Dasatinib Versus Imatinib In Patients with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP) In the DASISION Trial: 18-Month Follow-up

Abstract Abstract 206 Background: Dasatinib is 325-fold more potent than imatinib in vitro against unmutated BCR-ABL, and is an established second-line treatment for patients (pts) with CML-CP who are resistant, intolerant or have a suboptimal response to imatinib. The Phase 3 DASISION study compares dasatinib with imatinib as initial treatment for pts with newly diagnosed CML-CP. After a minimum of 12 months (mos) of follow-up, dasatinib 100 mg once daily demonstrated significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared to imatinib 400 mg once daily (Kantarjian, H, et al. N Engl J Med 2010;362:2260). Eighteen-mo follow-up data are presented here. Methods: 519 pts with newly diagnosed CML-CP (median disease duration of 1 mo) stratified by Hasford risk were randomized to either dasatinib 100 mg once daily (n=259), or imatinib 400 mg once daily (n=260). The study design and endpoints have been described previously. All analyses were based on intention-to-treat pts. Results: Median treatment duration at the present analysis was 18 mos for each drug, with 81% of pts in the dasatinib arm and 80% in the imatinib arm still remaining on study drug. Median dose intensity was 99 mg/d for dasatinib and 400 mg/d for imatinib. Efficacy and safety results in the present analysis were consistent with those reported previously after 12 mos of follow-up. The rate of confirmed CCyR (cCCyR, CCyR on consecutive analyses at least 1 mo apart) by 18 mos continued to be higher for dasatinib than for imatinib (78% vs 70%); P=0.0366). Based on time-in-cCCyR (a measure of durability) analysis involving all randomized pts, dasatinib-treated pts were 28% less likely to experience a progression event (as defined by European LeukemiaNet 2006) after achieving a cCCyR or never achieving a cCCyR compared to those on imatinib. The MMR rate at any time was superior for dasatinib compared to imatinib (57% vs 41%, P=0.0002). Based on time-to-response analysis, pts on dasatinib were 1.84-fold more likely to achieve a MMR than those on imatinib (HR=1.84, P <0.0001). Rates of cCCyR in dasatinib-treated pts with low, intermediate and high risk were 92, 71 and 73%, respectively. The corresponding rates in the imatinib arm were 72, 71 and 64%. Rates of MMR in dasatinib-treated pts with low, intermediate and high risk were 63, 56 and 51%, respectively. The corresponding rates in the imatinib arm were 48, 40 and 30%. A BCR-ABL transcript level of ≤ 0.0032% was achieved in 13% dasatinib-treated and 7% imatinib-treated pts. Rates of progression-free survival at 18 mos were 94.9% for dasatinib and 93.7% for imatinib; the corresponding overall survival rates were 96.0% and 97.9%, respectively. Six pts (2.3%) in the dasatinib arm and 11 (4.3%) in the imatinib arm discontinued due to treatment failure as defined by 2006 European LeukemiaNet criteria. Six pts (2.3%) on dasatinib and 9 (3.5%) on imatinib had a transformation to accelerated or blast phase. Discontinuation of treatment due to drug-related adverse events (AEs) was infrequent for both dasatinib (6%) and imatinib (4%). Non-hematologic AEs (all grades) in ≥10% of pts (dasatinib vs imatinib) were fluid retention (23% vs 43%), diarrhea (18% vs 19%), nausea (9% vs 21%), vomiting (5% vs 10%), muscle inflammation (4% vs 19%), myalgia (6% vs 12%), musculoskeletal pain (12% vs 16%), fatigue (8% vs 11%) and rash (11% vs 17%). While superficial edema was less frequent with dasatinib than with imatinib (10% vs 36%), pleural effusion was seen only with dasatinib (12% vs 0%: grade 1, 2%; grade 2, 9%; grade 3, <1%), and did not impact the efficacy. Non-hematologic grade 3/4 AEs were infrequent in either arm (≤1%). Grade 3/4 cytopenias (dasatinib vs imatinib) were anemia (11% vs 7%), neutropenia (22% vs 20%) and thrombocytopenia (19% vs 10%). Two pts (0.8%) on dasatinib and 3 (1.2%) on imatinib had grade 3/4 bleeding. Cytopenia was the reason for discontinuation in 6 pts on the dasatinib arm (2.3%) and 3 on the imatinib arm (1.2%). Conclusions: After 18 mos of follow-up, dasatinib 100 mg once daily continues to demonstrate superior efficacy compared to imatinib. Dasatinib also continues to be generally well tolerated. These results support the potential use of dasatinib as initial treatment for pts with newly diagnosed CML-CP. Disclosures: Shah: Bristol-Myers Squibb, Novartis and Ariad: Membership on an entity's Board of Directors or advisory committees. Kantarjian:BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Hochhaus:Novartis, Bristol-Myers Squibb: Consultancy, Research Funding. Cortes:Brostol-Myers Squibb, Novartis and Wyeth: Honoraria. Bradley-Garelik:Bristol-Myers Squibb: Employment, Equity Ownership. Zhu:Bristol-Myers Squibb: Employment. Baccarani:Novartis, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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PreVent-ACaLL Short-term combined acalabrutinib and venetoclax treatment of newly diagnosed patients with CLL at high risk of infection and/or early treatment, who do not fulfil IWCLL treatment criteria for treatment. A randomized study with extensive immune phenotyping

Blood ◽

10.1182/blood-2019-121907 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4304-4304

Author(s):

Caspar Da Cunha-Bang ◽

Rudy Agius ◽

Arnon P. Kater ◽

Mark-David Levin ◽

Anders Österborg ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Severe Infection ◽

