An Observational, Retrospective Analysis of Retreatment with Carfilzomib in the Management of Patients with Multiple Myeloma

Background: Several studies have indicated that the depth and duration of treatment response in multiple myeloma are both reduced in the relapsed setting. With further lines of therapy, responses continue to weaken in depth and shorten in duration. The National Comprehensive Cancer Network (NCCN) Guidelines suggest that regimens may be repeated in the relapsed setting if there has been a duration of at least 6 months since that regimen was given; however, there is limited information regarding treatment response and duration in the setting of re-treating patients with agents previously utilized. Moreover, preliminary data has suggested that carfilzomib-based regimens in the frontline may be able to attain deeper and longer responses than alternative therapies, which has led to carfilzomib being used more frequently in the frontline. This motivated us to investigate the treatment response, depth, and safety of re-challenging patients with carfilzomib in the relapsed setting. Methods: In this retrospective chart review, we identified all patients who were treated with multiple courses of carfilzomib-based regimens at Memorial Sloan Kettering Cancer Center between January 1, 2014 and November 30, 2018. Our primary objectives were to assess the response, duration of response and treatment, and safety of re-exposure to carfilzomib-based regimens. Responses were assessed as per IMWG 2016 consensus criteria (Lancet Oncol 2016). In this review we describe the clinical course, safety, and efficacy of re-challenging patients with carfilzomib in the relapsed and refractory settings. Results: Fifteen patients were identified as having received multiple, independent lines of carfilzomib-based therapy. The median age of the cohort was 58 years (49-76) with 53% male (8); two patients had R-ISS stage 1, eight stage 2, and five stage 3 disease. Five of these patients received their initial carfilzomib in the frontline as part of KRD; four of whom attained a sCR with the fifth attaining a VGPR. The remaining ten patients received their initial carfilzomib in the second-line (4) or 3rd and subsequent lines (6). Upon re-exposure to carfilzomib, patients were heavily treated with a median of four lines of therapy (2-15). All but three patients had at least one adverse cytogenetic abnormality; eight with 17p-, five with 13q-, three with t4;14, and six with 1q+. Regimens utilized in the relapsed setting included KRD (N=4), KPD (N=3), Cyklone (N=2), KD + HDAC inhibitor (N=3), KD (N=1), KCD (N=1), and KRD + daratumumab (N=1). Four patients received carfilzomib at a dose of 27 mg/m2 while the remaining 10 received > 36 mg/m2. Responses were seen in all but four patients (two VGPR, five PR, and four MR), with one patient experiencing progression during carfilzomib with no response; notably, this patient only attained a MR to primary carfilzomib therapy and their second exposure was the 15th line of therapy. The median time to next therapy was 4.8 months (1.9-19.4) with one patient being bridged to autologous hematopoietic cell transplantation (HCT), one to allogeneic HCT, and three are currently receiving ongoing carfilzomib treatment (13.9, 2.8, 2.5 months with VGPR, MR, and PR, respectively). Exacerbation of baseline hypertension was identified in three patients, but these instances were treated successfully with standard medications with no further complications. No additional cardiovascular events were identified in the frontline or re-treatment settings. Conclusions: We report that in a heavily pre-treated, high risk patient cohort, patients previously treated with carfilzomib-based regimens may be safely re-challenged with carfilzomib. Importantly, none of these patients experienced cardiovascular adverse effects other than exacerbation of underlying hypertension, further supporting the ability to safely re-treat a select group of patients with carfilzomib. We conclude that depending on the patient and treatment history, re-challenging with carfilzomib at relapse may be appropriate salvage therapy, particularly as a bridge towards HCT and/or clinical trials. Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Lesokhin:Genentech: Research Funding; Serametrix Inc.: Patents & Royalties; Janssen: Research Funding; GenMab: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landau:Prothena: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Giralt:Amgen: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Miltenyi: Research Funding; Jazz Pharmaceuticals: Consultancy; Actinium: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Johnson & Johnson: Consultancy, Research Funding; Kite: Consultancy. Landgren:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Merck: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽

10.1182/blood-2019-124403 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1835-1835 ◽

Cited By ~ 4

Author(s):

Katrina M Piedra ◽

Hani Hassoun ◽

Larry W. Buie ◽

Sean M. Devlin ◽

Jessica Flynn ◽

...

Keyword(s):

Multiple Myeloma ◽

Venous Thromboembolism ◽

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Cancer Trial ◽

Oncology Research ◽

Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: 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; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: 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, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

Download Full-text

Universal: An Allogeneic First-in-Human Study of the Anti-Bcma ALLO-715 and the Anti-CD52 ALLO-647 in Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2020-140641 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 24-25 ◽

Cited By ~ 1

Author(s):

Sham Mailankody ◽

Jeffrey V. Matous ◽

Michaela Liedtke ◽

Surbhi Sidana ◽

Shahbaz Malik ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Response Assessment ◽

