Masszi, Tamás

PURPOSE At the primary analysis of CASTOR (median follow-up, 7.4 months), daratumumab plus bortezomib and dexamethasone (D-Vd) significantly prolonged progression-free survival versus bortezomib and dexamethasone (Vd) alone in relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the final analysis for overall survival (OS). METHODS CASTOR was a multicenter, randomized, open-label, phase III study during which eligible patients with ≥ 1 line of prior therapy were randomly assigned to Vd (up to eight cycles) with or without daratumumab (until disease progression). After positive primary analysis and protocol amendment, patients receiving Vd were offered daratumumab monotherapy after disease progression. RESULTS At a median (range) follow-up of 72.6 months (0.0-79.8), significant OS benefit was observed with D-Vd (hazard ratio, 0.74; 95% CI, 0.59 to 0.92; P = .0075). Median OS was 49.6 months with D-Vd versus 38.5 months with Vd. Prespecified subgroup analyses demonstrated an OS advantage with D-Vd versus Vd for most subgroups, including patients age ≥ 65 years and patients with one or two prior lines of therapy, International Staging System stage III disease, high-risk cytogenetic abnormalities, and prior bortezomib treatment. The most common (≥ 10%) grade 3/4 treatment-emergent adverse events with D-Vd versus Vd were thrombocytopenia (46.1% v 32.9%), anemia (16.0% v 16.0%), neutropenia (13.6% v 4.6%), lymphopenia (10.3% v 2.5%), and pneumonia (10.7% v 10.1%). CONCLUSION D-Vd significantly prolonged OS in patients with RRMM, with the greatest OS benefit observed in patients with one prior line of therapy. To our knowledge, our results, together with the OS benefit observed with daratumumab plus lenalidomide and dexamethasone in the phase III POLLUX study, demonstrate for the first time an OS benefit with daratumumab-containing regimens in RRMM (ClinicalTrials.gov identifier: NCT02136134 [CASTOR]).

SummaryFedratinib, an oral Janus kinase‐2 (JAK2) inhibitor, reduces splenomegaly and improves symptom burden in patients with myelofibrosis. Regulatory approval of fedratinib 400‐mg daily was based on results of an updated analysis of the pivotal phase III, placebo‐controlled JAKARTA trial in patients with JAK‐inhibitor‐naïve myelofibrosis. At week 24, spleen volume response rate was 47% and symptom response rate was 40% with fedratinib 400 mg, versus 1% and 9% respectively, with placebo. Common adverse events were diarrhoea, nausea, anaemia, and vomiting. No Wernicke encephalopathy occurred in patients receiving fedratinib 400 mg/day. These updated data support use of first‐line fedratinib in patients with myelofibrosis.

PURPOSE The double-blind, placebo-controlled, phase III TOURMALINE-MM1 study demonstrated a statistically significant improvement in progression-free survival with ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd in patients with relapsed or refractory multiple myeloma. We report the final analyses for overall survival (OS). PATIENTS AND METHODS Patients were randomly assigned to ixazomib-Rd (n = 360) or placebo-Rd (n = 362), stratified by number of prior therapies (1 v 2 or 3), previous proteasome inhibitor (PI) exposure (yes v no), and International Staging System disease stage (I or II v III). OS (intent-to-treat population) was a key secondary end point. RESULTS With a median follow-up of 85 months, median OS with ixazomib-Rd versus placebo-Rd was 53.6 versus 51.6 months (hazard ratio, 0.939; P = .495). Lower hazard ratios, indicating larger magnitude of OS benefit with ixazomib-Rd versus placebo-Rd, were seen in predefined subgroups: refractory to any (0.794) or last (0.742) treatment line; age > 65-75 years (0.757); International Staging System stage III (0.779); 2/3 prior therapies (0.845); high-risk cytogenetics (0.870); and high-risk cytogenetics and/or 1q21 amplification (0.862). Following ixazomib-Rd versus placebo-Rd, 71.7% versus 69.9% of patients received ≥ 1 anticancer therapy, of whom 24.7% versus 33.9% received daratumumab and 71.8% versus 76.9% received PIs (next-line therapy: 47.5% v 55.8%). Rates of new primary malignancies were similar with ixazomib-Rd (10.3%) and placebo-Rd (11.9%). There were no new or additional safety concerns. CONCLUSION Median OS values in both arms were the longest reported in phase III studies of Rd-based triplets in relapsed or refractory multiple myeloma at the time of this analysis; progression-free survival benefit with ixazomib-Rd versus placebo-Rd did not translate into a statistically significant OS benefit on intent-to-treat analysis. OS benefit was greater in subgroups with adverse prognostic factors. OS interpretation was confounded by imbalances in subsequent therapies received, especially PIs and daratumumab.