Newly Diagnosed ◽

Risk Of Infection ◽

Advisory Committees ◽

Educational Grant ◽

Travel Grant ◽

Grade 3

Background Patients with Chronic Lymphocytic Leukemia (CLL) have an increased risk of infections both prior to and upon treatment. Infections are the major cause of death for these patients, the 5-year incidence of severe infection prior to treatment is approximately 32 % with a 30-day mortality of 10 % (Andersen et al., Haematologica, 2018). Chemoimmunotherapy is still 1st line standard of treatment for patients without del17p or TP53 mutation despite association with neutropenia, immunesuppression and infections. The combination of BTK inhibitors and the bcl-2 inhibitor venetoclax has demonstrated synergy in vitro and in vivo, while translational data indicate that the CLL-related immune dysfunction can be improved on treatment with reduced risk of infections. Employing the Machine-Learning based CLL treatment infection model (CLL-TIM) that we have developed, patients with a high (>65%) risk of infection and/or need of CLL treatment within 2 years of diagnosis can be identified (CLL-TIM.org). The significant morbidity and mortality due to infections in treatment-naïve CLL warrants trials that challenge the dogma of only treating symptomatic CLL. Thus, we initiated the randomized phase 2 PreVent-ACall trial of 12 weeks acalabrutinib + venetoclax to reduce risk of infections. Methods Design and statistics A phase 2, randomized, open label, multi-center clinical trial for newly diagnosed patients with CLL. Based on the CLL-TIM algorithm, patients with high risk of severe infection and/or treatment within 2 years from diagnosis can be identified. Approximately 20% of newly diagnosed CLL patients will fall into this high-risk group. First patient in trial planned for September 2019, primary outcome expected in 2021. Only patients identified as at high risk, who do not currently fulfil IWCLL treatment criteria are eligible. Patients will be randomized between observation in terms of watch&wait according to IWCLL guidelines or treatment. Primary endpoint Grade ≥3-Infection-free survival in the treatment arm compared to the observation arm after 24 weeks (12 weeks after end of treatment). Study treatment Acalabrutinib 100 mg BID from cycle 1 day 1 for 12 weeks. Venetoclax, ramp up during the first five weeks starting cycle 1 day 1, thereafter 400 mg once daily for a total of 12 weeks counted from cycle 1 day 1. Patients A sample size of 25 patients in each arm, 50 patients in total. Major inclusion criteria CLL according to IWCLL criteria ≤1 year prior to randomizationHigh risk of infection and/or progressive treatment within 2 years according to CLL-TIM algorithmIWCLL treatment indication not fulfilledAdequate bone marrow functionCreatinine clearance above 30 mL/min.ECOG performance status 0-2. Major exclusion criteria Prior CLL treatmentRichter's transformationPrevious autoimmune disease treated with immune suppressionMalignancies other than CLL requiring systemic therapies or considered to impact survivalRequirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers or anticoagulant therapy with vitamin K antagonistsHistory of bleeding disorders, current platelet inhibitors / anticoagulant therapyHistory of stroke or intracranial hemorrhage within 6 months Trial registry number EUDRACT NUMBER: 2019-000270-29 Clinicaltrials.gov number: NCT03868722 Perspectives: As infections is a major cause of morbidity and mortality for patients with CLL prior to any treatment, we aim at changing the natural history of immune dysfunction in CLL. The PreVent-ACaLL trial includes an optional extension into a phase 3 part with the primary outcome of grade ≥3 infection-free, CLL treatment-free survival two years after enrollment to address the unmet need of improved immune function in CLL for the first time. Figure Disclosures Da Cunha-Bang: AstraZeneca: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Other: Travel Grant; Roche: Other: Travel Grant. Levin:Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant . Österborg:BeiGene: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Abbvie: Research Funding; Kancera AB: Research Funding. Niemann:Novo Nordisk Foundation: Research Funding; Gilead: Other: Travel grant; Janssen: Consultancy, Other: Travel grant, Research Funding; Roche: Other: Travel grant; CSL Behring: Consultancy; Acerta: Consultancy, Research Funding; Sunesis: Consultancy; Astra Zeneca: Consultancy, Research Funding; Abbvie: Consultancy, Other: Travel grant, Research Funding. OffLabel Disclosure: acalabrutinib and venetoclax in combination for CLL.

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Clapd (Clarithromycin, Pomalidomide, Dexamethasone) Therapy In Relapsed Or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.1955.1955 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1955-1955 ◽

Cited By ~ 6

Author(s):

Tomer M Mark ◽

Angelique Boyer ◽

Adriana C Rossi ◽

Dennis Kwon ◽

Roger N Pearse ◽

...

Keyword(s):

Partial Response ◽

Board Of Directors ◽

Research Funding ◽

Complete Response ◽

Response Analysis ◽

Muscular Weakness ◽

Advisory Committees ◽

Disease Response ◽

Grade 3

Abstract Background Pomalidomide is a distinct IMiD® immunomodulatory agent with activity in subjects with relapsed or refractory MM (RRMM), including those with prior lenalidomide treatment. We have previously reported that the addition of clarithromycin enhances the anti-myeloma activity of pomalidomide+dexamethasone (Pom/Dex) in the treatment of RRMM (Mark et al, ASH 2012). We now report updated results with extended follow up from a phase 2 trial of large group of patients treated with ClaPd in RRMM. Methods One hundred nineteen patients with heavily pretreated RRMM were enrolled into a single-institution study to investigate the effectiveness and tolerability of ClaPd. Eligible subjects had at least 3 prior lines of therapy, one line of which must have included lenalidomide. ClaPd is clarithromycin 500mg twice daily; pomalidomide 4mg for days 1-21, and dexamethasone 40mg on days 1,8,15,22 of a 28-day cycle. All subjects had thromboprophylaxis with 81mg aspirin daily. Disease response evaluation was performed monthly with immunoelectrophoresis and free light chain analysis; bone marrow biopsy with skeletal imaging was used to confirm MM progression or complete response (CR). Treatment was continued as tolerated by the patient until disease progression. Results One hundred fourteen patients had completed at least 1 cycle of ClaPd and were eligible for disease response analysis at data cut-off. All patients were included in the safety analysis. Patients had undergone a median of 5 (range 3-15) prior lines of therapy. The proportion of patients who were refractory to lenalidomide, refractory to bortezomib, and double (lenalidomide+bortezomib) refractory were 85%, 79%, and 68% respectively. The median number of ClaPd cycles received was 7 (range 1-34). Overall response rate (ORR, ≥PR, entire cohort/double-refractory subgroup) was 61.4/56.4% [stringent complete remission (sCR): 4.4/4%, complete response (CR): 0.9/1.3%, very good partial response (VGPR): 14.9/11.5%, partial response (PR): 41.2/38.5%, minimal response (MR): 7/9%, stable disease (SD): 21.9/21.8%, progressive disease (PD): 9.6/12.8%, ³VGPR rate of 20.2/16.7%]. Clinical benefit (³ MR) was achieved in 68.4/65.4%. Median time to PR and maximum response was 1 (range 1-7) and 2 (range 1-18) cycles, respectively. After a mean follow up time of 11.9 months, 40 patients (34%) remain free from progression, with a median progression free survival of 8.1 months (95% CI: 5.1, 9.8). Median duration of response (DOR) was 9.3 months (95% CI: 7.2,16.1). Median overall survival (OS) has not been reached with 68 patients (57%) alive at last follow-up. Median PFS, DOR, OS were not significantly different in the double-refractory subgroup at 6.3 (CI 4.7, 8.7; p = 0.21), 8.6 (CI 6.5, 16.1; p = 0.87), and 16.8 months (CI 12.4, 28.7; p = 0.11) respectively. The most common (³% grade 3 and 4 toxicities were: neutropenia (49%), thrombocytopenia (39%), anemia (27%), pneumonia (10%), fatigue 8%, and muscular weakness 7%. Febrile neutropenia was uncommon at 2%. There were 6 cases of lower extremity venous thrombosis (5%, 1 grade 1, 4 grade 2, 1 grade 3) and no instances of pulmonary embolism. Mild peripheral neuropathy was present in 32% (19% grade 1, 13% grade 2), 0% grade 3 or 4). Grade 2 congestive heart failure, due to dexamethasone, emerged in 1 subject (0.8%). Four patients (3.3%) withdrew due to treatment related toxicity (1 with Grade 3 muscular weakness, 2 due to Grade 3 fatigue, 1 grade 4 neutropenic sepsis). There was no treatment related mortality. Conclusions ClaPd is a highly effective and tolerable regimen for heavily treated RRMM that has progressed after prior treatments. Response to ClaPd is rapid and sustained at > 8 months in the majority of subjects. The presence of double refractory disease did not significantly impact clinical outcomes. The ORR and PFS compare favorably and toxicity profile is similar to other published reports of Pom/Dex. Disclosures: Mark: Celgene: Consultancy, Honoraria, 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. Zafar:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Onyx: Speakers Bureau. Pekle:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Niesvizky:Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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A Phase III Study Of ASCT Vs Cyclophosphamide-Lenalidomide-Dexamethasone and Lenalidomide-Prednisone Maintenance Vs Lenalidomide Alone In Newly Diagnosed Myeloma Patients

