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The addition of vorinostat to lenalidomide maintenance for patients with newly diagnosed multiple myeloma of all ages: results from 'Myeloma XI', a multicentre, open-label, randomised, phase III trial

Jenner, Matthew W; Pawlyn, Charlotte; Davies, Faith E; Menzies, Tom; Hockaday, Anna; Olivier, Catherine; Jones, John R; Karunanithi, Kamuraj; Lindsay, Jindriska; Kishore, Bhuvan; Cook, Gordon; Drayson, Mark T; Kaiser, Martin F; Owen, Roger G; Gregory, Walter; Cairns, David A; Morgan, Gareth J; Jackson, Graham H
Lenalidomide is an effective maintenance agent for patients with myeloma, prolonging first remission and, in transplant eligible patients, improving overall survival (OS) compared to observation. The 'Myeloma XI' trial, for newly diagnosed patients, aimed to evaluate whether the addition of the histone deacetylase inhibitor vorinostat to the lenalidomide maintenance backbone could improve outcomes further. Patients included in this analysis were randomised to maintenance therapy with lenalidomide alone (10 mg/day on days 1-21 of each 28-day cycle), or in combination with vorinostat (300 mg/day on day 1-7 and 15-21 of each 28-day cycle) with treatment continuing until unacceptable toxicity or progressive disease. There was no significant difference in median progression-free survival between those receiving lenalidomide-vorinostat or lenalidomide alone, 34 and 40 months respectively (hazard ratio [HR] 1.18, 95% confidence interval [CI] 0.96-1.44, p = 0.109). There was also no significant difference in median OS, not estimable and 75 months respectively (HR 0.99, 95% CI 0.76-1.29, p = 0.929). Subgroup analysis demonstrated no statistically significant heterogeneity in outcomes. Combination lenalidomide-vorinostat appeared to be poorly tolerated with more dose modifications, fewer cycles of maintenance therapy delivered and higher rates of discontinuation due to toxicity than lenalidomide alone. The trial did not meet its primary end-point, there was no benefit from the addition of vorinostat to lenalidomide maintenance.
PMID: 36541152
ISSN: 1365-2141
CID: 5394992

Characterizing the role of the immune microenvironment in multiple myeloma progression at a single cell level

Schinke, Carolina; Poos, Alexandra M; Bauer, Michael A; John, Lukas; Johnson, Sarah K; Deshpande, Shayu; Carrillo, Luis; Alapat, Daisy; Rasche, Leo; Thanendrarajan, Sharmilan; Zangari, Maurizio; Al Hadidi, Samer; van Rhee, Frits; Davies, Faith E; Raab, Marc S; Morgan, Gareth J; Weinhold, Niels
Early alterations within the bone marrow microenvironment that contribute to the progression of multiple myeloma (MM) from its precursor stages could hold the key to identifying novel therapeutic approaches, yet the intrinsic variability in cellular populations between patients together with differences in sample processing and analysis methods have made it difficult to identify consistent changes between datasets. Here, we used single-cell RNA sequencing of BM cells from precursor stages, monoclonal gammopathy of unknown significance (MGUS), smoldering MM (SMM) and newly diagnosed MM and analyzed our data in combination with a previously published dataset that used a similar patient population and sample processing. Despite vast interpatient heterogeneity, some alterations were seen consistently in both datasets. We identified changes in immune cell populations as disease progressed that were characterized by a substantial decrease in memory and naïve CD4 T cells and an increase in CD8+ effector T cells and T-regulatory cells. These alterations were further accompanied by an enrichment of non-clonal memory B cells and an increase of CD14 and CD16 monocytes in MM compared to its precursor stages. These results provide crucial information of the immune changes associated with the progression to clinical MM and can help to develop immune based strategies for patient stratification and early therapeutic intervention.
PMID: 35977111
ISSN: 2473-9537
CID: 5299972

A phase I/II open-label study of molibresib for the treatment of relapsed/refractory hematologic malignancies