BACKGROUND: MF is characterized by anemia, splenomegaly, debilitating constitutional symptoms, and shortened survival. Fedratinib is an oral JAK2 inhibitor approved in the United States for treatment (Tx) of adult patients (pts) with intermediate (INT)-2 or high-risk MF. The randomized, placebo (PBO)-controlled, phase III JAKARTA trial evaluated clinical outcomes with fedratinib in pts with JAK-inhibitor-naïve MF. Initial findings from the JAKARTA study have been reported (Pardanani, JAMA Oncol, 2015). JAKARTA data were recently reanalyzed in preparation for regulatory review. OBJECTIVE: Evaluate the clinical efficacy and safety with fedratinib 400 mg/day in updated analyses of the JAKARTA study. METHODS: JAKARTA was an international, randomized, double-blind, PBO-controlled study that enrolled pts aged ≥ 18 years with INT-2 or high-risk primary, post-PV, or post-ET MF. Pts were randomly assigned 1:1:1 to fedratinib 400 mg, fedratinib 500 mg, or PBO, administered orally once-daily for ≥ 6 consecutive 4-week cycles ("randomized Tx period"). After completing 6 Tx cycles (or earlier in the case of disease progression), pts randomized to PBO could crossover to fedratinib. The primary endpoint was the spleen volume response rate (SVRR), the proportion of pts who achieved a ≥ 35% spleen volume reduction from baseline (BL) confirmed by MRI/CT at end of cycle 6 (EOC6), confirmed by follow-up scan 4 weeks later. Secondary endpoints included SVRR without 4-week confirmation, durability of spleen response, and symptom response rate (proportion of pts with a ≥ 50% reduction from BL in total symptom score [TSS] on the modified Myelofibrosis Symptom Assessment Form [MFSAF]) at EOC6. An exploratory analysis evaluated proportions of pts with ≥ 50% reductions from BL at EOC6 in individual MFSAF symptom scores: night sweats, pruritus, abdominal discomfort, early satiety, pain under ribs on left side, and bone or muscle pain. These analyses are limited to pts randomized to fedratinib 400 mg (the approved starting dose of fedratinib) or to PBO. Efficacy analyses were performed for the intention-to-treat (ITT) population and safety was assessed in all pts who received ≥ 1 dose of study drug. RESULTS: 96 pts were randomized to fedratinib 400 mg and 96 pts to PBO. In the fedratinib and PBO arms, median ages at BL were 63 (range 39-86) and 66 (27-85) years, respectively, 65% and 60% of pts had primary MF, 76% and 73% had constitutional symptoms, median spleen volumes were 2652 (316-6430) and 2660 (662-7911) mL, and median TSS were 15.3 (0-57) and 12.4 (0-53). Median durations of exposure were 15.5 months in the fedratinib 400 mg arm and 6 months in the PBO arm. With a confirmation scan 4 weeks after EOC6, SVRR was significantly higher in the fedratinib arm (37% [95%CI 27%, 46%]) vs. the PBO arm (1% [0%, 3%]) (P < 0.0001). Without the confirmation scan, SVRR at EOC6 was 47% (95%CI 37%, 57%) in the fedratinib 400 mg arm and 1% (0%, 3%) in the PBO arm (P < 0.0001; Figure). Estimated median duration of spleen response with fedratinib was 18.2 months. Symptom response rate at EOC6 for evaluable pts (ie, with TSS data available at BL and EOC6) was 40% (36/89) with fedratinib and 9% (7/81) with PBO (P < 0.0001). Fedratinib was associated with higher response rates vs. PBO in all 6 MFSAF symptoms: abdominal discomfort (41% vs. 15%, respectively), night sweats (58% vs. 22%), bone or muscle pain (33% vs. 14%), early satiety (51% vs. 18%), pruritus (39% vs. 20%), and pain under the ribs on the left side (42% vs. 24%). The most common Tx-emergent adverse events (TEAEs) during the randomized Tx period were grade 1-2 gastrointestinal events (Table). New or worsening grade 3 anemia and grade ≥ 3 thrombocytopenia laboratory abnormalities were reported in 34% and 12% of fedratinib-treated pts, most (75%) occurring within 3-4 months of Tx initiation. Compared