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Diagnosis and monitoring for light chain only and oligosecretory myeloma using serum free light chain tests
Heaney, Jennifer L J; Campbell, John P; Griffin, Anne E; Birtwistle, Jane; Shemar, Meena; Child, J Anthony; Gregory, Walter M; Cairns, David A; Morgan, Gareth; Jackson, Graham; Drayson, Mark T
This study aims to guide the integration of serum free light chain (sFLC) tests into clinical practice, including a new rapid test (Seralite® ). Blood and urine analysis from 5573 newly diagnosed myeloma patients identified 576 light chain only (LCO) and 60 non-secretory (NS) cases. Serum was tested by Freelite® and Seralite® at diagnosis, maximum response and relapse. 20% of LCO patients had urine FLC levels below that recommended for measuring response but >97% of these had adequate sFLC levels (oligosecretory). The recommended Freelite® sFLC ≥100 mg/l for measuring response was confirmed and the equivalent Seralite® FLC difference (dFLC) >20 mg/l identified. By both methods, ≥38% of NS patients had measurable disease (oligosecretory). Higher sFLC levels were observed on Freelite® at all time points. However, good clinical concordance was observed at diagnosis and in response to therapy. Achieving at least a very good partial response according to either sFLC method was associated with better patient survival. Relapse was identified using a Freelite® sFLC increase >200 mg/l and found 100% concordance with a corresponding Seralite® dFLC increase >30 mg/l. Both Freelite® and Seralite® sensitively diagnose and monitor LCO/oligosecretory myeloma. Rapid testing by Seralite® could fast-track FLC screening and monitoring. Response by sFLC assessment was prognostic for survival and demonstrates the clinical value of routine sFLC testing.
PMID: 28573706
ISSN: 1365-2141
CID: 3695372
Assessing the effect of obesity-related traits on multiple myeloma using a Mendelian randomisation approach [Letter]
Went, M; Sud, A; Law, P J; Johnson, D C; Weinhold, N; Försti, A; van Duin, M; Mitchell, J S; Chen, B; Kuiper, R; Stephens, O W; Bertsch, U; Campo, C; Einsele, H; Gregory, W M; Henrion, M; Hillengass, J; Hoffmann, P; Jackson, G H; Lenive, O; Nickel, J; Nöthen, M M; da Silva Filho, M I; Thomsen, H; Walker, B A; Broyl, A; Davies, F E; Langer, C; Hansson, M; Kaiser, M; Sonneveld, P; Goldschmidt, H; Hemminki, K; Nilsson, B; Morgan, G J; Houlston, R S
PMCID:5520395
PMID: 28622301
ISSN: 2044-5385
CID: 3695392
Adverse Metaphase Cytogenetics Can Be Overcome by Adding Bortezomib and Thalidomide to Fractionated Melphalan Transplants
Jethava, Yogesh S; Mitchell, Alan; Epstein, Joshua; Zangari, Maurizio; Yaccoby, Shmuel; Tian, Erming; Waheed, Sarah; Khan, Rashid; Papanikolaou, Xenofon; Grazziutti, Monica; Cottler-Fox, Michele; Petty, Nathan; Steward, Douglas; Panozzo, Susan; Bailey, Clyde; Hoering, Antje; Crowley, John; Sawyer, Jeffrey; Morgan, Gareth; Barlogie, Bart; van Rhee, Frits
Purpose: To determine whether a reduction in the intensity of Total Therapy (TT) reduces toxicity and maintains efficacy.Experimental Design: A total of 289 patients with gene expression profiling (GEP70)-defined low-risk multiple myeloma were randomized between a standard arm (TT4-S) and a light arm (TT4-L). TT4-L employed one instead of two inductions and consolidations. To compensate for potential loss of efficacy of TT4-L, bortezomib and thalidomide were added to fractionated melphalan 50 mg/m2/d for 4 days.Results: Grade ≥3 toxicities and treatment-related mortalities were not reduced in TT4-L. Complete response (CR) rates were virtually identical (P = 0.2; TT4-S, 59%; TT4-L, 61% at 2 years), although CR duration was superior with TT4-S (P = 0.05; TT4-S, 87%; TT4-L, 81% at 2 years). With a median follow-up of 4.5 years, there was no difference in overall survival (OS) and progression-free survival (PFS). Whereas metaphase cytogenetic abnormalities (CAs) tended to be an adverse feature in TT4-S, as with predecessor TT trials, the reverse applied to TT4-L. Employing historical TT3a as training and TT3b as test set, 51 gene probes (GEP51) significantly differentiated the presence and absence of CA (q < 0.0001), seven of which function in DNA replication, recombination, and repair. Applying the GEP51 model to clinical outcomes, OS and PFS were significantly inferior with GEP51/CA in TT4-S; such a difference was not observed in TT4-L.Conclusions: We identified a prognostic CA-linked GEP51 signature, the adversity of which could be overcome by potentially synergizing anti-multiple myeloma effects of melphalan and bortezomib. These exploratory findings require confirmation in a prospective randomized trial. Clin Cancer Res; 23(11); 2665-72. ©2016 AACR.
