Clinical Activity of Bosutinib by Mutational Status In Patients with Previously Treated Philadelphia Chromosome–positive Leukemias.

Abstract Abstract 3434 Bosutinib (SKI-606) is a dual Src/Abl tyrosine kinase inhibitor (TKI) with minimal inhibitory activity against PDGFR or c-kit. Previous reports of this open-label, phase 1/2 study have demonstrated the efficacy and safety of oral daily treatment with 500 mg bosutinib in adult patients with Philadelphia chromosome–positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML) following resistance or intolerance to imatinib (second-line setting; Cortes JE, et al. ASCO 2010. Abstract #6502) and dasatinib or nilotinib (third-line setting; Khoury HJ, et al. ASCO 2010. Abstract #6514), or with Ph+ advanced leukemias (ie, accelerated or blast phase CML, acute lymphocytic leukemia) following imatinib failure in the second- and third-line settings (Gambacorti-Passerini C, et al. ASCO 2010. Abstract #6509). Failure of therapy with imatinib and other TKIs may result from mutations in the Abl kinase domain that affect drug binding. Therefore, the current analysis compared the rates of hematologic and cytogenetic responses to 500 mg bosutinib in patients with and without Bcr-Abl kinase domain mutations. Of the 570 patients treated, 53% were male and the median age was 53 years (range, 18–91). Median duration of follow-up was 24.1 months (range, 0.6–53.8) for patients with CP CML in the second-line setting, 22.6 months (range, 0.3–47.3) for patients with CP CML in the third-line setting, and 12.1 months (range, <0.1-45.5) for patients with advanced leukemias. Among the 222 (39%) patients with baseline sequencing analyses across all study cohorts, 119 (54%) patients had 27 unique Bcr-Abl mutations (Table). Patients with and without mutations had similar rates of complete hematologic response (CHR; 78% vs 82%, respectively) and major cytogenetic response (MCyR; 56% vs 53%, respectively). Comparable rates of response to bosutinib were observed across P-loop and non–P -loop Bcr-Abl kinase domain mutations, except for the T315I mutation. In particular, although a small number of patients was evaluable for individual mutations, hematologic and cytogenetic responses were observed with mutations such as F317L, F359V/I/C, and E255K/V, which are commonly associated with resistance following sequential treatment with multiple TKI therapies. Although response rates among patients with the T315I mutation were lower, 2 of 6 (33%) evaluable patients achieved a CHR and 1 of 7 (14%) patients achieved a MCyR. Among patients with mutations, the rate of CHR was higher for those with CP CML in the second-line (95%) and third-line (83%) settings than for those with advanced leukemias (46%). The rate of MCyR was highest among patients with CP CML in the second-line setting (73%). In conclusion, bosutinib was associated with substantial clinical activity in multiple patient populations independent of the presence or absence of Bcr-Abl kinase domain mutations and across all types of mutations, with the exception of the T315I mutation. Response n/n evaluablea (%) Bcr-Abl kinase domain mutation type n CHR MCyR Overall population Any mutation 119 35/45 (78) 44/79 (56) P-loop 35 9/11 (82) 12/21 (57) L248V 5 2/2 (100) 2/4 (50) G250E 11 2/2 (100) 3/5 (60) Y253F 1 1/1 (100) 0/1 Y253H 9 2/3 (67) 4/6 (67) E255K 6 2/3 (67) 2/4 (50) E255V 3 0 1/1 (100) Non–P-loop 84 26/34 (76) 32/58 (55) M244V 6 3/3 (100) 3/5 (60) K263E 1 0 1/1 (100) L273M 1 1/1 (100) 1/1 (100) V299L 1 0 0 F311L 1 0 1/1 (100) T315I 19 2/6 (33) 1/7 (14) F317L 16 4/5 (80) 4/11 (36) G321R 1 1/1 (100) 0 N331S 1 0 1/1 (100) M351T 11 3/4 (75) 6/9 (67) E355G 1 1/1 (100) 1/1 (100) E355G/M244V 1 1/1 (100) 0/1 F359C 3 0 1/2 (50) F359I 4 3/3 (100) 3/3 (100) F359V 8 6/6 (100) 4/7 (57) L384P 1 0/1 0/1 H396P 2 1/1 (100) 2/2 (100) H396R 1 0 0 I432T 1 0 0/1 E453K 1 0 1/1 (100) F486S 3 0/1 2/3 (67) No mutation 103 42/51 (82) 38/72 (53) Second-line CP CML population Any mutation 46 19/20 (95) 29/40 (73) Third-line CP CML population Any mutation 26 10/12 (83) 5/17(29) Advanced leukemia population Any mutation 47 6/13 (46) 10/22 (45) a Evaluable patients had a baseline and post-baseline hematologic or cytogenetic assessments, respectively. Patients who had experienced early progression or death before having a post-baseline assessment were also evaluable. Disclosures: Gambacorti-Passerini: Pfizer Inc: Research Funding. Khoury:BMS, Novartis: Honoraria. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Martinelli:BMS: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; GlaxoSmithKline: Honoraria. Kelly:Pfizer: Employment, Equity Ownership. Besson:Pfizer: Employment, Equity Ownership. McMullan:Pfizer: Employment, Equity Ownership. Brummendorf:Pfizer: Membership on an entity's Board of Directors or advisory committees. Cortes:Pfizer Inc: Consultancy, Research Funding.

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A Two-Fold Rise of BCR-ABL Transcript Levels Advises BCR-ABL Mutation Analysis in Imatinib-Treated Chronic Myeloid Leukemia (CML) - an Analysis of the Randomized CML-Study IV

Blood ◽

10.1182/blood.v124.21.3138.3138 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3138-3138

Author(s):

Benjamin Hanfstein ◽

Niklas Westhoff ◽

Rüdiger Hehlmann ◽

Susanne Saussele ◽

Michael Lauseker ◽

...