with PBO, fedratinib-treated pts more frequently experienced increased serum creatinine, amylase, and lipase; these were mainly grade 1-2 in severity. TEAEs led to Tx discontinuation for 14% of fedratinib pts and 8% of PBO pts. CONCLUSIONS: Fedratinib 400 mg/day significantly reduced splenomegaly and symptom burden in pts with JAK-inhibitor-naïve MF. Relatively few pts discontinued fedratinib therapy due to TEAEs, suggesting these events are manageable. These data corroborate results initially reported for the JAKARTA trial, and further support the efficacy and safety of fedratinib in this pt population. Disclosures Masszi: AbbVie: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Drummond:Pfizer: Consultancy, 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, Speakers Bureau; Gilead: 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, Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicine Corporation: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jourdan:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Vannucchi:Blueprint: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Ribrag:AZD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; nanostring: Honoraria, Membership on an entity's Board of Directors or advisory committees; EPZ: Honoraria, Membership on an entity's Board of Directors or advisory committees; epizyme (EPZ): Research Funding; argenX: Research Funding; pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; servier: Consultancy; gustave roussy comprehensive cancer center: Current Employment. Rambaldi:Abbvie: Honoraria; Jazz: Honoraria; Astellas: Honoraria; Omeros: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Roche: Honoraria; MSD: Honoraria. Rose:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Zhang:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Harrison:Promedior: Honoraria; Roche: Honoraria; Sierra Oncology: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Incyte Corporation: Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Janssen: Speakers Bureau; AOP Orphan Pharmaceuticals: Honoraria; CTI Biopharma Corp: Honoraria, Speakers Bureau.

AbstractObjectivesIn the TOURMALINE‐MM1 phase 3 trial in relapsed/refractory multiple myeloma, ixazomib‐lenalidomide‐dexamethasone (IRd) showed different magnitudes of progression‐free survival (PFS) benefit vs placebo‐Rd according to number and type of prior therapies, with greater benefit seen in patients with >1 prior line of therapy or 1 prior line of therapy without stem cell transplantation (SCT).MethodsRNA sequencing data were used to investigate the basis of these differences.ResultsThe PFS benefit of IRd vs placebo‐Rd was greater in patients with tumors expressing high c‐MYC levels (median not reached vs 11.3 months; hazard ratio [HR] 0.42; 95% CI, 0.26, 0.66; P < .001) compared with in those expressing low c‐MYC levels (median 20.6 vs 16.6 months; HR 0.75; 95% CI, 0.42, 1.2). Expression of c‐MYC in tumors varied based on the number and type of prior therapy received, with the lowest levels observed in tumors of patients who had received 1 prior line of therapy including SCT. These tumors also had higher expression levels of CD19 and CD81.ConclusionsPFS analyses suggest that lenalidomide and ixazomib target tumors with different levels of c‐MYC, CD19, and CD81 expression, thus providing a potential rationale for the differential benefits observed in the TOURMALINE‐MM1 study. This trial was registered at www.clinicaltrials.gov as: NCT01564537

