Impact of Maintenance Therapy on Nature of First Relapse in Multiple Myeloma Patients Underwent Autologous Stem Cell Transplant

Abstract Lenalidomide maintenance therapy, initiated around day 100 after autologous stem cell transplantation (ASCT), has been associated a significantly longer time to disease progression and significantly improved overall survival (OS) among patients with multiple myeloma (MM) (McCarthy et al. NEJM 2012). However, the impact of maintenance therapy on the nature of MM relapse is largely unknown. Generally relapse can be categorized in two broad categories as symptomatic, or biochemical relapse. Symptomatic relapse is characterized mostly by high calcium, renal failure, anemia and bony lesions, i.e., CRAB criteria. Biochemical relapse is defined by a resurgence of secretory function of malignant plasma cells without CRAB criteria. We hypothesized that long-term continuous exposure to lenalidomide induces crucial changes in the myeloma microenvironment leading to a discordance between the resurgence of secretory function and the recurrence of aggressive behavior of myeloma cells leading to a higher frequency of biochemical. To define the impact of maintenance therapy on the pattern of disease recurrence and determinants of a more aggressive or indolent relapse course, we retrospectively analyzed two cohorts of MM patients that underwent ASCT. Methods: All MM patients with measurable disease who received ASCT at the University Hospital, Cleveland, OH from 2007 to 2016 were reviewed (Fig. 1). Patients that had received an allogeneic transplant or tandem ASCT, those transplanted more than one year after induction therapy, and those that died during the first three months post-transplantation were excluded. Baseline and treatment characteristics, response status, and monitoring data prior to relapse were extracted. If the serologic relapse had coincided with clinical relapse, defined as per CRAB criteria, patient was categorized as clinical relapse, and otherwise as biochemical relapse. Type of MM was categorized as paraprotein only (PO), paraprotein and light chain (PL), light chain escape (LE) and clinical only (CO) relapse (Table 1). Baseline and treatment characteristics are detailed in Table 2. The univariate association between the type of relapse and key patient and clinical characteristics were assessed using t-test or Fisher's exact test as appropriate. Results: Study population included 124 pts who relapsed after ASCT (Fig. 1), divided in two cohorts based on history of receiving any maintenance therapy or no maintenance (77 vs. 47 patients, respectively). 21 pts were excluded based on the above criteria. Median age was 59.8 years old (range: 36-79). The median time from diagnosis to ASCT was 10 months. There was only one CO relapse in the maintenance cohort. There was no difference in rate of high risk disease between two cohorts. The maintenance agents included immunomodulatory drugs in 70 pts (91%), proteasome inhibitors in 5 pts (6%) and a combination of both in 2 pts (3%). PFS was 40.1 months in the maintenance group vs. 29.2 months in the no maintenance group (p=0.0001). There was no statistically significant difference in serum paraprotein values at diagnosis or relapse between the two cohorts (Fig. 1A). LCE was more common in the maintenance group. Thirteen patients (28%) in the no maintenance cohort had CRAB relapse compared to 35 patients (45%) in the maintenance cohort (hazard ratio: 0.71, 95% CI: 0.51-0.92, p=0.031). The type of end organ dysfunction at clinical relapse is shown in bar graphs in Fig. 2B. Conclusions: Taken together, our results suggest that although maintenance therapy postpones disease relapse in the post-HSCT setting, it also impacts dynamics of the resurgence of secretory function within myeloma cells and shifts the nature of recurrence toward less biochemical relapse. Future studies will employ next generation sequencing prior to and during maintenance therapy combined with high sensitivity flow cytometry to identify the molecular basis of relapse. Genomics and cell surface markers may then more accurately predict relapse in MM patients on maintenance therapy. Disclosures Caimi: Genentech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau. Malek:Amgen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau.

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In Multiple Myeloma, Minimal Residual Disease (MRD) Is an Early Predictor of Progression and Is Modulated By Maintenance Therapy with Lenalidomide

Blood ◽

10.1182/blood.v124.21.3394.3394 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3394-3394 ◽

Cited By ~ 2

Author(s):

Manuela Gambella ◽

Paola Omedè ◽

Stefania Oliva ◽

Milena Gilestro ◽

Vittorio Emanuele Muccio ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Board Of Directors ◽