PMCID:6080620
PMID: 27810902
ISSN: 1078-0432
CID: 3695302
Extensive Remineralization of Large Pelvic Lytic Lesions Following Total Therapy Treatment in Patients With Multiple Myeloma
Mohan, Meera; Samant, Rohan S; Yoon, Donghoon; Buros, Amy F; Branca, Antonio; Montgomery, Corey O; Nicholas, Richard; Suva, Larry J; Morello, Roy; Thanendrarajan, Sharmilan; Schinke, Carolina; Yaccoby, Shmuel; van Rhee, Frits; Davies, Faith E; Morgan, Gareth J; Zangari, Maurizio
Osteolytic bone lesions are a hallmark of multiple myeloma (MM) bone disease. Bone destruction is associated with severely imbalanced bone remodeling, secondary to increased osteoclastogenesis and significant osteoblast suppression. Lytic lesions of the pelvis are relatively common in MM patients and are known to contribute to the increased morbidity because of the high risk of fracture, which frequently demands extensive surgical intervention. After observing unexpected radiological improvement in serial large pelvic CT assessment in a patient treated in a total therapy protocol, the radiographic changes of pelvic osteolytic lesions by PET/CT scanning in patients who received Total Therapy 4 (TT4) treatment for myeloma were retrospectively analyzed. Sixty-two (62) patients with lytic pelvic lesions >1 cm in diameter were identified at baseline PET/CT scanning. Follow-up CT studies showed that 27 of 62 patients (43%) with large baseline pelvic lesions achieved significant reaccumulation of radiodense mineralization at the lytic cortical site. The average size of lytic lesions in which remineralization occurred was 4 cm (range, 1.3 to 10 cm). This study clearly demonstrates that mineral deposition in large pelvic lesions occurs in a significant proportion of MM patients treated with TT4, potentially affecting patient outcomes, quality of life, and future treatment strategies. © 2017 American Society for Bone and Mineral Research.
PMCID:5466479
PMID: 28240368
ISSN: 1523-4681
CID: 3648882
Search for rare protein altering variants influencing susceptibility to multiple myeloma
Scales, Matthew; Chubb, Daniel; Dobbins, Sara E; Johnson, David C; Li, Ni; Sternberg, Michael J; Weinhold, Neils; Stein, Caleb; Jackson, Graham; Davies, Faith E; Walker, Brian A; Wardell, Christopher P; Houlston, Richard S; Morgan, Gareth J
The genetic basis underlying the inherited risk of developing multiple myeloma (MM) is largely unknown. To examine the impact of rare protein altering variants on the risk of developing MM we analyzed high-coverage exome sequencing data on 513 MM cases and 1,569 healthy controls, performing both single variant and gene burden tests. We did not identify any recurrent coding low-frequency alleles (1-5%) with moderate effect that were statistically associated with MM. In a gene burden analysis we did however identify a promising relationship between variation in the marrow kinetochore microtubule stromal gene KIF18A, which plays a role in control mitotic chromosome positioning dynamics, and risk of MM (P =3.6x10-6). Further analysis showed KIF18A displays a distinct pattern of expression across molecular subgroups of MM as well as being associated with patient survival. Our results inform future study design and provide a resource for contextualizing the impact of candidate MM susceptibility genes.
