Faculty Bibliography

Despite  improvements in outcome, 15-25% of newly diagnosed multiple myeloma (MM) patients have treatment resistant high-risk (HR) disease with a poor survival. The lack of a genetic basis for HR has focused attention on the role played by epigenetic changes. Aberrant expression and somatic mutations affecting genes involved in the regulation of tri-methylation of the lysine (K) 27 on histone 3 H3 (H3K27me3) are common in cancer. H3K27me3 is catalyzed by EZH2, the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2). The deregulation of H3K27me3 has been shown to be involved in oncogenic transformation and tumor progression in a variety of hematological malignancies including MM. Recently we have shown that aberrant overexpression of the PRC2 subunit PHD Finger Protein 19 (PHF19) is the most significant overall contributor to HR status further focusing attention on the role played by epigenetic change in MM. By modulating both the PRC2/EZH2 catalytic activity and recruitment, PHF19 regulates the expression of key genes involved in cell growth and differentiation. Here we review the expression, regulation and function of PHF19 both in normal and the pathological contexts of solid cancers and MM. We present evidence that strongly implicates PHF19 in the regulation of genes important in cell cycle and the genetic stability of MM cells making it highly relevant to HR MM behavior. A detailed understanding of the normal and pathological functions of PHF19 will allow us to design therapeutic strategies able to target aggressive subsets of MM.

Introduction: The incidence of multiple myeloma (MM) varies by ethnicity with Black patients approximately twice as likely to develop MM compared to White or Asian (Black: White males 2.9:1, females 2.2:1). The National Cancer Registration and Analysis Service (NCRAS) in 2015 reported the incidence of MM by ethnicity in England over 10 years to be 85.5% White; 5.4% Black; 3.6% Asian and 1.9% Other. Ethnic minorities have been reported to be under-represented in clinical trials partly because of socio-economic factors; however, it is unknown if these disparities exist in state funded health care systems where access to healthcare is free and should be equitable.
Method(s): Ethnicity, baseline demographics, progression-free survival (PFS) and overall survival (OS) were collected from patients enrolled into 1 ^st line UK academic transplant eligible (TE) and transplant non-eligible (TNE) - Myeloma IX, XI and XIV trials, and at 1 ^st relapse - Myeloma X and XII clinical trials. These trials enrolled from 2003 to 2021. The Myeloma XII and XIV (FiTNEss) trials are currently enrolling, all other trials have closed. Ethnicity was coded by White, Black, Asian and Other in line with Office for National Statistics (ONS) categories. Patients were enrolled across 120 centres covering a wide geographical distribution in the UK. These studies were designed to have permissive eligibility criteria to enrol as close to real world patients as possible. Baseline characteristics were summarised descriptively and comparisons made using the chi-squared test. Comparisons with population-level data used one-sample chi-squared tests. Survivor functions were estimated using the Kaplan-Meier method and were compared using the logrank test. Cox proportional hazards models with suitable interaction terms were used to test for heterogeneity. All tests were called significant at the 5% level.
Result(s): 7,291 patients were enrolled across 5 randomised controlled trials over 18 years. Overall, the ethnic distribution was White 93.8%, Black 2.2%, Asian 1.8%, Other 0.6% and unknown 1.6%. The skew to enrolment of White patients was more apparent in the TNE studies (Myeloma IX non-intensive: White 97.4%, Black 1.3%, Asian 0.4%; Myeloma XI non-intensive: White 94.5%, Black 1.8%, Asian 1.6%, Myeloma XIV: White 94.2%, Black 0%, Asian 3.2%). This was different to the incidence of myeloma cases across the UK with the difference most apparent in TNE studies (TE trials (observed vs NCRAS, P < 0.0001); TNE trials (observed vs NCRAS, P < 0.0001); 1 ^st relapse trials (observed vs NCRAS, P = 0.035)). Enrolment distribution by ethnicity was consistent over the 18 years, with no change in diversity over time despite there being an increase in UK non-white populations. In the Myeloma IX trial, there was no significant difference in age at enrolment; however, the performance status in Black patients was worse than non-Black (P = 0.045), there was fewer cytogenetic high risk Black patients (P = 0.007) and less ISS 1 Black patients vs non-Black (P = 0.0416). There were no demographic differences by ethnicity in the Myeloma XI trial. The outcomes of patients by PFS or OS by ethnic group was similar within each trial (figure 1). An overall improvement in OS for was demonstrated over time from Myeloma IX to the Myeloma XI trial with the incorporation of novel agents (median OS MRC-Myeloma IX: 48 months vs. median OS NCRI Myeloma-XI: 70 months, P < 0.0001). There was no evidence of heterogeneity of effect with respect to ethnicity (P = 0.456) suggesting all ethnic sub-groups benefited from this improvement in OS.