Abstract Background Fedratinib (SAR302503) is a JAK2-selective inhibitor that has provided clinically meaningful reductions in MF-associated splenomegaly and symptoms in Phase I and II studies (J Clin Oncol 2011;29:789. Haematologica 2013;98:S1113). Here, we present efficacy and safety data from the Phase III JAKARTA study of fedratinib versus placebo in patients with MF (NCT01437787). Methods In this international double-blind, placebo-controlled, 3-arm study, patients aged ≥18 years with IPSS intermediate-2 or high-risk MF, platelet count ≥50 × 109/L, and splenomegaly were randomized (1:1:1) to receive placebo or fedratinib 400 mg or 500 mg, orally, once daily, in consecutive 4-week cycles. Patients who received placebo were eligible to cross-over to fedratinib (randomized 1:1 to 400 mg or 500 mg) following 6 cycles of treatment, or prior to Cycle 6 if the patient had disease progression. The primary endpoint was spleen response rate (RR) (≥35% reduction in spleen volume from baseline measured by MRI or CT at Week 24, and confirmed 4 weeks later). Secondary endpoints included symptom RR (≥50% reduction in total symptom score from baseline at Week 24, measured through a daily electronic eDiary using the modified Myelofibrosis Symptom Assessment Form [Cancer 2011;117:4869. Blood 2011;118:401]), and safety of fedratinib. Results A total of 289 patients were randomized: median age 65 years; 59% male; 63% primary MF; 48% high-risk MF; 67% JAK2V617F positive; 16% platelet count <100 × 109/L; median baseline spleen volume 2568 mL (range 316–8244); median baseline total symptom score 14.7 (0–57). Median (range) exposures for placebo, 400 mg and 500 mg groups were 24 (2–34), 30 (1–55) and 28 (1–60) weeks, respectively. Spleen RRs at Week 24 (placebo 1%; 400 mg 47%; 500 mg 49%), and confirmed at Week 28 (placebo 1%; 400 mg 36%; 500 mg 40%), were significantly (p<0.0001) higher in both fedratinib groups compared with placebo (Table). Nineteen patients had a spleen response at Week 24 not confirmed 4 weeks later (spleen reduction 25–35% [n=10]; image not available/evaluable [n=8]; image taken outside time window [n=1]). Spleen RRs by baseline platelet level are shown in the table. Patients treated with fedratinib had significantly (p<0.0001) greater improvements in MF symptoms compared with placebo (Table). The most common all grade non-hematologic treatment-emergent adverse event (TEAE) was diarrhea (16%, 66% and 56% of patients in the placebo, 400 mg and 500 mg groups, respectively). Grade 3/4 diarrhea was reported in 5% of patients in both the 400 mg and 500 mg dose groups. The most common hematologic TEAE was anemia (any grade 91%, 99% and 98%; Grade 3/4 25%, 43% and 60% in the placebo, 400 mg and 500 mg groups, respectively). Rates of Grade 3/4 thrombocytopenia were 9% (placebo), 17% (400 mg), and 27% (500 mg). Incidences of Grade 3/4 liver function tests (placebo/400 mg/500 mg) were: bilirubin, 2%/2%/1%; ALT, 0%/3%/3%; and AST, 1%/2%/2%. Overall treatment discontinuation rates up to 24 weeks of treatment were 25% (placebo), 22% (400 mg) and 32% (500 mg). Twenty-five patients died during the study (10, 5 and 10 in the placebo, 400 mg and 500 mg groups, respectively); the most common causes of death: disease progression (placebo [n=5]; 400 mg [n=3]; 500 mg [n=4]) and adverse events (placebo [n=4]; 400 mg [n=1]; 500 mg [n=4]). Conclusions In this Phase III, randomized, placebo-controlled, 3-arm study of 289 MF patients, treatment with fedratinib 400 mg or 500 mg once-daily demonstrated clinically meaningful and statistically significant reductions in splenic volume and MF-associated symptom burden versus placebo. Fedratinib had an acceptable safety profile, with the adverse events reported consistent with those observed in previous studies. This study was sponsored by Sanofi. Disclosures: Pardanani: Sanofi, Bristol Myers Squibb, PharmaMar and JW Pharma: Clinical trial support Other. Harrison:Novartis: Research Funding; Novartis, Sanofi, YM Bioscience, Celgene, SBio, Gilead: Honoraria; Novartis, Sanofi, Shire: Speakers Bureau; Novartis, Sanofi, YM Bioscience, SBio, Gilead: Membership on an entity’s Board of Directors or advisory committees. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Cervantes:Novartis: Speakers Bureau; Novartis and Sanofi: Membership on an entity’s Board of Directors or advisory committees. Mesa:Incyte, Genentech, Lilly, MS Pharma, Gilead: Research Funding. Jourdan:Sanofi: Honoraria. Vannucchi:Novartis: Membership on an entity’s Board of Directors or advisory committees. Drummond:Sanofi, Novartis, Celgene: Honoraria; TargeGen, Novartis: Speakers Bureau; Sanofi, Novartis, Celgene: Consultancy. Passamonti:Novartis, Celgene, Incyte, Sanofi, Roche: Honoraria. Neumann:Sanofi: Employment. Gao:Sanofi: Employment.