Keyword(s):

Mutation Analysis ◽

Myeloid Leukemia ◽

Research Funding ◽

Kinase Domain ◽

Positive Clone ◽

Transcript Levels ◽

Optimal Response ◽

Abl Kinase ◽

Equity Ownership ◽

Kinase Domain Mutations

Abstract Introduction: The clonal selection of a mutant BCR-ABL positive clone can be observed in about one of two patients with imatinib-resistant chronic myeloid leukemia (CML). The early detection of BCR-ABL kinase domain mutations is crucial, since it allows to change the tyrosine kinase inhibitor (TKI) regimen in a timely manner and may therefore prevent disease progression and the accumulation of further genetic lesions. European LeukemiaNet (ELN) recommendations suggest a mutation analysis if optimal response criteria are not achieved at 3, 6, 12 or 18 months, or whenever a loss of optimal response occurs (Soverini et al., Blood 2011). Several attempts have been made to derive this indication from a specific increase of BCR-ABL levels. Here we report on the correlation of a rise in BCR-ABL transcript levels and the prevalence of BCR-ABL kinase domain mutations in imatinib-treated patients of the CML-Study IV. Methods: A total of 1,173 patients were enrolled until 2009 and randomized to one of four imatinib-based treatment arms. BCR-ABLIS of 988 patients was determined in 7,876 samples by quantitative RT-PCR in the central laboratory (median sample number per patient: 8.4, range 1-37; median follow up: 34 months, range 0-86), representing the eligible patients for the study. Thereby, the estimated intra-laboratory variance is assumed to be about 20%. A first rise of BCR-ABLIS to at least two-fold and >0.1% between two samples of a patient's molecular course defined a sample suspected of bearing a mutant BCR-ABL positive clone. A mutation analysis was performed on this critical sample by direct sequencing of ABL exons 4 to 10. Results: A critical rise in BCR-ABLIS was observed in 231 of 988 patients (23%) after a median of 15.2 months on treatment (range 2.8-59.4). In the corresponding sample 33 mutant clones could be detected in 31 patients (13%). Thereby a steeper rise of BCR-ABLIS was correlated with a higher incidence of BCR-ABL mutations in the respective group (table). A total of 18 different mutations could be detected, the most frequent were: M244V, n=7 (21%); E255K, n=4 (12%); T315I, n=3 (9%); L248V, G250E, L387M and F486S, n=2 (6%), respectively. Mutations occur in a substantial proportion (8%) of patients with an only 2 to 3-fold rise of BCR-ABLIS transcript levels (table). Therefore, the most sensitive cut-off should be applied and mutation analysis may be triggered by a doubling of BCR-ABL transcripts at levels >0.1% IS. Conclusion: BCR-ABL kinase domain mutations occur already in a substantial proportion of patients with a doubling of BCR-ABL transcript levels, which should determine mutation analysis. Table 1. Rise of BCR-ABL expression Patients (n) Patients with BCR-ABL mutations (n) Patients with BCR-ABL mutations (%) Inter-sample interval(median, days) 2 to 3-fold 72 6 8.3 98 3 to 5-fold 50 3 6.0 100 5 to 10-fold 39 4 10.3 99 10 to 100-fold 49 10 20.4 98 > 100-fold 21 8 38.1 125 > 2-fold (total) 231 31 13.4 101 Disclosures Hanfstein: Novartis: Research Funding; Bristol-Myers Squibb: Honoraria. Hehlmann:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding. Saussele:Novartis: Honoraria, Research Funding, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria, Travel, Travel Other. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Neubauer:MedUpdate: Honoraria, Speakers Bureau. Kneba:Novartis: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pfirrmann:Novartis: Consultancy; Bristol-Myers Squibb: Honoraria. Hochhaus:Pfizer: Consultancy, Research Funding; ARIAD: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Müller:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.

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Low Level BCR-ABL Mutations Below the Detection Limit of Current Standard Screening Techniques Occur Predominantly in the CD34+ Progenitor Cell Compartment in Chronic Phase CML Patients At Diagnosis. A Substudy of the ENEST1st Trial

Blood ◽

10.1182/blood.v120.21.1671.1671 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1671-1671

Author(s):

Jacqueline Maier ◽

Karoline Schubert ◽

Michael Cross ◽

Sabine Leiblein ◽

Kathrin Wildenberger ◽

...

Keyword(s):