Minimal Residual Disease ◽

Residual Disease ◽

Clinical Relapse ◽

Advisory Committees ◽

Off Label ◽

The Impact ◽

Minimal Residual

Abstract Background. Minimal residual disease (MRD) detection by multi-parameter flow cytometry (MFC) and real time quantitative PCR (RQ-PCR) is highly predictive of outcome in multiple myeloma (MM) patients (pts). Less is known on the ability of maintenance therapy to modulate MRD levels. The primary end-point of this study was to monitor MRD during maintenance therapy and to evaluate the impact on outcome. Patients and Methods. In the RV-MM-EMN-441 study (NCT01091831), after induction and consolidation pts received maintenance therapy with either Lenalidomide alone (R) or Lenalidomide-Dexamethasone (RD) until progression. Pts achieving at least very good partial response (VGPR) after induction/consolidation treatment were eligible for the MRD sub-study. MRD analysis was performed on bone marrow (BM) samples at diagnosis, after consolidation, after 3 and 6 courses of maintenance, and thereafter every 6 months until progression. MFC complete remission (CR) was defined by <1E-04 monoclonal plasmacells (PCs). Molecular-CR was defined by <1E-05 according to EuroMRD guidelines. MFC and molecular progression were defined by confirmed 25% increase of malignant plasma cells. Results. MRD sub-study included 50 pts with a median age of 57 years (range 40-65). After consolidation 34/50 (68%) pts achieved VGPR, 16/48 (32%) achieved CR according to IMWG criteria (Rajkumar et al. Blood 2011). After a median follow-up of 44 months, 22/50 (44%) progressed and 7/50 (14%) deaths were recorded, with a 4-year PFS of 49% and 4-year OS of 87%. In the MFC analysis 19/50 pts (38%) achieved MFC-CR after consolidation, while other additional 7/50 pts (14%) achieved MFC-CR during maintenance. Among pts who achieved MFC–CR (< 1E-04), 7/26 (27%) pts progressed after a median of 30 months; among those who did not reach MFC–CR, 15/24 (62%) pts progressed after a median of 26 months (p=0.009). In 18/19 pts MFC-progression anticipated clinical relapse of a median of 9 months. In 1/19 pts, clinical extra-medullary progression anticipated MFC-progression. A molecular marker was identified in 25/50 pts (50%); 4/25 pts (16%) achieved molecular-CR after consolidation, while other additional 3/25 pts (20%) achieved molecular-CR during maintenance. Among pts who achieved molecular–CR (<1E-05), 2/7 (28%) pts progressed after a median of 34 months; among those who did not reach molecular–CR, 11/18 (61%) pts progressed after a median of 30 months (p=0.15). In 12/13 pts molecular-progression anticipated clinical relapse of a median of 8 months. In 1/13 pts, clinical extra-medullary progression anticipated molecular-progression. Conclusions. Lower MRD values, both with MFC and RQ-PCR procedures, predict better outcome. 30% of patients achieved MFC-CR (7/26) or molecular-CR (3/7) during maintenance therapy suggesting that MRD levels can be modified by maintenance. MRD progression anticipates clinical relapse of approximately 8 months. Disclosures Off Label Use: lenalidomide used as off-label. Ferrero:MUNDIPHARMA: Honoraria. Gay:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Patriarca:Merck Sharp & Dohme: Honoraria; Janssen and Cilag: Honoraria; Celgene: Honoraria. Petrucci:CELGENE: Honoraria; JANSSEN-CILAG: Honoraria; SANOFI: Honoraria; BRISTOL MYERS SQUIBB: Honoraria. Caravita:Celgene: Honoraria. Di Raimondo:CELGENE: Honoraria; JANSSEN-CILAG: Honoraria. Musto:CELGENE: Honoraria; JANSSEN-CILAG: Honoraria. Boccadoro:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Palumbo:Array BioPharma: Honoraria; Onyx Pharmaceuticals: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Genmab A/S: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Honoraria.

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A Randomized Phase 2 Trial Comparing Carfilzomib-Dexamethasone Vs Observation As Maintenance after Induction with Carfilzomib-Cyclophosphamide-Dexamethasone in Salvage ASCT in Multiple Myeloma: A Trial By the Nordic Myeloma Study Group

Blood ◽

10.1182/blood-2019-122141 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 601-601 ◽

Cited By ~ 1

Author(s):

Henrik Gregersen ◽

Valdas Peceliunas ◽

Kari Remes ◽

Fredrik H. Schjesvold ◽

Niels Abildgaard ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Observation Group ◽

Phase 2 ◽

Advisory Committees ◽

Phase 2 Trial ◽

First Relapse ◽

Maintenance Group

Background: Salvage autologous stem cell transplantation (ASCT) is used in selected patients with relapsed multiple myeloma after up-front ASCT. However, there are limited data on the optimal induction therapy before salvage ASCT. There is strong support for the use of maintenance therapy after upfront ASCT in newly diagnosed multiple myeloma whereas data on maintenance therapy after salvage ASCT are sparse. The Nordic Myeloma Study Group (NMSG) initiated the CARFI trial (NCT02572492), an open randomized phase II study, to investigate the efficacy and safety of carfilzomib as part of induction and conditioning in salvage ASCT and to evaluate the role of carfilzomib/dexamethasone maintenance after salvage ASCT. Methods: Patients with first relapse after up-front ASCT were treated with an induction regime containing four cycles of CAR-CY-DEX (iv carfilzomib 20 mg/sqm → 36 mg/sqm on days 1, 2, 8, 9, 15 and 16, tablet cyclophosphamide 300 mg/sqm on days 1, 8 and 15 and tablet dexamethasone 20 mg on days 1, 2, 8, 9, 15 and 16 in each 28-days cycle). The subsequent conditioning regimen contained iv carfilzomib 27 mg/sqm on day -2 and -1, and iv melphalan 200 mg/sqm on day -2. The patients had not received any maintenance therapy after upfront ASCT. Two months after ASCT patients were randomized (1:1) to observation or maintenance therapy with iv carfilzomib 27 mg/sqm → 56 mg/sqm every second week and tablet dexamethasone 20 mg every second week. The randomization was stratified according to relapse 1 - 2 year or > 2 years after up-front ASCT, ISS stage and standard versus high-risk cytogenetics. Primary endpoint was comparison of time to progression (TTP) after up-front ASCT and TTP after salvage ASCT with CAR-CY-DEX induction. Another primary endpoint was to compare TTP between carfilzomib-dexamethasone maintenance and observation in patients treated with salvage ASCT. Results: 200 patients were enrolled in the study and 32 of these went off study during the induction and after ASCT. The remaining 168 patients were randomized to carfilzomib-dexamethasone (82 patients) or observation (86 patients). The median age was 62 (interquartile range: 56; 66) years and the median follow-up from time of inclusion was 20.1 (14.1 - 27.6) months. The median TTP after up-front ASCT was 33.2 (31.0-37.8) months compared with 28.1 (24.9-31.5) months after salvage ASCT. The two groups randomised to maintenance therapy or observation were balanced regarding age, time from myeloma diagnosis, treatment at diagnosis, performance status, ISS stage and high-risk cytogenetics (Table 1). The median TTP from randomisation was 28.8 (95% CI: 24.4-NR) months in the maintenance group and 18.5 (95% CI: 14.3-22.0) months in the observation group (hazard ratio 0.42 (95% CI: 0.26-0.68, P = 0.0003)) (Figure I). For the maintenance group TTP from inclusion was 35.4 (30.9-NR) months compared with TTP of 31.3 (29.4-37.8) months (P = 0.71) after up-front ASCT for these patients. A total of 53 serious adverse events (SAE) were reported in 25 patients on carfilzomib-dexamethasone maintenance and 33 SAEs in 21 patients in the observation group. The majority of the SAEs were infections; 39 in the maintenance group and 25 in the observation group, divided into viral infection (10 versus 3), septicemia (2 versus 0) and pneumonia (12 versus 7). Three SAEs classified as cardiac-pulmonary were observed in the maintenance group (syncope, atrial fibrillation and pulmonary embolism) in contrast to three in the observation group (atrial fibrillation and dyspnea(2)). Conclusion: In this randomized phase 2 trial, maintenance therapy with carfilzomib and dexamethasone prolonged median TTP with approximately 10 months following salvage ASCT in multiple myeloma. The difference between TTP after upfront ASCT and TTP after salvage ASCT with carfilzomib based induction therapy was small which supports the use of salvage ASCT followed by maintenance in selected patients at first relapse. Disclosures Remes: Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Congress Support; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Congress Support; Amgen: Other: Congress Support; Celgene: Other: Congress Support; Sanofi: Other: Congress Support. Schjesvold:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Novartis: Honoraria; MSD: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; SkyliteDX: Honoraria; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Abildgaard:Amgen: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda: Research Funding. Vangsted:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Jansen: Honoraria. Blimark:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees.

