results after a median follow up of 137 months. All hazard ratios (HR) are given with 95% confidence intervals (CI).
Results:
Overall survival at 12 years was 32% (CI 27-37%) in the VAD arm versus 36% (CI 31-41%) in the PAD arm without significant difference in the univariate Cox model (HR 0.87, CI 0.73 - 1.03, p=0. 11 or in multivariate Cox model including ISS stage and treatment arm (HR 0.87, CI 0.73 - 1.04, p=0.12; the primary analysis) as specified in the study protocol. When other factors including age, sex, ISS stage, WHO performance status, Immunoglobulin-type, Durie and Salmon-stage, LDH, del 13q, study group and renal impairment (RI, defined as serum creatinine ≥ 2 mg/dl) were added to the Cox model, treatment in the PAD arm was a significant factor for improved OS (HR 0.84, CI 0.7 - 1.0, p=0.048). Of the remaining factors age (HR 1.02, CI 1.01 - 1.03, p=0.002), female sex (HR 0.83, CI 0.69 - 0.99, p=0.044), ISS stage (HR 1.19, CI 1.04 - 1.35, p=0.01), WHO performance status (HR 1.32, CI 1.17 - 1.48, p<0.001), IgA (HR 1.56, CI 1.18 - 2.06, p=0.002), LDH>ULN (HR 1.44, CI 1.14 - 1.82, p=0.002), del 13q (HR 1.42, CI 1.17 - 1.73, p<0.001) and RI (HR 1.42, CI 1.04 - 1.95, p=0.026) were significantly associated with OS. Tests for heterogeneity revealed two factors as significant: RI and del17p (only fully evaluated for the GMMG cohort). For patients with RI the OS probability at 12 years was 39% in the PAD arm versus 5% in the VAD arm (HR 0.34, CI 0.20 - 0.59, p<0.0001, Fig. 1). 12 year OS in patients without RI was 36% in the PAD arm and 35% in the VAD arm without significant difference (HR 0.97, CI 0.81 - 1.17, p=0.77, Fig,1). In the GMMG cohort (receiving tandem-HDT) del17p results were available and patients with del17p had a significantly better OS in the PAD arm than in the VAD arm (HR 0.36, CI 0.17 - 0.77, p=0.006), while no significant difference between treatment arms was found in patients without del17p (HR 1.01, CI 0.75 - 1.37, p=0.92).
Discussion:
Long-term results of the HOVON-65/GMMG-HD4 trial show that one third of patients receiving HDT with either thalidomide-based or bortezomib-based maintenance are still alive at 12 years. In contrast to earlier analyses with shorter follow up (1,2) the use of bortezomib in the induction and maintenance treatment provided a significant OS benefit when adjusting for other risk in a multivariate Cox model, although not in the primary analysis. A particular OS benefit was found in patients with RI receiving bortezomib before and after HDT and this could completely abolish the negative prognostic impact of RI. Similarly bortezomib used in combination with tandem-HDT improved OS in patients with del17p so that more than a third of these patients with high-risk MM survived more than 10 years. Our results underline that despite the growing options for treatment at relapse the choice of an optimal first-line therapy is of critical prognostic importance, in particular for patients with high-risk myeloma.
References:
1) Sonneveld et al., J Clin Oncol, 2012; 30:2946-2955
2) Goldschmidt et al., Leukemia 2018; 32: 383-390
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Scheid:Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Bertsch:Celgene: Other: travel support; Sanofi: Other: travel support. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Weisel:Celgene: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria; Adaptive Biotech: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Kersten:Gilead: Honoraria; Kite Pharma: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Miltenyi: Honoraria; Roche: Honoraria, Research Funding; Takeda Oncology: Research Funding; Celgene: Honoraria, Research Funding. Mai:Mundipharma: Other: travel support; Takeda: Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support; Celgene: Consultancy, Honoraria, Other: travel support. Hillengass:Amgen: Consultancy, Honoraria; Janssen: Honoraria. Stilgenbauer:AbbVie, AstraZeneca, Celgene, Gilead Sciences, Inc., GSK, Hoffmann La-Roche, Janssen, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Broyl:Celgene, amgen, Janssen,Takeda: Honoraria. Bos:Kiadis Pharma: Other: Shareholder (of Cytosen, acquired by Kiadis); Celgene: Research Funding. Dührsen:Amgen: Consultancy, Honoraria, Research Funding; CPT: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Teva: Honoraria; Novartis: Consultancy, Honoraria; Alexion: Honoraria; Gilead: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Honoraria; Celgene: Research Funding. Salwender:Celgene: Honoraria, Other: Travel or accommodations; Sanofi: Honoraria, Other: Travel or accommodations; Takeda: Honoraria, Other: Travel or accommodations; Bristol-Myers Squibb: Honoraria, Other: Travel or accommodations; AbbVie: Honoraria; Amgen: Honoraria, Other: Travel or accommodations; Janssen Cilag: Honoraria, Other: Travel or accommodations. Goldschmidt:Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Molecular Partners: Research Funding; Dietmar-Hopp-Stiftung: Research Funding; Mundipharma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; John-Hopkins University: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; John-Hopkins University: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Research Funding; Janssen: Consultancy, Research Funding. Sonneveld:Amgen: Honoraria, Research Funding; BMS: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; SkylineDx: Research Funding.
