Octogenarians with AML Can Have Durable Remissions with Venetoclax and Hypomethylating Agent Therapy Despite Significant Dose Reductions

Abstract Introduction Venetoclax in combination with a hypomethylating agent (VEN-HMA) has become a standard of care for older or unfit patients with newly diagnosed AML. Although primarily administered in the outpatient setting, VEN-HMA is associated with significant cytopenias and infectious complications, requiring careful monitoring and dose adjustments. Patients treated with VEN-HMA on clinical trials had a median age of ~75 years. The optimal dose and schedule, safety, and efficacy of VEN-HMA in octo- and nonagenarians is not clearly defined. Methods We performed a retrospective analysis of AML patients ≥80-years-old who received at least 1 day of VEN-HMA at our institution from 11/2018 to 7/2021. Patients with de novo or secondary AML with or without prior HMA or chemotherapy were included. Venetoclax starting dose was 200-400 mg for 14-28 days. Dose adjustments for drug interactions with azole anti-fungals were implemented. HMA was started at 50-75 mg/m2 for 5-7 days of azacitidine or 20mg/m2 for 5 days of decitabine. Dose reduction was defined as any decrease from the starting dose and schedule. Patients who did not complete cycle 1 were included in the overall survival and safety analysis but excluded from response assessment. Results Among 21 patients ≥80-years-old treated with VEN-HMA (20 newly diagnosed, 1 relapsed/refractory), median age was 82 years (range: 80-89) (Table 1), 57% had antecedent MDS, and 38% received HMAs previously. Most patients (81%) were ELN adverse risk, 38% had a complex karyotype, 24% had a TP53 mutation, and 43% had ECOG PS of 2-3. Median overall survival for all patients was 8.0 months (0.5-31.4 months). At time of analysis, 12 patients (57%) were still alive and in remission on VEN-HMA with a median follow-up of 11.5 months (range 2.3-31.4 months). Five patients (24%) died during cycle 1 from sepsis. Of these 5 patients, 4 had a TP53 mutation, 3 had prior MDS, and 3 had received prior therapy for lymphoma. In the remaining 16 patients, median overall survival was 9.9 months (2.3-31.4 months) and the CR/CRh rate was 81% (13/16 patients). Median duration of response was 8.9 months (range 1.0-30.0). Consistent with previous reports, all patients who achieved CR/CRh did so by the end of cycle 2 (median 2 cycles). Most patients also received the standard dose and schedule of VEN (75%) and HMA (57%) during the first cycle. All patients (100%) required venetoclax dose and schedule reduction, with a median final venetoclax dose of 200 mg and duration of 14 days. Average final cycle length was 35 days. Most patients (69%) also required dose reduction of HMA. Median duration of treatment was 7.5 months (range 0.5-31.4). Treatment emergent grade 3-4 anemia occurred in 67% of patients, thrombocytopenia in 81%, and neutropenia in 86%; 17 patients (81%) had treatment emergent febrile neutropenia. There were no infectious deaths in patients who survived cycle 1. The median number of neutropenic fever episodes per patient was 1 (0 to 2). The 4 deaths after cycle 1 were due to progressive disease (n=3) or relapse (n=1). Conclusion VEN-HMA can be safely and effectively given to octogenarians with careful monitoring and dose adjustments. All patients required dose reduction of venetoclax after CR/CRh was achieved, and most also required adjustment of HMA. Despite this, over half of patients achieved durable remissions. The greatest risk of infectious death was in the first cycle, in patients who were heavily pre-treated and enriched for TP53 mutations. When compared to historical controls, outcomes in octogenarians who survive the first cycle appear similar to younger age groups. This work highlights the need for a prospective multi-center effort to optimize the dose and schedule of VEN-HMA in older patient populations. Figure 1 Figure 1. Disclosures Bradley: AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sekeres: Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Watts: Rafael Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Aptevo Therapeutices: Research Funding.

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Impact of Idelalisib Treatment Interruption with or without Dose Reduction on Outcomes in Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia

Blood ◽

10.1182/blood-2019-124541 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5468-5468

Author(s):

Shuo Ma ◽

Rebecca J Chan ◽

Lin Gu ◽

Guan Xing ◽

Nishan Rajakumaraswamy ◽

...

Keyword(s):