Detection Limit ◽

Research Funding ◽

Progenitor Cell ◽

Chronic Phase ◽

Kinase Domain ◽

Cell Compartment ◽

Screening Techniques ◽

Abl Kinase ◽

Cd34 Cells ◽

Kinase Domain Mutations

Abstract Abstract 1671 The presence of BCR-ABL kinase domain mutations below the detection limit of conventional screening techniques (low level mutations, LLM) predicts outcome of subsequent therapy in patients with imatinib resistance (Parker et. al JCO 2011 and Blood 2012). We have further evaluated LLM in the context of the ENEST1st trial, which addresses the frequency of complete molecular responses after 18 months on nilotinib 300mg BID (NI) in newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase (CP). Here, we have investigated the incidence of detectable LLM in the CD34+ progenitor cell compartment in comparison to total white cells (TWBC). Sixty nine ENEST1st study patients with CP CML provided 10ml of peripheral blood or 2ml bone marrow after written informed consent. CD34+ selection was carried out by MACS® (Miltenyi Biotec) and the CD34+ purity was subsequently determined by fluorescent activated cell sorting (FACS). The results were compared to those derived from stored TWBC from 23 of the same patients and a further 16 patients at diagnosis. Aliquots of 105 CD34+ or at least 106 TWBC were used for RNA extraction, cDNA synthesis and BCR-ABL amplification followed by Ligation PCR (L-PCR) for mutations T315I, Y253H, E255K/V, and F359V. This method has previously been shown to achieve a dynamic detection range of 100% to <0.1% mutant allele (3–3.5 log). No patients showed BCR-ABL kinase domain mutations detected by Sanger sequencing spanning ABL exons 4–9. Forty five of 69 patients (65%) with 105 CD34+ cells and a documented CD34+ purity of >50% were available for BCR-ABL amplification. Amplification was successful from 36 (52%) of these CD34+ samples and from 38 of the 39 (97%) TWBC samples. A total of 180 L-PCR assays of CD34+ cells identified 29 (16%) mutations (T315Ix12, Y253Hx7, E255Kx8/Vx1 and F359Vx1) in CD34+ cells from 21/36 patients (58%). In comparison, 190 assays of TWBC identified 10 (5%) mutations (T315Ix3, Y253Hx6, E255Vx1, p=0.0005) in 8/38 patients (21%, p=0.001 Fishers exact test). Significantly more T315I (33%) and E255K (22%) mutations were observed in CD34+ cells than in TWBC (8%, p=0.007 and 0% p= 0.003 respectively). The quantitative levels of all mutant alleles were median 0.135 (range 0.06–0.535) and 0.1 (range 0.04-0, 25) BCR-ABLmutant/ BCR-ABLunmutated for mutations in CD34+ cells and TWBC, respectively and were not significantly different. Where both CD34+ and TWBC were available from the same patient (n=23), 11 patients showed a total of 18 mutations in the CD34+ fraction but only one of these mutations was confirmed in TWBC. One additional mutation was detectable in the TWBC. The remaining 12 patients with no detectable mutation in the CD34+ fraction showed 3 mutations (2x Y253H, T315I) in 2 patients in TWBC only. In conclusion, LLM with either no (T315I) or intermediate (Y253H, E255K/V, F359V) sensitivity to nilotinib are detectable in CP CML patients at a frequency of 21% in the TWBC but with a significantly higher frequency of 58% in the enriched CD34+ progenitor cell compartment. Longterm patient follow up on the ENEST1st and ENESTobserve studies will allow analysis of the relationship between LLM and clinical outcomes on nilotinib. Disclosures: Hochhaus: Novartis, BMS, MSD, Ariad, Pfizer: Consultancy Other, Honoraria, Research Funding. Frank:Novartis: Employment. Lange:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Complete Molecular and Hematologic Response in Adult Patients with Relapsed/Refractory (R/R) Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia (ALL) Following Treatment with Blinatumomab: Results from a Phase 2 Single-Arm, Multicenter Study (ALCANTARA)

Blood ◽

10.1182/blood.v126.23.679.679 ◽

2015 ◽

Vol 126 (23) ◽

pp. 679-679 ◽

Cited By ~ 32

Author(s):

Giovanni Martinelli ◽

Hervé Dombret ◽

Patrice Chevallier ◽

Oliver G. Ottmann ◽

Nicola Goekbuget ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Philadelphia Chromosome ◽

Pcr Amplification ◽

Employment Equity ◽

Advisory Committees ◽

T315i Mutation ◽

Equity Ownership ◽

Grade 3

Abstract Introduction. Prognosis of patients (pts) with R/R Philadelphia chromosome-positive (Ph+) ALL is dismal despite the introduction of tyrosine kinase inhibitors (TKI) which may be used as single agents or in combination regimens. Blinatumomab is a bispecific T-cell engaging (BiTE®) antibody construct that has shown antileukemic activity. Among adults with R/R Ph-negative ALL receiving blinatumomab, 43% achieved complete remission (CR) or CR with partial hematologic recovery (CRh) during the first two cycles (Topp MS et al. Lancet Oncol 2015;16:57). We evaluated the efficacy and tolerability of blinatumomab in pts with R/R Ph+ ALL who progressed after or were intolerant to a 2nd or later (2+) generation TKI. Methods. Eligible adult pts (≥18 years) had Ph+ B-precursor ALL and had relapsed after or were refractory to at least one 2+ generation TKI; or were intolerant to 2+ generation TKI and intolerant or refractory to imatinib. All pts had to have >5% blasts in the bone marrow and Eastern Cooperative Oncology Group performance status ≤ 2. Blinatumomab was dosed by continuous IV infusion (4 weeks on/2 weeks off) for up to 5 cycles (9 μg/d on days 1-7 in cycle 1, and 28 μg/d thereafter). The primary endpoint was CR or CRh during the first two cycles; minimal residual disease (MRD) response based on RT-PCR amplification of BCR-ABL per central laboratory, relapse-free survival (RFS), overall survival (OS), and allogeneic hematopoietic stem cell transplant (alloHSCT) rate were key secondary endpoints. Complete MRD response was defined as no RT-PCR amplification of BCR-ABL at a sensitivity of 10-5. Results. Of 45 treated pts, 44 were resistant to 2+ generation TKI; one patient was resistant to imatinib and never exposed to 2+ generation TKI (protocol deviation). 53% of pts were men. Median (range) age was 55 (23-78) years (≥65 years, 27%). Ten pts (22%) had a BCR-ABL gene with T315I mutation. All pts had received prior TKI (dasatinib, 87%; ponatinib, 51%; imatinib, 56%; nilotinib, 36%; bosutinib, 2%), with 60% having received ≥ 2 prior 2+ generation TKI; most pts (96%) had received prior chemotherapy. 38% of pts had ≥ 2 prior relapses and 44% had prior alloHSCT. Efficacy outcomes for key endpoints are shown in the table. 16 pts achieved CR/CRh during the first two cycles for a response rate of 36% (95% CI: 22%, 51%); of those, 14 pts achieved CR, most of them (10/14, 71%) in cycle 1. The patient who never received 2+ generation TKI did not respond to treatment. 12 of the 14 pts (86%) with CR and two of the two pts with CRh achieved a complete MRD response. Among the 10 pts with T315I mutation, four achieved CR/CRh; all four also achieved a complete MRD response. Eight CR/CRh responders (50%) relapsed, three during treatment (including two with CR who did not achieve complete MRD response). One patient died in CR post alloHSCT. Median (95% CI) RFS was 6.7 (4.4, not estimable) months (median follow-up, 9.0 months); median OS was 7.1 (5.6, not estimable) months (median follow-up, 8.8 months). Patient incidence of grade ≥ 3 treatment-emergent adverse events (AEs) was 82%, most commonly febrile neutropenia (27%), thrombocytopenia (22%), anemia (16%), and pyrexia (11%). Five pts had fatal AEs; one (septic shock) was considered treatment-related by the investigator. Three pts discontinued because of AEs. Cytokine release syndrome (CRS) occurred in three pts (all grade 1 or 2). 21 pts (47%) had neurologic events (paraesthesia, 13%; confusional state, 11%; dizziness, 9%; tremor, 9%); three pts had grade 3 neurologic events (aphasia, hemiplegia; and depressed level of consciousness and nervous system disorder), one of which (aphasia) required treatment interruption. Conclusion. In this population of pts with R/R Ph+ ALL who have very poor prognosis after failure of 2+ generation TKI therapy, treatment with CD19-targeted immunotherapy blinatumomab as single agent showed antileukemic activity. AEs were consistent with those previously reported for pts with R/R Ph-negative ALL treated with blinatumomab. Table 1. Table 1. Disclosures Martinelli: Novartis: Speakers Bureau; BMS: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy; Roche: Consultancy; MSD: Consultancy. Dombret:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ottmann:Astra Zeneca: 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; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Goekbuget:Bayer: Equity Ownership; Eusapharma/Jazz: Consultancy, Honoraria, Research Funding; Erytech: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Medac: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; SigmaTau: Consultancy, Honoraria, Research Funding; Kite: Consultancy; Gilead Sciences: Consultancy; Sanofi: Equity Ownership; Amgen: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria. Topp:Astra: Consultancy; Regeneron: Consultancy; Affimed: Consultancy, Research Funding; Roche: Consultancy, Other: Travel Support; Jazz: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Honoraria, Other: Travel Support. Fielding:Amgen: Consultancy, Honoraria. Sterling:Amgen: Employment, Equity Ownership. Benjamin:Amgen: Employment, Equity Ownership. Stein:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Research Funding.