Background Ixazomib is the first orally administered PI studied in the clinic. The feasibility of combining ixazomib weekly and lenalidomide-dexamethasone (Rd) in the first all-oral PI- and immunomodulatory drug-containing triplet regimen was evaluated in a phase 1/2 trial of 65 pts with newly diagnosed MM. Results indicated a 90% ORR (62% ≥VGPR) using ixazomib 4 mg (recommended phase 2/3 dose), with a manageable safety profile, including 14% gr ≥3 skin/subcutaneous tissue disorders and limited (4% gr 3) peripheral neuropathy (PN) (Kumar et al, Lancet Oncol 2014). These data provided the rationale for phase 3 investigation of IRd vs placebo-Rd in pts with RRMM in this randomized, double-blind, placebo-controlled, international, multicenter study. Methods Adults with RRMM after 1-3 prior lines of therapy who were not refractory to prior lenalidomide or PI-based therapy were randomized 1:1 to receive ixazomib 4 mg or matching placebo weekly on d 1, 8, and 15, plus lenalidomide 25 mg PO on d 1-21 (dose reduced for renal impairment per local label/practice) and dexamethasone 40 mg PO on d 1, 8, 15, and 22, in 28-d cycles. Randomization was stratified by number of prior therapies (1 vs 2/3), PI exposure (naïve vs exposed), and ISS disease stage (I/II vs III). Cycles were repeated until disease progression or unacceptable toxicity. Primary endpoint was PFS as assessed by an independent review committee blinded to treatment, per IMWG criteria. Key secondary endpoints were OS and OS in high-risk pts with del(17). Sample size was determined to provide 80% power for the OS endpoint and adequate power to test PFS. Three interim analyses (IAs) and a final analysis were planned to test PFS and OS; here, we report data from the first IA, the final analysis for PFS. Results 722 pts were randomized (360 IRd; 362 Rd). Baseline characteristics were balanced between groups; overall median age was 66 yrs (30-91), 70% were PI-exposed, 88% were ISS stage I/II, 59% had received 1 prior therapy, and 77%/11%/11% were relapsed/refractory/relapsed and refractory, with 6% primary refractory. Based primarily (97%) on central laboratory evaluation, 19% had high-risk cytogenetics by FISH (del(17), t(4;14), or t(14;16)), including 10% del(17). Prior therapies included 69% bortezomib, 45% thalidomide, and 12% lenalidomide. The study met the primary endpoint at the first IA (median follow-up 14.8 vs 14.6 mos with IRd vs Rd), demonstrating a 35% improvement in PFS with IRd vs Rd (HR 0.742; p=0.012; Table). In pts with high-risk cytogenetics, the PFS HR was 0.543 with IRd vs Rd (HR 0.596 in pts with del(17)), with a median PFS similar to the overall IRd group, indicating ixazomib may overcome the negative impact of cytogenetic alterations. OS data were not yet mature. Key response data are shown in the Table. Pts received a median of 13 (1-26) vs 12 (1-25) cycles of IRd vs Rd; 55% and 52% of pts remained on treatment. With IRd vs Rd, 68% vs 61% of pts had gr ≥3 AEs (driven by thrombocytopenia), 40% vs 44% had serious AEs, 13% vs 11% discontinued all study drugs due to AEs, and 3% vs 5% died on treatment. AEs observed with IRd were consistent with reported safety profiles for the individual agents. Common gr ≥3 AEs were neutropenia (19% vs 16%), anemia (9% vs 13%), thrombocytopenia (13% vs 5%), and pneumonia (6% vs 