Overall Survival ◽

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Dose Reduction ◽

Clinical Outcomes ◽

Research Funding ◽

Treatment Interruption ◽

Lymphocytic Leukemia ◽

Hodgkin's Lymphoma ◽

Advisory Committees

Introduction: Idelalisib (IDELA) is the first-in-class PI3Kδ inhibitor and is approved as a monotherapy for relapsed or refractory (R/R) follicular lymphoma and in combination with rituximab for R/R chronic lymphocytic leukemia (CLL). We previously evaluated IDELA treatment interruption as a mechanism to mitigate treatment-emergent adverse events (TEAEs) and found that limited interruption with clinically appropriate re-challenging resulted in superior clinical outcomes. These findings did not comprehensively address the potential confound of interruptions inherently being associated with longer duration of therapy (DoT). Furthermore, the compound effect of IDELA dose reduction together with treatment interruption on IDELA efficacy was not assessed. Objectives: 1) To evaluate whether the benefit of IDELA interruption is retained in patients on therapy >180 days, a duration previously found to be associated with longer overall survival among patients who discontinued IDELA due to an AE; and 2) To compare clinical outcomes of patients who reduced IDELA dosing in addition to interrupting IDELA with those of patients who interrupted IDELA without additional dose reduction. Methods: Using data from Gilead-sponsored trials of patients with R/R indolent non-Hodgkin's lymphoma (iNHL) treated with IDELA monotherapy (N=125, Gopal et al., N. Engl. J. Med., 2014) or with R/R CLL treated with IDELA + anti-CD20 (N=110, Furman et al., N. Engl. J. Med., 2014; and N=173, Jones et al., Lancet Haematol., 2017), DoT, progression-free survival (PFS), and overall survival (OS) were compared between patients on IDELA therapy >180 days with vs. without interruption and between patients who experienced Interruption and Dose Reduction (IDR) vs. patients who experienced Interruption but NoDose Reduction (INoDR) at any point during IDELA treatment. Interruption was defined as missing at least one IDELA treatment day due to an AE and dose reduction could have occurred before or after the first interruption. PFS and OS were estimated using the Kaplan-Meier method and were compared using a log-rank test. Results: Sixty-nine of 125 patients with R/R iNHL (55.2%) and 222 of 283 patients with R/R CLL (78.4%) remained on IDELA therapy >180 days with 29 (42.0%) and 103 (46.4%) of them, respectively, experiencing interruption on or after day 180 (Table 1). The proportions of patients with interruption before day 180 were similar within each of these populations. Among patients on therapy >180 days, those with treatment interruption on or after 180 days had a longer median (m) DOT than patients without interruption (Table 1). Both PFS and OS were longer in CLL patients who interrupted compared to those who did not interrupt (mPFS=28.9 mos. vs. 17.3 mos. and mOS=not reached [NR] vs. 40.4 mos. for with interruption vs. without interruption, respectively, Table 1 and Figure 1). In patients with iNHL, no difference was observed in PFS or OS between patients who interrupted vs. those who did not (Table 1). Of patients who experienced at least one AE-induced interruption at any point during IDELA therapy (n=63 iNHL and n=157 CLL), 47 iNHL patients (74.6%) and 84 CLL patients (53.5%) also had dose reduction. Two iNHL patients (1.6%) and 5 CLL patients (1.8%) had IDELA dose reduction but no interruption. Both iNHL and CLL patients with IDR experienced a similar PFS compared to patients with INoDR (mPFS=16.5 mos. vs. 14.2 mos. for iNHL and 21.8 mos. vs. 22.1 mos. for CLL with IDR vs. INoDR, respectively, Table 2). However, OS was longer in both iNHL and CLL patients with IDR compared to INoDR (mOS=61.2 mos. vs. 35.3 mos. for iNHL and NR vs. 42.4 mos. for CLL, respectively, Table 2; CLL patients shown in Figure 2). Discussion: IDELA treatment interruption is not associated with rapid clinical deterioration, as observed with some B-cell receptor signaling pathway inhibitors. No clear relationship between IDELA DoT and frequency of interruption was observed. When normalized for DoT >180 days, IDELA treatment interruption retained its clinical benefit in the CLL population. When utilized together with IDELA interruption, dose reduction did not lead to inferior clinical outcomes but instead extended OS in both iNHL and CLL populations. Adherence to treatment interruption and dose reduction guidance as outlined in the IDELA USPI may optimize IDELA tolerability and efficacy for patients with iNHL and CLL. Disclosures Ma: Janssen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Juno: Research Funding; Incyte: Research Funding; Xeme: Research Funding; Beigene: Research Funding; Novartis: Research Funding; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Kite: Consultancy; Acerta: Research Funding; Bioverativ: Consultancy; Genentech: Consultancy. Chan:Gilead Sciences, Inc.: Employment, Equity Ownership. Gu:Gilead Sciences, Inc.: Employment. Xing:Gilead Sciences, Inc.: Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Employment. Ruzicka:Gilead Sciences, Inc.: Employment. Wagner-Johnston:Gilead: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jannsen: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees.

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Minimal Residual Disease Eradication with Venetoclax in Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2020-134237 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 12-14

Author(s):

Alexander Coltoff ◽

Joseph G. Jurcic ◽

Peter Campbell ◽

Daniel J. Lee ◽

Mark L Heaney ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Median Overall Survival ◽