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Ponatinib Efficacy and Safety in Patients with the T315I Mutation: Long-Term Follow-up of Phase 1 and Phase 2 (PACE) Trials

Blood ◽

10.1182/blood.v124.21.4552.4552 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4552-4552 ◽

Cited By ~ 7

Author(s):

Michael J. Mauro ◽

Jorge E. Cortes ◽

Andreas Hochhaus ◽

Michele Baccarani ◽

Timothy P. Hughes ◽

...

Keyword(s):

Research Funding ◽

Progressive Disease ◽

Phase 1 ◽

Efficacy And Safety ◽

Employment Equity ◽

Long Term Follow Up ◽

T315i Mutation ◽

Equity Ownership

Abstract Background: Resistance to tyrosine kinase inhibitors (TKIs) in patients (pts) with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib is the only approved oral TKI that inhibits the T315I mutant, which is uniformly resistant to other TKIs. Here we report long-term follow-up of the efficacy and safety of ponatinib in pts with the T315I mutation at baseline from the Phase 1 (Ph1) and PACE trials. Methods: The Ph1 trial (NCT01207440) evaluated safety and anti-leukemic activity of ponatinib (2-60 mg qd) in pts with CML or Ph+ ALL (N=81); the PACE trial (NCT00660920) evaluated efficacy and safety of ponatinib (45 mg qd) in CML and Ph+ ALL pts (N=449) resistant/intolerant to dasatinib or nilotinib or with the T315I mutation. Data reported are for pts with the T315I mutation at baseline, detected by Sanger sequencing at a central lab. Results: The Ph1 and PACE trials included 19 (29%) and 128 (29%) pts with the T315I mutation, respectively. Median age and median time since diagnosis were 47 and 2.7 years for Ph1, and 53 and 3.6 years for PACE.Pts were heavily pretreated: 89% in Ph1 and 84% in PACE had received ≥2 prior TKIs. As of Jan 6, 2014, median follow-up was 42 (1-59) months in Ph1, and 20 (0.1-40) months in PACE; 58% Ph1 (92% CP-CML) and 33% PACE (52% CP-CML) pts remained on study. Most-common reasons for discontinuation: administrative decision (16%) and progressive disease (16%) for Ph1, and progressive disease (31%) and adverse events (AEs; 13%) for PACE. Of the pooled chronic phase (CP)-CML pts, 75%, 72%, and 61% achieved MCyR, CCyR, and MMR, respectively, with deeper responses (MR4, MR4.5) observed in over a third of the pts (Table). MaHR was achieved in 58%, 27% and 38% of pooled AP-CML, BP-CML and Ph+ ALL pts, respectively. For Ph 1 CP-CML pts, 3-year CCyR duration estimates were 80%. For PACE CP-CML pts, 2-year MCyR/CCyR duration, PFS and OS estimates were 93%/79%, 72% and 82%, respectively. Only 1 CP-CML pt in PACE lost MCyR and 1 transformed to AP-CML. For AP-CML, BP-CML, and Ph+ ALL, estimated OS/PFS at 2 years was 69%/54%, 14%/10%, and 10%/N/A, respectively. The most frequent treatment-emergent AEs (TEAEs) observed in Ph1 CP-CML pts were dry skin (83%), rash (83%), arthralgia (75%), fatigue (75%), headache (67%), abdominal pain (58%), hypertension (58%), hypertriglyceridemia (58%), myalgia (58%), and nausea (58%). None of the 19 serious TEAEs that occurred in Ph1 CP-CML pts occurred in >1 pt. The most common (≥25%) TEAEs in PACE CP-CML pts were rash (48%), dry skin (42%), headache (41%), abdominal pain (39%), nausea (36%), constipation (33%), fatigue (33%), thrombocytopenia (28%), myalgia (28%), hypertension (27%), arthralgia (25%), and upper respiratory tract infection (25%). Most common (≥5 %) serious TEAEs in PACE CP-CML pts were acute myocardial infarction (8%), pancreatitis (8%), atrial fibrillation (6%), coronary artery disease (6%), congestive cardiac failure (5%), pneumonia (5%), cerebral infarction (5%), pyrexia (5%), increased lipase (5%), and dyspnea (5%). Arterial thrombotic events occurred in 1 (8%) Ph1, and 20 (31%) PACE pts. Venous thromboembolic events occurred in 1 (8%) Ph1, and 3 (5%) PACE pts. Despite the higher median dose intensity for T315I CP-CML pts (38 vs 30.8 mg/day overall CP-CML) in PACE, the safety profiles were similar. For CP-CML pts in PACE, responses achieved by 12 months were generally maintained after dose reduction primarily to manage AEs: 100% maintained MCyR; 100% maintained CCyR, and 79% maintained MMR. Conclusions: In Ph+ leukemia pts with the T315I mutation, where effective treatment options are limited, ponatinib continued to exhibit deep and durable responses with up to 6 years follow-up. Dose reductions to manage AEs did not impact maintenance of cytogenetic responses. The response rates and safety profile of T315I pts were comparable to, if not better than, those observed in the overall population of refractory CML and Ph+ ALL pts in ponatinib clinical trials. Table. Responses at Any Time in Ponatinib Treated Pts with T315I Mutation Phase 1 PACE Phase 1 and PACE Pooled n (%) n (%) n (%) CP-CML N=12 N=64 N=76 MCyR 11 (92) 46 (72) 57 (75) CCyR 10 (83) 45 (70) 55 (72) MMR 9 (75) 37 (58) 46 (61) MR4 7 (58) 25 (39) 32 (42) MR4.5 4 (33) 21 (33) 25 (33) AP-CML N=1 N=18 N=19 MaHR 0 11 (61) 11 (58) BP-CML N=2 N=24 N=26 MaHR 0 7 (29) 7 (27) Ph+ ALL N=4 N=22 N=26 MaHR 2 (50) 8 (36) 10 (38) Disclosures Mauro: ARIAD Pharmaceuticals, Inc.: Consultancy. Cortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Guilhot:ARIAD Pharmaceuticals, Inc.: Honoraria. Deininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Kantarjian:ARIAD Pharmaceuticals, Inc., Pfizer, Amgen: Research Funding. Shah:ARIAD Pharmaceuticals, Inc., BMS: Research Funding. Flinn:ARIAD Pharmaceuticals, Inc.: Research Funding. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding.