Conclusion(s): Enrolment of ethnic minorities into academic clinical trials in the UK was below that expected despite enrolling from >100 geographically spread sites and intended equitable access to healthcare. All ethnic groups derived an OS benefit from novel agents within trials that were not otherwise routinely available; however, a substantial proportion of ethnic minorities were not enrolled particularly TNE patients, thereby limiting their survival gains. Understanding causes of inequality and addressing these is a priority for the UK-MRA to ensure that all groups can potentially benefit, and trial results are representative of the UK population. [Formula presented] Disclosures: Popat: Abbvie, Takeda, Janssen, and Celgene: Consultancy; AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria; Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Janssen and BMS: Other: travel expenses. Craig: Celgene: Research Funding; Merck Sharpe & Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Davies: Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Cairns: Amgen: Research Funding; Merck Sharpe and Dohme: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Olivier: Merck Sharpe and Dohme: Research Funding; Takeda: Research Funding; Amgen: Research Funding; Celgene / BMS: Research Funding. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Cook: BMS/Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy. OffLabel Disclosure: Revlimid and carfilzomib combinations are used off label
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Introduction: Inappropriate activation of Wnt/beta-catenin signaling plays a role in some cancers. beta-catenin (beta-cat) levels in the cell can be regulated by a cadherin-mediated sequestration into membrane-bound and free cytosolic pools, with the later translocating to the nucleus and driving TCF-mediated transcriptional activity following Wnt signal transduction. While sequencing has shown that MM lacks the mutations that typically lead to constitutive beta-cat activation seen in other cancers, we and others have demonstrated that Wnt/beta-catenin signaling is nonetheless activated in MM and can regulate MM growth. The mechanism driving beta-cat stabilization and activation in MM is unclear. E- and N-cadherin (N-cad) expression is elevated in MM compared to plasma cells from healthy donors. We hypothesized that that cadherins can regulate Wnt/beta-catenin signaling in MM.
Material(s) and Method(s): We detected different forms of beta-cat expression in a panel of human MM cell lines (HMCLs) and CD138 PC from MM patients by several approaches. Cadherin gain- or loss-of-function MM models were produced by expressing wild-type N-cad in MMS1 and ARP1 (lack endogenous N-cadherin expression) using a lentiviral system to create stable cell lines (N-Cad/MMS1 and N-cad/ARP1) and empty vector control (EV/MMS1, and EV-ARP1). We knocked down N-cadherin in the JJN3 cell line expressing high level of endogenous N-cadherin using shRNA specific for N-cad (shNcad/JJN3) or scrambled control shRNA (shCont/JJN3) by lentiviral-mediated transfection. We used a TCF reporter system to evaluate beta-cat transcriptional activity as previously described.