Dawson, Mark A; Borthakur, Gautam; Huntly, Brian; Karadimitris, Anastasios; Alegre, Adrian; Chaidos, Aristeidis; Vogl, Dan T; Pollyea, Daniel A; Davies, Faith E; Morgan, Gareth J; Glass, Jacob; Kamdar, Manali; Mateos Manteca, Maria-Victoria; Tovar, Natalia; Yeh, Paul; García Delgado, Regina; Basheer, Faisal; Marando, Ludovica; Gallipoli, Paolo; Wyce, Anastasia; Krishnatry, Anu Shilpa; Barbash, Olena; Bakirtzi, Evi; Ferron-Brady, Geraldine; Karpinich, Natalie O; McCabe, Michael T; Foley, Shawn W; Horner, Thierry; Dhar, Arindam; Kremer, Brandon E; Dickinson, Michael
PURPOSE/OBJECTIVE:Molibresib is a selective, small molecule inhibitor of the BET protein family. This was an open-label, two-part, Phase I/II study investigating molibresib monotherapy for the treatment of hematological malignancies (NCT01943851). EXPERIMENTAL DESIGN/METHODS:Part 1 (dose escalation) determined the recommended Phase 2 dose (RP2D) of molibresib in patients with acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL), or multiple myeloma. Part 2 (dose expansion) investigated the safety and efficacy of molibresib at the RP2D in patients with relapsed/refractory myelodysplastic syndrome (MDS; as well as AML evolved from antecedent MDS) or cutaneous T cell lymphoma (CTCL). The primary endpoint in Part 1 was safety and the primary endpoint in Part 2 was objective response rate (ORR). RESULTS:There were 111 patients enrolled (87 in Part 1, 24 in Part 2). Molibresib RP2Ds of 75 mg QD (for MDS) and 60 mg QD (for CTCL) were selected. Most common Grade 3+ AEs included thrombocytopenia (37%), anemia (15%) and febrile neutropenia (15%). Six patients achieved complete responses (three in Part 1 [two AML, one NHL], three in Part 2 [MDS]), and seven patients achieved partial responses (six in Part 1 [four AML, two NHL], one in Part 2 [MDS]). The ORRs for Part 1, Part 2, and the total study population were 10% (95% CI: 4.8-18.7), 25% (95% CI: 7.3-52.4), and 13% (95% CI: 6.9-20.6), respectively. CONCLUSIONS:While anti-tumor activity was observed with molibresib, use was limited by gastrointestinal and thrombocytopenia toxicities. Investigations of molibresib as part of combination regimens may be warranted.
PMID: 36350312
ISSN: 1557-3265
CID: 5357332

Whole-genome analysis identifies novel drivers and high-risk double-hit events in relapsed/refractory myeloma

Ansari-Pour, Naser; Samur, Mehmet K; Flynt, Erin; Gooding, Sarah; Towfic, Fadi; Stong, Nicholas; Ortiz Estevez, Maria; Mavrommatis, Konstantinos; Walker, Brian A; Morgan, Gareth J; Munshi, Nikhil C; Avet Loiseau, Herve; Thakurta, Anjan
Large-scale analyses of genomic data from newly-diagnosed multiple myeloma patients (ndMM) have been undertaken, however, large-scale analysis of relapsed/refractory multiple myeloma (rrMM) has not been performed. We hypothesize that somatic variants chronicle the therapeutic exposures and clonal structure of myeloma from ndMM to rrMM stages. We generated whole genome sequencing (WGS) data from 418 tumors (386 patients) derived from six rrMM clinical trials and compared them with WGS from 198 unrelated ndMM patients in a population-based case-control fashion. We identified significantly enriched events at the rrMM stage, including drivers (DUOX2, EZH2, TP53), biallelic inactivation (TP53), non-coding mutations in bona fide drivers (TP53BP1, BLM), copy number aberrations (CNA; 1qGain, 17pLOH) and double-hit events (Amp1q-ISS3, 1qGain-17pLOH). Mutational signature analysis identified a subclonal defective mismatch repair signature enriched in rrMM and highly active in high mutation burden tumors, a likely feature of therapy-associated expanding subclones. Further analysis focused on the association of genomic aberrations enriched at different stages of resistance to immunomodulatory agent (IMiDsÃ’)-based therapy. This analysis revealed that TP53, DUOX2, 1qGain and 17pLOH increased in prevalence from ndMM to lenalidomide (LEN)- to pomalidomide (POM)-resistant stages while enrichment of MAML3 along with IGL and MYC translocations distinguished POM from the LEN subgroup. Genomic drivers associated with rrMM are those that confer clonal selective advantage under therapeutic pressure. Their role in therapy evasion should be evaluated further in longitudinal patient samples, to confirm these associations with the evolution of clinical resistance and to identify molecular subsets of rrMM for the development of targeted therapies.
PMID: 36223594
ISSN: 1528-0020
CID: 5360992

Clinical Characteristics and Outcomes of IgD Myeloma: Experience across UK National Trials