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The Effect of Maintenance Therapy Following Salvage Autologous Stem Cell Transplant in Multiple Myeloma Patients

Blood ◽

10.1182/blood-2018-99-111379 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3439-3439

Author(s):

Brandon B. Wang ◽

Mark A. Fiala ◽

Mark A. Schroeder ◽

Tanya Wildes ◽

Armin Ghobadi ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Stem Cell Transplant ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Advisory Committees ◽

The Impact

Abstract Background: In the current era, autologous stem cell transplant (ASCT) remains an effective form of treatment for patients diagnosed with multiple myeloma (MM), but it is not curative and a relapse is inevitable. A second, or salvage, ASCT provides better outcomes than conventional chemotherapy but it is infrequently used. Maintenance therapy after initial ASCT has been adopted as the standard in the US; however, there is limited data on the effects of maintenance therapy following salvage ASCT and the benefits are still unclear. Methods: We performed retrospective chart review of all patients with MM who received a second, salvage ASCT at time of first relapse at Washington University in St. Louis from 2008 to 2016. We identified two cohorts of patients, those who received maintenance therapy following salvage ASCT and those who did not. Patients who received maintenance therapy post-initial ASCT were excluded as the objective of this study was to determine the impact of maintenance post-salvage ASCT and maintenance post-initial ASCT may confound the results. Results: Sixty-five patients (who underwent second/salvage ASCT) were identified. Three were excluded from the analysis-two had treatment-related mortality following salvage ASCT and one received maintenance other than a proteasome inhibitor (PI) or an immunomodulatory drug (IMID). The maintenance cohort consisted of 31 patients, with 68% (n = 21) males and 32% (n = 10) females; the median age at salvage ASCT was 61 years (range 38-73). The no-maintenance cohort consisted of 31 patients as well with 45% (n = 14) males and 55% (n = 17) females. Their median age at salvage ASCT was 62 years (range 44-74). The characteristics of the two cohorts are summarized in Table 1. Most patients received PIs and/or IMIDs as part of their induction regimens prior to initial ASCT. All received melphalan conditioning. The response to treatment was similar between the two cohorts, with respective CR rates of 68% (n = 21) and 77% (n = 24) and median progression-free survival (PFS) of 46 months compared to 33 months. Following relapse, 16% (n = 5) of patients in the no-maintenance cohort proceeded directly to salvage ASCT without re-induction. All other patients received re-induction, mostly with PIs and/or IMIDs, with a median of 4 cycles for the maintenance cohort and 2 cycles for the no-maintenance cohort. For conditioning prior to salvage ASCT, 4 patients received Velcade-BEAM conditioning as part of a prospective trial at our site (NCT01653418); 3 from the maintenance cohort and 1 from the no-maintenance cohort. The rest received melphalan conditioning. Both cohorts had a CR rate of 52% (n = 16) post-salvage ASCT. Maintenance therapy after salvage ASCT consisted of lenalidomide (74%, n = 23), bortezomib (23%, n = 7), or pomalidomide (3%, n = 1). Three of the patients on bortezomib were originally started on lenalidomide but were switched due to intolerance. At time of data collection, the median follow-up was 49 months (range 9-105) for the maintenance cohort and 61 months (range 19-113) for the no-maintenance cohort. 45% (n = 14) of patients in the maintenance cohort and 90% (n = 28) of the no-maintenance cohort had relapsed. In the maintenance cohort, PFS following salvage ASCT was similar to what was observed following initial ASCT. The median estimated PFS post-salvage ASCT was 53 months (95% CI 42-64) compared to 46 months post initial ASCT (p = 0.144). Conversely, in the no-maintenance cohort PFS following salvage was only about 60% that of initial ASCT (21 months [95% CI 18-24]; compared to 33 months; p = 0.002). Conclusion: These results suggest that maintenance following salvage ASCT is associated with improved outcomes. Although patients who received maintenance post-initial ASCT were excluded, the benefits of maintenance post-salvage ASCT may extend to them as well. Ongoing prospective clinical trials will further clarify these benefits. Disclosures Schroeder: Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wildes:Janssen: Research Funding. Vij:Jazz Pharmaceuticals: 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, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharma: 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; Takeda: 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.

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Early Versus Late Discontinuation of Maintenance Therapy in Multiple Myeloma

Blood ◽

10.1182/blood-2021-146698 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3796-3796

Author(s):

Jordan Nunnelee ◽

Muhammad Salman Faisal ◽

Qiuhong Zhao ◽

Francesca Cottini ◽

Patrick Elder ◽

...