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The Cost-Effectiveness of Bortezomib for the Initial Treatment of Multiple Myeloma in the United States.

Blood ◽

10.1182/blood.v114.22.1379.1379 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1379-1379

Author(s):

Si-Tien Wang ◽

Hui Huang ◽

Hongliang Shi ◽

Mei Sheng Duh ◽

Kristina Chen ◽

...

Keyword(s):

Cost Effectiveness ◽

Health Outcomes ◽

Incremental Cost ◽

Research Funding ◽

The United States ◽

Line Treatment ◽

Second Line ◽

Employment Equity ◽

Equity Ownership ◽

The Cost

Abstract Abstract 1379 Poster Board I-401 Background: Data from the phase III VISTA trial demonstrated superiority in terms of clinical effectiveness of bortezomib (Velcadë) plus melphalan and prednisone (VMP) relative to melphalan and prednisone alone (MP) in the initial treatment of patients with multiple myeloma (MM). The aim of this study was to utilize data from the VISTA study and published literature to compare lifetime health outcomes and the cost-effectiveness of these regimens as induction therapy for MM patients ineligible for autologous stem cell transplantation (ASCT). An indirect comparison of VMP versus thalidomide plus MP (MPT) was also conducted using published results from the IFM 99-06 clinical trial for MPT (Facon et al, Lancet 2007). The goal of this study and the derived model was to assess the relative costs and outcomes from these two trials, recognizing the limitations imposed by using data derived from independent studies. Methods: A Markov model from the US payer's perspective was developed. Simulations were performed for hypothetical cohorts of newly diagnosed MM patients with an average age of 70 years at treatment initiation and who were not eligible for ASCT. The model includes seven health states representing periods of treatment response (stable disease/minimal response, partial response, or complete response), treatment-free interval, progressive disease, second-line treatment and death. Monthly transition probabilities were estimated from patient-level VISTA trial data for VMP and MP (with a data cut-off of June 15, 2007), and from the published phase lll IFM 99-06 trial for MPT. Costs included per-protocol drug and medical costs, treatment-related adverse events, second-line treatment, and resource utilization during treatment-free interval and progressive disease. Unit costs of medications and resources were obtained from published literature. All costs were adjusted to 2009 US dollars. State-specific utility estimates were derived from patient-level EQ-5D data from the VISTA trial using US-specific weights. Health outcomes were expressed in life-years (LYs) and quality-adjusted life-years (QALYs). Both cost and health outcomes were discounted at 3%. Incremental cost-effectiveness ratios (ICERs) were calculated for VMP versus MP, and VMP versus MPT, over a lifetime horizon (approximated by 20 years). One-way sensitivity analyses were conducted by running the model with upper and lower values of key parameters to assess the general robustness of model findings and identify key drivers. Results: Model base case results for the incremental cost-effectiveness of VMP relative to MP and MPT are shown in the Table. Comparison of the model's overall survival (OS) projections with the observed differences indicates a conservative approximation of the treatment differences for VMP. The estimated OS was 4.187 years with VMP versus 2.864 years with MP and versus 4.140 years with MPT over a lifetime horizon. Lifetime direct medical costs range from $57,864 for MP to $129,902 for MPT. The cost per LY and QALY gained with VMP compared with MP is $40,051 and $56,109, respectively. VMP is dominant (cost saving and better outcomes) compared with MPT, costing 17.7% less and providing slightly more QALYs on average. One-way sensitivity analyses suggest general robustness of model findings and the key drivers include VMP/MP hazard ratio from second-line treatment to death, and the MPT/MP hazard ratio for treatment discontinuation. Conclusions: In newly diagnosed MM patients ineligible for ASCT, VMP is projected to improve long-term health outcomes, offering a substantial survival benefit compared with MP. The incremental cost-effectiveness of VMP versus MP is within the generally accepted cost-effectiveness range of $50,000 to $100,000 per QALY, suggesting that VMP is cost-effective compared with MP in the United States. Within this cost-effectiveness model, compared with MPT, VMP is dominant, yielding lower costs and better health outcomes. Disclosures: Wang: Milllennium: Research Funding. Huang: Milllennium: Employment, Equity Ownership. Shi: Millennium Pharmaceuticals, Inc.: Employment. Duh: Milllennium: Consultancy, Research Funding. Chen: Milllennium: Research Funding. Chang: Milllennium: Research Funding. Korves: Milllennium: Research Funding. Dhawan: Johnson and Johnson Research Pharmaceuticals: Employment. Cakana: Johnson & Johnson: Employment, Equity Ownership. van de Velde: Johnson & Johnson: Employment, Equity Ownership. Esseltine: Milllennium: Employment, Equity Ownership. Garrison: Milllennium: Consultancy.