Blood ◽

10.1182/blood.v122.21.763.763 ◽

2013 ◽

Vol 122 (21) ◽

pp. 763-763 ◽

Cited By ~ 16

Author(s):

Antonio Palumbo ◽

Francesca Gay ◽

Andrew Spencer ◽

Francesco Di Raimondo ◽

Adam Zdenek ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Study Endpoint ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3 ◽

To Receive

Abstract Background High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). The introduction of novel agents challenged the role of ASCT at diagnosis. We conducted a multicenter 2X2 randomized trial comparing conventional chemotherapy plus lenalidomide with ASCT followed by maintenance with lenalidomide-prednisone (RP) or lenalidomide (R) alone in newly diagnosed young MM (NDMM) patients. Methods Eligible patients with NDMM ≤ 65 years were enrolled. All patients received Rd induction (four 28-day cycles of lenalidomide 25 mg day 1–21 and low-dose dexamethasone 40 mg day 1,8,15,22) followed by stem cell mobilization. Patients were randomized to receive consolidation with CRD [six 28-day cycles of cyclophosphamide (300 mg/m2 day 1,8,15), dexamethasone (40 mg days 1,8,15,22) and lenalidomide (25 mg days 1–21)] or MEL200-ASCT (melphalan 200 mg/m2 with stem-cell support). Patients were randomly assigned to receive subsequent maintenance with RP (28-day cycles of lenalidomide 25 mg days 1–21 plus prednisone 50 mg every other day) or R alone (28-day cycles of lenalidomide 25 mg days 1–21). Primary study endpoint was progression-free survival (PFS); secondary endpoints included safety, responses and overall survival (OS). Data cut off was May 30th, 2013. Results Three-hundred and eighty-nine patients were enrolled in the trial. Patient characteristics were well balanced between CRD (n=194) and MEL200-ASCT (n=195), and between R (n=195) and RP (n=194) arms. Median follow-up was 31 months. In the intent to treat (ITT) analysis, the median PFS was not reached with MEL200-ASCT and 28 months with CRD (the respective 3-year PFS was 60% vs. 38%, HR=0.62, 95%CI: 0.49-0.85, P=0.003). Median time from enrolment to maintenance was 14 months. In the population of patients eligible for maintenance, 2-year PFS from the start of maintenance was 73% for RP and 56% for R patients (HR= 0.57, 95%CI: 0.34-0.93; P=0.03). In the subgroup of patients who received MEL200-ASCT, 2-year PFS from the start of maintenance was 83% for patients who received RP and 64% for those who received R alone (HR=0.36 95%CI: 0.15-0.87, P=0.02). In the subgroup of patients who received CRD, 2-year PFS from the start of maintenance was 64% for patients who received RP and 47% for those who received R alone (HR=0.75, 95%CI: 0.40-1.39, P=0.36). At present, no differences in OS were noticed between patients randomised to received CRD or MEL200-ASCT, and between patients who received RP or R maintenance. As expected, the rates of grade 3-4 hematologic (85% vs. 26%, P<0.001) and non-hematologic (35% vs. 19%, P=0.003) adverse events (AEs) were higher in the MEL200-ASCT arm compared with the CRD arm. The main non-hematologic AEs were infections (18% vs. 5%, P=0.001) and gastrointestinal AEs (18% vs. 3%, P<0.001). Rates of grade 3-4 hematologic (8% vs. 7%, P=0.85) and non-hematologic (12% vs. 13%, P=0.88). AEs were similar in the RP and R arms. The main non-hematologic AEs in both RP and R groups were infections (3% vs. 3%). At present, 6 second primary malignancies and 3 cases of cutaneous basalioma have been reported. Conclusions MEL200-ASCT significantly prolonged PFS in comparison with CRD. At present no difference in OS was reported, this may be due to the low number of events and to the length of follow-up. The increase in toxicity with MEL200-ASCT did not adversely impact on efficacy. The addition of prednisone to lenalidomide maintenance significantly reduced the risk of progression in comparison with lenalidomide alone, without increasing the toxicity. Updated data with longer follow-up will be presented at the meeting. Disclosures: Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Gay:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Spencer:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Larocca:Celgene: Honoraria. Caravita:Celgene: Honoraria, Research Funding. Petrucci:Celgene: Honoraria. Hajek:Celgene: Honoraria; Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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A Phase 1/2 Study of G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (G-CLAM) in Adults with Newly Diagnosed Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

Blood ◽

10.1182/blood.v128.22.1068.1068 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1068-1068 ◽

Cited By ~ 1

Author(s):

Anna B. Halpern ◽

Megan Othus ◽

Emily M Huebner ◽

Kaysey F. Orlowski ◽

Bart L. Scott ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Induction Chemotherapy ◽