Keyword(s):

Multiple Myeloma ◽

Adverse Events ◽

Maintenance Therapy ◽

Board Of Directors ◽

Short Term ◽

Early Discontinuation ◽

Advisory Committees ◽

Term Maintenance ◽

Maintenance Group

Abstract Background: Indefinite maintenance therapy after autologous stem cell transplant (ASCT) is the current standard of care in multiple myeloma (MM). However, in the real world, patients often discontinue treatment due to various reasons. In this study, we sought to analyze the effect of and reasons for early discontinuation of maintenance therapy on survival outcomes, studying patients who received less than 3 years of maintenance therapy (short-term maintenance group) or more than 3 years (continuous maintenance group). Methods: We retrospectively reviewed 340 patients who underwent ASCT from 2005-2016 and received maintenance therapy for at least six months without progression. The patients started maintenance therapy after 100 days of ASCT. Lenalidomide (89%) and bortezomib (10%) were the most commonly used agents for maintenance therapy. The primary endpoints included were progression-free survival (PFS) and overall survival (OS). All the endpoints were measured from the time of ASCT. The discontinuation was defined as permanently stopping the maintenance therapy. Patient, disease, and transplant-related characteristics were compared between the two groups using the Mann-Whitney U test for continuous variables, and chi-squared or Fisher's exact test for categorical variables. The probabilities of PFS and OS were calculated using the Kaplan-Meier (KM) method and compared using log-rank test. Results: One hundred and two (n= 102; 30%) patients discontinued maintenance therapy in the first 3 years (short-term maintenance group), while 238 patients remained on maintenance therapy for ≥ 3 years (continuous maintenance group). The groups had similar baseline characteristics in terms of age, gender, ISS staging, cytogenetics, response before ASCT, and melphalan dosing. About 20% of patients in both groups were older than 65 years. Among those alive at the last contact, the median follow up were 5.4 years and 6.1 years for the short-term and continuous maintenance therapy group, respectively. At the time of the last follow-up, 131/238 (55%) patients in the continuous maintenance group were still on maintenance therapy. The median PFS in the short-term maintenance group was 5.1 years (95% CI: 4.4-7.4) and median OS was 9.8 years (95% CI: 8.2- to NR), whereas in the continuous maintenance group both median PFS (95% CI: 8.5- NR) and OS were not reached. This latter group had significantly longer PFS and OS than the short-term maintenance group with a 5-year estimated PFS of 80% (95%CI: 74-85%) vs. 50% (95% CI: 39-60%) (p<0.001) and OS of 96% (95% CI: 92-98%) vs. 79% (95% CI: 69-86%) (p<0.001) (Figure 1). This remained significant after adjusting for race, post-transplant remission status and ISS staging, with an hazard ratio for risk of relapse or death of 0.31, 95% CI: 0.21-0.45; and HR for risk of death of 0.34, 95% CI: 0.18-0.64. The most common reasons for early discontinuation of maintenance therapy (< 3 years) were adverse events related to maintenance therapy (58%). Four patient (4%) patients developed second primary malignancy (SPM) in this group. The most frequent hematological adverse events (AEs) were pancytopenia and isolated neutropenia. Fatigue and diarrhea were the most common non-hematological AEs. The reasons for stopping maintenance in the continued maintenance group were disease progression (24%) and adverse events (14%), while five patients (2%) developed SPM. Conclusion: In our institutional experience, 30 percent of MM patients discontinued maintenance therapy within 3 years of ASCT due to AEs or patient preference. These patients had inferior PFS and OS after ASCT compared to patients on continuous maintenance. Therefore, continuation of maintenance therapy should be strongly encouraged as safely possible and strategies like dose reduction or switching therapy are recommended. Figure 1 Figure 1. Disclosures Bumma: Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Multiple Myeloma Cells Induce Lipolysis in Adipocytes and Uptake Fatty Acids through Fatty Acid Transporter Proteins

Blood ◽

10.1182/blood-2020-142625 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 41-42

Author(s):

Cristina Panaroni ◽

Keertik Fulzele ◽

Tomoaki Mori ◽

Chukwuamaka Onyewadume ◽

Noopur S. Raje

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Fatty Acid ◽

Board Of Directors ◽

Metabolic Reprogramming ◽

Glycerol Production ◽

Advisory Committees ◽

Myeloma Cells ◽

Long Chain

Multiple myeloma (MM) originates in the bone marrow where adipocytes occupy 65% of the cellular volume in a typical myeloma patient. Cancer associated adipocytes support the initiation, progression, and survival of solid tumors via mechanisms including adipokine secretion, modulation of the tumor microenvironment, and metabolic reprogramming of cancer cells. Although MM cells are surrounded by abundant bone marrow adipocytes (BMAd), the nature of their interaction remains unclear. Recent studies have elucidated the role of BMAds in supporting the survival of MM cells, in part, through secreted adiponectin. Increased fatty acid (FA) metabolism may result in metabolic reprogramming of cancer cells impacting their growth and survival. Here, we hypothesize that MM cells extract FA from adipocytes for their growth. We first characterized mesenchymal stem cells (MSCs) from MGUS, smoldering MM (SMM), and newly diagnosed MM (NDMM) patients by flow cytometry analysis. MSCs showed significant increase in Pref1, leptin receptor and perilipin A, suggesting increased adipogenic commitment. MSCs from healthy donors (HD), MGUS, SMM, and NDMM patients were induced to differentiate into adipocytes and then co-cultured with human MM MM.1S cells. After 72 hr of co-culture, CyQUANT assay demonstrated significant increase in proliferation of MM.1S cells in the presence of BMAd from HD; this was further increased in the presence of BMAd from MGUS/SMM and NDMM. These data suggest that the BMAd support the growth of MM cells and this effect is more pronounced in patient derived BMAd. A PCR-array targeting lipid metabolism on BM fat aspirates showed significant deregulation of genes involved in FA synthesis and lipolysis. Taken together, our data suggest that BMAd in MM patients are altered to further support the aggressive expansion of MM cells. The proliferative-supportive role of adipocytes was further validated in co-culture of OP9 murine BM stromal preadipocytes with 5TGM1 murine MM cells. To study the bidirectional interaction of MM/ BMAd, mature OP9 adipocytes were co-cultured with 5TGM1 or human OPM2 MM cells for 24 hr. Intracellular lipid droplets were labelled with Deep Red LipidTox stain. The lipid droplet sizes were significantly decreased in the presence of both 5TGM1 and OPM2 cells compared to OP9 alone. The decrease in lipid size suggested that MM cells may induce lipolysis in adipocytes. Indeed, 24hr co-culture of 5TGM1 cells with OP9 mature adipocytes significantly increased lipolysis 3-fold as measured by glycerol secretion in conditioned media. Co-culture of OP9 adipocytes with other MM cell lines of human origin, MM.1S, INA6, KMS-12 PE, and OPM2 also significantly increased the glycerol production as much as 4-fold. Taken together these data indicate that MM cells induce lipolysis in adipocytes. In contrast, treatment of 5TGM1 cells with synthetic catecholamine isoproterenol did not induce lipolysis, or glycerol production, indicating lack of triglyceride storage. Next, we hypothesized that the free FAs released from adipocytes are taken up by MM cells for various biological processes. To test this, 5TGM1, MM.1S and OPM2 cells were incubated with BODIPY-C12 and BODIPY-C16, the BODIPY-fluorophore labelled 12-carbon and 16-carbon long chain FA. All MM cells showed saturated uptake of the FA within 10 minutes suggesting that MM cells have efficient FA transporters. To confirm this uptake, unstained 5TGM1, OPM2 and KMS12 PE cells were co-cultured with the LipidTox-labelled OP9 mature adipocytes. After 24 hours, flow cytometric analysis showed LipidTox signal in MM cells. These data demonstrate that FAs released by MM induced adipocyte lipolysis are taken up by MM cells. Long-chain FAs such as BODIPY-C12 and BODIPY-C16 are transported into cells through FA transporter protein (FATP) family of lipid transporters. We therefore analyzed patient samples which showed that CD138+ plasmacells and myeloma cells expressed high levels of FATP1 and FATP4 whereas, their expression was absent in lineage-sibling T-cells. Moreover, pretreatment with Lipofermata, a FATP inhibitor, was able to decrease the uptake of BODIPY-C12 and -C16 in 5TGM1 cells. Taken together, our data show that myeloma cells induce lipolysis in adipocytes and the released free FAs are then uptaken by myeloma cells through FATPs. Inhibiting myeloma cell induced lipolysis or uptake of FA through FATPs may be a potential anti-tumor strategy. Disclosures Fulzele: FORMA Therapeutics, Inc: Current Employment, Other: Shareholder of Forma Therapeutics. Raje:Amgen: Consultancy; bluebird bio: Consultancy, Research Funding; Caribou: Consultancy, Membership on an entity's Board of Directors or advisory committees; Immuneel: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Immuneel: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy.