Agbuduwe, Charles; Iqbal, Gulnaz; Cairns, David A; Menzies, Tom; Dunn, Janet; Gregory, Walter Martin; Kaiser, Martin F; Owen, Roger G; Pawlyn, Charlotte; Child, J Anthony; Davies, Faith E; Morgan, Gareth J; Jackson, Graham H; Drayson, Mark T; Basu, Supratik
IgD myeloma is a subtype often considered to have adverse features and inferior survival but there is a paucity of data from large clinical studies. We compare the clinical characteristics and outcomes of IgD myeloma patients from UK Phase III myeloma trials analysed in two groups; old (1980-2002) and recent (2002-2016) clinical trials, based on the time of adoption of novel myeloma therapies. IgD myeloma patients comprised 44/2789 (1.6%) and 70/5773 (1.2%) of the old and recent trials respectively. Overall, IgD myeloma was associated with male predominance, low-level paraproteinemia (<10g/l) and lambda light chain preference. The frequency of ultra-high risk cytogenetics was similar in IgD myeloma compared with other subtypes (4.3% vs 5.3%, p>0.99). Despite the old trial series being a younger group (median age: 59 years vs 63 years, p=0.015), there was a higher frequency of bone lesions, advanced stage at diagnosis, worse performance status and severe renal impairment compared with the recent trials. Furthermore, the early mortality rate was significantly higher for the old trial series (20% vs 4%, p=0.01). The overall response rate following induction therapy was significantly higher in the recent trials (89% vs 43%, p<0.0001) and this was consistent with improved median overall survival (48 months; 95% CI 35-67 months vs 22 months, 95% CI 16-29 months). Survival outcomes for IgD myeloma have significantly improved and are now comparable to other myeloma types due to earlier diagnosis, novel therapies and improved supportive care. (Myeloma IX International Standard Randomised Controlled Trial Number: 68454111, Myeloma XI International Standard Randomised Controlled Trial Number: 49407852).
PMID: 35790108
ISSN: 2473-9537
CID: 5280292

The spatio-temporal evolution of multiple myeloma from baseline to relapse-refractory states

Rasche, Leo; Schinke, Carolina; Maura, Francesco; Bauer, Michael A; Ashby, Cody; Deshpande, Shayu; Poos, Alexandra M; Zangari, Maurizio; Thanendrarajan, Sharmilan; Davies, Faith E; Walker, Brian A; Barlogie, Bart; Landgren, Ola; Morgan, Gareth J; van Rhee, Frits; Weinhold, Niels
Deciphering Multiple Myeloma evolution in the whole bone marrow is key to inform curative strategies. Here, we perform spatial-longitudinal whole-exome sequencing, including 140 samples collected from 24 Multiple Myeloma patients during up to 14 years. Applying imaging-guided sampling we observe three evolutionary patterns, including relapse driven by a single-cell expansion, competing/co-existing sub-clones, and unique sub-clones at distinct locations. While we do not find the unique relapse sub-clone in the baseline focal lesion(s), we show a close phylogenetic relationship between baseline focal lesions and relapse disease, highlighting focal lesions as hotspots of tumor evolution. In patients with ≥3 focal lesions on positron-emission-tomography at diagnosis, relapse is driven by multiple distinct sub-clones, whereas in other patients, a single-cell expansion is typically seen (p < 0.01). Notably, we observe resistant sub-clones that can be hidden over years, suggesting that a prerequisite for curative therapies would be to overcome not only tumor heterogeneity but also dormancy.
PMCID:9349320
PMID: 35922426
ISSN: 2041-1723
CID: 5287682

Perspectives on the Risk-Stratified Treatment of Multiple Myeloma

Davies, Faith E; Pawlyn, Charlotte; Usmani, Saad Z; San-Miguel, Jesus F; Einsele, Hermann; Boyle, Eileen M; Corre, Jill; Auclair, Daniel; Cho, Hearn Jay; Lonial, Sagar; Sonneveld, Pieter; Stewart, A Keith; Bergsagel, P Leif; Kaiser, Martin F; Weisel, Katja; Keats, Jonathan J; Mikhael, Joseph R; Morgan, Kathryn E; Ghobrial, Irene M; Orlowski, Robert Z; Landgren, C Ola; Gay, Francesca; Caers, Joseph; Chng, Wee Joo; Chari, Ajai; Walker, Brian A; Kumar, Shaji K; Costa, Luciano J; Anderson, Kenneth C; Morgan, Gareth J
The multiple myeloma treatment landscape has changed dramatically. This change, paralleled by an increase in scientific knowledge, has resulted in significant improvement in survival. However, heterogeneity remains in clinical outcomes, with a proportion of patients not benefiting from current approaches and continuing to have a poor prognosis. A significant proportion of the variability in outcome can be predicted on the basis of clinical and biochemical parameters and tumor-acquired genetic variants, allowing for risk stratification and a more personalized approach to therapy. This article discusses the principles that can enable the rational and effective development of therapeutic approaches for high-risk multiple myeloma.
PMID: 35653112
ISSN: 2643-3249
CID: 5277622