bortezomib maintenance thalidomide maintenance
Multiple myeloma is a malignant B-cell neoplasm that involves the skeleton in approximately 80% of the patients. With an average age of 60 years and a 5-years survival of nearly 45% Brenner et al. ...(Blood 111:2516-2520, 35) the onset is to be classified as occurring still early in life while the disease can be very aggressive and debilitating. In the last decades, several new imaging techniques were introduced. The aim of this review is to compare the different techniques such as radiographic survey, multidetector computed tomography (MDCT), whole-body magnetic resonance imaging (WB-MRI), fluorodeoxyglucose positron emission tomography- (FDG-PET) with or without computed tomography (CT), and ⁹⁹mTc-methoxyisobutylisonitrile (⁹⁹mTc-MIBI) scintigraphy. We conclude that both FDG-PET in combination with low-dose CT and whole-body MRI are more sensitive than skeleton X-ray in screening and diagnosing multiple myeloma. WB-MRI allows assessment of bone marrow involvement but cannot detect bone destruction, which might result in overstaging. Moreover, WB-MRI is less suitable in assessing response to therapy than FDG-PET. The combination of PET with low-dose CT can replace the golden standard, conventional skeletal survey. In the clinical practise, this will result in upstaging, due to the higher sensitivity.
Introduction: Early mortality is up to 10% in newly diagnosed multiple myeloma (MM) with no improvement in subsequent study generations until 2002 (Augustson et al., JCO, 2005). Recent data on the ...causes of early mortality in transplant-eligible (te) MM patients during induction therapy (IT) and associated risk factors are not available.
Patients and Methods: This retrospective multi-cohort analysis included 1515 patients from three subsequently conducted phase III multicenter trials for teMM (HD3, HD4, MM5) from the German-speaking Myeloma Multicenter Group (GMMG).
The analyzed IT period was defined from the first dose of IT until the last dose of IT plus 30 days or until start of stem cell mobilization. Patients were analyzed as treated if they received at least one dose of trial medication and no more than three IT cycles. Early deaths were defined as any deaths in the defined period. Severe infections (SI) were defined as any infection ≥ grade 3 according to the Common Terminology Criteria for Adverse Events (CTCAE). Three cycles of a three-drug IT were applied in each trial: vincristine, doxorubicin (DOX), dexamethasone (DEX; VAD) vs. thalidomide, DOX, DEX (TAD) in the HD3 trial (09/2001-09/2004, Breitkreutz et al., Leukemia, 2007; n=529); VAD vs. bortezomib (BTZ), DOX, DEX (PAD) in the HD4 trial (05/2005-05/2008, Sonneveld et al., JCO, 2012; n=388); and PAd vs. BTZ, cyclophosphamide (CYC), DEX (VCD) in the MM5 trial (07/2010-11/2013, Mai et al., Leukemia, 2015; n=598). Major inclusion / exclusion criteria were similar between the trials, except for the maximum age for inclusion: 65 years (HD3, HD4) vs. 70 years (MM5).
Uni- and multivariate logistic regression models were built to assess risk factors. Trial effect was accounted for. Based on the risk factors for SI during IT, a predictive score for SI-related / overall mortality during IT was developed. Data from the Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON) -50 (VAD and TAD IT, 11/2001-05/2005, Lokhorst et al., Blood, 2010, n=528) and HOVON-65 (VAD and PAD IT, 05/2005-05/2008, Sonneveld et al., JCO, 2012; n=430) multicenter phase III trials for teMM were used to validate the prognostic score for mortality during IT.
Results: Severe infections occurred in 22.3% vs. 27.3% vs. 10.0% vs. 18.8% of patients in the HD3, HD4, MM5, and pooled population, respectively. In the HD3, HD4, MM5 and pooled cohort, 6.2% vs. 3.1% vs. 1.3% vs. 3.5% (n=33/12/8/53) of patients died during IT, respectively. Infections were the single largest cause of death during IT (n=26, 49.1%).