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Results of a Phase I Study of Pnk-007, Allogeneic, Off the Shelf NK Cell, Post Autologous Transplant in Multiple Myeloma (NCT02955550)

Blood ◽

10.1182/blood-2019-128467 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4451-4451

Author(s):

Sarah A. Holstein ◽

Sarah Cooley ◽

Parameswaran Hari ◽

Sundar Jagannath ◽

Catherine R Balint ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Phase I Study ◽

Nk Cell ◽

Single Infusion ◽

Advisory Committees ◽

Cd34 Cells ◽

Equity Ownership

Background: PNK-007 is an allogeneic, off the shelf cell therapy product enriched for CD56+/CD3- NK cells expanded from placental CD34+ cells. PNK-007 cells exhibit cytotoxicity against various cancer cell types, including multiple myeloma (MM), and secrete cytokines during co-culture with cancer cells. This is a Phase I study of single infusion PNK-007 after autologous stem cell transplant (ASCT) in MM. Methods: Placental CD34+ cells were cultivated in the presence of cytokines for 35 days to generate PNK-007 under cGMP standards followed by release testing. HLA matching and KIR mismatching were not used. Four treatment arms were evaluated on patients (pts) following ASCT: 10 million (M) cells/kg Day (D) 14 with or without recombinant human IL-2 (rhIL-2), 30M cells/kg D14 with rhIL-2, or 30M cells/kg D7 with rhIL-2. rhIL-2 was administered subcutaneously at 6M units every other day for up to 6 doses to facilitate PNK-007 expansion. Pts received variable pre-ASCT induction therapy. Maintenance therapy was permitted after the Day 90-100 visit (D90). Subjects were followed for up to 1-year. Results: 15 pts who received PNK-007 (12 of whom received rhIL-2) were followed on this study. Pts aged 44-69 yrs included 12 newly diagnosed (ND)MM and 3 relapsed/refractory (RR)MM. The 3 RRMM pts had received 1, 2 or 5 prior lines of therapy, with 2 pts having previous ASCT. All pts had been exposed to immunomodulatory drug (IMiDs) and proteasome inhibitors (PIs). No serious adverse events (AEs) were attributable to PNK-007 and no dose-limiting toxicity, GvHD, graft failure or graft rejection were observed. 12/15 pts started maintenance therapy following the transplant while participating in this study, at the physician's discretion. Based on physician assessed responses by International Myeloma Working Group pre-ASCT, of the NDMM pts 10/12 achieved VGPR or better (1 CR and 9 VGPR), 1/12 achieved PR and 1/12 was not assessed during pre-ASCT induction. By D90 10/12 pts achieved VGPR or better (5 CR or sCR and 5 VGPR), 1/12 maintained PR and 1/12 stable disease. At 1-year 9/11 achieved VGPR or better (4 CR or sCR and 5 VGPR), 2/11 were not assessed and 1 was removed from the study prior to 1 year due to failure to respond to ASCT. Of the RRMM pts 2/3 achieved PR and 1/3 was not assessed during pre-ASCT induction, by D90 2/3 achieved VGPR and the pt that had not been assessed pre-ASCT achieved PR. At 1-year, 1 pt maintained VGPR, 1 pt was not assessed and 1 pt did not continue to the 1-year visit. Using a validated Euro-flow minimal residual disease (MRD) assay of bone marrow aspirate (BMA) samples, of the NDMM pts 4/12 were MRD negative (MRD-) pre-ASCT; by D90 9/12 were MRD-. At 1-year 6/12 were MRD-, 2/12 had insufficient BMA to perform testing, 2/12 refused BMA procedure, 1/12 did not convert to MRD-, and 1 was removed from the study prior to 1-year due to failure to respond to ASCT. Of the RRMM pts 0/3 were MRD- pre-ASCT with 1/3 having insufficient BMA to perform testing; by D90 1/3 were MRD-. At 1-year 1/3 was MRD-, 1/3 did not convert to MRD- and 1 pt did not continue to the 1-year visit. PNK-007 infusion did not interfere with immune reconstitution kinetics. Platelet, neutrophil, and absolute lymphocyte counts recovered by day 28 post-ASCT in 12/15 patients. All pts' sera tested negative for the presence of anti-HLA antibodies at all timepoints indicating the absence of humoral immunity and alloantibodies to PNK-007. Conclusion: PNK-007 is the first fully allogeneic, off the shelf CD34+ derived NK cell product in MM clinical trials. A single infusion of PNK-007 up to 30M cells/kg with and without rhIL-2 was well tolerated in the post-ASCT setting. We established the feasibility of infusing PNK-007 as early as 7 days post-ASCT without negative impact on blood count recovery or successful engraftment. BMA MRD- status was observed in 7/9 MRD evaluable pts at 1-year post ASCT. These clinical data are encouraging and warrant further evaluation. Disclosures Holstein: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Sorrento: Consultancy; GSK: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees. Cooley:Fate Therapeutics, Inc: Employment, Equity Ownership. Hari:Cell Vault: Equity Ownership; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria. Jagannath:BMS: Consultancy; Merck: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau. Balint:Celgene: Equity Ownership; Celularity, Inc: Employment. Van Der Touw:Celularity, Inc: Employment. Zhang:Celularity Inc: Employment. Hariri:Celularity Inc: Employment. Vij:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria; Janssen: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Research Funding.