Research Funding ◽

Phase 1 ◽

Hematologic Toxicity ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3 ◽

Dose Levels

Abstract Introduction:"7+3" with standard doses of cytarabine and an anthracycline has remained the mainstay of induction chemotherapy for newly diagnosed AML. Since some studies have shown improved outcomes with high-dose cytarabine, cladribine, or escalated doses of anthracyclines, we conducted a phase 1/2 study (NCT02044796) of G-CLAM using escalated doses of mitoxantrone for newly diagnosed AML or high-risk MDS (>10% blasts). Methods: Patients≥18 years were eligible if they had treatment-related mortality (TRM) scores of ≤6.9 (corresponding to a predicted risk of early death with standard induction chemotherapy of ≤6.9%) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤2.5 times upper limit of normal). Excluded were patients with uncontrolled infection or concomitant illness with expected survival <1 year. In phase 1, cohorts of 6-12 patients were assigned to 1 of 4 total dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day, days 1-3, compared to 10 mg/m2/day used in standard dose G-CLAM previously established in relapsed/refractory AML). Other drug doses were G-CSF 300 or 480 μg/day (for weight </≥76 kg; days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). In phase 2, patients were treated at the maximum tolerated dose (MTD) of mitoxantrone. A second identical course of G-CLAM was given if complete remission (CR) was not achieved with cycle 1. Up to 4 cycles of consolidation with G-CLA (mitoxantrone omitted) were allowed if CR or CR with incomplete platelet or blood count recovery (CRp/i) was achieved with 1-2 cycles of induction therapy. Dose-limiting toxicities (DLTs) were: 1) grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7-day delay of the subsequent treatment cycle; 2) grade ≥4 non-hematologic toxicity if recovery to grade ≤2 within 14 days, both excluding febrile neutropenia, infection or constitutional symptoms. Results: Among 33 patients (median age of 57.3 [range: 26-77], median TRM score 2.31 [0.16-5.90]) treated in phase 1, one DLT occurred at dose levels 3 and 4 (respiratory failure in both cases), establishing G-CLAM with mitoxantrone at 18 mg/m2/day as the MTD. Sixty-two patients, including 6 treated in phase 1, received G-CLAM at MTD. Patient characteristics were as follows: median age 58 (21-81) years, median TRM score 2.85 (0.06-6.73), with AML (n=52) or high-risk MDS (n=10). Cytogenetics were favorable in 6, intermediate in 44, and adverse in 12 (MRC criteria); 11 patients had NPM1 and 6 had FLT3 mutations. Fifty-two patients (83.9%, 95% confidence interval: 72.3-92.0%) achieved a CR (n=48 [77.4%: 65.0-87.1%]), or CRp/i (n=4 [6.5%: 1.8-15.7%]) with 1-2 cycles of therapy. Only 3 patients required 2 cycles to best response. Among the 48 CR patients, 43 (89.6%) were negative for measurable residual disease (MRDneg) by flow cytometry. Four patients had morphologic leukemia free state, 1 patient with myeloid sarcoma had a partial remission, 4 had resistant disease, and 1 died from indeterminate cause. One patient died within 28 days of treatment initiation (septic shock). Median times to an absolute neutrophil count ≥500/μL and a platelet count of ≥50,000/μL were 26 and 23 days. Besides infections and neutropenic fever, maculopapular rash, and hypoxia (fluid overload/infection-related) were the most common grade ≥3 adverse events. In addition to the phase 1/2 MTD cohort, there were 15 patients treated in an expansion cohort and 3 eligible patients treated off protocol with mitoxantrone at 18 mg/m2. For these 80 patients combined treated at MTD, the CR and CR/CRp/i rates were 76.3% and 81.2%. After multivariable adjustment, compared to 300 patients treated with 7+3 on the SWOG S0106 trial, G-CLAM with mitoxantrone 18mg/ m2 was associated with an increased probability of CR (odds ratio [OR]= 3.08, p=.02), CR/CRp/i (OR=2.96, p=.03), a trend towards improved MRDnegCR (OR= 3.70, p=.06), and a trend towards improved overall survival ([OS]; hazard ratio=0.34, p=.07). For the entire study cohort, the 6 and 12-month relapse-free survival were 73% (64-83%) and 62% (42-74%) and the 6 and 12-month OS were 89% (82- 96%) and 77% (67-88%). Conclusions: G-CLAM with mitoxantrone up to 18 mg/m2/day is well tolerated and has potent anti-leukemia activity. This regimen may warrant further randomized comparison with 7+3. We also plan to examine the addition of sorafenib to G-CLAM in newly diagnosed AML patients regardless of FLT3 status. Disclosures Othus: Glycomimetics: Consultancy; Celgene: Consultancy. Scott:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding. Erba:Ariad: Consultancy; Gylcomimetics: Other: DSMB; Pfizer: Consultancy; Sunesis: Consultancy; Jannsen: Consultancy, Research Funding; Juno: Research Funding; Novartis: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Research Funding; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Celator: Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Amgen: Consultancy, Research Funding.

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EARLY Results of TOTAL Therapy 7 (TT7): High Response Rates of NEWLY Diagnosed High Risk Myeloma to Daratumumab

Blood ◽

10.1182/blood-2019-131887 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4569-4569 ◽

Cited By ~ 1

Author(s):

Frits van Rhee ◽

Sharmilan Thanendrarajan ◽

Carolina D. Schinke ◽

Jeffery R. Sawyer ◽

Adam Rosenthal ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Response Rates ◽

Newly Diagnosed ◽

Advisory Committees ◽

Early Results ◽

Research Grant

Background. The TT approach has significantly improved the outcome of multiple myeloma (MM) by combining new drugs with a regimen that comprises induction, tandem autologous stem cell transplantation (ASCT), consolidation and maintenance. However, a group of 15% of patients with high risk multiple myeloma (HRMM) have derived little benefit despite similar response rates to induction chemotherapy and ASCT when compared to low risk MM. The poor outcome of HRMM is explained by early relapse post ASCT resulting in a short progression free survival (PFS) with only 15-20% of patients surviving long-term. Daratumumab (Dara) is a human IgG1k anti-CD38 monoclonal antibody that has shown favorable results in early single-arm studies and more recently in phase III studies for relapsed/refractory and newly diagnosed MM. In TT7, we introduced Dara during all phases of therapy, including immune consolidation early post ASCT, to improve responses rate and PFS in HRMM. Methods. Patients had newly diagnosed HRMM as defined by high risk cytogenetic abnormalities, presence of extramedullary disease, >3 focal lesions on CT-PET, elevated LDH due to MM, or ISS II/III with cytogenetic abnormality. Dara (16mg/kgx1) was added to induction with KTD-PACE (carfilzomib, thalidomide, dexamethasone; and four-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide). Conditioning for tandem autologous stem cell transplantation (ASCT) was with fractionated melphalan (50mg/m2x4) (fMEL) based on prior observations that patients with adverse cytogenetics fare better with fMEL rather than single high dose MEL200mg/m2.In the inter tandem ASCT period immunological consolidation with Dara (16mg/kg) alone for 2 doses was followed by Dara (16mg/kg) on day 1 combined with K (36mg/m2) and D (20mg) weekly for 2 cycles. DaraKD was administered to avoid treatment free periods allowing for myeloma regrowth. The 2nd ASCT was followed by further immunological consolidation with Dara (16mg/k) for 2 doses, and maintenance therapy for 3 yrs with 3-months block of alternating Dara-KD (dara 16mg/kg day 1; K 36mg/m2 and dex 20mg weekly) and Dara-lenalidomide (R)D (dara 16mg/kg day 1; R 15mg day 1-21 q28 and D 20mg weekly). Results. TT7 enrolled 43 patients thus far. The median follow-up was 11 months (range: 1-22). The median age was 61 yrs (range 44-73). Sixteen patients were ≥65 yrs (37.2%). A mean of 29.4x106 CD34+ cells/kg (range: 4.6-86.4) were collected. 36 patients completed ASCT #1 (83.7%) and 18 (41.9%) ASCT #2, whilst 14 patients have proceeded to the maintenance phase. R-ISS II/III or metaphase cytogenetic abnormalities were present in 85.1 and 58.1% of patients, respectively. Elevated LDH or >3FL on CT-PET were noted in 30 and 41.8%. The 1-yr cumulative incidence estimates for reaching VGPR and PR were 87 and 83%, respectively. A CR or sCR was achieved in 68 and 46%. The 1-yr estimates of PFS and OS were 91.6 and 87.2%. 40 subjects are alive, whilst 5 progressed on study therapy and 3 subsequently died. 38 patients are progression free at the time of reporting. Dara was well-tolerated and no subjects discontinued therapy due to dara-related side effects. The CR and sCR rates compared favorably to the predecessor HRMM TT5 protocol where CR and sCR rates were 59 and 27%. Conclusion. The early results of TT7 point to increased response rates of HRMM to a dara-based TT regimen with especially higher rates of CR and sCR. Longer follow-up is required to determine if these early results translate into superior PFS and OS. Figure Disclosures van Rhee: Karyopharm Therapeutics: Consultancy; Kite Pharma: Consultancy; Adicet Bio: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy. Walker:Celgene: Research Funding. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding.

