Thousands of non-coding variants have been associated with increased risk of human diseases, yet the causal variants and their mechanisms-of-action remain obscure. In an integrative study combining ...massively parallel reporter assays (MPRA), expression analyses (eQTL, meQTL, PCHiC) and chromatin accessibility analyses in primary cells (caQTL), we investigate 1,039 variants associated with multiple myeloma (MM). We demonstrate that MM susceptibility is mediated by gene-regulatory changes in plasma cells and B-cells, and identify putative causal variants at six risk loci (SMARCD3, WAC, ELL2, CDCA7L, CEP120, and PREX1). Notably, three of these variants co-localize with significant plasma cell caQTLs, signaling the presence of causal activity at these precise genomic positions in an endogenous chromosomal context in vivo. Our results provide a systematic functional dissection of risk loci for a hematologic malignancy.
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. (
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In this review article we discuss the role of the memory T cells in multiple myeloma (MM) and how they may influence immune responses in patients that received immunomodulating drugs and check point ...therapy.
Recently, we identified ELL2 as a susceptibility gene for multiple myeloma (MM). To understand its mechanism of action, we performed expression quantitative trait locus analysis in CD138
plasma cells ...from 1630 MM patients from four populations. We show that the MM risk allele lowers ELL2 expression in these cells (P
= 2.5 × 10
; β
= -0.24 SD), but not in peripheral blood or other tissues. Consistent with this, several variants representing the MM risk allele map to regulatory genomic regions, and three yield reduced transcriptional activity in plasmocytoma cell lines. One of these (rs3777189-C) co-locates with the best-supported lead variants for ELL2 expression and MM risk, and reduces binding of MAFF/G/K family transcription factors. Moreover, further analysis reveals that the MM risk allele associates with upregulation of gene sets related to ribosome biogenesis, and knockout/knockdown and rescue experiments in plasmocytoma cell lines support a cause-effect relationship. Our results provide mechanistic insight into MM predisposition.
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.
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.
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.
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.
NCT01208766.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background. The Revised International Staging system (R-ISS) is the standard risk stratification model used for newly diagnosed (ND) multiple myeloma (MM) (Palumbo et al. JCO 2015). R-ISS identifies ...3 groups of patients (pts) with different PFS and OS. However, 60% of pts are considered as intermediate-risk (R-ISS II), possibly including pts with different risk of progression/death. Recently, 1q copy number alterations (CNAs), which were not included in the R-ISS, proved to be a poor prognostic factor in NDMM pts.
The European Myeloma Network (EMN), under the umbrella of the HARMONY project, collected more than 7000 patient data from European clinical trials. The aim of this analysis is to revise the R-ISS risk stratification model, by analyzing the prognostic value of each single baseline risk feature, including 1q CNAs, to improve prognostication in NDMM pts.
Methods. Data from 15 European clinical trials enrolling NDMM pts from 2005 to 2014 were collected through EMN and registered in HARMONY platform. HARMONY is a European public-private partnership focusing on hematologic malignancies with unmet medical needs, including MM. OMOP Common Data Model was used to harmonize data. All pts received an immunomodulatory agent (IMiD) and/or a proteasome inhibitor (PI) upfront. In a multivariate Cox regression analysis adjusted for age, sex and therapy, we evaluated the impact of each risk feature on overall survival (OS) and progression-free survival (PFS). The hazard of death conferred by the most significant variables was used to create an additive risk score.
Results. 7077 NDMM pts were registered in the HARMONY platform and included in the analysis. Data were mature with a median follow-up of 75 months; median age was 62 years. The majority of pts were transplant-eligible (65%). 40% of the pts received IMiDs only, 15% PIs only, 46% both drug classes during their first-line treatment.
In a multivariate Cox model, ISS (II vs I HR 1.55 p<0.001, III vs I HR 2.02 p<0.001), del(17p) (HR 1.74, p<0.001), LDH (HR 1.65, p<0.001), t(4;14) (HR 1.56, p<0.001) and 1q CNAs (HR 1.45, p<0.001) had the highest impact on OS. ISS (II vs I HR 1.35 p<0.001, III vs I HR 1.53 p<0.001), t(4;14) (HR 1.49, p<0.001), del(17p) (HR 1.41, p<0.001), 1q CNAs (HR 1.37, p<0.001) and LDH (HR 1.33, p<0.001) had the most remarkable impact on PFS. t(14;16) had a significant effect on OS (HR 1.34, p=0.006) but not on PFS (HR 1.15, p=0.13); thus, it was not included in the model.