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A Phase III Study to Determine the Efficacy and Safety of Lenalidomide in Combination with Melphalan and Prednisone (MPR) in Elderly Patients with Newly Diagnosed Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.613.613 ◽

2009 ◽

Vol 114 (22) ◽

pp. 613-613 ◽

Cited By ~ 17

Author(s):

Antonio Palumbo ◽

Meletios A. Dimopoulos ◽

Michel Delforge ◽

Martin Kropff ◽

Robin Foa ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Board Of Directors ◽

Primary Endpoint ◽

Interim Analysis ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Time To Progression ◽

First Line ◽

Advisory Committees

Abstract Abstract 613 Background: Lenalidomide (Revlimid®) is an oral immunomodulatory agent with clinical efficacy in patients with multiple myeloma (MM). In patients with relapsed/refractory MM, lenalidomide plus dexamethasone improved time to progression (TTP) and overall survival (OS) in comparison with dexamethasone alone. In newly diagnosed MM patients, the current study compares the efficacy and safety of melphalan, prednisone and lenalidomide (MPR) with that of MP alone. Methods: Key inclusion criteria were: ≥65 years of age, newly diagnosed and symptomatic MM. 459 patients were randomly assigned to receive MPR followed by lenalidomide maintenance therapy or MPR followed by placebo maintenance therapy or MP followed by placebo maintenance therapy (Figure 1). The study induction and maintenance phases were followed by an open label lenalidomide extension and a follow-up phase. All patients received aspirin 100 mg/day as thrombo-prophylaxis. The primary endpoint of the study is progression free survival (PFS). The secondary endpoints are OS, time-to-progression, response rate, time to response, response duration, time-to-next anti-myeloma therapy, safety, quality of life and exploratory assessment of cytogenetic abnormalities. Primary comparison is based on the intent-to-treat population comparing PFS between MPR followed by lenalidomide with MP followed by placebo; secondary comparisons are between MPR followed by lenalidomide and MPR followed by placebo, and between MPR followed by placebo and MP followed by placebo. Results: The first patient was enrolled in February 2007. A pre-planned interim analysis to evaluate the efficacy and safety was performed at 50% information. An independent central adjudication committee determined the assessment and timing of progressive disease prior to the interim analysis. At the interim analysis, it was determined by the Data Monitoring Committee (DMC) that the study had crossed the O'Brien Fleming superiority boundary for the primary endpoint, demonstrating a highly statistically significant improvement in PFS for patients treated with MPR compared with MP as first-line treatment for MM patients. The topline results will be availabel at the time of the meeting. Conclusions: MPR is an effective and safe regimen for front-line use in MM. PFS was significantly improved in patients who received MPR followed by lenalidomide maintenance compared with those who received MP followed by placebo maintenance. MPR followed by lenalidomide maintenance is a new therapeutic option and can be considered a new standard for patients older than 65 years old. Disclosures: Palumbo: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide is not approved for first line use in multiple myeloma. Dimopoulos:Celgene: Honoraria. Delforge:Janssen-Cilag: Consultancy, Honoraria; Celgene: Honoraria, Speakers Bureau. Kropff:Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Foa:Celgene: Membership on an entity's Board of Directors or advisory committees. Yu:Celgene: Employment. Herbein:Celgene: Employment. Mei:Celgene: Employment. Jacques:Celgene: Employment. Catalano:Celgene: Research Funding.

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Investigational Agent MLN9708 Target Tumor Suppressor MicroRNA-33b in Multiple Myeloma Cells

Blood ◽

10.1182/blood.v118.21.136.136 ◽

2011 ◽

Vol 118 (21) ◽

pp. 136-136

Author(s):

Ze Tian ◽

Jian-Jun Zhao ◽

Jianhong Lin ◽

Dharminder Chauhan ◽

Kenneth C. Anderson

Keyword(s):