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Ixazomib-Lenalidomide-Dexamethasone (IRd) Consolidation Following Autologous Stem Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma: A Large Multi-Center Phase II Trial

Blood ◽

10.1182/blood-2018-99-109920 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 123-123 ◽

Cited By ~ 3

Author(s):

Ravi Vij ◽

Nitya Nathwani ◽

Thomas G. Martin ◽

Mark A. Fiala ◽

Abhinav Deol ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Hematologic Toxicity ◽

Consolidation Therapy ◽

Newly Diagnosed ◽

Advisory Committees ◽

Oral Regimen ◽

Grade 3

Abstract Background: Maintenance therapy post-autologous stem cell transplantation (ASCT) has shown to improve progression-free and overall survival in multiple myeloma (MM) and has largely become the standard of care. Consolidation therapy, a brief duration of more-intensive chemotherapy administered prior to maintenance, has been shown to further deepen responses and may improve long-term outcomes. Ixazomib, lenalidomide and dexamethasone (IRd) is an all oral regimen that has been shown to be active in newly diagnosed MM as well as relapsed disease. In this study, we are analyzing the safety and efficacy of IRd as consolidation therapy after ASCT (NCT02253316). Methods: Eligible patients, age 18-70 with newly diagnosed MM undergoing ASCT during first-line treatment, are being consented prior to ASCT. Approximately 4 months following ASCT, patients receive 4 cycles of consolidation therapy with IRd [ixazomib 4 mg on days 1, 8 and 15 of a 28-day cycle, lenalidomide 15 mg on days 1 through 21, and dexamethasone 40 mg on days 1, 8 and 15]. The primary end point is minimal residual disease (MRD) status. MRD is being assessed by ClonoSEQ where possible and by multi-color flow where not. Toxicity, IMWG response rate, PFS, and OS are secondary end points. One month after the last consolidation cycle, patients are randomized (1:1) to maintenance therapy with single-agent ixazomib (4 mg on days 1, 8 and 15) or lenalidomide (15 mg daily). In total, 240 patients will be enrolled on the trial. This presentation coincides with planned interim analysis 2 which included data from the consolidation phase only. Results: As of July 2018, 172 patients with NDMM have been enrolled from 10 centers within the US. The median age was 57 (range 28-70) and 67% were male. 76% were white, 10% African-American/Black, and 13% were another race. 39% were ISS Stage I, 30% were Stage II, and 20% were Stage III. All patients received proteasome inhibitors and/or IMIDs as front-line induction and melphalan as conditioning for ASCT. IRd consolidation started at a median of 110 days post-ASCT (range 80-138). IRd has been well tolerated. Only 4% (6/154) of patients have been unable to complete the 4 cycles of consolidation to date due to toxicity. Grade 3 hematologic toxicity has been uncommon; 4% neutropenia, 3% thrombocytopenia, and 2% anemia. There has been no grade 4 hematologic toxicity. Non-hematologic grade 3-4 toxicities have included: infection (8%), nausea/vomiting/diarrhea (3%), and transaminitis (1%). No grade 3-4 peripheral neuropathy has been reported. One case of grade 5 pneumonia was reported but was not considered related to study treatment. Following ASCT, the MRD-negative rate was 26% and this improved to 37% following consolidation. In the subset of patients with Clonoseq results available, the MRD negative rate improved from 19% to 27%. Clinical response rate improved similarly; prior to consolidation the VGPR or better rate was 76% including 39% CR/sCR. Following consolidation, the VGPR or better rate was 85% including 56% CR/sCR. 137 patients went on to receive maintenance with either ixazomib (n = 71) or lenalidomide (n = 66). At time of submission, the median follow-up from start of IRd is 14 months and 28 patients have relapsed/progressed and 6 have expired. An interim analysis is planned for 2019, representing the first comparison of ixazomib and lenalidomide maintenance. Conclusion: IRd consolidation following ASCT appears to be safe and effective. The all oral regimen is convenient for patients which greatly simplifies follow-up in the peri-transplant period. Study enrollment is scheduled to complete in Q1 of 2019. Disclosures Vij: Karyopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansson: Honoraria, Membership on an entity's Board of Directors or advisory committees. Martin:Amgen: Research Funding; Sanofi: Research Funding; Roche: Consultancy. Deol:Kite Pharmaceuticals: Consultancy; Novartis: Consultancy. Kaufman:Janssen: Consultancy; Karyopharm: Other: data monitoring committee; BMS: Consultancy; Abbvie: Consultancy; Roche: Consultancy. Hofmeister:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding. Gregory:Poseida Therapeutics, Inc.: Research Funding. Berdeja:Amgen: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bristol-Myers Squibb: Research Funding; Bluebird: Research Funding; Genentech: Research Funding; Glenmark: Research Funding; Novartis: Research Funding; Teva: Research Funding; Sanofi: Research Funding. Chari:Pharmacyclics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: 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, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; The Binding Site: Consultancy.

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Two Year Update of Phase II Trial of Pembrolizumab, Lenalidomide and Dexamethasone As Post -Autologous Stem Cell Transplant Consolidation in Patients with High-Risk Multiple Myeloma

Blood ◽

10.1182/blood-2019-125155 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1911-1911 ◽

Cited By ~ 2

Author(s):

Meena Bansal ◽

David S. Siegel ◽

Jaeil Ahn ◽

Rena Feinman ◽

David H. Vesole ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Advisory Committees ◽