Publicly Traded ◽

Advisory Committees ◽

Oncology Research ◽

Car T ◽

Grade 3 ◽

Dose Levels

Background Allogeneic (off the shelf) chimeric antigen receptor (CAR) T cell therapy addresses the logistical challenges, availability and variable product quality of autologous CAR T therapy. ALLO-715 is a genetically modified anti-BCMA AlloCAR Ttm cell product in which the TCR alpha constant gene is disrupted to reduce the risk of graft-versus-host disease (GvHD) and the CD52 gene is disrupted with Talen® technology to permit the use of ALLO-647, an anti-CD52 mAb, for selective and prolonged host lymphodepletion (LD). Methods This is an open-label, Phase 1 trial (NCT04093596) in adults with R/R multiple myeloma who have received ≥3 prior lines of therapy including a proteasome inhibitor, immunomodulator, and anti-CD38 mAb. Patients (pts) must be refractory to their last treatment line. Patients receive LD followed by ALLO-715 at 1 of 4 dose levels (DL) in a 3+3 dose escalation design: 40, 160, 320, and 480 x 106 CAR+ T cells. Several LD regimens are being evaluated. These include: FCA (fludarabine (F) 90 mg/m2, cyclophosphamide (C) 900 mg/m2, and ALLO-647 (A) 39 mg divided over 3 days), FCA+ (same F and C but ALLO-647 (A+) dose of 90 mg divided over 3 days); as well as CA (same C and A divided over 3 days, but no F given). Results As of 08 July 2020, 19 pts had enrolled and 15 had received ALLO-715 at 3 DLs: 3 pts at DL1 (3 FCA and 0 CA); 7 pts at DL2 (4 FCA and 3 CA); 5 pts at DL3 (3 FCA and 2 CA). As of the data cutoff, no pts had received FCA+ or ALLO-715 DL4. Patients were heavily pre-treated and in advanced stage of disease with a median of 5 (range 3-11) prior lines of therapy and 31.6% ISS Stage III at screening. All but 1 had a prior autologous stem cell transplant. 52.6% (10/19) of patients had high risk cytogenetics, and 26.3% (5/19) had extramedullary disease. The most common Grade ≥3 adverse events were anemia (41.2%), neutropenia (41.2%), lymphopenia (29.4%), and thrombocytopenia (29.4%). Four episodes of Grade ≥3 infections occurred in 4 pts. Three of these were Grade 3 and included parvovirus B19, staphylococcal bacteremia, and pneumonia, which resolved with treatment. The fourth was a Grade 5 episode that occurred on day 8 post-ALLO-715 infusion in a rapidly progressing, refractory myeloma pt who, on day 1, developed a non-neutropenic fever and multifocal pneumonia with negative blood and sputum cultures. The patient progressed to respiratory failure and only comfort care was pursued. This death was considered related to conditioning (CA). No DLTs to ALLO-715 had been reported as of the data cutoff. In addition, no neurotoxicity (ICANS) or GvHD had been reported as of the data cutoff. Cytokine release syndrome was reported in 4 pts (24%). Three episodes were Grade 1 and 1 was Grade 2 (Lee Grading); all resolved without tocilizumab or corticosteroids. Fifteen pts were efficacy evaluable (defined as receiving ALLO-715, and undergoing at least one response assessment or discontinuing prior to the first response assessment), with a median follow-up of 2 months (range 0, 10 months). A higher dose of ALLO-715 (DL3) was associated with greater anti-cancer activity with 3/5 pts responding per IMWG (60%, 95% CI 14.7, 94.7). In pts who received DL3 FCA, 2/3 responded (1 sCR and 1 VGPR, Table 1). All DL3 pts who responded experienced at least a VGPR and achieved MRD negative status by local MRD testing. All responses were initially observed at day 14. Four (80%) out of the 5 responders were still in response at the time of the data cutoff. ALLO-715 cell expansion by qPCR was observed at all dose levels. Conclusions These early data suggest that ALLO-715 and ALLO-647 have a manageable safety profile. ALLO-715 shows evidence of clinical activity in the allogeneic setting in pts with R/R multiple myeloma and suggests that higher cell doses are associated with greater anti-cancer activity. Enrollment is ongoing in cohorts with higher ALLO-715 (480M CAR+ T-cells) and ALLO-647 (90mg). Updated safety, efficacy, PK/PD data will be presented. Clinical trial information: NCT04093596. Disclosures Mailankody: Physician Education Resource: Honoraria; PleXus Communications: Honoraria; Takeda Oncology: Research Funding; Janssen Oncology: Research Funding; Allogene Therapeutics: Research Funding; Juno Therapeutics, a Bristol-Myers Squibb Company: Research Funding. Matous:Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Sidana:Janssen: Consultancy. Nath:Actinium: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria. Oluwole:Bayer: Consultancy; Spectrum Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy. Karski:Crisper Therapeutics: Current equity holder in publicly-traded company; Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company; Nektar Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Lovelace:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company. Zhou:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company. Nandakumar:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company. Balakumaran:Allogene Therapeutics: Current Employment, Current equity holder in publicly-traded company; Merck: Ended employment in the past 24 months. Hari:BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; GSK: Consultancy; Incyte Corporation: Consultancy.

Download Full-text

Alternative Dosing of Cyclophosphamide, Bortezomib and Corticosteroids (CyBorD) for Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.5142.5142 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5142-5142

Author(s):

Viet Q. Ho ◽

Elizabeth Finley-Oliver ◽

Kenneth H. Shain ◽

Melissa Alsina ◽

Leonel Ochoa ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Standard Dose ◽