MGP Panel is a comprehensive targeted genomics panel for molecular profiling of multiple myeloma patients

Sudha, Parvathi; Ahsan, Aarif; Ashby, Cody; Kausar, Tasneem; Khera, Akhil; Kazeroun, Mohammad; Hsu, Chih-Chao; Wang, Lin; Fitzsimons, Evelyn; Salminen, Outi; Blaney, Patrick; Czader, Magdalena; Williams, Jonathan; Abu Zaid, Mohammad I; Ansari-Pour, Naser; Yong, Kwee L; van Rhee, Frits; Pierceall, William E; Morgan, Gareth J; Flynt, Erin; Gooding, Sarah; Abonour, Rafat; Ramasamy, Karthik; Thakurta, Anjan; Walker, Brian A
PURPOSE/OBJECTIVE:We designed a comprehensive multiple myeloma (MM) targeted sequencing panel to identify common genomic abnormalities in a single assay and validated it against known standards. EXPERIMENTAL DESIGN/METHODS:The panel comprised 228 genes/exons for mutations, 6 regions for translocations, and 56 regions for copy number abnormalities (CNAs). Toward panel validation, targeted sequencing was conducted on 233 patient samples and further validated using clinical fluorescence in situ hybridization (FISH) (translocations), multiplex ligation probe analysis (MLPA) (CNAs), whole genome sequencing (WGS) (CNAs, mutations, translocations) or droplet digital PCR (ddPCR) of known standards (mutations). RESULTS:Canonical IgH translocations were detected in 43.2% of patients by sequencing, and aligned with FISH except for one patient. CNAs determined by sequencing and MLPA for 22 regions were comparable in 103 samples and concordance between platforms was R2=0.969. VAFs for 74 mutations were compared between sequencing and ddPCR with concordance of R2=0.9849. CONCLUSIONS:In summary, we have developed a targeted sequencing panel that is as robust or superior to FISH and WGS. This molecular panel is cost effective, comprehensive, clinically actionable and can be routinely deployed to assist risk stratification at diagnosis or post-treatment to guide sequencing of therapies.
PMID: 35522533
ISSN: 1557-3265
CID: 5216472

Epigenomic translocation of H3K4me3 broad domains over oncogenes following hijacking of super-enhancers

Mikulasova, Aneta; Kent, Daniel; Trevisan-Herraz, Marco; Karataraki, Nefeli; Fung, Kent T M; Ashby, Cody; Cieslak, Agata; Yaccoby, Shmuel; van Rhee, Frits; Zangari, Maurizio; Thanendrarajan, Sharmilan; Schinke, Carolina; Morgan, Gareth J; Asnafi, Vahid; Spicuglia, Salvatore; Brackley, Chris A; Corcoran, Anne E; Hambleton, Sophie; Walker, Brian A; Rico, Daniel; Russell, Lisa J
Chromosomal translocations are important drivers of hematological malignancies whereby proto-oncogenes are activated by juxtaposition with super-enhancers, often called enhancer hijacking. We analysed the epigenomic consequences of rearrangements between the super-enhancers of the immunoglobulin heavy locus (IGH) and proto-oncogene CCND1 that are common in B cell malignancies. By integrating BLUEPRINT epigenomic data with DNA breakpoint detection, we characterised the normal chromatin landscape of the human IGH locus and its dynamics after pathological genomic rearrangement. We detected an H3K4me3 broad domain (BD) within the IGH locus of healthy B cells that was absent in samples with IGH-CCND1 translocations. The appearance of H3K4me3-BD over CCND1 in the latter was associated with overexpression and extensive chromatin accessibility of its gene body. We observed similar cancer-specific H3K4me3-BDs associated with super-enhancer hijacking of other common oncogenes in B cell (MAF, MYC and FGFR3/NSD2) and in T-cell malignancies (LMO2, TLX3 and TAL1). Our analysis suggests that H3K4me3-BDs can be created by super-enhancers and supports the new concept of epigenomic translocation, where the relocation of H3K4me3-BDs from cell identity genes to oncogenes accompanies the translocation of super-enhancers.
PMID: 34933939
ISSN: 1549-5469
CID: 5108822

Chromosomal abnormalities in multiple myeloma

Mikulasova, Aneta; Morgan, Gareth J; Walker, Brian A
PMID: 35710551
ISSN: 2056-676x
CID: 5281712