Best Response ◽

Grade 3

Introduction: Patients with high-risk multiple myeloma (HRMM) who have undergone autologous stem cell transplant (ASCT) will inevitably relapse and have a progression free survival (PFS) ranging from 8-14 months (Gaballa et al, American Journal of Hematology, 2016) and 24-39 months while on lenalidomide (Len) maintenance therapy (Jackson et al, The Lancet Oncology, 2019). Unlike in solid tumors, PD-1 blockade has no single agent activity in relapsed and refractory multiple myeloma (MM) patients suggesting that immune stimulating agents, immunomodulatory agents (IMiDs), such as lenalidomide (Len) or pomalidomide (Pom) are necessary in combination with anti-PD-1 blockade to increase depth and duration of response post-ASCT. The Keynote-023 study revealed an overall response rate (ORR) of 76% with the combination of pembrolizumab (Pem), Len and dexamethasone (Dex). Similarly, the Keynote 135 study using the combination of Pem, Pom, and Dex revealed an ORR of 60%. Unfortunately, the phase III studies comparing an IMiD vs Pem with the IMiD upfront at the early relapsed setting were halted because of increased deaths on the Pem arm and a decreased median PFS. With our Phase II study currently on clinical hold by the FDA, we are presenting here the 2-year follow-up of the original patient cohort including some preliminary safety and efficacy data of Pem-Len-Dex in HRMM patients as post-ASCT consolidation (NCT02906332). Methods: Patients with HRMM who have undergone induction therapy followed by single or tandem melphalan-based ASCT were considered eligible 2-6 months post ASCT. HRMM criteria are defined by any of the following: ISS stage 3; del 13q by cytogenetics; FISH with 1q amplification, 1p deletion (del), p53 del, t(4;14), t(14;16), t(14;20), hypodiploidy; or a high-risk gene expression profile score. Patients were excluded if they had progression of disease at time of screening or if there was evidence of organ dysfunction. Patients received Pem 200 mg IV at day 1;Len 25 mg po daily at days 1-14; and Dex 40 mg daily at days 1,8,15 of a 21-day cycle for a total of 2 cycles and then an additional 2 cycles of Pem + Len without Dex at the same dose and frequency. Survival outcomes post-ASCT were measured using the log-rank test. Results: Of 15 patients screened, 12 received at least one dose of therapy and were deemed evaluable. One patient withdrew consent and did not follow up after cycle 2. Baseline characteristics are shown in Table 1. Thirty-three percent were ISS 3, 66.7% had a p53 deletion by FISH, 41.6% received induction Bortezomib-Len-Dex; 33% received induction Carfilzomib-Len-Dex, and the remaining 24.9% received other bortezomib-based induction. Best ORR during the 2 year follow up showed 8 patients (73%) achieving stringent complete remission, 2 patients (18%) showing complete remission and 1 (9%) achieving very good partial remission. Table 2 shows best response to treatment by cycle of therapy. Table 3 shows best response during follow-up visits, which were 3 months apart. Of the 11 patients who completed therapy, 8 had minimal residual disease (MRD) status assessed and among them, 7 were MRD negative by flow cytometry, tested 30 days after the fourth cycle. With a median follow-up of 32.2 months, median PFS was 27.6 months. The PFS rates at 1 year and 2 year are 91.3% and 65.2%, respectively. All patients had adverse events (AEs), AEs were attributed to Pem, Len, or Dex rather than from ASCT. Of the 90 AEs that were reported, 5.6% were grade 3 and 94% were grade 1 or 2 (Table 3). The most common hematologic AE was neutropenia (41.7%), with 3 pts (25%) grade 1 and 2, and 2 pts (16.6%) grade 3. The most common non-hematologic AEs were intermittent constipation (16.6%), diarrhea (16.6%), fatigue (8.3%), and increased ALT (8.3%) and were graded as 1 or 2. Non-hematologic grade 3 AEs occurred in 2 pts and included hypoxia and maculopapular rash. There was 1 serious AE, H. influenza pneumonia requiring inpatient admission, which was not considered to be related to Pem. Conclusions: The combination of Pem, Len, and Dex given to HRMM patients in the post-ASCT consolidation setting is well tolerated. In comparison to historical controls of HRMM patients post-ASCT with a median PFS of 8-14 months, the PFS rates of 91.3% and 65.2% at 1 and 2 year post-ASCT respectively suggest an efficacy signal for the use of Pem, Len, and Dex as post-ASCT consolidation. Larger prospective studies are needed to validate these results. Disclosures Siegel: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Biran:Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding.

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Impact of Bortezomib- or Lenalidomide-Based Induction Treatment on High Risk Cytogenetic Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Enrolled in the Gimema-MM-03-05 and EMN01 Trials

Blood ◽

10.1182/blood.v130.suppl_1.744.744 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 744-744 ◽

Cited By ~ 1

Author(s):

Alessandra Larocca ◽

Massimo Offidani ◽

Pellegrino Musto ◽

Francesca Patriarca ◽

Lorenzo De Paoli ◽

...

Keyword(s):