Optimal Schedule ◽

Cancer Center ◽

Advisory Committees ◽

Refractory Multiple Myeloma ◽

Dose Reductions

Abstract Abstract 5142 Background: The combination of an alkylating agent and bortezomib has been shown to be synergistic both preclinically and in the clinical arena. Although the combination of cyclophosphamide, bortezomib and corticosteroids (CyBorD) has been evaluated by several investigators, many have used different doses and schedule of cyclophosphamide and an optimal schedule has not been established. Herein, we report the safety and efficacy of this combination in patients with relapsed and refractory multiple myeloma. Methods: All patients with myeloma that received this schedule of CyBorD at the Moffitt Cancer Center were included. CyBorD was comprised of cyclophosphamide 1000 mg/2 IV on Day 1, Bortezomib 1.3 mg/m2 IV on Days 1, 4, 8, and 11 and either low dose dexamethasone (equivalent of 120– 160mg/cycle) or prednisone (100 mg PO day 1–5). Demographic, laboratory and clinical data was collected and evaluated via descriptive statistics. Response and progression are defined as per the IMWG uniform response criteria. Results: A total of 20 patients were identified and included for analysis. Demographic data is shown in table 1. At baseline, 35% of patients were platelet transfusion dependent, and the median ß2m was 6.2mg/L. 8 patients (40%) received prophylactic GCSF and 9 patients (45%) received secondary GCSF after significant neutropenia was noted. Overall response rate (PR and better) was 50% (70% minimal response and better), including 1 complete response (CR) and 5 very good partial response (VGPR). Median progression free survival was 3.4 months (95% CI 0–7.5 months) and median overall survival was 11.9 months (95% CI 3.3–20.0). The incidence of grade 3/4 neutropenia and thrombocytopenia was 80% and 75%, respectively. Grade 2 and 3 peripheral neuropahty developed in 1 and 1 patient respectively. Nine patients required dose reductions of cyclophosphamide (only 2 of the 8 who received prophylactic GCSF therapy) and 3 patients required dose reductions of the bortezomib. Conclusion: In this cohort of patients with high burden of disease, intermediate dose cyclophosphamide administered once every 3 weeks in combination with standard dose and schedule of bortezomib results in a meaningful response rate (albeit short PFS) with mainly hematologic toxicities that are manageable with growth factor support. Disclosures: Off Label Use: Cyclophosphamide in combination with bortezomib for relapsed/refractory multiple myeloma. Finley-Oliver:Millenium: Speakers Bureau. Alsina:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allergan: Research Funding. Djulbegovic:Millenium: Research Funding. Baz:Millenium: Research Funding, Speakers Bureau; Celgene: Research Funding.

Download Full-text

Transcriptomic Correlates of Response to Selinexor in Multiple Myeloma Reveal a Predictive Signature

Blood ◽

10.1182/blood-2021-150522 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 457-457

Author(s):

Paula Restrepo ◽

Sherry Bhalla ◽

Adolfo Aleman ◽

Violetta Leshchenko ◽

Sarita Agte ◽

...

Keyword(s):

Gene Expression ◽

Clinical Trial ◽

Multiple Myeloma ◽

Treatment Response ◽

Board Of Directors ◽

Research Funding ◽

Gene Expression Signature ◽

Advisory Committees ◽

Depth Of Response ◽

Boston Study

Abstract Selinexor acts by inhibiting the nuclear export protein XPO1; however, its mRNA expression does not correlate with response, and the biological mechanisms underlying treatment response for different patients remain unclear. There is a critically unmet need for validated genomic biomarkers to help guide treatment recommendations to selinexor based therapy. Here, we characterized the transcriptomic correlates of response to selinexor in data from 189 patients from multiple studies of selinexor-based therapy and identified and validated a 3-gene expression signature predictive of treatment response. We performed RNA sequencing on CD138+ cells from 103 patients who participated in the BOSTON study, a phase III, open-label clinical trial of patients with multiple myeloma (MM) who were treated with selinexor, bortezomib and dexamethasone (XVd) after 1-3 lines of standard therapy versus a bortezomib and dexamethasone (Vd) regimen (Grosicki et al 2020 Lancet; Fig 1A-B). Then, we performed differential expression, followed by pathway analysis, to compare patients with long and short progression-free survival (PFS) in the XVd arm of the BOSTON dataset across various PFS and overall depth-of-response (OR) cutoffs. Here, we identified a total of 24 unique downregulated genes and 33 unique upregulated genes that were associated with longer PFS or better depth of response in the XVd arm (FDR < 0.05). Pathway analyses revealed downregulation of apoptosis and MYC targets in patients with selinexor-associated longer PFS or better depth of response (FDR < 0.05), consistent with the known relationship between depth and duration of response in MM. Using the differentially expressed genes, we employed time-to-event univariate Cox proportional hazard models (CPH) with repeated 4-fold cross validation, log-rank testing, and spearman correlations to identify a novel signature that predicts PFS in the BOSTON dataset. This analysis revealed a GSVA score composed of three genes, WNT10A, DUSP1, and ETV7, that were upregulated in XVd patients with PFS > 120 days. Further, this signature accurately distinguished patients with long term PFS in the XVd arm of the BOSTON study (Fig 1C; log rank P = 0.017; spearman Rho = 0.46, P = 0.0007; CPH, FDR=0.047, HR=0.36 [95% CI = 0.14-0.84]). We also found that the signature significantly tracks with a depth of response of VGPR or better (Fig 1D, Wilcoxon P = 0.025). Finally, we validated the accuracy of our signature using transcriptomic data from two external cohorts: the STORM trial of penta-refractory MM (N = 64; Chari et al., NEJM), and a cohort of patients treated with selinexor-based regimens at Mount Sinai who were not part of a clinical trial (N = 21). This signature validated successfully in the STORM study (Fig 1E, log-rank P = 0.02; spearman Rho = 0.18, P = 0.14; CPH P = 0.08, HR=0.63 [95% CI = 0.47-1.03 ]) and in the non-trial Mount Sinai cohort (Fig 1G, log-rank P = 0.0033; spearman Rho = 0.6, P = 0.0043; CPH P = 0.004, HR = 0.215 [95% = 0.15-0.72]). Additionally, the association of the signature expression with depth-of-response validated in the STORM cohort (Fig 1F; Wilcoxon P = 0.021), further supporting the robustness of our signature. We used the MMRF-COMMPASS dataset (N=700) as a negative control and found that the signature is not predictive of PFS in patients who were treated with non-selinexor based, standard of care therapies. Together, these results support the conclusion that our signature is specific to selinexor treatment response and is not reflective of overall prognosis. We are currently performing experimental validation of the three genes in cell line experiments to better understand the mechanisms underlying their predictive power. We are also evaluating the utility of augmenting gene-expression based biomarkers with an ex-vivo mass-based biomarker assay to more accurately predict response to selinexor. In summary, we report a novel gene expression signature for response to selinexor-based therapy in patients with MM. We have validated our findings in several external transcriptomic datasets of MM patients treated with selinexor-based regimens. This signature has important clinical significance as it could identify patients most likely to benefit from treatment with selinexor-based therapy, especially in earlier lines of therapy. Figure 1 Figure 1. Disclosures Stevens: Travera: Current Employment. Richter: Adaptive Biotechnologies: Speakers Bureau; Celgene: Consultancy; Janssen: Consultancy; BMS: Consultancy; Karyopharm: Consultancy; Antengene: Consultancy; Sanofi: Consultancy; X4 Pharmaceuticals: Consultancy; Oncopeptides: Consultancy; Adaptive Biotechnologies: Consultancy; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Secura Bio: Consultancy; Astra Zeneca: Consultancy. Richard: Karyopharm, Janssen: Honoraria. Chari: Takeda: Consultancy, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Secura Bio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Millenium/Takeda: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jagannath: Bristol Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Sanofi: Consultancy; Legend Biotech: Consultancy; Takeda: Consultancy. Walker: Karyopharm Therapeutics Inc.: Current Employment. Landesman: Karyopharm Therapeutics: Current Employment, Current equity holder in publicly-traded company. Parekh: Foundation Medicine Inc: Consultancy; Amgen: Research Funding; PFIZER: Research Funding; CELGENE: Research Funding; Karyopharm Inv: Research Funding.