8%). Gastrointestinal events included 42% vs 36% diarrhea (6% vs 2% gr 3), 26% vs 21% nausea (2% vs 0% gr 3), and 22% vs 11% vomiting (1% vs <1% gr 3). PN rates were 28% vs 21% (2% vs 2% gr 3), 35% vs 21% had rash events (4% vs 1% gr 3), 4% vs 6% had renal failure (2% vs 3% gr ≥3), and 4% vs 3% had heart failure (2% vs 2% gr ≥3). Conclusion At this first prespecified IA, addition of ixazomib to Rd in pts with RRMM increased median PFS to 20.6 from 14.7 mos without a substantial increase in overall toxicity, including cardiac and PN toxicity. Benefit with IRd was also noted in pts with high-risk cytogenetics, including those with del(17), in whom median PFS was similar to all IRd-treated pts indicating that ixazomib may have a favorable impact on the adverse prognosis associated with genetic mutations. If approved, this all-oral combination of IRd may become a new standard of care in this setting. Table. Key efficacy data IRd Rd HR / OR Median PFS, mos 20.6 14.7 HR 0.742; 95% CI: 0.587-0.939; p=0.012 Confirmed ORR, % 78.3 71.5 OR 1.44; p=0.035 CR 11.7 6.6 OR 1.87; p=0.019 ≥VGPR 48.1 39.0 OR 1.45; p=0.014 Median time to first response (ITT analysis), mos 1.1 1.9 Median duration of response (≥PR), mos 20.5 15.0 Disclosures Moreau: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Investigational proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone for patients with relapsed/refractory multiple myeloma. Masszi:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Bahlis:Johnson & Johnson: Speakers Bureau; Johnson & Johnson: Consultancy; Amgen: Consultancy; Johnson & Johnson: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sandhu:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Ganly:Novartis: Honoraria; Roche: Honoraria; Medipics: Equity Ownership. Baker:Janssen-Cilag New Zealand: Membership on an entity's Board of Directors or advisory committees. Stoppa:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Simpson:Celgene: Honoraria; Janssen-Cilag: Honoraria; Onyx Pharmaceuticals: Research Funding; Roche: Honoraria. Gimsing:Amgen: Honoraria. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria. Garderet:Bristol-Myers Squibb: Consultancy. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria. Kumar:AbbVie: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Skyline, Noxxon: Honoraria; Millenium/Takeda: Research Funding. Touzeau:AbbVie: Research Funding. Laubach:Novartis: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Lin:Millennium Pharmaceuticals, Inc.: Employment. Berg:Millennium Pharmaceuticals, Inc.: Employment. DiBacco:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Richardson:Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Introduction: Single-agent carfilzomib has shown encouraging activity in patients with relapsed and refractory multiple myeloma who harbor high-risk cytogenetic abnormalities (Jakubowiak et al, Leukemia 2013;27:2351-56). The phase 3 study ASPIRE (NCT01080391; N=792 patients) demonstrated that progression-free survival (PFS) was significantly improved with carfilzomib, lenalidomide, and dexamethasone (KRd), compared with lenalidomide and dexamethasone (Rd) in patients with relapsed multiple myeloma (RMM) (Stewart et al, N Engl J Med 2015;372:142-52). We present a pre-planned subgroup analysis of the efficacy and safety of KRd vs Rd in the ASPIRE study according to baseline cytogenetic risk status. Methods: Adults with RMM (1-3 prior lines of therapy) were eligible. Patients were randomized (1:1) to KRd or Rd. Treatment was administered in 28-day cycles. Patients in the KRd arm received carfilzomib as a 10-minute intravenous infusion on days 1, 2, 8, 9, 15, and 16 (starting dose, 20 mg/m2 on days 1 and 2 of cycle 1; target dose, 27 mg/m2 thereafter) during cycles 1-12; carfilzomib was omitted on days 8 and 9 during cycles 13-18 and was discontinued after 18 cycles. All