PMCID:5482649
PMID: 28404951
ISSN: 1949-2553
CID: 3648912
The varied distribution and impact of RAS codon and other key DNA alterations across the translocation cyclin D subgroups in multiple myeloma
Stein, Caleb K; Pawlyn, Charlotte; Chavan, Shweta; Rasche, Leo; Weinhold, Niels; Corken, Adam; Buros, Amy; Sonneveld, Pieter; Jackson, Graham H; Landgren, Ola; Mughal, Tariq; He, Jie; Barlogie, Bart; Bergsagel, P Leif; Davies, Faith E; Walker, Brian A; Morgan, Gareth J
We examined a set of 805 cases that underwent DNA sequencing using the FoundationOne Heme (F1H) targeted sequencing panel and gene expression profiling. Known and likely variant calls from the mutational data were analyzed for significant associations with gene expression defined translocation cyclin D (TC) molecular subgroups. The spectrum of KRAS, NRAS, and BRAF codon mutations varied across subgroups with NRAS mutations at Q61 codon being common in hyperdiploid (HRD) and t(11;14) myeloma while being rare in MMSET and MAF. In addition, the presence of RAS-RAF mutations was inversely associated with NFκB pathway activation in all subgroups excluding MAF. In the MMSET subgroup, cases with low FGFR3 expression frequently had RAS-RAF mutations. Conditional inference tree analysis determined that mutation and homozygous deletion of TP53, CDKN2C, and RB1 were key prognostic factors associated with adverse outcome in a non-relapse clinical setting. In conclusion, this study highlights the heterogeneity in the distribution and clinical outcomes of RAS codon and other mutations in multiple myeloma dependent upon primary molecular subgroup.
PMCID:5438613
PMID: 28427158
ISSN: 1949-2553
CID: 3648922
Assessment of Total Lesion Glycolysis by 18F FDG PET/CT Significantly Improves Prognostic Value of GEP and ISS in Myeloma
McDonald, James E; Kessler, Marcus M; Gardner, Michael W; Buros, Amy F; Ntambi, James A; Waheed, Sarah; van Rhee, Frits; Zangari, Maurizio; Heuck, Christoph J; Petty, Nathan; Schinke, Carolina; Thanendrarajan, Sharmilan; Mitchell, Alan; Hoering, Antje; Barlogie, Bart; Morgan, Gareth J; Davies, Faith E
Purpose: Fluorine-18 fluorodeoxyglucose positron emission tomography with CT attenuation correction (18F-FDG PET/CT) is useful in the detection and enumeration of focal lesions and in semiquantitative characterization of metabolic activity (glycolytic phenotype) by calculation of glucose uptake. Total lesion glycolysis (TLG) and metabolic tumor volume (MTV) have the potential to improve the value of this approach and enhance the prognostic value of disease burden measures. This study aims to determine whether TLG and MTV are associated with progression-free survival (PFS) and overall survival (OS), and whether they improve risk assessments such as International Staging System (ISS) stage and GEP70 risk.Experimental Design: 192 patients underwent whole body PET/CT in the Total Therapy 3A (TT3A) trial and were evaluated using three-dimensional region-of-interest analysis with TLG, MTV, and standard measurement parameters derived for all focal lesions with peak SUV above the background red marrow signal.Results: In multivariate analysis, baseline TLG > 620 g and MTV > 210 cm3 remained a significant factor of poor PFS and OS after adjusting for baseline myeloma variables. Combined with the GEP70 risk score, TLG > 205 g identifies a high-risk-behaving subgroup with poor expected survival. In addition, TLG > 205 g accurately divides ISS stage II patients into two subgroups with similar outcomes to ISS stage I and ISS stage III, respectively.Conclusions: TLG and MTV have significant survival implications at baseline and offer a more precise quantitation of the glycolytic phenotype of active disease. These measures can be assessed more readily than before using FDA-approved software and should be standardized and incorporated into clinical trials moving forward. Clin Cancer Res; 23(8); 1981-7. ©2016 AACR.