Download Full-text

Clinical Validation of Treatment Response Predictions Using a Genomics Driven Computational Biology Modelling Multiple Myeloma Algorithm

Blood ◽

10.1182/blood-2018-99-118686 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1893-1893

Author(s):

Ravi Vij ◽

Justin King ◽

Mark A. Fiala ◽

Neeraj Kumar Singh ◽

Mohammed Sauban ◽

...

Keyword(s):

Multiple Myeloma ◽

Computational Biology ◽

Clinical Response ◽

Treatment Response ◽

Board Of Directors ◽

Research Funding ◽

Patient Specific ◽

Similar Response ◽

Advisory Committees ◽

Combination Regimens

Abstract Background: Multiple myeloma (MM) is an incurable and heterogeneous haematological malignancy in which immune suppression and complex biology affect the disease and its response to treatment. Several new treatments have been approved for MM in recent years providing numerous options for patients with relapsed/refractory disease. However, there is no validated method for selecting the best treatment combination for each patient, making patient management difficult. The ability to predict treatment response based on disease characteristics could improve clinically outcomes. Aim: This was a validation of a genomics-informed response prediction using computational biology modelling (CBM) in patients with relapsed/refractory MM. Methods: Input data from fluorescence in-situ hybridization (FISH), karyotype, and a MM specific next generation sequencing capture array were analysed using CBM. This was a retrospective review of patients which were treated with different combinations based on patient/physician choice. The CBM uses PubMed and other online resources to generate patient-specific protein network maps of activated and inactivated pathways. The specific drug combination for each patient was simulated and the quantitative drug effect was measured on a composite MM disease inhibition score (i.e., cell proliferation, viability, apoptosis and paraproteins). The predicted outcomes were then compared to the clinical response (≥PR or < PR per IMWG) to assess the accuracy of this CBM predictive approach. Results: 27 patients were selected for the study; 3 failed CBM due to missing inputs and in 3 clinical response was not able to be assessed, leaving 21 eligible for the analysis. The median age at presentation was 57 years (range 37-76) and 52% were male. The median prior lines of MM therapy was 5 (range 1-15). 38% were refractory to bortezomib, 62% to lenalidomide, 52% to carfilzomib, 57% to pomalidomide, and 43% to daratumumab. 81% had a prior autologous stem cell transplant. The treatments modelled included IMiD-based regimens (n = 9), PI-based regimens (n = 6), chemo-based regimens (n = 3), selinexor (n = 2), PI/IMiD combination regimens (n = 1). Sixteen were clinical responders and 5 were non-responders. CBM predictions matched for 17 of 21 treatments overall, 15 of 16 clinical responders and 2 of 5 non-responders. The statistics of prediction accuracy against clinical outcome are presented in Table 1. Interestingly, the CBM identified drugs within the combination regimens which may not have impacted efficacy. For example, the CBM predicted that one patient treated with bortezomib, venetoclax, and dexamethasone would have had similar response if venetoclax had been omitted from the regimen. Conclusion: We have demonstrated that a CBM approach, which incorporates genomics, can help predict response in patients with relapsed or refractory MM. Prospective studies using the CBM as part of treatment decision-making will help determine its application into clinical settings. Disclosures Vij: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; Karyopharma: Honoraria, 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees. Singh:Cellworks Research India Private Limited: Employment. Sauban:Cellworks Research India Private Limited: Employment. Husain:Cellworks Research India Private Limited: Employment. Lakshminarayana:Cellworks Research India Private Limited: Employment. Talawdekar:Cellworks Research India Private Limited: Employment. Mitra:Cellworks Research India Private Limited: Employment. Abbasi:Cell Works Group Inc.: Employment. Vali:Cell Works Group Inc.: Employment.