patients received lenalidomide 25 mg on days 1-21 and dexamethasone 40 mg on days 1, 8, 15, and 22. The primary end point was PFS. Secondary end points included overall survival, overall response rate (ORR), duration of response (DOR), health-related quality of life, and safety. Cytogenetic risk status was assessed using fluorescence in situ hybridization. The high-risk group consisted of patients with the genetic subtype t(4;14) or t(14;16) or with deletion 17p in ≥60% of plasma cells, according to central review of bone marrow samples obtained at study entry. The standard-risk group consisted of all other patients with known baseline cytogenetics. The cutoff value of 60% for the proportion of plasma cells with deletion 17p was used on the basis of recommendations from the International Myeloma Workshop Consensus Panel 2 (Munshi et al. Blood 2011;117:4696-700). Results: A total of 792 patients were randomized to KRd (n=396) or Rd (n=396). In patients with known baseline cytogenetics, baseline cytogenetic risk status was similar between the treatment arms (high-risk: KRd, 24.6%; Rd, 23.4%; standard-risk: KRd, 75.4%; Rd, 76.6%). Efficacy outcomes by cytogenetic risk status are presented in the Table. Median PFS in the high-risk group (n=100) was 23.1 months (95% confidence interval [CI]: 12.5-24.2) for KRd vs 13.9 months (95% CI: 9.5-16.7) for Rd (hazard ratio [HR]: 0.639; 95% CI: 0.369-1.106). Median PFS in the standard-risk group (n=317) was 29.6 months (95% CI: 24.1-not estimable) for KRd vs 19.5 months (95% CI: 14.8-26.0) for Rd (HR: 0.657; 95% CI: 0.480-0.901). ORRs were 79.2% (KRd) vs 59.6% (Rd) in the high-risk group, and 91.2% (KRd) vs 73.5% (Rd) in the standard-risk group. In the high-risk group, 29.2% (KRd) and 5.8% (Rd) of patients achieved a complete response (CR) or better, including 16.7% (KRd) and 3.8% (Rd) with a stringent complete response (sCR). In the standard-risk group, 38.1% (KRd) and 6.5% (Rd) of patients achieved ≥CR, including 15.0% (KRd) and 3.5% (Rd) with an sCR. Median DOR in the high-risk group was 22.2 months for KRd vs 14.9 months for Rd. Median DOR in the standard-risk group was 30.4 months for KRd vs 20.4 months for Rd. The rate of grade ≥3 adverse events was 89.1% (KRd) vs 78.4% (Rd) in the high-risk group, and 85.6% (KRd) vs 84.5% (Rd) in the standard-risk group. Rates of grade ≥3 adverse events of interest (dyspnea, hypertension, acute renal failure, cardiac failure, ischemic heart disease, and peripheral neuropathy) by cytogenetic risk status are presented in the Table. Conclusion: In patients with high-risk cytogenetics, treatment with KRd resulted in a median PFS of nearly 2 years, which was a 9-month improvement relative to that in patients treated with Rd. Treatment with KRd also led to a 10-month improvement in median PFS vs Rd in patients with standard-risk cytogenetics; similar reductions in the risk of progression or death with Kd vs Vd were observed in both cytogenetics risk groups. Treatment with KRd also led to higher response rates, greater response depth, and a longer DOR compared with Rd in patients with high- or standard-risk cytogenetics. KRd had a favorable benefit-risk profile in patients with RMM, irrespective of baseline cytogenetic risk status, and improved outcomes in patients with high-risk disease. Disclosures Fonseca: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Applied Biosciences: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Onyx/Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Binding Site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Dimopoulos:Celgene: Honoraria; Onyx: Honoraria; Genesis: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Spicka:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Masszi:Novartis: Consultancy; Janssen-Cilag: Consultancy; BMS: Consultancy; Takeda: Consultancy. Hájek:Janssen-Cilag: Honoraria; Celgene, Merck