Result(s): We surveyed 25 HMCLs and CD138-selected plasma cells from 72 newly diagnosed MM for active beta-cat with an antibody that specifically recognizes the unphosphorylated active form of beta-cat. Higher levels of cytosolic and/or nuclear beta-cat protein were seen in 13 of 25 (52%) HMCLs and 36 of 72 (50%) primary MM PC. Correlation of beta-cat protein levels with global mRNA expression levels in primary PC revealed significant correlation with only one gene, CDH2 (N-cad). Remarkably, those primary MM with high beta-cat levels but low CDH2 levels expressed high levels of E-cadherin/CHD1 mRNA. This posed the question of whether CDH2 is a direct target of TCF/beta-cat transcriptional activity or whether high levels of CDH2 lead to increased levels of beta-cat protein via sequestration. Both CDH2 mRNA and protein were correlated with beta-cat protein but not beta-cat mRNA in 23/25 HMCLs. Co-immunoprecipitation revealed that N-cad and beta-cat complexes could be identified in HMCLs and primary MM. Consistent with N-cad-mediated stabilization of beta-cat both total and unphosphorylated beta-cat levels and TCF activity were significantly elevated in N-cad/MMS1 and N-Cad/ARP1 cells relative to controls. In contrast, shRNA mediated knockdown of N-cad led to a loss of both N-cad and beta-cat protein levels and TCF-dependent transcription activity relative to controls. These findings provide evidence that beta-cat/TCF signaling can be regulated by N-cad in MM. CDH2 mRNA is significantly elevated in the MS and HY subgroups of MM. To search for a potential mechanism of CDH2 transcriptional regulation in MS MM, we compared TCF activity and beta-cat protein levels in MS versus non-MS HMCLs. TCF activity and active beta-cat were elevated in MS versus non-MS forms of MM and B-cell lymphoma lacking N-cadherin. To determine if MMSET is required to up-regulate N-cad expression, we depleted the full-length MMSET protein in KMS11 cells. The results revealed a dramatic loss of total and unphosphorylated beta-cat protein, but not mRNA, and loss of both CDH2 mRNA and protein relative to controls. These data suggest that MMSET can regulate the transcription of the CDH2 gene. MMS1 and ARP1 cells stably expressing N-cad exhibited enhanced adhesion to bone marrow stromal cells and decreased sensitivity to bortezomib (Bzb). In contrast, blocking N-cadherin-mediated adhesion by CDH2 shRNA increased sensitivity to Bzb. These results suggests that N-cad/beta-cat complexes can contribute to adhesion-mediated drug resistance in MM.
Conclusion(s): Taken together, these findings establish that beta-cat is stabilized by N-cadherin-, and likely E-cadherin-, adhesins junction formation in MM. This in turn leads to an increased pool of beta-cat that can drive TCF transcriptional activation as well participate in cadherin-mediated cell adhesion and drug resistance. Disclosures: Davies: Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Walker: Bristol Myers Squibb: Research Funding; Sanofi: Speakers Bureau.
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Introduction Despite efficacious modern induction combination therapies a subset of myeloma patients have high-risk disease which manifests as either primary refractory disease or early relapse following initial response. The presence of known molecular high-risk lesions explain the majority of these cases but understanding the factors influencing the poor phenotypic outcome for the remainder will help us improve outcomes further. This exploratory analysis of the Myeloma XI+ trial aimed to understand the population of patients with phenotypic high-disease in the context of carfilzomib and lenalidomide induction therapy. Methods The UK NCRI Myeloma XI trial is a phase III randomised controlled trial that recruited 2568 newly diagnosed transplant eligible patients, of which 526 were randomised to receive the induction combination KRdc comprising carfilzomib (K, 36mg/m2 IV d1-2, 8-9,15-16 (20mg/m2 #1d1-2)), lenalidomide (R, 25mg PO d1-21), dexamethasone (d, 40mg PO d1-4,8-9,15-16) and cyclophosphamide (c, 500mg PO d1,8) as part of an adaptive trial design. Induction therapy was planned for a minimum of 4 cycles or to maximum response prior to autologous stem cell transplant (ASCT). There was a subsequent randomisation to lenalidomide maintenance or observation at 3 months post ASCT. Primary refractory disease was defined as not achieving at least a minimal response (MR) at maximum response after at least 4 cycles of induction therapy or progression at any time during induction regardless of initial response. Early relapse (ER) after ASCT was defined as progression within 12 months of ASCT. Molecular risk was defined as the presence of one (high risk) or more than one (ultra-high risk) of the following lesions: del(17p), gain(1q), t(4,14), t(14;16) or t(14;20). Results The incidence of primary refractory disease with the KRdc combination was very low. Only 8/526 (1.5%) patients were primary refractory, all having progression during induction therapy with a median progression free survival of only 126 days. The number of patients is too small to draw any firm conclusions regarding the characteristics associated with primary refractory disease. 