Download Full-text

Changes in Uninvolved Immunoglobulins during Multiple Myeloma Therapy

Blood ◽

10.1182/blood.v128.22.3251.3251 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3251-3251

Author(s):

Praful Ravi ◽

Shaji Kumar ◽

Wilson I Gonsalves ◽

Francis K Buadi ◽

Martha Q. Lacy ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Treatment Response ◽

Board Of Directors ◽

Light Chain ◽

Research Funding ◽

Advisory Committees ◽

Percentage Difference ◽

Lower Likelihood

Abstract Background Suppression of uninvolved immunoglobulins is a common finding in multiple myeloma and the preservation of uninvolved immunoglobulins at diagnosis is associated with improved progression-free and overall survival. However, little is known about the impact of myeloma treatment on levels of uninvolved immunoglobulins, and the link between changes in uninvolved immunoglobulins during therapy and treatment response, disease progression and survival. Methods We identified patients who received therapy for newly diagnosed multiple myeloma at our institution between 2001 and 2014, and who had data available on absolute lymphocyte count (ALC) and quantitative uninvolved immunoglobulins (Ig) before commencing treatment. The ALC and levels of uninvolved Ig after 4 cycles of therapy were abstracted from the electronic medical record; patients who switched or stopped treatment, or died, before this time point were excluded. To assess change in ALC, the percentage difference in ALC between baseline and 4 cycles was calculated; for uninvolved Ig, the average of the percentage difference between baseline and 4 cycles for each uninvolved Ig (IgA and IgM for IgG myeloma, IgG and IgM for IgA myeloma, IgG and IgA for IgM and IgD myeloma, and IgG, IgM and IgA for light-chain only myeloma) was calculated. Treatment response at 4 cycles was retrospectively assigned according to International Myeloma Working Group criteria. Time to treatment failure (TTF) was defined as time from start of initial therapy to start of next line of therapy or death (if no additional treatment was received). A landmark analysis was used to calculate overall survival (OS) from the date of follow-up after 4 cycles of therapy. The Kruskal-Wallis, Chi-Square, and log rank tests were used to detect differences in medians, proportions, and survival times respectively. Results A total of 421 patients were included in this analysis. The median age was 63 years (range 33-91), 254 patients (60.3%) were male and median follow-up was 6.5 years (95% CI 5.6-7.3); the vast majority of patients had IgG (n=247 [58.7%]), IgA (n=98 [23.3%]) or light-chain only myeloma (n=68 [16.2%]). First line therapy comprised of pulse-dose dexamethasone (DEX, n=92 [21.9%]), lenalidomide-dexamethasone (RD, n=176 [41.8%]), bortezomib-dexamethasone (VD, n=22 [5.2%]), bortezomib-cyclophosphamide-dexamethasone (VCD, n=84 [20.0%]), and bortezomib-lenalidomide-dexamethasone (VRD, n=47 [11.2%]). Across the entire cohort, the median change in ALC and uninvolved Ig after 4 cycles of treatment was -11.0% (range: -92.7 to +718.8) and +9.0% (-77.7 to +1094.4) respectively; treatment with VCD was associated with the greatest median declines in ALC (DEX: -0.1%; RD: -9.9%; VD: -20.8%; VCD: -40.9%; VRD: -15.3%) and uninvolved Ig (DEX: -0.5%; RD: +15.5%; VD: +44.0%; VCD: -14.0%; VRD: +76.0%, both p<0.001). Conversion from suppression to normalization of the primary uninvolved Ig (IgA in IgG myeloma, and IgG in all other myeloma types) after 4 cycles was seen more frequently with the use of RD (13.1%) and VRD (12.8%) compared to DEX (4.7%), VCD (1.3%), or VD (4.8%), χ2=21.8, p=0.040. When considering only patients in whom the primary uninvolved Ig remained suppressed between baseline and 4 cycles, a ≥25% reduction in the primary uninvolved Ig occurred more frequently with the use of DEX (51.5%) and VCD (34.5%) compared to RD (24.8%), VD (23.5%) or VRD (25.7%), χ2=15.1, p=0.005 (Table 1). Although an average reduction in uninvolved Ig between baseline and 4 cycles (ΔIg<0) was independently associated with a lower likelihood of achieving very good partial response (VGPR) of better on multivariate analysis adjusting for age, sex and treatment regimen (OR=0.40 [0.24-0.63], p<0.001), there were no differences in TTF (2.0yrs vs. 2.0yrs, p=0.783) or OS (8.0yrs vs. 8.0yrs, p=0.721) between patients with ΔIg<0 (n=169) and those with ΔIg≥0 (n=222). Conclusions Myeloma treatments produce differential impacts on immune parameters, with VCD causing the greatest reduction in lymphocytes and uninvolved Ig, implying general targeting of plasma cells, in comparison to lenalidomide, which appeared to be more tumor-specific with relative sparing of lymphocytes and uninvolved Ig. While an average decrease in uninvolved Ig was an independent predictor of a lower likelihood of achieving VGPR or better after 4 cycles of therapy, it was not associated with a shorter TTF or poorer OS. Disclosures Kumar: BMS: Consultancy; Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Kesios: Consultancy; Millennium: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Research Funding. Dispenzieri:GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding; Jannsen: Research Funding; Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Amgen: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Bergsagel:Amgen, BMS, Novartis, Incyte: Consultancy; Novartis: Research Funding.