Besides trial effects (HD4, odds ratio OR=1.42, p=0.03; MM5, OR=0.37, p>0.001, both vs. HD3), pooled multivariate analyses identified World Health Organization performance status >1 (WHO>1, OR=1.97, p<0.001), age >60 years (age>60, OR=1.42, p=0.01) and lactate dehydrogenase > upper level of normal (LDH>ULN, OR=1.45, p=0.04) as trial-independent significant predictors for SI during IT. Combination of these factors allowed the stratification in three groups according to the risk of SI during IT: high risk (HiR, WHO>1 plus age>60 and/or LDH>ULN, n=95, SI incidence: 37.9%), low risk (LoR, no risk factors or age>60 only, n=1046, SI incidence: 15.8%) and intermediate risk (ImR, neither HiR nor LoR, n=310, SI incidence: 21.6%). In the HiR group, the incidence of death from any cause or SI was 14.7%/8.4% vs. 6.1%/2.6% vs. 1.4%/0.9% in the ImR and LoR groups, respectively. The increased risk of death from any cause or SI in the HiR and ImR group was independent of trial effects (HiR group: OR any cause/SI=11.46/10.19, both p<0.001 and ImR group: OR any cause/SI=4.83/3.23, p<0.001/0.02; vs. LoR group).
To validate the constructed risk score, we analyzed the HOVON-50 and HOVON-65 trials (n=922): 5.8% (n=53) of patients died during IT. Similar to the GMMG cohort, the HiR group included 7.7% of patients with an overall mortality of 18.3% vs. 6.1% and 4.3% in the ImR (21.4% of patients) and LoR groups (70.9% of patients) during IT, respectively. Again, the increased risk for death from any cause during IT was independent of trial effects (HiR group: OR=4.90, p<0.001).
Conclusions: Our validated risk score for early mortality in teMM identifies a subgroup of patients with an excessive mortality during IT. These patients are at risk to miss the benefits of modern anti-MM therapy, thus intensive clinical monitoring and the development of strategies to prevent early mortality are needed.
Mai:Onyx: Other: Travel grants; Mundipharma: Other: Travel grants; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Other: Travel grants; Celgene: Other: Travel grants. Salwender:Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Honoraria and travel support: Janssen Cilag, Celgene, BMS.: Honoraria, Other: Travel support. Lokhorst:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; OncoImmune: Research Funding. Zweegman:Takeda: Other: advisory board participation, Research Funding; Janssen: Other: advisory board participation, Research Funding; Celgene: Other: advisory board participation, Research Funding; Amgen: Other: advisory board participation. Hillengass:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; honoraria from Amgen, BMS, Celgene: Honoraria; BMS: Honoraria; Sanofi: Research Funding. Raab:Novartis: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Speakers Bureau. Hose:Sanofi: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; EngMab: Research Funding. Merz:Takeda: Honoraria, Research Funding; Celgene: Other: Travel grant; Janssen: Other: Travel grant. Kersten:Millennium/Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Mundipharma: Honoraria; Novartis Pharmaceuticals Corporation: Honoraria; Kite Pharma: Honoraria; Roche: Honoraria, Research Funding; Gilead Sciences: Honoraria; BMS: Honoraria; MSD: Honoraria; Amgen: Honoraria. Scheid:Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Weisel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sonneveld:Celgene Corporation, Amgen, Janssen, Karyopharm, SkylineDx, PharmaMar: Consultancy; Celgene Corporation, Amgen, Janssen, Karyopharm, PharmaMar, SkylineDx: Honoraria; Celgene, Amgen, Janssen, Karyopharm, Takeda: Consultancy, Honoraria, Research Funding. Goldschmidt:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Morphosys: Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.
The heavy/light chain (HLC) immunoassay quantifies the different heavy chain/light chain combinations of each immunoglobulin (Ig) class. This makes the HLC assay suited to quantify monoclonal ...immunoglobulins (M-protein) and for monitoring of patients with monoclonal gammopathies. This method is particularly advantageous for those samples in which electrophoretic quantification of the M-protein is not possible.
In this study we tested the analytical performance of the HLC assay in 166 routine clinical samples and in 27 samples derived from the Dutch external quality assessment (EQA) for M-protein diagnostics (74 participating laboratories). Analytical accuracy was assessed by verification that the sum of the HLC-pairs equaled total Ig concentration. Sensitivity of the HLC assay was determined in a direct method comparison with immunofixation electrophoresis (IFE).
Comparison of HLC data with routine Ig diagnostics in 27 EQA samples showed very good correlation for both the quantification of polyclonal and monoclonal IgG, IgA and IgM (Pearson correlations r were 0.94, 0.99 and 0.99, respectively; slopes were 0.94, 1.07 and 0.98, respectively). The overall concordance between IFE and the HLC ratio was high (93%) with a Cohen κ coefficient of 0.84. Discrepancies between both assays were mainly caused by the higher sensitivity of IFE to detect monoclonality.
We conclude that the HLC assay is an accurate method to quantify M-proteins that can improve monitoring of M-proteins in the beta fraction that cannot be quantified using electrophoretic techniques.
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