Residual Disease ◽

Institutional Research ◽

Negative Group ◽

Advisory Committees ◽

Research Grants

Introduction The combination of the BCL-2 inhibitor venetoclax with an HMA (HMA/Ven) has improved outcomes in previously untreated patients with AML not eligible for intensive induction therapy. In a phase Ib study, 67% of patients achieved a complete remission (CR) or CR with incomplete recovery of blood counts (CRi) with a median overall survival (OS) of 17.5 months (DiNardo CD et al. Blood 2019; 133(1):7-17). HMA/Ven has also demonstrated efficacy in a heavily pretreated population with relapsed or refractory (R/R) AML, the majority of whom had prior HMA exposure (DiNardo CD et al. Am J Hematol 2018; 93(3):401-7). Measurable residual disease (MRD) is recognized as an independent prognostic indicator important for risk stratification and treatment planning (Schuurhuis GJ et al. Blood 2018; 131(12):1275-91). To date, however, there have been few reports on the effect of HMA/Ven on MRD. Methods This is a retrospective case series of patients with AML at a single-center tertiary-care institution. Patients ≥ 18 years of age who were treated with HMA/Ven between January 2017 and June 2020, either in the upfront or salvage setting, for AML were included. Outcomes included CR/CRi rate, MRD response, relapse free survival (RFS), and OS. MRD was assessed via multicolor flow cytometry with a sensitivity of 10-3 (0.1%). Results Nineteen patients were identified, 12 (63%) of whom were female. The median age at the time of HMA/Ven initiation was 71 years (range, 21 - 87 years). Ten (53%) patients had de novo AML and 9 had secondary or therapy-related AML. By 2017 ELN criteria, 3 (16%) patients had favorable-risk, 9 (47%) had intermediate-risk, and 7 (37%) had adverse-risk AML. Nine (47%) patients had R/R AML; 5 received HMA/Ven as first salvage therapy, and 4 as 2nd or greater salvage. Three (16%) patients had prior HMA exposure. No patient had prior venetoclax exposure. Median follow-up was 9.1 months (range, 1-21.1 months). Ten (53%) patients received azacitidine and 9 (47%) were given decitabine. Venetoclax doses ranged from 50 to 400 mg daily, depending on participation in a clinical trial and concomitant medications. Eight patients achieved a CR and 7 patients achieved a CRi for a combined CR/CRi rate of 79%. The CR/CRi rate was 90% (9/10) in the upfront setting, and 66% (6/9) in the salvage setting. The median time and number of cycles to best clinical response was 2.3 months (range, 0.9-3.9 months) and 2 (range, 1-3 cycles), respectively. Eleven (73%) of the 15 responders achieved MRD clearance after a median of 2 cycles (range, 1-3 cycles) (Table 1). Two of 4 (50%) MRD-positive patients relapsed, while 4 (36%) of 11 MRD-negative patients relapsed (Figure 1). Relapse occurred at a median of 2.0 months (range, 1.3-2.7 months) in the MRD positive group and 11.0 months (range, 2.8-14 months) in the MRD negative group. One patient died of infectious complications while MRD negative. Three patients, all of whom were treated for R/R disease, proceeded to an allogeneic stem cell transplant (HSCT). Two were MRD negative at the time of HSCT and all remained in remission. At the time of data cutoff, 7 (64%) of 11 MRD-negative patients were alive, and all 4 MRD-positive patients were alive. Causes of death in the MRD-negative group included disease relapse (3 patients) and infection (1 patient). Median overall survival in the entire cohort (range, 32 days-NR) was not reached. Conclusions HMA/Ven was highly effective as both upfront and salvage therapy. Surprisingly, the salvage CR/CRi rate in this series was 66%, allowing half of the responders to proceed to HSCT. The majority (73%) of responders achieved MRD negativity. While MRD status influenced RFS, 36% of MRD-negative patients relapsed. Additionally, the same percentage of MRD-negative patients died during follow-up, versus none of the patients with MRD-positivity. This indicates the need for more sensitive methods to assess MRD and for novel therapeutic strategies to eliminate MRD, thereby improving long-term outcomes. Larger prospective studies are needed to define the role of MRD assessment with venetoclax-containing regimens. Disclosures Jurcic: AbbVie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Syros Pharmaceuticals:Research Funding;PTC Therapeutics:Research Funding;Arog Pharmaceuticals:Research Funding;Kura Oncology:Research Funding;Forma Therapeutics:Research Funding;Astellas:Research Funding;Genentech:Research Funding;Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees;Daiichi-Sankyo:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;BMS:Consultancy, Research Funding.Campbell:AstraZeneca:Consultancy.Lee:Genentech:Research Funding;Sumitomo Dainippon Pharma Oncology, Inc.:Research Funding;AbbVie:Research Funding;Novartis:Research Funding;Bayer:Research Funding;Celgene:Consultancy;Forty Seven:Research Funding.Heaney:Blueprint Medicines Corporation:Research Funding;BMS:Research Funding;CTI Biopharma:Consultancy, Research Funding;Deciphera:Research Funding;Incyte:Research Funding;Novartis:Consultancy, Research Funding;Sierra Oncology:Research Funding;AbbVie:Consultancy;Partner Therapeutics:Consultancy.Lamanna:Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Octapharma:Research Funding;Juno:Other: Institutional research grants, Research Funding;Gilead:Consultancy, Membership on an entity's Board of Directors or advisory committees;Astra Zeneca:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Pharmacyclics: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, Other: Institutional research grants, Research Funding;Bei-Gene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Abbvie:Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding;Oncternal, Verastem, TG Therapeutics:Other: Institutional research grants, Research Funding;MingSight:Other: Institutional research grants, Research Funding;Loxo:Research Funding;Celgene:Consultancy, Membership on an entity's Board of Directors or advisory committees;Columbia University Medical Center:Current Employment.

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The Ki67/CD138 Ratio Independently Predicts Overall Survival in the Upfront Treatment of Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v124.21.2016.2016 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2016-2016

Author(s):

Tomer M Mark ◽

Peter Forsberg ◽

Ihsane Ouansafi ◽

Adriana C Rossi ◽

Roger N Pearse ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Complete Response ◽

Newly Diagnosed ◽

First Line ◽

Advisory Committees ◽

Line Therapy

Abstract Background: Assessment of malignant plasma cell cycling via plasma cell labeling index (PCLI) has been a validated prognostic tool in multiple myeloma (MM) but the test requires specialized technical expertise and is not widely available. Ki67 is a well-known protein marker of cellular proliferation on immunohistochemical (IHC) staining with prognostic utility in other malignancies. In an effort to develop a simpler system to provide analogous information to PCLI, we used a novel IHC co-staining technique for CD138 and Ki67 to quantify plasma cells in active cycling. We then performed a retrospective analysis of the ratio of Ki67/CD138 (Ki67%) in newly diagnosed patients with multiple myeloma receiving 1st-line therapy to correlate with clinical outcomes. Methods: A retrospective cohort study of patients (pts) with treated symptomatic MM was performed by interrogation of the clinical database at the Weill Cornell Medical College / New York Presbyterian Hospital. For inclusion in the analysis, subjects must have started first-line treatment in the period of 2005-2010, and had available bone marrow biopsies. Double-staining with Ki67 and CD138 was performed by IHC. The Ki67% was calculated as the percent of plasma cells expressing CD138 that were also found to express Ki67. Treatment outcomes were stratified and compared based on %Ki67. Response was determined by monthly serum protein electrophoresis / immunofixation (IFX) with free light chain analysis according to International Multiple Myeloma Working Group (IMWG) guidelines. Pts who were IFX negative but had no subsequent bone marrow biopsy were classified as being in unconfirmed complete remission. Results: We identified 151 patients with newly diagnosed MM and available %Ki67 expression who received first-line therapy over the period of 2005-2010. Patient were subdivided into two groups based on %Ki67: Low: %ki67 <= 5%, n = 87; and High: %Ki67 >5, n=64, to allow for comparison of treatment response and survival analysis. Specific therapeutic agent exposure history did not differ significantly between patients. Both groups had similar depth of response rates (ORR) to front-line therapy, Table 1. Median progression-free survival for the high versus low %Ki67 groups approached statistical significance at 54 months (95% CI 30.8,67.4) versus 26.9 months (95% CI 21.6,40.2), respectively (P = 0.083). At data cut-off, there were 30 deaths in the low %Ki67 group (1-yr OS 93%, 5-yr OS 71%) and 36 deaths in the high %Ki67 group (1-yr OS 94%, 5-yr OS 62%). Median overall survival (OS) was not reached for Ki67% <= 5% (95% CI 97.3,NR) vs. 78.9 months (95% CI 55.9,93.1) for Ki67% > 5%, (P = 0.0434), Figure 1. Multivariate cox regression for factors with influence on OS showed that only high-risk cytogenetics (HR 2.05, 95% CI 1.17, 2.92, P = 0.027), ISS (HR 1.835, 95% CI 1.33, 3.60, P = 0.000), and %Ki67 group status had an independent effect on survival outcome. Low (<=5%) versus high (>5%) %Ki67 influenced overall survival with a hazard ratio of 1.76 (CI 1.07,2.92, P = 0.027). Survival after ASCT was significantly longer in the low %Ki67 group with median OS not reached (95%CI, 97.3, NR) versus 86.9 months (95% CI 43.9, NR) for high %Ki67 group (P = 0.04). Discussion: The ratio of IHC double positive Ki67 and CD138 of > 5% is an independent prognostic marker for overall survival in newly diagnosed MM undergoing 1st line therapy. The %Ki67 serves as a simpler and widely available analog to PCLI that can be presently performed in most hematopathology laboratories. Table 1: First Line Treatment and Best Response (modified IMWG Criteria) Ki67% <= 5(N = 87)n (%) Ki67% > 5(N = 64)n (%) P Treatment Exposure* Lenalidomide 59 (67.8) 48 (75) 0.34 Thalidomide 30 (34.5) 14 (21.9) 0.09 Bortezomib 25 (28.7) 14 (21.9) 0.34 Alkylating agent 11 (12.6) 4 (6.3) 0.19 ASCT 27 (31) 22 (34.4) 0.66 Best Response Overall Response (>= Partial response) 77 (88.4) 57 (89.1) 0.41 Complete response 15 (17.2) 22 (34.4) Unconfirmed complete response** 14 (16.1) 8 (12.5) Very good partial response 23 (26.4) 15 (23.4) Partial response 25 (28.7) 12 (18.8) Stable disease 9 (10.3) 5 (7.8) Progressive disease 1 (1.2) 2 (3.1) * Percentages do not add to 100% due to instances of concurrent therapy use ** Unconfirmed complete response: immunofixation negative, but no confirmatory bone marrow biopsy available Figure 1 Overall Survival by %Ki67 Figure 1. Overall Survival by %Ki67 Disclosures Mark: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding, Speakers Bureau. Rossi:Celgene: Speakers Bureau. Pekle:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Perry:Celgene: Speakers Bureau. Coleman:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Honoraria. Niesvizky:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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A Phase I Study of Selinexor in Combination with Daunorubicin and Cytarabine in Patients with Newly Diagnosed Poor-Risk Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v128.22.4040.4040 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4040-4040 ◽