Sensitivity Analysis ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

Risk Of Death ◽

Significant Difference ◽

Reduced Risk

Abstract Introduction : Cytogenetic abnormalities by fluorescence in situ hybridization (FISH) are clinically relevant prognostic factors in MM. Data in transplant ineligible patients treated with bortezomib or lenalidomide in first-line therapy for high-risk (HiR) patients is limited. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. This sub-analysis evaluates the impact of cytogenetics on outcomes in transplant-ineligible patients with newly diagnosed MM (NDMM) treated with bortezomib-based induction (BORT) or lenalidomide-based (LEN) treatment. Methods : In the GIMEMA-MM-03-05-trial, patients were randomized to bortezomib-melphalan-prednisone-thalidomide for 9 cycles followed by maintenance with bortezomib-thalidomide (VMPT-VT) vs VMP for 9 cycles, without maintenance. In the EMN01-trial, patients were randomized to melphalan-prednisone-lenalidomide (MPR) or cyclophosphamide-prednisone-lenalidomide (CPR) or lenalidomide plus low-dose dexamethasone (Rd) for 9 cycles, followed by maintenance with lenalidomide alone or plus prednisone continuously. Results of these studies have previously been reported (Palumbo A et al JCO 2010 and 2014; Magarotto V et al Blood 2016 127(9)). Cytogenetics were assessed using FISH. Patients were categorized into cytogenetic risk groups according to International Myeloma Working Group criteria. HiR cytogenetics included del(17p), t(4;14), and t(14;16); all other patients were categorized as standard risk (StR). Subgroup analyses were performed to determine the consistency of treatment effects of BOR vs LEN in the different subgroups using interaction terms between treatment and FISH, ISS, age, sex, Karnofsky PS and LDH. The different effect of BORT vs LEN in cytogenetic subgroups was confirmed by one sensitivity analysis where the follow-up of the BORT study was reduced to make the follow-up times similar; and by another sensitivity analysis with multiple imputation method for missing cytogenetic value. Results : 902 of 1165 patients from the intent-to-treat population had available cytogenetic profiles, with 243 (27%) patients in the HiR group and 659 (73%) in the StR group. In the BORT vs LEN groups, median age was 71 vs 73 years (p<0.001), ISS3 20% vs 27% (P=0.65), HiR patients were 29% vs 26%, StR patients were 71% vs 74% (p=0.32) and the median follow-up was 72.3 and 63.6 months, respectively. In the subgroup analysis, a significant difference was found in the cytogenetic subgroup with a superior advantage of BORT versus LEN in HiR group, whereas no significant difference was found between BORT and LEN in the other subgroups analyzed (ISS, age, sex, Karnofsky PS and LDH) (interaction-p=0.01) (Fig. 1 B). BORT treatment resulted in a reduced risk of death or progression compared with LEN in patients with HiR. In HiR patients, median PFS was 30.8 with BORT compared with 14.8 months with LEN (HR: 0.54; 95% CI: 0.41-0.72); in StR, median PFS was 29.1 with BORT compared with 22.1 months with LEN (HR: 0.87; 95%; CI: 0.72-1.05) (Fig. 1 A). Considering the standard of care VMP and Rd, in the HiR group (n=95) VMP resulted in a 48% reduced risk of death or progression compared with Rd (HR: 0.53; 95% CI: 0.34-0.83), whereas no significant difference in PFS was found in the StR group (n=273) (HR: 1.00; 95% CI: 0.75-1.33), interaction-p=0.02. BORT treatment resulted in a reduced risk of death in patients with HiR cytogenetics: median OS was 62.4 months with BORT compared with 43.2 months with LEN (HR: 0.68; 95% CI: 0.47-0.96); in StR, median OS was 78.1 months with BORT and was not reached with LEN (HR: 1.06; 95% CI: 0.82-1.36), interaction-p=0.04 (Fig. 1 A). In patients with del(17p) (n=131) median PFS was 18.0 vs 12.9 months for BORT vs LEN (HR: 0.71; 95% CI: 0.49-1.04), interaction-p=0.73. In patients with t(4;14) (n=118) median PFS was 31.5 vs 15.2 months for BORT vs LEN (HR: 0.41; 95% CI: 0.27-0.62) interaction-p=0.002. In patients with t(14;16) (n=31) median PFS was 36.2 vs 9.8 months for BORT vs LEN treated patients (HR: 0.34; 95% CI: 0.16-0.76), interaction-p=0.045. Conclusions : BORT treatment resulted in a PFS and OS benefit vs LEN in patients with HiR cytogenetics. Treatment with VMP led to a significant reduction of the risk of death or progression vs Rd in HiR patients. These results support VMP induction as a standard treatment option for patients with NDMM who are ineligible for transplant with HiR cytogenetics. Disclosures Larocca: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Offidani: celgene: 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. Musto: Janssen: Honoraria; Celgene: Honoraria. Patriarca: MSD Italia: Honoraria; Janssen: Honoraria. Corradini: Gilead: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Bosi: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Petrucci: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Boccadoro: Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding; AbbVie: Honoraria.

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Phase I/II Trial of the Efficacy and Safety of Combination Therapy with Lenalidomide/Bortezomib/Dexamethasone (RVD) and Panobinostat in Transplant-Eligible Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v126.23.187.187 ◽

2015 ◽

Vol 126 (23) ◽

pp. 187-187 ◽

Cited By ~ 5

Author(s):

Jatin J. Shah ◽

Lei Feng ◽

Elisabet E. Manasanch ◽

Donna Weber ◽

Sheeba K Thomas ◽

...

Keyword(s):

High Risk ◽

Adverse Events ◽

Board Of Directors ◽

Induction Therapy ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

Depth Of Response ◽

High Risk Disease ◽

Grade 3

Abstract Background: Induction therapy prior to autologous stem cell transplantation (ASCT) continues to improve with the use of multi-drug combination regimens. Panobinostat (pano), a deacetylase inhibitor, was recently approved in combination with bortezomib/dexamethasone for relapsed myeloma based on the phase III PANORMA I trial for RRMM. The addition of pano in PANORAMA demonstrated a near doubling in CR rate from 15 to 27%. We previously reported phase I trial data of RVD + pano in newly diagnosed myeloma (NDMM) and demonstrated the pano can be safely combined with RVD. Based on the encouraging preliminary data we pursued a phase II dose expansion to further explore the potential improvement in depth of response with RVD + pano in NDMM. Methods: The primary objective was to determine the safety/tolerability of pano and RVD in NDMM. Secondary objectives were to determine efficacy as measured by the CR/nCR rate after 4 cycles, ORR, tolerability/toxicity, and progression free survival. Patients had to have NDMM with indication for therapy and be eligible for ASCT with adequate organ function. Panobinostat 10 mg was administered on days 1, 3, 5, 8, 10, 12; bortezomib 1.3 mg/m2 was administered subcutaneously on days 1, 4, 8, 11; lenalidomide 25 mg on days 1-14; dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 on a 21 day cycle. Adverse events (AEs) were graded by NCI-CTCAE v4 and responses were assessed by the modified International Uniform Response Criteria. Results: 42 patients (pts) were enrolled; 12 in the dose escalation and 30 in the dose expansion. The median age was 60 (range 44-79); male (n=30); ISS stage I (n=28); ISS stage II (n=10); ISS stage III (n=4); 14/42 pts had high risk myeloma (1 pt with t(4:14) and del17p; 1 pt with del 17p and 1q21; and 12 pts with only 1q21 amplification). Among 42 pts, 2 completed only 1-2 cycles and 1 pt was inevaluable for response. Among the 39 pts who completed 4 cycles and were evaluable for efficacy the ORR (≥PR) after 4 cycles was 93% (36/39) including nCR/CR in 17/39 (44%), VGPR in 10/39 (26%), PR in 9/39 (23%), and SD in 3/39 (8%) pts. In 12 of 14 pts with high risk disease, who were evaluable for response, the ORR was 100% (12/12); the nCR/CR in 6/12 pts; VGPR in 4/12 pts; and 2/12 pts achieved a PR. 25/42 (59%) pts completed induction therapy and underwent consolidation with ASCT; 5 pts completed induction therapy, came off study and did not proceed to ASCT. 8 pts choose a delayed transplant approach, completed induction therapy and stem cell collection. 6 of those 8 pts remain on trial with maintenance therapy (len/dex/pano) per protocol. 2 pts, neither with high risk disease, progressed after cycles 10 and 11 with extramedullary disease and plasma cell leukemia/central nervous system involvement, respectively. 4 additional patients have completed 2, 3, and 5 cycles of therapy and are pending ASCT. Grade 3-4 hematologic adverse events included anemia (5); neutropenia (10); thrombocytopenia (16). Grade 3-4 nonhematologic toxicities included ALT elevation (1); AST elevation (1); constipation (2); diarrhea (4); dyspnea (2); fatigue/muscle weakness (5); syncope (2); MI (1); nausea (3); peripheral neuropathy (2); rash (1); DVT/VTE (3). Infectious complications included grade 2 (G2) urinary tract infection (2); G2 upper respiratory tract infection (5); pneumonia (5); osteomyelitis/musculoskeletal (3); infection (3). Treatment emergent serious adverse events related to therapy observed were: G3 pneumonia (9); G2 fever (5), G3-4 venous thromboembolic events (2); G3 diarrhea (2); atrial fibrillation (2). Other events included 1 pt each with G3 cellulitis, G3 myocardial infarction (MI), G3 febrile neutropenia, G2 diarrhea, G2 seizure, G3 hypotension and G3 sinusitis. 1 pt had a second primary malignancy - a newly diagnosed breast cancer during cycle 9 of therapy. Conclusions: Panobinostat 10 mg can be safely combined with full dose RVD in NDMM. The side effect profile with use of subcutaneous bortezomib demonstrated minimal gastrointestinal toxicity/diarrhea and was a well-tolerated combination. The combination of RVD+ pano lead to rapid disease control with high response rate after 4 cycles of therapy and ORR of 93% and significant depth of response with a 4 cycle nCR/CR rate of 44%. Enrollment in dose expansion is near completion and full data will be presented at ASH and supports the study of panobinostat in a randomized trial for NDMM. Disclosures Shah: Celgene: Consultancy, Research Funding. Thomas:Celgene: Research Funding; Novartis: Research Funding; Idera Pharmaceuticals: Research Funding. Orlowski:Genentech: Consultancy; Acetylon: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Research Funding; Spectrum Pharmaceuticals: Research Funding; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Research Funding; BioTheryX, Inc.: Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals: Consultancy, Research Funding; Forma Therapeutics: Consultancy.