Download Full-text

COVID-19 in Patients with Hematologic Malignancies: A Single-Center Experience

Blood ◽

10.1182/blood-2020-140719 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 36-37

Author(s):

Lindsay Wilde ◽

Adam F. Binder ◽

Matthew Carabasi ◽

Joanne Filicko-O'Hara ◽

John L. Wagner ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Pharmaceutical Research ◽

B Cell Lymphoma ◽

Hematologic Malignancies ◽

Cell Transplant ◽

Advisory Committees ◽

Presenting Symptoms ◽

Oncology Research

Introduction :The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and subsequent coronavirus-19 (COVID-19) pandemic has impacted hematologic malignancies (HM) care worldwide. Reported risk factors for severe COVID-19 presentation include older age, medical comorbidities, and cardiac disease - many of which apply to patients with HM (Guan et al., 2020; Zhou et al., 2020). Additionally, patients with HM may be at even higher risk of infections with or complications from SARS-CoV-2 due to immune dysfunction from their underlying disease or treatment (He et al., 2020). However, data regarding rates of infection and outcomes in this population are limited. Here we describe the demographic characteristics, coexisting conditions, presenting symptoms, treatment, and outcomes of a cohort of patients with HM and COVID-19 infection at network sites across the Sidney Kimmel Cancer Center- Jefferson Health. Methods : We created an HM-specific COVID-19 database within our health system. Patients were identified for inclusion in the database by physician referral and query of the electronic medical record. Epidemiological, clinical, and laboratory data, therapy details, and outcomes on patients were obtained by accessing electronic medical records. A retrospective study of patients with a diagnosis of a HM- within 5 years of COVID-19 diagnosis-and a confirmed diagnosis of COVID-19 were was conducted using this database. A confirmed diagnosis of COVID-19 was defined as a positive result on a real-time RT-PCR assay of a specimen collected by nasopharyngeal swab. Results: More than 3,000 telehealth or in-person patient visits were conducted for patients with HM in the Jefferson Health Network between March 9, 2020 and July 15, 2020. During that period, 21 patients with HM had a confirmed diagnosis of COVID-19. Median age was 67 years (range 21-89). The majority of patients (86%) had at least 1 comorbid medical condition, and 76% had a history of tobacco use. The most common HM was multiple myeloma (7/21, 33%), followed by diffuse large B-cell lymphoma (3/21, 14%). 12/21 (52%) patients were on active cancer treatment at the time of COVID-19 diagnosis, and patients had received a median of 2 lines of cancer therapy (range 0-6). All 12 patients who were on active therapy at the time of COVID-19 diagnosis experienced a treatment interruption. Two patients had undergone prior autologous stem cell transplant (SCT) and 1 had undergone prior allogeneic SCT. Details on HM diagnosis and treatment are presented in Table 1. Twenty patients required hospital admission at the time of COVID-19 diagnosis, 7/21 were admitted to the ICU, and 6/21 required intubation. The most common presenting symptoms were fever (48%), cough (43%), and shortness of breath (43%), and lymphopenia (absolute lymphocyte count (ALC) <1,000 B/L) was common at presentation (56%). More than half (13/21, 62%) of patients received some COVID-19 directed therapy, while 8 were treated with supportive care alone. As of July 15, 2020 18/21 (86%) patients were alive. Characteristics of the 3 patients who died are described in Table 2. Conclusion : In contrast to published reports, we found that the number of confirmed COVID-19 in patients with HM at our center was surprisingly low, with only 21 cases in 4 months. Furthermore, the mortality rate of 14% was lower than expected when compared to published cohorts of similar patients, which have shown mortality rates as high as 40% (He et al., 2020; Malard et al., 2020; Martín-Moro et al., 2020). Postulated reasons for the low number of infections include the early adoption of universal masking and robust utilization of telehealth to promote social distancing. In our small cohort, multiple myeloma was the most frequent HM diagnosis associated with COVID-19 infection, but this may be related to the prevalence of MM in our geographic area. The vast majority of HM patients with symptomatic COVID-19 were former smokers. Disclosures Binder: Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy. Alpdogan:Seattle Genetics: Consultancy; Kiowa Kirin: Consultancy. Kasner:Otsuka Pharmaceutical: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Martinez-Outschoorn:Otsuka Pharmaceutical: Research Funding. Palmisiano:Genentech: Research Funding; AbbVie: Research Funding. Flomenberg:Tevogen: Consultancy, Honoraria. Porcu:Cell Medica: Research Funding; Daiichi: Consultancy, Honoraria; Galderma: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kiowa Kirin: Research Funding; Kura Oncology: Research Funding; Miragen: Research Funding; Verastem: Consultancy; Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding.

Download Full-text

The Genomic and Transcriptomic Landscape of Double-Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2019-122197 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3056-3056 ◽

Cited By ~ 1

Author(s):

Bachisio Ziccheddu ◽

Giulia Biancon ◽

Chiara De Philippis ◽

Filippo Bagnoli ◽

Francesco Maura ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Alkylating Agents ◽