Cited By ~ 3

Author(s):

Kendra L. Sweet ◽

Rami S. Komrokji ◽

Eric Padron ◽

Christopher L Cubitt ◽

Leyla Khavarian ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Febrile Neutropenia ◽

Phase I ◽

Board Of Directors ◽

Induction Chemotherapy ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

Poor Risk

Abstract Background: Induction chemotherapy for older adults with poor-risk AML has remained largely unchanged over the past 40 years, with complete remission (CR) rates ranging from 20-50%. Five-year overall survival (OS) ranges from 2-15%, illustrating the need for novel treatment strategies. Selinexor is an oral selective inhibitor of nuclear export (SINE) that has shown promising single agent activity in AML (NCT01607892). By inhibiting the primary export protein, XPO1, selinexor localizes tumor suppressor proteins to the nucleus leading to their activation. Furthermore, selinexor inhibits DNA damage repair, rationalizing its use in combination with DNA damaging agents. Preclinical data from our institution suggest Selinexor synergizes with daunorubicin when used in CD34+ AML cells. Here we report early results from a phase I clinical trial with selinexor plus cytarabine and daunorubicin in patients (pts) with newly diagnosed, poor-risk AML. Methods: This is a single institution phase I clinical trial with a 3+3 design and an expansion phase at the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary endpoint was to determine the MTD/RP2D of selinexor. Secondary endpoints included rate of CR/CRi, overall survival (OS), relapse free survival (RFS) and toxicity assessment. Eligible pts had a diagnosis of previously untreated AML (non-M3), with poor-risk features based on karyotype, mutational profile, secondary AML (sAML) arising from an antecedent hematologic disorder (AHD) or prior chemotherapy, or age ≥60 years. Prior treatment for an AHD was allowed. Induction included daunorubicin 60 mg/m2/day on days 1-3 and cytarabine 100 mg/m2/day CIVI days 1-7 (7+3) with two dose cohorts of selinexor: 60 mg and 80 mg PO. Selinexor was given on days 1, 3, 8, 10, 15 and 17. Re-induction with 5+2 plus selinexor was allowed if indicated. Once in CR, pts received 1-2 cycles of consolidation with 5+2 plus selinexor followed by maintenance selinexor on days 1 and 8 of a 21 day cycle for up 12 months. Selinexor was given at the same dose for all phases of the study. Pts could proceed to hematopoietic stem cell transplant (HCT) at any time after achieving CR. Results: 21 pts (14 (67%) M / 7 (33%) F) were enrolled from June 2015 to June 2016. Median age was 68 years (range 37-77); 18 (86%) were age ≥60 and 9 (43%) were age ≥70. Nineteen (90%) pts were considered poor-risk (unrelated to age), and two (10%) were eligible due to age ≥60 only. Each cohort enrolled 4 pts, and 13 pts were enrolled in the expansion. One pt in each cohort was replaced before completing the 28-day DLT period; one withdrew consent and the second died on day 23 from acute renal failure related to antibiotics. At data cutoff, 18 pts were included in the safety and efficacy assessment. Three additional patients have not completed induction. The early death rate (≤60 days) was 4.8%. No DLTs occurred in the dose-escalation cohorts. The MTD of selinexor was not reached and the RP2D was 80 mg twice weekly. The most common grade 3/4 non-hematologic, treatment emergent AEs in all pts were febrile neutropenia (56%), diarrhea (22%), hyponatremia (22%) and sepsis (17%). Nine patients (50%) achieved CR/CRi. Of the 14 pts treated at the RP2D (selinexor 80 mg), 6 (43%) achieved CR/CRi. In the entire cohort, the median age of the responders was 69 (61-77) and 4 (44%) were age ≥70. Seven (78%) were considered high-risk. Four (44%) had sAML. Two (22%) required a second induction. The median time to response was 47 days (range 28-77) At a median follow up of 8.7 months in the 9 responding pts, 7 (78%) remain in remission. Overall, 4 pts (44%) underwent HCT, and 1 (11%) relapsed just prior to HCT. Conclusion: Results from this phase I trial suggest that selinexor 80mg PO twice weekly can be safely administered in combination with induction chemotherapy using cytarabine and daunorubicin to pts with poor-risk AML, including older pts. The most prominent AEs were febrile neutropenia, diarrhea and hyponatremia. Response rates are encouraging and many elderly pts proceeded to transplant, suggesting this regimen warrants further investigation in this challenging population. Disclosures Sweet: Karyopharm: Honoraria, Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sullivan:Karyopharm: Research Funding. Shah:Incyte: Research Funding; Rosetta Genomics: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria; Pfizer: Honoraria.