401/526 (76%) of patients underwent high dose melphalan and ASCT on trial after KRdc induction. Those that did not proceed to ASCT on trial were either ineligible, mostly due to not completing the minimum required induction therapy, or were deemed not fit to undergo the procedure based on patient/clinician decision. Of those patients who underwent ASCT, 36/401 (9.0%) relapsed within 12 months (ER). These ER patients had both a shorter PFS2 and second PFS suggesting a continued association with adverse outcome beyond first line therapy. Patients in the ER group were compared with those patients not relapsing until beyond 12 months after ASCT (nER). There was no difference in the sex, age or paraprotein or light chain sub-type of patients. There was evidence of a greater impact of bone marrow disease burden in the ER group with a lower haemoglobin (median 99 g/L vs 115, p = 0.0216), lymphocyte count (1.3 x10^9/L vs 1.8, p = 0.0012) and platelet count (187 x10^9/L vs 252, p = 0.0049) at baseline. Median bone marrow aspirate plasma cell infiltration was ER 33% vs nER 23%. There were no significant differences in ISS stage (ER ISS I 19%, II 50%, III 22%, nER ISS I 35%, II 36%, III 22%, p = 0.1434), lactate dehydrogenase, albumin or beta-2 microglobulin. Patients in the ER group were less likely to have received lenalidomide maintenance (ER 12/36 [33%] vs nER 222/365 [61%]). For some (4/36) not receiving lenalidomide was due to relapse occurring prior to reaching the maintenance randomisation point (100 days post-ASCT). For those with available data 75% of patients in the ER group had molecular high (50%) or ultra-high (25%) risk disease, whilst 25% had standard risk using the trial definition. The individual lesions accounting for high-risk status were: gain(1q) in ER 42% vs nER 35%; t(4;14) ER 50% vs nER 10%; del(17p) ER 8% vs nER 7%. Discussion The combination of a second-generation immunomodulatory agent and proteasome inhibitor in the KRdc induction regimen is associated with deep responses and only a very small proportion of patients have primary refractory disease. Early relapse after KRdc and ASCT occurred in 9% of patients and was associated with high bone marrow disease burden and molecular high-risk features. Disclosures: Pawlyn: Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / BMS: 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. Davies: Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Menzies: Celgene / BMS: Research Funding; Amgen: Research Funding; Merck Sharpe and Dohme: Research Funding. Henderson: BMS / Celgene: Research Funding; Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Cook: Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Jenner: BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy. Jones: Janssen: Honoraria; BMS/Celgene: Other: Conference fees. Kaiser: AbbVie: Consultancy; Takeda: Consultancy, Other: Educational support; Seattle Genetics: Consultancy; Amgen: Honoraria; Pfizer: Consultancy; Karyopharm: Consultancy, Research Funding; GSK: Consultancy; Janssen: Consultancy, Other: Educational support, Research Funding; BMS/Celgene: Consultancy, Other: Travel support, Research Funding. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Jackson: celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; J and J: Consultancy, Honoraria, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. OffLabel Disclosure: The KRdc combination is off label
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PURPOSE/OBJECTIVE:Patients with relapsed and refractory multiple myeloma (RRMM) have a poor prognosis and limited treatment options after exposure to an immunomodulatory drug, proteasome inhibitor (PI), and anti-CD38 antibody (triple-class exposure [TCE]). However, current understanding about the management of these patients and associated health care resource use (HCRU) is limited outside the United States. The objective of the International Treatment pattern and resource use Evaluation for Multiple myeloma In a Study of triple-class Exposed patients (ITEMISE) study was to use a physician-developed survey fielded to hematologists across Europe and Canada to assess the treatment, management, HCRU, and end-of-life care for patients with RRMM after TCE. METHODS:The ITEMISE study used a 3-phase Delphi-like approach that consisted of in-depth interviews with 7 hematology experts; the development of a cross-sectional survey fielded to hematologists across