Multiple Myeloma ◽

Tumor Suppressor ◽

Board Of Directors ◽

Expression Profiling ◽

Research Funding ◽

Advisory Committees ◽

Myeloma Cells ◽

Investigational Agent ◽

Reporter Activity

Abstract Abstract 136 Investigational Agent MLN9708 Target Tumor Suppressor MicroRNA-33b in Multiple Myeloma Cells Ze Tian, Jianjun Zhao, Jianhong Lin, Dharminder Chauhan, Kenneth C. Anderson Medical Oncology, Dana Farber Cancer Institute and Harvard Medical School, Boston, MA, 02115 MicroRNAs (miRNAs) are 19–25 nucleotide-long noncoding RNA molecules that regulate gene expression both at the level of messenger RNA degradation and translation. Emerging evidence shows that miRNAs play a critical role in tumor pathogenesis by functioning as either oncogene or tumor suppressor genes. The role of miRNA and their regulation in response to proteasome inhibitors treatment in Multiple Myeloma (MM) is unclear. Here, we utilized MLN9708, a selective orally bio-available proteasome inhibitor to examine its effects on miRNA alterations in MM.1S MM cells. Upon exposure to aqueous solutions or plasma, MLN9708 rapidly hydrolyzes to its biologically active form MLN2238. Our previous study using both in vitro and in vivo models showed that MLN2238 inhibits tumor growth and triggers apoptosis via activation of caspases. Moreover, MLN2238 triggered apoptosis in bortezomib-resistant MM cells, and induced synergistic anti-MM activity when combined with HDAC inhibitor SAHA, dexamethasone, and lenalidomide. In the current study, we treated MM.1S cells with MLN2238 (12 nM) for 3 hours and harvested; total RNA was subjected to miRNA profiling using TaqMan® Array Human miRNA A-Card Set v3.0 and the data was analyzed using dChip analysis. Results showed that MLN2238 modulates miRNA expression with a total of 36 miRNA changing their expression profiling (δδCT>1.5 or δδCT <-1.5; 19 were upregulated and 17 showed a downregulation). Among all miRNA, miR-33b was highly (δδCT>7) upregulated in response to MLN2238 treatment. We therefore hypothesized that miR-33b may play a role in MM pathogenesis as well as during MLN2238-induced proteasome inhibition in MM cells. We first utilized quantitative polymerase chain reaction (q-PCR) to validate the changes in miRNA expression profiling. Results confirmed that MLN2238 treatment triggers significant increase in the miR-33b expression in MM.1S cells (2.1 and 2.2 folds at 3h and 6h, respectively; P<0.001). Examination of normal PBMCs and plasma cells showed higher expression of miR-33b than patient MM cells (P<0.001). We further investigated the functional role of miR-33b in MM cells at baseline and during MLN2238 treatment. Drug sensitivity, cell viability, apoptosis, colony formation, and migration assays were performed using cell TilTer-Glo, Annexin V-FITC/PI staining, MTT staining, and Transwell assays, respectively. Signaling pathways modulated post miR-33b overexpression were evaluated by q-PCR, immunoblot, and reporter assays. Our findings show that overexpression of miR-33b significantly decreased cell viability, cell migration, colony formation, as well as increased apoptosis and sensitivity of MM cells to MLN2238 treatment. Targetscan analysis predicted pim-1 as a putative downstream target of miR-33b. Overexpression of miR-33b downregulated pim-1 mRNA and protein expression. To further corroborate these data, we co-tranfected miR-33b and Pim-1-wt or Pim-1-mt in 293T and MM.1S cell lines. In concert with our earlier findings, miR-33b decreases pim-1-wt, but not pim-1-mt reporter activity in both cell lines. Reflecting the overexpression study results, MLN2238 treatment also decreases pim-1-wt, but not pim1-mt reporter activity. Moreover, a biochemical inhibitor of pim1/2 triggered apoptosis in MM cells. Finally, overexpression of miR-33b inhibits tumor growth (P<0.001) and prolongs survival (P<0.001) in both subcutaneous and disseminated human MM xenograft models. In summary, our study suggests that miR-33b is a tumor suppressor, which plays a role during MLN2238-induced apoptotic signaling in MM cells, and provide the basis for novel therapeutic strategies targeting miR-33b in MM. Disclosures: Anderson: Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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; Acetylon: Equity Ownership.

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Multiple Myeloma (MM): Impact of Immunoglobulin Isotype on the Speed of Response

Blood ◽

10.1182/blood.v126.23.4191.4191 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4191-4191 ◽

Cited By ~ 1

Author(s):

Helene Caillon ◽

Michel Attal ◽

Philippe Moreau ◽

Thomas Dejoie

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

Clinical Trials ◽

Board Of Directors ◽

Advisory Committees ◽

Speed Of Response ◽

Measurable Disease ◽

Multiple Myelomas ◽

The Impact ◽

Monoclonal Components

Abstract Background: Detection and/or measurement of monoclonal components by serum protein electrophoresis (SPE) is essential for evaluation of response in multiple myeloma according to the International Myeloma Working Group (IMWG) criteria. Patient peak on SPE has a single presentation due to the extreme heterogeneity of monoclonal components based on isotype of immunoglobulin (Ig), charge, polymerization, viscosity, precipitation … Regarding the Ig isotype, distribution of myelomas has been known for a long time with about 55 % of IgG myelomas, 25 % of IgA myelomas, and 15% of light chain multiple myelomas (LCMM). Therefore differences in terms of various physical and chemical characteristics are observed according to isotype such as half-lives (IgG : 7-21 days ; IgA : 6 days ; only a few hours for light chains of Ig). Considering both differences about frequency and clearance according to Ig isotype, we addressed the question of the impact of isotype on the speed of response in multiple myeloma. Objective: The aim of this study was to assess if the different isotypes of monoclonal components involved in multiple myeloma have an impact on the velocity and the depth of response. Design and methods: Data from two recent clinical trials conducted by IFM were analysed. The first analysis was based on patients enrolled in the IFM DFCI 2009 clinical trial who benefited of each of the three MRD points planned in this trial (after induction and autograft for one arm, pre-maintenance and post-maintenance). Patients were categorized on the isotype of the monoclonal component involved : IgG, IgA or IgD intact immunoglobulin multiple myelomas (IIMM) with serum measurable disease according to IMWG criteria (i.e. serum monoclonal peak ≥ 10 g/L), LCMM, and IIMM without any serum measurable disease (i.e. serum monoclonal peak < 10 g/L).The percentage of patients who achieved at least a very good partial response (VGPR) was evaluated globally as well as for each category defined. The same analysis was carried out for the IFM 2013-04 clinical trial with one response assessment, after four induction cycles. Results: Concerning IFM DFCI 2009 trial, 398 patients evaluated on the three MRD points could be included in this analysis, divided into 185 and 213 in each arm of treatment. Within the total enrolment, two types of response kinetics could be distinguished : for IgA, IgD IIMM, IIMM without serum measurable disease and LCMM, the gain of response between post-induction +/- autograft and post-maintenance is on average 11,1 points (6,7 - 15) when IgG myelomas presented a difference of VGPR percentage of 27,9 points. The same observation could be made for each arm of treatment : 16,6 and 5,8 points of VGPR percentage gained in each arm for the "faster response" group as defined previously, whereas 33,3 and 23,3 points were gained for IgG myelomas. Apart from this difference of kinetics, we notably observed that IgG myelomas never reached VGPR rates obtained with other isotype myelomas. About IFM 2013-04 trial, 264 patients could be evaluated in our analysis after four cycles of VTD (131) or VCD (133) for induction. 98,0% of IgA myelomas achieved at least VGPR after induction (96,3% for VTD arm and 100% for VCD arm) whereas only 50,6% for IgG myelomas (57,3% and 43,2%) and 68,3% for LCMM (46,7% for VTD arm and 80,8 for VCD arm). Conclusion: This study shows that time of evaluation is a key factor regarding the different speed of response for each isotype of Ig. IgA myelomas and LCMM have a faster response than IgG myelomas. IgG myelomas have a lower biochemical response than other isotype myelomas. Consequently, for an accurate interpretation of data in clinical trials, patients should be equally distributed in each arm of treatment according to their isotype. Ideally, to be compared, clinical trials should always have the same isotype distribution, especially when an early evaluation is performed such as after induction. Disclosures Attal: jansen: Honoraria; celgene: Membership on an entity's Board of Directors or advisory committees. Moreau:Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees.