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Characteristics Affecting Durability and Tolerability of Imatinib in Patients Switched from Brand to Generic and Newly Diagnosed Patients Initially Prescribed Generic Imatinib for Chronic Myeloid Leukemia

Blood ◽

10.1182/blood-2020-137250 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 14-17

Author(s):

Ariel Denson ◽

Kristyn Y. DiSogra ◽

Justin Arnall ◽

Srinivasa R. Sanikommu ◽

Nilay A. Shah ◽

...

Keyword(s):

Adverse Effect ◽

Adverse Effects ◽

Board Of Directors ◽

Dose Reduction ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

Treatment Delays ◽

Generic Products ◽

Dose Reductions

Introduction Gleevec, Imatinib mesylate, is the first in class BCR-ABL tyrosine kinase inhibitor initially approved to treat CML. In February 2016, generic imatinib products became available. As generic products are not required to offer comparative efficacy and safety data, differences may arise. Small reports have found no significant differences in response durability and tolerability in patients transitioned from Gleevec to generic imatinib. Further, lower cost of generic products often influence treatment decisions and patient compliance. We sought to evaluate response durability, tolerability, financial costs, and adherence in patients with chronic phase CML (cpCML) who switched from Gleevec to generic imatinib and newly diagnosed cpCML patients initiated on generic imatinib. Methods We conducted a single-center, retrospective chart review of adult patients who received imatinib therapy for cpCML between June 1, 2015 to November 14, 2019. Patients who received ≥6 months of brand through the Specialty Pharmacy Service (SPS) at Atrium Health prior to switching to generic were included in Group 1 (Switch). Patients who initiated therapy with generic imatinib dispensed from SPS were included in Group 2 (New Start). Durability of response was described determined via peripheral blood BCR-ABL transcripts by PCR and reported major molecular response (MMR) after 12 months generic imatinib therapy. Additional factors characterizing the durability and tolerability of therapy included adverse effects due to drug, dose modifications, adherence rate, prescription cost per month, and frequency of switch between generic products. Results Of 298 patients assessed, 12 patients were evaluable. There were 7 Switch patients and 5 New Start patients. Figure 1. All 12 patients met WHO diagnostic cpCML criteria. No patients in either group had accelerated or blast phase CML, no patients received maintenance imatinib following allogeneic HCT. In the Switch Group, 4 patients (57%) achieved MMR after 12 months of generic therapy. Of the 3 patients that did not achieve MMR, 1 patient relocated prior to 12-month assessment, 1 patient was noted to be non-compliant, and 1 patient had several treatment delays and dose reductions due to toxicities. 1 New Start patient achieved MMR at 12 months. Of those not achieving MMR, 1 was started on a reduced dose (100 mg /day) due to renal dysfunction, 1 had a PDC of 49.10% due to treatment delays while receiving treatment for a different malignancy, and 2 patients had logarithmic decreases in BCR-ABL but had not crossed the MMR threshold after 12 months of therapy. 5 Switch patients (71.4%) reported at least 1 adverse effect related to therapy, 3 of these (42.9%) required dose reduction. The adverse effects requiring dose reductions in the New Start patients included thrombocytopenia (n=2) and myalgia (n=1). All New Start patients reported at least 1 adverse effect with none of these patients requiring a dose reduction. Cost stayed the same or was reduced for 85.7% of the Switch patients, 1 patient experienced a cost increase and did not have co-pay assistance, and 2 patients received copay assistance. Cost of generic therapy was <$10/month in 85.7% of the Switch and 80% of the New Start patients. No patients experienced disease progression and PDC was >90% after 12 months on generic therapy for 71.4% Switch patients and 80% New Start patients. Table 1. and Table 2. Conclusion Patients with cpCML switched from brand to generic imatinib and patients newly started on generic imatinib appear to have durable responses and tolerance to generic imatinib. Dose reductions and non-adherence may have contributed to inadequate disease control in patients not achieving MMR in both groups. Patients switched from brand to generic imatinib may develop new side effects necessitating dose reduction. Thrombocytopenia may be more common in patients switched from brand to generic imatinib. Adherence to brand and generic imatinib is high and medication is affordable with most patients paying <$10/month. Our study is limited by a small sample size and retrospective nature. Prospective large studies are needed to compare tolerability and durability differences between brand and generic imatinib and available imatinib generic products. Disclosures Knight: Foundation for Financial Planning: Research Funding. Ai:Celgene: Speakers Bureau; Incyte: Speakers Bureau. Grunwald:Premier: Consultancy; Astellas: Consultancy; Janssen: Research Funding; Merck: Research Funding; Janssen: Research Funding; Forma Therapeutics: Research Funding; Forma Therapeutics: Research Funding; Astellas: Consultancy; Premier: Consultancy; Trovagene: Consultancy; Trovagene: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Trovagene: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Abbvie: Consultancy; Merck: Consultancy; Merck: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amgen: Consultancy; Cardinal Health: Consultancy; Merck: Consultancy; Cardinal Health: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Cardinal Health: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Incyte: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Consultancy; Incyte: Consultancy, Research Funding; Genentech/Roche: Research Funding; Premier: Consultancy; Genentech/Roche: Research Funding; Genentech/Roche: Research Funding; Forma Therapeutics: Research Funding. Avalos:Juno: Membership on an entity's Board of Directors or advisory committees; Best Practice-Br Med J: Patents & Royalties: receives royalties from a coauthored article on evaluation of neutropenia. Copelan:Amgen: Membership on an entity's Board of Directors or advisory committees. Chojecki:Novartis: Other: Investigator Meeting Attendance; Incyte: Research Funding.