Belgium, Canada, France, Germany, Italy, the Netherlands, Spain, Sweden, Switzerland, and the United Kingdom from August to October 2020; and a final workshop of hematology experts to validate the pooled findings. Hematologists were asked to consider the management of patients in the first 3 treatment lines after TCE, including treatment options, treatment duration and outcomes, and frequency of outpatient visits and hospitalizations. FINDINGS/RESULTS:The survey was completed by 202 hematologists (60% from academic hospitals, 38% from other public hospitals, and 2% from private hospitals). Hematologists estimated that 55% of patients would receive active treatment after TCE, the equivalent of fourth-line treatment onward since diagnosis of multiple myeloma. Immunomodulatory drug, anti-CD38 antibody plus immunomodulatory drug, and PI-based regimens (received by 22.5%, 17.8%, and 15.1% of patients, respectively) were reported for first treatment strategy after TCE. Pomalidomide, daratumumab, lenalidomide, bortezomib, and carfilzomib were the most frequently selected antimyeloma agents. Associated outcomes of median overall survival, progression-free survival, and objective response rate for first treatment after TCE were estimated as 12 months, 4 months, and 40%, respectively. HCRU included outpatient visits and unplanned hospitalizations that were commonly reported during treatment after TCE. IMPLICATIONS/CONCLUSIONS:Findings indicate an intent to actively treat patients after TCE with a range of combination regimens frequently consisting of immunomodulatory drugs, PIs, and anti-CD38 antibodies, highlighting the lack of standard of care and suggesting a large clinical unmet need. Estimated clinical outcomes are consistent with data from US studies and indicate the poor prognosis for patients after TCE. Substantial HCRU is associated with management of patients after TCE across Europe and Canada, signifying a high patient and societal impact and a need for better treatment options to reduce this burden.

Proteins in the antiapoptotic B-cell lymphoma 2 (BCL-2) family play a role in the pathophysiology of multiple myeloma (MM). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis of MM cells, and its efficacy may be potentiated through combination with agents that increase BCL-2 dependency or have complementary mechanisms of action. The safety, tolerability, pharmacokinetics, and antitumor activity of venetoclax in combination with carfilzomib and dexamethasone (VenKd) in adults with relapsed/refractory MM (RRMM) were investigated in this phase 2 dose-escalation study. Oral venetoclax (400 or 800 mg) was administered daily in combination with intravenous carfilzomib (27, 56, or 70 mg/m2) and oral dexamethasone (20 or 40 mg) in 4 dose-finding cohorts. The expansion cohort received venetoclax 800 mg, carfilzomib 70 mg/m2, and dexamethasone 40 mg. Forty-nine patients received treatment. Median prior lines of therapy was 1 (range, 1-3), and median time in the study was 27 months. The most common treatment-emergent adverse events were diarrhea (65%), fatigue (47%), nausea (47%), and lymphopenia (35%). Serious adverse events occurred in 26 (53%) patients. Of 3 treatment-emergent deaths, 1 was considered treatment related. The overall response rate was 80% in all patients, 92% in patients with t(11;14) (n = 13), and 75% in patients without (n = 36). The rate of complete response or better was 41%. Median progression-free survival was 22.8 months. Treatment with VenKd was well tolerated and showed promising response rates in this RRMM patient population, with greater responses observed in patients with t(11;14). This trial is registered at www.clinicaltrials.gov as #NCT02899052.

The proteasome inhibitors (PIs), carfilzomib and bortezomib, are widely used to treat myeloma but head-to-head comparisons have produced conflicting results. We compared the activity of these PIs in combination with cyclophosphamide and dexamethasone (KCd vs VCd) in second line treatment using fixed duration therapy and evaluated the efficacy of carfilzomib maintenance. MUKfive was a phase II controlled, parallel group trial that randomised patients (2:1) to KCd (201) or VCd (99); responding patients on carfilzomib were randomised to maintenance carfilzomib (69) or no further treatment (72). Primary endpoints were (i) very good partial response (VGPR, non-inferiority, OR 0.8) at 24 weeks, and (ii) progression-free survival (PFS). More participants achieved ≥VGPR with carfilzomib compared to bortezomib (40.2% vs. 31.9%, OR=1.48, 90%CI:0.95,2.31; non-inferior), with a trend for particular benefit in adverse risk disease. KCd was associated with higher overall response (≥PR, 84.0% vs. 68.1%, OR=2.72, 90%CI:1.62,4.55, p=0.001). Neuropathy (grade ≥3 or ≥2 with pain) was more common with bortezomib (19.8% vs. 1.5%, p.

Not available.