These prognostic variables were simultaneously present in 2227 pts and the most frequent reason of exclusion of the remaining pts was 1q CNAs that was missing in some of the trials. We exploited the OS impact of these risk features in pts with complete data to create an additive scoring system (Table 1).
Pts were then stratified into 4 groups: Low (n=429 (19.3%), score 0), Low-Intermediate (n=686 (30.8%), score 0.5-1, Intermediate-High (n=917 (41.2%), score 1.5-2.5 and High (n=195 (8.8%), score 3-5. Each group showed significantly different OS (Figure 1A) and PFS (Figure 1B).
Median OS was not reached vs 109.2 vs 68.5 vs 37.9 months and median PFS was 68 vs 45.5 vs 30.2 vs 19.9 months in the above 4 risk groups, respectively.
With this new stratification model, R-ISS stage II pts (n=1372) were better distributed into Low-Intermediate (n=517), Intermediate-High (n=811) and High risk (n=44) groups, confirming that this wide group included heterogeneous pts with a different risk of progression and/or death.
This new risk stratification maintained its prognostic value in subgroup analysis of transplant-eligible and transplant-ineligible pts and in pts receiving IMiDs, PIs or both.
Conclusion. This analysis on a large number of patient data collected thanks to a well-established European collaboration demonstrated that the existing R-ISS stratification model may be improved.
This additive scoring system based on the impact of single risk features could be the future risk stratification model for NDMM, so called “R2-ISS”.
About half of the pts can be classified as Low or Low-Intermediate risk and about half of the pts can be classified as Intermediate-High or High risk, representing an opportunity to design risk-adapted approaches in a meaningful number of pts.
Moreover, such additive risk score easily allows the inclusion of new prognostic variables in the future as they continue to emerge. The inclusion of new patient data is ongoing, and validation in an independent cohort is planned.
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D’Agostino:GSK: Membership on an entity’s Board of Directors or advisory committees. Waage:Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy; Shire: Honoraria. Zamagni:Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Takeda: Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau; Amgen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Speakers Bureau. Mateos:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; PharmaMar-Zeltia: Consultancy; Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Takeda: Consultancy, 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; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Larocca:Takeda: Membership on an entity’s Board of Directors or advisory committees; Celgene: 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; Amgen: Honoraria; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; GSK: Honoraria. van de Donk:Takeda: Other: Ad Board; Genentech: Other: Ad Board; Bayer: Other: Ad Board; BMS: Other: Ad Board, Research Funding; Amgen: Other: Ad Board, Research Funding; Celgene: Other: Ad Board, Research Funding; Novartis: Other: Ad Board; Janssen: Other: Ad Board, Research Funding. Cairns:Celgene, Amgen, Merck: Research Funding; Celgene: Other: Travel Support. Salwender:Takeda: Honoraria; Bristol-Myers Squibb/Celgene: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria; Sanofi: Honoraria; GlaxoSmithKline: Honoraria; AbbVie: Honoraria. 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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Multiple myeloma (MM) is a hematologic malignancy characterized by accumulation of plasma cells in the bone marrow (BM). Bone destruction is a complication of the disease and is usually associated ...with severe morbidity. The balance between receptor activator of nuclear factor-κB (NF-κB) ligand and osteoprotegerin (OPG) is of major importance in bone homeostasis. We have recently shown that serum OPG levels are lower in patients with myeloma than in healthy individuals. Here we show that myeloma cells can bind, internalize, and degrade OPG, thereby providing a possible explanation for the lower levels of OPG in the BM of patients with MM. This process is dependent on interaction of OPG with heparan sulfates on the myeloma cells. The results suggest a novel biologic mechanism for the bone disease associated with MM and that treatment of the bone disease with OPG lacking the heparin-binding domain should be considered.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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