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Determinants of Clinical Trial Participation and Impact on Survival Outcomes Among Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2019-131776 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5833-5833

Author(s):

Gabriella C Malave ◽

Prashant Kapoor ◽

Angela Dispenzieri ◽

Morie A. Gertz ◽

Martha Q. Lacy ◽

...

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Trial Participation ◽

Newly Diagnosed ◽

Clinical Trial Participation ◽

Advisory Committees ◽

Baseline Characteristics

Background: The overall participation of cancer patients in interventional clinical trials in the United States remains very low, with ~5% of patients being enrolled in clinical trials nationwide. The outcomes of patients with MM have improved significantly over the past decade, but available data suggest that the participation rates for patients with MM is comparable to other cancers. The drivers of participation and the potential impact of clinical trial participation have not been systematically studied in MM. Patients and Methods: We identified 228 patients who were enrolled into clinical trials for initial therapy of newly diagnosed MM between 2004 and 2018, and 4 controls for each of these patients. Controls were patients with NDMM, who were diagnosed closest in time to the index patients and did not participate in an interventional treatment trial. Various baseline characteristics as well as overall survival were compared between the two groups. Results: The baseline characteristics of the two groups are as shown in the Table. Patients who entered clinical trials were more likely to be female, resided closer to the clinic, and were more likely to have a prior history of MGUS. They were more likely to have higher ISS Stage, and a higher serum LDH, but there was no difference in the FISH risk status. Other indices of disease burden such as lower hemoglobin and platelets, higher serum creatinine were all seen more often in the control group, but may have been influenced by the trial entry criteria. Looking at the outcomes, the overall survival was longer among those enrolled into clinical trials compared to those who did not [median 103 (95% CI; 86, 136) vs. 63 (95% CI; 53, 69) months, p<0.001 (Figure). Conclusions: The current study provides important clues regarding demographic determinants of trial participation and disease biology related features that reflect likelihood of trial participation. Overall survival was significantly longer among the trial participants, which likely represent a mix of reasons including baseline status of patients, intensity of monitoring and efficacy of novel treatment approaches. Table Disclosures Kapoor: Janssen: Research Funding; Celgene: Honoraria; Cellectar: Consultancy; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding; Takeda: Honoraria, Research Funding. Dispenzieri:Alnylam: Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Akcea: Consultancy; Intellia: Consultancy. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Spectrum: Honoraria, Research Funding. Lacy:Celgene: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy. Leung:Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees. Russell:Imanis: Equity Ownership. Kumar:Takeda: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

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Characterization of Exceptional Responders to Autologous Stem Cell Transplantation in Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-119623 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4615-4615

Author(s):

Ashley Paquin ◽

Morie A. Gertz ◽

Hafsa Chaudhry ◽

Shaji K. Kumar ◽

Francis K. Buadi ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Maintenance Therapy ◽

Board Of Directors ◽

Mayo Clinic ◽

Research Funding ◽

Complete Response ◽

Newly Diagnosed ◽

Advisory Committees ◽

Time Point

Abstract Aims: Autologous stem cell transplantation (ASCT) is an important component in the treatment of newly diagnosed multiple myeloma (MM). However, relapse following ASCT is considered almost inevitable, with a median time to progression (TTP) of approximately 23-26 months (without maintenance) and 40-46 months (with maintenance)(Attal MA et al. N Engl J Med 2012; 366:1782-1791; McCarthy PM et al. N Engl J Med 2012; 366:1770-1781). However, some patients can experience a prolonged period of remission with ASCT. The purpose of this study was to identify and characterize patients who have an exceptional response to upfront ASCT without maintenance therapy, and to determine the frequency of relapse in such patients. Methods: We searched the Mayo Clinic Multiple Myeloma bone marrow transplant database for patients who were diagnosed with MM between Aug 1, 1988 to Jan 3, 2006, and underwent ASCT within 12 months of initial diagnosis. For the purposes of this study, we defined exceptional responders as patients who were free of progression for 96 months or more, which is 2-3 fold more than the median TTP expected in this population. Since maintenance therapy was not standard of care at the time, only a small minority (6) of patients with prolonged TTP had received maintenance therapy; these patients were excluded since the study was focused on exceptional response with ASCT alone. One patient who had a tandem autologous transplant was excluded. Results: 509 patients underwent transplant during the study period. Of those, 46 (9%) met criteria for exceptional response. Twenty seven (59%) were female, 19 (41%) were male. Median age was 57.28 years, range, 31.9-73.0. Of 45 patients with response data available, the best response status was complete response or better in 32 patients (73.3%), VGPR in 4 patients (8.9%), and PR in 8 patients (17.7%). FISH data were available during the disease course for 41 patients. Of these, the majority, 28 patients (68.3%), had no abnormalities detected by the probes used; 3 patients (7.3%) had high risk cytogenetics (t(4;14) in 2 patients and t(14;16) in one patient) , 4 (9.8%) had trisomies; 6 patients had other isolated abnormalities. At last follow up, 23 patients have progressed (50%); 14 (30.4%) have died, including one who died without progression to MM. The median overall survival from time of diagnosis of the exceptional responders was 18.5 years, range 9.2-22 years. From the landmark time of 96 months, the median TTP was 6.2 years, range, 0.4-10.6 years (Figure 1); No plateau was seen in the TTP curve. From the landmark time of 96 months, the median OS was 10.5 years, range, 0.4-14 years. Conclusions: We conclude that approximately 10% of patients with newly diagnosed myeloma have an exceptional response to a single ASCT without maintenance therapy. These patients have a remarkable overall survival, both from diagnosis and from the landmark time point where they are classified as having achieved an exceptional response. Although TTP from the landmark time point is excellent, with median TTP of 6.2 years, there appears to be no plateau in the curve indicating ongoing risk of relapse despite a prolonged period of disease stability. Exceptional responders tended to have normal FISH studies (likely an indicator of responsive, low-tumor burden disease), and nearly 20% achieved this state despite not attaining a complete response. Figure. Figure. Disclosures Gertz: Research to Practice: Consultancy; Apellis: Consultancy; spectrum: Consultancy, Honoraria; Medscape: Consultancy; celgene: Consultancy; janssen: Consultancy; Teva: Consultancy; Abbvie: Consultancy; annexon: Consultancy; Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Amgen: Consultancy; Physicians Education Resource: Consultancy. Kumar:KITE: 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; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: 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; AbbVie: 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, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; AbbVie: 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. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Dingli:Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Russell:Vyriad: Equity Ownership. Kapoor:Takeda: Research Funding; Celgene: Research Funding.