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Automated and Rapid Detection of BCR-ABL Kinase Domain Mutations in IM Resistant Patients with Ph+ Leukemias.

Blood ◽

10.1182/blood.v114.22.2590.2590 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2590-2590

Author(s):

Ruriko Tanaka ◽

Shinya Kimura ◽

Toshiya Hosomi ◽

Mitsuharu Hirai ◽

Rina Nagao ◽

...

Keyword(s):

Tyrosine Kinase ◽

Second Generation ◽

Direct Sequencing ◽

Kinase Domain ◽

Myelogenous Leukemia ◽

Abl Kinase ◽

T315i Mutation ◽

Kinase Domain Mutations ◽

Quenching Probe ◽

Higher Sensitivity

Abstract Abstract 2590 Poster Board II-566 Chronic myelogenous leukemia (CML) is caused by a consistent genetic abnormality, termed the Philadelphia chromosome (Ph). It results in the production of BCR-ABL fusion protein, a constitutively active tyrosine kinase. Imatinib mesylate (IM, Gleevec®), the first generation tyrosine kinase inhibitor (TKI), has revolutionized therapy for CML patients. However, resistance for IM develops in a significant proportion of cases, and is predominantly mediated by single point mutations within the BCR-ABL kinase domain. Second generation TKIs such as dasatinib (Sprycel®) and nilotinib (Tasigna®) represent viable alternatives for IM-resistant or intolerant CML patients. Each mutated BCR-ABL has different sensitivity to those TKIs. Thus, it is significantly important to detect early the existence of BCR-ABL mutations and their specificities in treating Ph+ leukemias. We have developed a novel automated method that has high sensitivity to detect a few copies of mutation sequences that are mixed in many copies of normal sequences. This method consists of PCR amplification step and Tm (melting temperature) analysis step that uses a quenching probe. And we have already shown that this system has clinical efficacy in JAK2V617F mutation that is one of the genetic hallmarks of chronic myeloproliferative diseases. (Tanaka R, et al. Leuk Res, 2008). When a whole blood sample or a purified DNA sample reacts with reagents, PCR and Tm analysis automatically processed in the same tube, and whole procedure finishes in approximately 1 hour. The detection of mutation is extremely accurate because the quenching probe is designed perfectly matched for mutated sequence. As Tm value of mutation sequence is higher than that of normal one, it is easy to detect the existence of mutation from the Tm analysis data. We have constructed the probes for 14 mutations concerned for IM-resistance (M244V, G250E, Q252H, Y253F, Y253H, E255V, E255K, T315I, T315A, F317L, M351T, E355G, F359V, and H396R). Considering the clinical significance of T315I mutation, which renders resistance to all currently available TKIs, we refined this method to higher sensitivity for detecting T315I mutation. First, we analyzed the sensitivity of this system on BCR-ABL. In dilution assays using wt and mutated plasmid, the system reliably quantified the mutation in a population containing as few as 3.0% mutant. Moreover, for T315I setting, we successfully detected as few as 0.3% (30 copies from 10,000 copies) mutations by a higher-sensitive assay. Next, we examined the clinical samples. Each sample was also examined by direct sequencing in comparison to our method. Kinase domain mutations were identified in 24 of the 50 (48%) patients. Our automated analysis was enabled to detect mutations in 19 patients, including p-loop mutations (G250E: n=3; E255K: n= 5), IM-binding domain mutations (T315I: n=10), and an activation-loop mutation (H396R: n=1). And all the positive cases (19 of 19) showed a concordance with the result of direct sequencing. On the other hand, 5 cases were detected just by direct sequencing, but all that cases were out of our setting mutations (Q252E, V379I, S417F, E459K). Impressively, in one case, only higher-sensitivity assay could reveal T315I mutation, although it was detected as a wild type both by direct sequence and our usual method. It suggests that the higher-sensitive system could detect low amount of T315I mutation in the earlier stage of disease. In conclusion, sensitivity of our system (3%) is significantly greater than that of direct sequencing (15 – 25%), and results can be obtained within one hour. By the serial monitoring, it is demonstrated the availability of the higher-sensitive analysis (0.3%) to detect T315I mutation. This rapid and accurate detection of clinically significant mutations enables us to contribute to better clinical practice in treating Ph+ leukemia patients, such as in selecting alternative strategies of IM dose escalation, second generation TKIs, or allogeneic stem cell transplantation. Disclosures: No relevant conflicts of interest to declare.