High Dose ◽

Advisory Committees ◽

Tp53 Mutations ◽

Travel Costs ◽

Oncology Research

In Multiple myeloma (MM) no treatment has a curative potential and even complete response to novel agents such as proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs) are followed by relapse over time. Next generation sequencing (NGS) has showed how MM at diagnosis is defined by several somatic mutations, but only few drivers, even fewer "druggable" mutations, and many found at a subclonal level. At relapse, targeted studies have shown occasional mutations in drug target genes but the genomic and transcriptomic determinants of chemoresistance in MM remains elusive. We selected 42 MM patients refractory to both lenalidomide and PIs. Whole exome sequencing was performed in 40 of them, and RNAseq in 27. Clinical annotation was available for all patients. Standard analysis pipelines where applied to analyze mutations, copy number alterations (CNAs), mutational signatures, gene expression and expressed mutations. Patients received a median of 3 lines of treatment, with median overall survival of 14.6 months from sampling. We found a median of 77.5 mutations per patient, which is more than what reported at diagnosis (Bolli et al, Nature Communications 2014;5:2997). 100% of samples showed evidence of subclonality, and 37% of them exhibited a higher number of subclonal than clonal variants. Therefore, even at this advanced stage the MM genome is evolving and is composed of different subclones that may display different chemosensitivity. The mutational landscape was also different. TP53 mutations were the second most common after KRAS (20% and 17.5%, respectively). Interestingly TP53 mutations all clustered in patients receiving bortezomib as the last line of treatment. Only 2 patients showed a CRBN mutation, both subclonal. Combining mutations and CNA analysis, the TP53 pathway was the most frequently inactivated (45% of patients). Altogether, mutations or deletions of genes in the CRBN E3 ubiquitin ligase complex were found in 32.5% of patients, while proteasomal subunit genes were infrequently hit. Refractory cases were also uniquely characterized by a novel signature linked to exposure to alkylating agents, whose activity was more pronounced after high-dose melphalan suggesting a mutagenic effect of the drug on residual cells at the time of transplant. Whether this has any pathogenetic role on the disease course remains to be elucidated. RNAseq analysis did not show any influence of treatment or mutational data on the clustering of samples, which was mainly influenced by karyotypic events. The main cluster was composed by non-hyperdiploid patients with both amp(1q) and del(13): these showed CCND2 and MCL1 upregulation, the latter representing a marker of venetoclax resistance and novel target of experimental treatments. Only 26.3% of mutations were expressed, and this correlated with the clonality level of the mutation. However, most mutations in driver genes were expressed, with the notable exception of those causing nonsense mediated decay. Overall, classical high-risk features or CRBN pathway mutations were found in 65% of the cohort. However, only amp(1q) predicted survival in our cohort. The lack of prognostic value of high-risk lesions is likely explained by a higher prevalence of such features in double-refractory stages. Our data suggest that gene mutation is not a preferred mode of evolution of drug resistance in MM. Chemoresistance of the bulk tumor population is likely attained though differential, yet converging evolution of different subclones that are overall highly variable from patient to patient and within the same patient. Disclosures Kastritis: Prothena: Honoraria; Genesis: Honoraria; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria. Dimopoulos:Sanofi Oncology: Research Funding. Cavo:bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Corradini:Janssen: Honoraria, Other: Travel Costs; Takeda: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; Gilead: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Celgene: Honoraria, Other: Travel Costs; Amgen: Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel Costs; KiowaKirin: Honoraria; Kite: Honoraria; BMS: Other: Travel Costs; Sanofi: Honoraria; Servier: Honoraria; Roche: Honoraria; Novartis: Honoraria, Other: Travel Costs. Bolli:Celgene: Honoraria; Novartis: Honoraria; Gilead: Other: travel expenses.

Download Full-text

Mytype: A Capture Based Sequencing Approach to Detect Somatic Mutations, Copy Number Changes and IGH Translocations in Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-119886 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5588-5588

Author(s):

Venkata Yellapantula ◽

Malin Hultcrantz ◽

Even H Rustad ◽

Heather J. Landau ◽

Christine Iacobuzio-Donahue ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Copy Number ◽