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Presence of Extrachromosomal DNA (ecDNA) Impacts Both Progression Free and Overall Survival and Is an Independent Poor Prognostic Marker in Multiple Myeloma

Blood ◽

10.1182/blood-2021-151647 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 461-461

Author(s):

Parth Shah ◽

Anil Aktas-Samur ◽

Mariateresa Fulciniti ◽

Raphael Szalat ◽

Masood A. Shammas ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Board Of Directors ◽

Copy Number ◽

Research Funding ◽

P Value ◽

Newly Diagnosed ◽

Extrachromosomal Dna ◽

Publicly Traded ◽

Advisory Committees

Abstract Background Focal amplifications and rearrangements drive tumor growth and evolution in cancer. Focally amplified regions often involve the juxtaposition of rearranged segments of DNA from distinct chromosomal loci into a single amplified region and nearly half of these regions can be explained by circular, extrachromosomal DNA (ecDNA) formation. Cancer-associated ecDNA shows a unique circular placing ecDNA at the interface of cancer genomics and epigenetics. As formation of ecDNA represents a manifestation of genomic instability, we have investigated presence and prognostic impact of ecDNA in multiple myeloma (MM). Methods Whole genome (WGS) and transcriptome (RNAseq) sequencing data from CD138 purified MM cells from 191 uniformly-treated newly diagnosed MM patients were used for this analysis. Copy number variants (CNV), single nucleotide variants (SNV) and structural variants (SV) were identified on all WGS samples using Facets, Mutect2 and Manta. Seed data from these CNV results was passed to the AmpliconArchitect tool to determine presence of focally amplified and rearranged segments of DNA. Seed CNV thresholds were set for a minimum CNV size of 100kb and a copy number of equal or greater to 5. Extrachromosomal calls were then annotated using the Amplicon Classifier to determine the presence of ecDNA. Multivariate survival analysis was performed after segregating samples into the conventional myeloma risk classifications including translocations, copy number alterations, ISS, age and mutations associated with risk. Differential expression analysis was performed on transcriptomic data using DEseq2. Results We identified 6.8% of the newly diagnosed patients with ecDNA, 12.5% with complex non-cyclic DNA amplifications and 10.1% with linear amplifications. ecDNA and complex events were targeting MM dependent genes, including MYC/PVT1, IRF4 as well as known driver genes such as CDYL and TRAF2. We further evaluated association between ecDNA, complex rearrangements, linear amplification and patients with none of these amplification types and found that patients with ecDNA had significantly poor PFS (median PFS 22 months vs. 41 months) and OS (median OS 41 months vs. 105 months). Patients having ecDNA in their MM cells did not show any significant enrichment for known translocations, double hit or TP53 mutations. In a multivariate model including ecDNA and all other known MM risk features, ecDNA was found to be an independent predictor of progression free survival.(HR 2.6, CI: 1.26 -5.6, p=0.0082) and overall survival (HR 7.94 CI:3.5-17.9 p < 0.0001). Patients with ecDNA have higher mutational load probability(8798 vs 6982, effect size = 0.64 , probability is 91.1). However, this was not reflected in heterogeneity by using MATH score. We found that patients with ecDNA are likely to have BRAF mutations (OR= 25.07 [2.57 - 330 95% CI], p value = 0.002), however overall RAS/RAF pathway mutations were similar to other patients. Patients with ecDNA showed fragile DNA with more breaks (median segments 197 vs. 125.5, p value = 0.001). Although ecDNA is defined as copy number gain with fragments having 5 or more copies, overall genomic gain between ecDNA and other patients were similar. However, overall genomic loss in patients with ecDNA were higher than others (7% vs. 4.2%, p = 0.06). By differential gene expression analysis we noted 98 differentially expressed genes in MM cells with ecDNA. The downregulated geneset involved pathways responsible for cell death as well as the RAS pathway. Interestingly, CD38 was upregulated in the ecDNA dataset suggesting greater potential for CD38 targeting therapies in these patients. Conclusions ecDNA, as an unique marker of perturbed genomic integrity, is observed in a subset of patients and is an independent prognostic marker in newly diagnosed MM patients. As patients with ecDNA are not fully captured by other risk features its incorporation in an expanded definition of a high risk group of multiple myeloma should be investigated. Future studies will endeavor to explore the biological mechanism through which ecDNA are formed and influences outcomes in myeloma. Figure 1 Figure 1. Disclosures Richardson: Sanofi: Consultancy; GlaxoSmithKline: Consultancy; Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; AbbVie: Consultancy; Oncopeptides: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy; Protocol Intelligence: Consultancy; Celgene/BMS: Consultancy, Research Funding; Secura Bio: Consultancy; Regeneron: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Perrot: Abbvie: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Moreau: Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene BMS: Honoraria; Oncopeptides: Honoraria. Thakurta: Oxford University: Other: Visiting Professor; BMS: Current Employment, Current equity holder in publicly-traded company. Anderson: Gilead: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: 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; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees. Munshi: Legend: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Adaptive Biotechnology: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Celgene: Consultancy; Pfizer: Consultancy.