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Initial Findings From the PACE Trial: A Pivotal Phase 2 Study of Ponatinib in Patients with CML and Ph+ ALL Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I Mutation

Blood ◽

10.1182/blood.v118.21.109.109 ◽

2011 ◽

Vol 118 (21) ◽

pp. 109-109 ◽

Cited By ~ 8

Author(s):

Jorge E. Cortes ◽

Dong-Wook Kim ◽

Javier Pinilla-Ibarz ◽

Philipp D. Le Coutre ◽

Charles Chuah ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Phase 1 ◽

Initial Response ◽

Employment Equity ◽

Advisory Committees ◽

Primary Endpoints ◽

T315i Mutation ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 109 Background: Despite progress in chronic myeloid leukemia (CML) therapy with tyrosine kinase inhibitors (TKIs), patients (pts) who fail dasatinib or nilotinib or pts with T315I mutation have no treatment options. Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active against the native enzyme and all tested resistant mutants, including the uniformly resistant T315I mutation. Methods: The PACE trial (Ponatinib Ph+ALL and CML Evaluation) was initiated in September 2010. The objective of this international, single-arm, open-label, phase 2 trial is to establish the efficacy and safety of ponatinib. Pts with refractory CML in chronic, accelerated or blast phase (CP, AP or BP), or Ph+ acute lymphoblastic leukemia (ALL), resistant or intolerant (R/I) to dasatinib or nilotinib or with the resistant T315I mutation received 45 mg ponatinib orally once daily in one of 6 cohorts: CP R/I; CP T315I; AP R/I; AP T315I; BP/ALL R/I; BP/ALL T315I. The primary endpoints are major cytogenetic response (MCyR) for CP and major hematologic response (MaHR) for AP, BP or ALL. The trial is ongoing; projected enrollment is approximately 450. Data as of 18 July 2011 are reported. Results: At analysis, 403 pts were enrolled; 397 were treated and eligible. The median age was 59 (range, 18–94) years, 52% were male. Diagnoses were: CP R/I, n=188; CP T315I, 48; AP R/I, 52; AP T315I, 15; BP/ALL R/I, 51; BP/ALL T315I, 43. Median time from initial diagnosis to start of ponatinib was 6.2 years. Prior TKIs included imatinib (93%), dasatinib (85%), nilotinib (66%), and bosutinib (8%); 94% failed >2 prior TKIs, and 57% failed >3 prior TKIs. Overall, 88% had a history of resistance to dasatinib or nilotinib, and 12% were purely intolerant. Mutation status was determined centrally by MolecularMD. Overall, 106 pts had the T315I mutation. Of 291 R/I pts, 110 (38%) had non-T315I BCR-ABL mutations, most frequently F317L (10%), F359V (5%), E255K (4%), and G250E (4%). To date, 343 (85%) pts remain on therapy, 60 (15%) have discontinued (42 BP/ALL): 24 (6%) progressive disease (20 BP/ALL); 11 (3%) AE (3 pain, 3 thrombocytopenia, 1 each haemorrhage, loss of consciousness, enterocolitis, cytokine release syndrome, hepatotoxicity/pleuro-pericardial effusion after overdose); 8 (2%) died (3 related; 7 BP/ALL); 17 (4%) other. The most common drug-related AEs (≥10% any grade) were thrombocytopenia (19%; 15% grade 3/4), rash (18%), dry skin (13%), myalgia (12%), abdominal pain (11%; 3% grade 3/4), headache (11%), arthralgia (11%). Overall, 67 (17%) pts experienced at least 1 related SAE. The most common related SAEs (>5 cases) were pancreatitis 15 cases (3.7%), 5 cases each (1.2%) diarrhea, anemia, febrile neutropenia, and pyrexia. At the time of reporting, 159/397 eligible pts were evaluable for the primary endpoints. Median follow-up was 57 days. Of CP pts, 83 had an assessment at 3 months (10 at 6 months) or discontinued. In CP R/I, 25/60 (42%) attained MCyR (15 CCyR). In CP T315I, 13/23 (57%) had MCyR (11 CCyR). The overall CP MCyR rate was 38/83 (46%) (26 CCyR). Of AP, BP/ALL pts, 76 had an assessment at 1 month or later or discontinued. In AP, 17/23 (74%) R/I and 1/1 T315I pts achieved MaHR. In BP/ALL, 11/30 (37%) R/I and 6/22 (27%) T315I pts had MaHR. Conclusion: In this first analysis of the pivotal PACE trial, ponatinib has a favorable early safety profile, similar to that observed in phase 1, but with a lower incidence of pancreatitis. Initial response data after short follow-up indicate ponatinib has substantial anti-leukemic activity in this heavily pretreated population, and in pts with refractory T315I. These early efficacy signals replicate initial response results reported in the phase 1 setting. Updated data will be presented at the annual meeting. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kim:BMS: Consultancy, Honoraria, 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, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; ARIAD: Research Funding. Pinilla-Ibarz:ARIAD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Le Coutre:Novartis: Honoraria, Research Funding, Speakers Bureau; ARIAD: Research Funding. Paquette:ARIAD: Membership on an entity's Board of Directors or advisory committees. Apperley:Novartis: Honoraria, Research Funding; Bristol Myers Sqibb: Honoraria; Ariad: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. DiPersio:Genzyme: Honoraria. Rea:Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Talpaz:ARIAD: Research Funding. Abruzzese:Novartis: Consultancy; BMS: Consultancy. Baccarani:Pfizer Oncology: Consultancy; Novartis: Consultancy; BMS: Consultancy; Ariad: Consultancy; Novartis: Research Funding; Pfizer Oncology: Honoraria; Novartis: Honoraria; BMS: Honoraria; Ariad: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees. Wong:MolecularMD: Employment, Equity Ownership. Lustgarten:ARIAD: Employment. Turner:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Kantarjian:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Research Funding.