Research Funding ◽

Somatic Mutations ◽

Physician Education ◽

Nucleotide Polymorphisms ◽

Advisory Committees ◽

Copy Number Aberrations ◽

Synonymous Mutations

Abstract Introduction At diagnosis, Multiple Myeloma (MM) is traditionally classified into two clinical and prognostic subgroups groups on the basis of initiating cytogenetic abnormalities: IGH translocations and hyperdiploidy. Currently, these events are clinically ascertained by Fluorescent In-Situ Hybridization (FISH). In recent years, comprehensive genome profiling studies have shown that MM pathogenesis is defined by a spectrum of acquired somatic lesions, many of which are biologically and clinically relevant. To this effect, targeted gene sequencing approaches are becoming routine in the upfront diagnostic settings. Here we present myTYPE, a MM-specific targeted next generation sequencing panel to identify germline and somatic substitutions, indels, Copy Number Aberrations (CNA) and IGH translocations. Methods A multiplex bait panel was designed to capture the exons of 120 genes implicated in MM pathogenesis, entire IGH locus as well as genome wide representation of single nucleotide polymorphisms (SNPs) (1 in 3Mb) to enable detection of arm level copy number events and recurrent focal events. These 120 genes were selected on the basis of 1) frequently mutated and driver genes in MM 2) genes in important signaling pathways, e.g the NFKB pathway 3) treatment targets and candidate genes for drug resistance, e.g. cereblon.To validate the efficacy of the assay, 16 constitutional bone marrow samples and 18 tumor samples were sequenced using myTYPE. For validation, 6/18 tumor/normal pairs sequenced using myTYPE were subject to WGS and remaining 12/18 tumor samples were subject to FISH. After sequencing, we obtained an overall median target coverage of 815x. Results After alignment, substitutions and indels were called using Caveman, Pindel and Strelka. CNAs were identified using Facets and IGH translocations were identified using Delly along with a modified version of BRASS. Below is a description of the genomic abnormalities captured by the myTYPE assay. SNVs and Indels For the 6 tumor/normal pairs sequenced using myTYPE and WGS, we obtained a total of 21 (median = 3) non-synonymous mutations using myTYPE. When limiting the WGS calls to myTYPE targets, we recovered 20/21 non-synonymous mutations identified by myTYPE. These involved SNVs and indels in key MM related drivers including NRAS, KRAS, FAM46C and TP53 among others. For the mutations identified by both myTYPE and WGS, there was a high correlation between the variant VAFs, R2= 0.99 and as expected is better in capturing subclonal mutations. IGH rearrangements and Copy Number Aberrations (CNA) Next we compared myTYPE and WGS results for recurrent CNAs in MM. We specifically looked at deletions of 1p, 13p, 16q, 17p and gains of 1q, 11q and found a 100% concordance of these aberrations identified by both assays. The remaining 12 samples sequenced using myTYPE also had orthogonal FISH. myTYPE identified a total of 7 IGH rearrangements, 4 of which are also reported by FISH. Three additional t(11;14) translocations were uniquely identified by myTYPE in cases that remained clinically uncharacterized. FISH was also used to probe deletions in 17q, 13q, 1p and 1q gain. All aberrations identified by FISH were also identified in myType. Additionally, 13q- in four samples and 1p- in one sample were uniquely identified by myTYPE. Conclusion In summary, we present a targeted assay capable of identifying somatic mutations, CNAs and IGH translocations of prognostic and diagnostic relevance in MM. When compared to conventional assays currently used in clinical practice, myTYPE identified at least one disease defining alterations in all samples screened. Evaluation of sensitivity and specificity will require larger clinical cohorts. Importantly, myTYPE enables comprehensive profiling, large sample multiplexing and short turn around times which renders it as an optimal assay for utilisation in the upfront clinical setting. Disclosures Korde: Amgen: Research Funding. Mailankody:Juno: Research Funding; Janssen: Research Funding; Takeda: Research Funding; Physician Education Resource: Honoraria. Landgren:Pfizer: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy.

Download Full-text

Feasibility and Activity Of Bortezomib-Based Therapy In Patients With Relapsed/Refractory Multiple Myeloma Previously Treated With Carfilzomib

Blood ◽

10.1182/blood.v122.21.1994.1994 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1994-1994

Author(s):

Arti Alagappan ◽

Rupin A Shah ◽

Sheeba K. Thomas ◽

Donna M. Weber ◽

Michael Wang ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Proteasome Inhibitor ◽

Research Funding ◽

Single Agent ◽

Cancer Center ◽

Cell Transplant ◽

Advisory Committees ◽

Refractory Multiple Myeloma ◽

Overall Response

Abstract Introduction Carfilzomib (Car) is a proteasome inhibitor (PI) that was recently approved for the treatment of relapsed or refractory multiple myeloma. It is indicated for patients (pts) who previously received the proteasome inhibitor bortezomib (Bz) and an immunomodulatory drug (thalidomide or lenalidomide (len)) and had disease refractory to the last line of therapy. With the increasing number of therapeutic options, the optimal sequencing strategy of PIs to maximize clinical benefit and patient outcomes is unclear. The objective of our study was to therefore evaluate the activity of Bz after Car exposure. Methods Pts who enrolled and received Carfilzomib-based therapy on clinical trials at The University of Texas M. D. Anderson Cancer Center were screened for subsequent Bz therapy. Carfilzomib was administered as a single agent, or with len/dexamethasone (dex). We evaluated the overall response and tolerability of Bz pre- and post-Car, and to Car-based therapy. Results 16 pts were identified with a mean age of 67 (range 48-85), including 11 women and 5 men. ISS stage was I in 10 pts, stage II in 1, and stage III in 5. Median lines of therapy prior to Car were 3 (1-9), and 11 pts had prior stem cell transplant. Prior to Car-based therapy, 5 pts were Bz naïve, 7 were Bz sensitive, and 4 were Bz intolerant. Among the 16 patients treated with Car as a single agent, or Car in combination with dex (n=1), len/dex (n=12), panobinostat (n=2) and pomalidomide/dex (n=1) the overall response rate (ORR) to Car-based therapy on protocol (≥MR) was 75% (12/16). Among the 16 pts who subsequently received Bz after Car, 4 patients remained sensitive to Car (2/4 were Bz naïve), 5 were intolerant to Car, and 7 were Car refractory (3/7 were Bz naïve). Patients received Bz in combination with various other therapeutics, including cyclophosphamide/dex (n=5), melphalan/dex (n=2), modified-CVAD (n=3), len/dex (n=5), pegylated doxorubicin/dex (n=7) and bendamustine (n=3). The ORR to Bz-based therapy after Car was 81% (13/16). Among the 7 patients who were refractory to Car, 5/7 patients had ≥MR to Bz based therapy, while 2 patients were Bz intolerant due to rash and neutropenia. Among the 13 pts who responded to Bz after Car, 10 patients had received prior Bz. 3/5 pts who were Bz naïve had ≥MR. 4/4 patients who were intolerant to prior Bz had ≥MR, and 6/7 Bz sensitive patients had ≥MR. Discussion Bortezomib-based therapy is feasible after carfilzomib exposure in patients including those who were previously intolerant to bortezomib. The ORR(≥MR) in this patient population to Bz-based therapy was 81%. Disclosures: Thomas: Millenium: Research Funding; Novartis Pharmaceuticals: Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Orlowski:Bristol-Myers Squibb: 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; Millennium: The Takeda Oncology Company: Honoraria, 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, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Shah:Celgene: Consultancy, Research Funding; Array: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.

Download Full-text