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Outcome with Lenalidomide Plus Dexamethasone Followed by Early Autologous Stem Cell Transplantation In the ECOG E4A03 Randomized Clinical Trial

Blood ◽

10.1182/blood.v116.21.38.38 ◽

2010 ◽

Vol 116 (21) ◽

pp. 38-38 ◽

Cited By ~ 11

Author(s):

David Samuel diCapua Siegel ◽

Susanna Jacobus ◽

S. Vincent Rajkumar ◽

Rafat Abonour ◽

Natalie Scott Callander ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Age Groups ◽

Early Mortality ◽

First Year ◽

Age Group ◽

Newly Diagnosed ◽

Advisory Committees

Abstract Abstract 38 INTRODUCTION: Lenalidomide and bortezomib have moved into the management of newly diagnosed multiple myeloma leading to dramatically improved outcomes. As a consequence, the role of upfront autologous peripheral blood stem cell transplant (ASCT) has become more controversial. The ECOG E4A03 clinical trial randomized newly diagnosed MM patients to lenalidomide with high-dose dexamethasone (LD) vs lenalidomide with low-dose dexamethasone (Ld) (Rajkumar et al Lancet Oncol 2010; 11: 29–37). Upon completing four cycles of therapy, pts had the option of ASCT or continuing on the assigned therapy. The purpose of this abstract is to determine the outcome of patients on this trial pursuing early ASCT according to various age-groups. MATERIALS and METHODS: This is a post hoc, retrospective analysis of overall survival within age subgroups stratified by early ASCT status. This is a landmark analysis including only pts surviving the first 4 cycles of therapy. RESULTS: In all three age-groups studied, 1, 2, and 3-year survival probability estimates with ASCT were excellent (Tables 1, 2, and 3). For patients under the age of 65 who survived the first 4 cycles of therapy, overall survival at 3-years was 94% with early ASCT, 78% in pts continuing protocol therapy. Although direct comparison with patients not going to early transplant is not possible because the assignment to early ASCT versus no early ASCT was not randomized, survival with ASCT at 3-years appeared higher. While we attempt to correct for age, the differences may be influenced by other factors such as performance status, comorbidities, response to therapy, etc. The presumption that treatment related mortality (TRM) should be more problematic for older pts undergoing ASCT is addressed by looking at the >65 and >70yo cohorts. In the >65 age group, one-year mortality is similar between the early ASCT population and the no early ASCT population. In the >70 age group, no adverse impact of early ASCT was seen in the first year on overall survival but the sample size is extremely small. In all age groups early ASCT seemed to mitigate some of the survival disadvantage associated with randomization to the LD arm. CONCLUSIONS: This analysis shows that the strategy of lenalidomide plus dexamethasone induction followed by early ASCT has a remarkably good outcome in terms of overall survival in all age groups studied and supports the continued role of early consolidative ASCT in newly diagnosed patients. The risk of early mortality was notably low in the first year in all age groups. The risk of early mortality seems to increase at 2 years for the LD pts not choosing early ASCT and at 3 years for the Ld pts not choosing early ASCT. Selection bias makes it difficult to compare results for pts that chose early ASCT directly to the patients who did not receive early ASCT in this trial. As such, these results emphasize the need for randomized trials investigating the timing of ASCT in myeloma in the era of novel therapy. Disclosures: Siegel: Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide for front line therapy. Abonour:Celgene: Speakers Bureau; Millennium Pharmaceuticals: Speakers Bureau. Callander:Millennium Pharmaceuticals: Research Funding. Fonseca:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding; Genzyme: Consultancy; Onyx: Research Funding; Otsuka: Consultancy; Medtronic: Consultancy. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Prognostic Implications of Multiple Cytogenetic High-Risk Abnormalities in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.5615.5615 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5615-5615

Author(s):

Moritz Binder ◽

S. Vincent Rajkumar ◽

Rhett P. Ketterling ◽

Angela Dispenzieri ◽

Martha Q. Lacy ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Cumulative Effect ◽

Newly Diagnosed ◽

Advisory Committees ◽

Kaplan Meier ◽

Prognostic Implications

Abstract Background: Cytogenetic evaluation using fluorescence in situ hybridization (FISH) at the time of diagnosis is essential for initial risk stratification in multiple myeloma. The presence of specific cytogenetic abnormalities is known to confer a poor prognosis, less is known about the cumulative effect of multiple cytogenetic high-risk abnormalities. We aimed to evaluate the prognostic implications of the presence of multiple cytogenetic high-risk abnormalities at the time of diagnosis. Methods: We studied 226 patients who were diagnosed with multiple myeloma between July 2004 and July 2014 at Mayo Clinic Rochester, underwent FISH evaluation within six months of diagnosis, and presented with cytogenetic high-risk abnormalities. High-risk cytogenetics were defined as t(4;14), t(14;16), t(14;20), del(17p), or gain(1q). Bone marrow aspirates were evaluated for deletions, monosomies, trisomies, and tetrasomies using chromosome- or centromere-specific FISH probes. IGH rearrangements were evaluated using an IGH break-apart probe and evaluating up to five potential partners (FGFR3, CCND1, CCND3, MAF, and MAFB). Kaplan-Meier overall survival estimates were calculated and the log-rank test was used to compare overall survival in patients with single and multiple cytogenetic high-risk abnormalities. A multivariable-adjusted Cox regression model was used to assess the effect of multiple cytogenetic high-risk abnormalities on overall survival adjusting for age, sex, and Revised International Staging System (R-ISS) stage. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis was 65 years (32 - 90), 129 (57%) of the patients were male. The median overall survival was 3.5 years (3.1 - 4.9) for the entire cohort (n = 226), 4.0 years (3.3 - 5.1) for those with one cytogenetic high-risk abnormality (n = 182, 80%), and 2.6 years (1.7 - 3.1) for those with two cytogenetic high-risk abnormalities (n = 44, 20%). There were no patients with more than two cytogenetic high-risk abnormalities. Ninety-eight patients (45%) had a high-risk translocation, 77 (35%) had del(17p), 39 (18%) had a high-risk translocation plus del(17p), and 5 (2%) had gain(1q) plus either a high-risk translocation or del(17p). Figure 1 shows the Kaplan-Meier overall survival estimates stratified by the number of cytogenetic high-risk abnormalities (n = 226). The presence of two cytogenetic high-risk abnormalities (compared to one) was of prognostic significance after adjusting for age, sex, and R-ISS stage (HR 2.01, 95% CI 1.27 - 3.19, p = 0.003, n = 205). Conclusions: Approximately one in five patients with newly diagnosed high-risk multiple myeloma presented with two high-risk abnormalities at the time of diagnosis. These patients experienced inferior overall survival suggesting a cumulative effect of multiple cytogenetic high-risk abnormalities. The relatively low number of observed gain(1q) was likely related to the fact that not all patients were evaluated for that abnormality. Therefore the presented hazard ratio represents a conservative effect estimate and may underestimate the true effect. Figure 1 Figure 1. Disclosures Dispenzieri: GSK: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Kumar:Janssen: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Array BioPharma: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Kesios: Consultancy; Glycomimetics: Consultancy.

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