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Analysis of Second-Line Lenalidomide Following Initial Relapse in the MM-015 Trial

Blood ◽

10.1182/blood.v120.21.944.944 ◽

2012 ◽

Vol 120 (21) ◽

pp. 944-944 ◽

Cited By ~ 3

Author(s):

Meletios A Dimopoulos ◽

Maria Teresa Petrucci ◽

Robin Foa ◽

John V. Catalano ◽

Martin Kropff ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Second Line ◽

Employment Equity ◽

Advisory Committees ◽

Line Therapy ◽

Third Line Therapy ◽

Equity Ownership ◽

Third Line ◽

Grade 3

Abstract Abstract 944 Background: MM-009/010 established lenalidomide (LEN) + dexamethasone (DEX) as a standard of care in the treatment (Tx) of relapsed/refractory multiple myeloma (RRMM; Dimopoulos, NEJM. 2007; Weber, NEJM. 2007). The greatest benefits were observed when LEN + DEX was used at first relapse (Stadtmauer, Eur J Haematol. 2009). MM-015 is a pivotal, double-blind, randomized, placebo-controlled phase 3 trial comparing the efficacy and safety of melphalan-prednisone-lenalidomide followed by lenalidomide maintenance (MPR-R) with fixed-cycle melphalan-prednisone (MP) and melphalan-prednisone-LEN (MPR) in elderly patients (pts) with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem-cell transplant. The final analysis demonstrated unprecedented improvement in progression-free survival (PFS) in pts receiving MPR-R vs MP (31 vs 13 months [mos]; P < 0.001) with manageable toxicity (Palumbo, NEJM. 2012). The aim of this post-hoc analysis was to assess post-progression outcomes by second-line Tx and by initial MM-015 Tx arm (MPR-R, MPR, and MP). Methods: Induction and maintenance Tx has been described (Palumbo, NEJM. 2012). Pts with progressive disease during MM-015 could enroll in an open-label extension phase (OLEP) to receive LEN 25 mg (D1-21) ± DEX 40 mg (D1-4, 9–12, and 17–20) or could receive any other anti-myeloma Tx outside of the protocol. This analysis includes data up to Apr 10, 2012 (median follow-up: 48 mos after initial randomization). Time to progression (TTP) was assessed from randomization to disease progression as assessed by investigator. Time from start of second line to start of third-line Tx was assessed as a surrogate for TTP in second line. Safety data were assessed only for pts enrolled in the OLEP. Results: A total of 459 pts were enrolled in MM-015. Consistent with the superior PFS of MPR-R, fewer pts from the MPR-R arm progressed compared with the MPR and MP arms: 54% (81/150) vs 77% (117/152), and 83% (127/153) respectively. Compared with the overall population, pts receiving second-line Tx had shorter median first-line TTP (29 vs 20 mos), particularly for the MPR-R arm. This suggests that the present subset of pts in the MPR-R arm who started second-line therapy represents the early progressors, those with worse prognosis or more aggressive disease (Table). More pts received second-line Tx in the MP (72%) and MPR (58%) arms vs MPR-R arm (30%, Table); second-line Tx type was heterogeneous for MPR-R pts. Median time from second- to third-line Tx was significantly longer for LEN-based Tx vs non-LEN-based Tx across the 3 arms: MPR-R (18 vs 13 mos; P = 0.044), MPR (23 vs 8 mos; P = 0.02), and MP (18 vs 10 mos; P = 0.001). Median time from second- to third-line therapy with bortezomib (BORT)-based regimens was 14, 16, and 12 mos, respectively. This corresponded to higher proportions of pts remaining on second-line LEN at 2 yrs (38%, 44%, and 40%) vs non-LEN (15%, 30%, and 13%) for MPR-R, MPR, and MP, respectively. When evaluating second-line BORT, 22%, 33%, and 17%, respectively, had not progressed from second- to third-line therapy at 2 years. Prior LEN maintenance did not appear to induce resistant relapses as time from second- to third-line Tx was similar for all arms (Table) and all comparisons: MPR-R vs MP (hazard ratio [HR] = 0.924; P = 0.69), MPR-R vs MPR (HR = 1.076; P = 0.71), and MPR vs MP (HR = 0.895; P = 0.53). With limited follow-up, no significant differences in post-relapse OS have been detected. Newly occurring grade 3/4 adverse events (AEs) reported for ≥ 5% of pts entering the OLEP (n = 153) were neutropenia (11%) and anemia (5%). Grade 3/4 deep vein thrombosis and peripheral neuropathy occurred in 3% and 1% of pts, respectively. Conclusions: LEN-based Tx was active in the second line, with comparable efficacy regardless of first-line therapy (MPR-R, MPR, or MP). Although pt numbers are relatively small, and this is a non-randomized comparison, results with second-line LEN-based therapy compared favorably to outcomes with other Tx. The OLEP tolerability profile was favorable, with limited newly occurring grade 3/4 AEs. Importantly, LEN maintenance does not appear to induce resistant relapses. These results support the known activity of LEN as second-line MM therapy. Disclosures: Dimopoulos: Celgene Corp: Honoraria. Off Label Use: Lenalidomide as frontline treatment of multiple myeloma. Petrucci:Celgene Corp: Honoraria. Foa:Celgene Corp: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Catalano:Celgene Corp: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Yu:Celgene Corp: Employment, Equity Ownership. Herbein:Celgene Corp: Employment, Equity Ownership. Jacques:Celgene Corp: Employment, Equity Ownership. Palumbo:Celgene Corp: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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