PMCID:5777601
PMID: 27698001
ISSN: 1078-0432
CID: 3648832
Immunologic approaches for the treatment of multiple myeloma
Rasche, Leo; Weinhold, Niels; Morgan, Gareth J; van Rhee, Frits; Davies, Faith E
The FDA approval of two monoclonal antibodies in 2015has heralded a new era of targeted immunotherapies for multiple myeloma (MM). In this review we discuss the recent approaches using different immunological components to treat MM. In particular, we review current monoclonal antibody based therapies, engineered T- and NK cell products, 'off-target' immunomodulation, and strategies utilizing allogeneic cell transplantation in MM. We discuss how an immunologic approach offers promise for the treatment of this genetically heterogeneous disease, and how patients with acquired drug resistance may particularly benefit from these therapies. We also describe some of the limitations of the current strategies and speculate on the future of personalized immunotherapies for MM.
PMCID:5604432
PMID: 28431262
ISSN: 1532-1967
CID: 3648932
Overexpression of EZH2 in multiple myeloma is associated with poor prognosis and dysregulation of cell cycle control
Pawlyn, C; Bright, M D; Buros, A F; Stein, C K; Walters, Z; Aronson, L I; Mirabella, F; Jones, J R; Kaiser, M F; Walker, B A; Jackson, G H; Clarke, P A; Bergsagel, P L; Workman, P; Chesi, M; Morgan, G J; Davies, F E
Myeloma is heterogeneous at the molecular level with subgroups of patients characterised by features of epigenetic dysregulation. Outcomes for myeloma patients have improved over the past few decades except for molecularly defined high-risk patients who continue to do badly. Novel therapeutic approaches are, therefore, required. A growing number of epigenetic inhibitors are now available including EZH2 inhibitors that are in early-stage clinical trials for treatment of haematological and other cancers with EZH2 mutations or in which overexpression has been correlated with poor outcomes. For the first time, we have identified and validated a robust and independent deleterious effect of high EZH2 expression on outcomes in myeloma patients. Using two chemically distinct small-molecule inhibitors, we demonstrate a reduction in myeloma cell proliferation with EZH2 inhibition, which leads to cell cycle arrest followed by apoptosis. This is mediated via upregulation of cyclin-dependent kinase inhibitors associated with removal of the inhibitory H3K27me3 mark at their gene loci. Our results suggest that EZH2 inhibition may be a potential therapeutic strategy for the treatment of myeloma and should be investigated in clinical studies.
PMCID:5380911
PMID: 28362441
ISSN: 2044-5385
CID: 3695352
Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells
Tumber, Anthony; Nuzzi, Andrea; Hookway, Edward S; Hatch, Stephanie B; Velupillai, Srikannathasan; Johansson, Catrine; Kawamura, Akane; Savitsky, Pavel; Yapp, Clarence; Szykowska, Aleksandra; Wu, Na; Bountra, Chas; Strain-Damerell, Claire; Burgess-Brown, Nicola A; Ruda, Gian Filippo; Fedorov, Oleg; Munro, Shonagh; England, Katherine S; Nowak, Radoslaw P; Schofield, Christopher J; La Thangue, Nicholas B; Pawlyn, Charlotte; Davies, Faith; Morgan, Gareth; Athanasou, Nick; Müller, Susanne; Oppermann, Udo; Brennan, Paul E
Methylation of lysine residues on histone tail is a dynamic epigenetic modification that plays a key role in chromatin structure and gene regulation. Members of the KDM5 (also known as JARID1) sub-family are 2-oxoglutarate (2-OG) and Fe2+-dependent oxygenases acting as histone 3 lysine 4 trimethyl (H3K4me3) demethylases, regulating proliferation, stem cell self-renewal, and differentiation. Here we present the characterization of KDOAM-25, an inhibitor of KDM5 enzymes. KDOAM-25 shows biochemical half maximal inhibitory concentration values of <100 nM for KDM5A-D in vitro, high selectivity toward other 2-OG oxygenases sub-families, and no off-target activity on a panel of 55 receptors and enzymes. In human cell assay systems, KDOAM-25 has a half maximal effective concentration of ∼50 μM and good selectivity toward other demethylases. KDM5B is overexpressed in multiple myeloma and negatively correlated with the overall survival. Multiple myeloma MM1S cells treated with KDOAM-25 show increased global H3K4 methylation at transcriptional start sites and impaired proliferation.
PMCID:5361737
PMID: 28262558
ISSN: 2451-9448
CID: 3695342