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Targeting EZH2 in Multiple Myeloma Could be Promising for a Subgroup of MM Patients in Combination with IMiDs

Blood ◽

10.1182/blood.v128.22.311.311 ◽

2016 ◽

Vol 128 (22) ◽

pp. 311-311 ◽

Cited By ~ 4

Author(s):

Laurie Herviou ◽

Alboukadel Kassambara ◽

Stephanie Boireau ◽

Nicolas Robert ◽

Guilhem Requirand ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Plasma Cells ◽

Newly Diagnosed ◽

Advisory Committees ◽

Myeloma Cells ◽

Ezh2 Expression ◽

Bone Marrow Plasma

Abstract Multiple Myeloma is a B cell neoplasia characterized by the accumulation of clonal plasma cells within the bone marrow.Epigenetics is characterized by a wide range of changes that are reversible and orchestrate gene expression. Recent studies have shown that epigenetic modifications play a role in multiple myeloma (MM) by silencing various cancer-related genes. We investigated the epigenetic genes differentially expressed between normal bone marrow plasma cells (BMPC ; N=5) and MM plasma cells from patients (N=206). Using SAM (Significance Analysis of Microarrays) analysis, only 12 genes significantly differentially expressed between BMPC and MM cells (ratio > 2 and FDR (false discovery rate) < 5%) were identified, including the EZH2 histone methyltransferase. EZH2, the enzymatic subunit of Polycomb Repressive Complex 2, is a histone methyltransferases able to repress gene expression by catalyzing H3K27me3 histone mark. EZH2 overexpression has been associated with numerous hematological malignancies, including MM. We thus studied EZH2 role in MM physiopathology and drug resistance. EZH2 expression was analyzed in normal bone marrow plasma cells (BMPCs; N=5), primary myeloma cells from newly diagnosed patients (MMCs; N=206) and human myeloma cell lines (HMCLs; N=40) using Affymetrix microarrays. EZH2 gene is significantly overexpressed in MMCs of patients (median 574, range 105 - 4562) compared to normal BMPCs (median = 432; range: 314 - 563) (P < 0.01). The expression is even higher in HMCLs (median 4481, range 581 - 8455) compared to primary MMCs or BMPCs (P < 0.001). High EZH2 expression is associated with a poor prognosis in 3 independent cohorts of newly diagnosed patients (Heidelberg-Montpellier cohort - N=206, UAMS-TT2 cohort - N=345 and UAMS-TT3 cohort - N =158). Furthermore, GSEA analysis of patients with high EZH2 expression highlighted a significant enrichment of genes involved in cell cycle, downregulated in mature plasma cells vs plasmablasts, and EZH2 targets. Specific EZH2 inhibition by EPZ-6438 EZH2 inhibitor induced a significant decrease of global H3K27me3 in all the HMCLs tested (P < 0.01) and inhibited MM cell growth in 5 out of the 6 HMCLs tested. The inhibitory effect of EZH2 inhibitor on MM cell growth appeared at day 6 suggesting that it is mediated by epigenetic reprogramming. To confirm that EZH2 is also required for the survival of primary MMCs from patients, primary MM cells (n = 17 patients) co-cultured with their bone marrow microenvironment and recombinant IL-6 were treated with EPZ-6438. As identified in HMCLs, EZH2 inhibition significantly reduced the median number of viable myeloma cells by 35% (P = 0.004) from a subset of patients (n=9) while the other group (n=8) was resistant. Of interest, EPZ-6438 induced a significant global H3K27me3 decrease in both groups of patient. RNA sequencing of 6 HMCLs treated with EPZ-6438 combined with H3K27me3 ChIP analyses allowed us to create an EZ GEP-based score able to predict HMCLs and primary MM cells sensitivity to EZH2 inhibitors. We also observed a synergy between EPZ-6438 and Lenalidomide, a conventional drug used for MM treatment. More interestingly, pretreatment of myeloma cells with EPZ-6438 significantly re-sensitize drug-resistant MM cells to Lenalidomide. Investigating the effect of EPZ-6438/Lenalidomide combination in MMC, we identified that IKZF1, IRF4 and MYC protein levels were significantly more inhibited by the combination treatment (65.5%, 63.9% and 14.8% respectively) compared with Lenalidomide (51.5%, 43% and 2.2%) or EPZ-6438 (45.2%, 38.7% and 6.2%) alone. Clinical trials are ongoing with EZH2 inhibitors in lymphoma and could be promising for a subgroup of MM patients in combination with IMiDs. Furthermore, the EZ score enables identification of MM patients with an adverse prognosis and who could benefit from treatment with EZH2 inhibitors. Disclosures Goldschmidt: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: 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; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Hose:EngMab: Research Funding; Takeda: Other: Travel grant; Sanofi: Research Funding.

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