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Updated Results of a Phase II Study of Lenalidomide-Elotuzumab As Maintenance Therapy Post-Autologous Stem Cell Transplant (AuSCT) in Patients (Pts) with Multiple Myeloma (MM)

Blood ◽

10.1182/blood-2018-99-116464 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1982-1982 ◽

Cited By ~ 5

Author(s):

Sheeba K. Thomas ◽

Jatin J. Shah ◽

Ashley N. Morphey ◽

Hans C. Lee ◽

Elisabet E. Manasanch ◽

...

Keyword(s):

High Risk ◽

Maintenance Therapy ◽

Board Of Directors ◽

Research Funding ◽

Memory Impairment ◽

Advisory Committees ◽

Best Response ◽

Grade 3

Abstract Background: Lenalidomide (LEN) monotherapy has been effective in extending progression free survival (PFS) after myeloablative AuSCT in pts with MM. Elotuzumab (ELO), a humanized IgG1 immunostimulatory monoclonal antibody against signaling lymphocytic activation molecule F7 (SLAM F7), is FDA approved in combination with LEN and dexamethasone (DEX) for treatment of MM pts who have received 1-3 prior therapies. The objective of this phase 2 trial is to evaluate the efficacy and safety of adding ELO to LEN as maintenance therapy post-myeloablative AuSCT. We report updated results of the primary (PFS) and secondary (overall survival [OS] and toxicity) endpoints. Patients and Methods: Between 4/15/2015-1/27/2016, 27 evaluable pts were treated on 28 day cycles with ELO, 10 mg/kg iv weekly for cycles 1-2, q2weeks for cycles 3-6, then 20 mg/kg once monthly for cycles 7+. Pts enrolled after 1/28/2016 (n=57 pts) have received ELO, 10 mg/kg IV weekly for cycles 1-2, and 20 mg/kg on day 1 from cycle 3 until disease progression (PD). LEN has been dosed at 10 mg/day for cycles 1-3, with a dose increase to 15 mg/day at physician discretion starting with cycle 4, in the absence of non-hematologic toxicity > grade 1 and significant cytopenias (ANC < 1000/mL, platelet count < 100,000/ml). For the 1st 8 weeks, pts <75 yrs receive 28 mg of DEX 3-24 hours pre-infusion, while pts ≥75yrs receive 8 mg; pts receive 4-10 mg iv DEX immediately pre-infusion for all cycles. Pts also receive zoster and thromboembolic prophylaxis commensurate with standard recommendations. The study's primary endpoint is PFS, defined as time from AuSCT to PD or death (whichever occurs first), or time of last contact. Secondary objectives are best response, OS, incidence of second primary malignancies (SPMs) and adverse event (AE) profile. Total enrollment of 100 pts is planned. Patients are followed until death, withdrawal of consent or removal from study. Eligible pts received ≤2 lines of induction therapy, and are 60-210 days post-AuSCT. Results: Pts (n=84) have been treated for a median of 16 cycles (2-43). At study entry, 27 (32%) had complete response (CR), 36 (43%) had very good partial remission (VGPR), 20 (24%) had partial remission (PR) and 1 (2%) had minor remission (MR). Best response achieved to date on study is CR in 44 pts (52%), VGPR in 31 pts (37%) and PR in 9 pts (11%). For those who have converted to CR on study, median time to CR was 2 months. Of 22 pts in CR who have been tested for minimal residual disease (MRD) to date, 20 are negative by flow cytometry (minimum of 2 million cells evaluated). Three of 20 have converted from VGPR to MRD negativity while on study. With a median follow up of 23 months, 96% of pts (n=81) remain alive. Ten pts have had PD; of these, 6 had high risk cytogenetics. Two died of PD while receiving salvage therapy. One additional pt died on study in VGPR, after developing acute cerebral encephalopathy with refractory status epilepticus of unclear etiology. Four pts withdrew for personal reasons, 4 were removed at physician discretion (prolonged cytopenias [1], drug rash [1], worsening memory impairment [1], therapy related myelodysplastic syndrome (t-MDS) [1]), and 2 lost insurance coverage. Estimated 3 year PFS is 81%. High risk cytogenetics adversely affected PFS (p=0.02). Grade 3-4 Hematologic AEs (no. of pts) were: neutropenia 32% (27), febrile neutropenia 15% (13), thrombocytopenia 8% (7), and anemia 7% (6). Grade 3-4 non-Hematologic AEs (no. of pts): respiratory infections 17% (15), diarrhea 14% (12), fatigue 13% (11), other infections 8% (7), peripheral neuropathy 7% (6), myalgias 6% (5), nausea/vomiting 4% (3), dizziness 2% (2), memory impairment 2% (2), maculopapular rash 2% (2), edema 1% (1). SPMs include intra-epidermal adenocarcinoma of the neck (1), mucinous appendiceal neoplasm (1), t-MDS (1), prostate cancer (1), and melanoma (1). Renal cell carcinoma was diagnosed in 1 pt, 15 months after removal from study for PD. Conclusions: Lenalidomide-elotuzumab is a well-tolerated maintenance therapy during which 33% of 84 pts had improvement in quality of response while on therapy, including 20% who converted to CR. The number of pts experiencing improvement may be underestimated due to ELO interference with paraprotein measurement on electrophoretic studies. Additional follow up is required to determine if the improved quality of responses translate into improvements in PFS and OS. Available data supports conduct of a Phase 3 trial. Disclosures Thomas: Array Pharma: Research Funding; Amgen Inc: Research Funding; Bristol Myers Squibb Inc.: Research Funding; Acerta Pharma: Research Funding; Celgene: Research Funding. Shah:Karyopharm Therapeutics: Employment. Lee:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies Corporation: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai Biopharmaceuticals: Consultancy; Takeda Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patel:Abbvie: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Poseida Therapeutics, Inc.: Research Funding.

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