Sharp & Dohme: Consultancy, Honoraria. Rosiñol:Celgene: Honoraria; Janssen: Honoraria. Mateos:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy; Onyx: Consultancy. Wang:Celgene: Research Funding. Niesvizky:Celgene: Consultancy, Speakers Bureau. Oriol:Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Jakubowiak:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: institutional funding for support of clinical trial conduct, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SkylineDx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palumbo:Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria; Novartis, Sanofi Aventis: Honoraria. Bensinger:Onyx: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Acetylon: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding. Kukreti:Lundbeck: Honoraria; Ortho: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Tonda:Onyx: Employment. Obreja:Amgen Inc: Employment. Moreau:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract Background : Polycythemia vera (PV) is a myeloproliferative neoplasm driven by JAK/STAT activation and is associated with erythrocytosis and a broad symptom burden that may negatively impact patient quality of life (QoL). Hydroxyurea (HU) is often used as first-line therapy for high-risk patients but may not effectively control or reduce symptom burden. RESPONSE is a phase III trial comparing ruxolitinib (RUX) with best available therapy (BAT) in patients with PV who were intolerant of or resistant to HU according to modified European LeukemiaNet (ELN) criteria. The primary study endpoint (a composite of hematocrit control and ≥35% spleen volume reduction at Week 32) was achieved by 21% of patients in the RUX arm vs 1% in the BAT arm (P<0.0001); 77% of patients in the RUX arm achieved at least one component of the primary endpoint. The current analysis was conducted to evaluate the effect of RUX on PV-related symptoms and QoL measures in the RESPONSE trial. Methods : Patients with PV aged ≥18 years, resistant to or intolerant of HU (modified ELN criteria) with splenomegaly, and who required phlebotomy for hematocrit control were randomized 1:1 to receive open-label RUX 10 mg twice daily (BID) or BAT (administered based on investigator judgment). Dose adjustments were permitted (RUX, 5-mg BID increments [25 mg BID max]; BAT was adjusted per investigator judgment). Objectives of this analysis included assessment of improvement in symptom burden as assessed by patient-reported outcomes using the 14-item modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF), the Pruritus Symptom Impact Scale (PSIS), the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), and the Patient Global Impression of Change. The 14-item MPN-SAF (graded from 0 [absent] to 10 [worst imaginable]) comprised symptoms related to cytokines (tiredness, itching, muscle ache, night sweats, and sweats while awake), hyperviscosity (vision problems, dizziness, concentration problems, headache, numbness/tingling, ringing in ears, and skin redness), and splenomegaly (abdominal discomfort and early satiety). Changes in total symptom score (TSS; maximum score = 140) and individual symptom scores from baseline to Week 32 were summarized by treatment group. For the EORTC QLQ-C30 Global Health Status/QOL score, the percentage of patients with a minimally important difference (MID) from baseline (10-point change) at Week 32 was summarized. Results : Overall, 222 patients were randomized (RUX, 110; BAT, 112). Median age (range) was similar between arms (RUX, 62.0 [34.0–90.0]; BAT, 60.0 [33.0–84.0]); the RUX and BAT arms were 60% and 71% male, respectively. At Week 32, a higher proportion of patients in the RUX vs the BAT arms had a ≥50% improvement in MPN-SAF TSS (49% vs 5%, respectively) and MPN-SAF symptom cluster scores (cytokine, 64% vs 11%; hyperviscosity, 37% vs 13%; splenomegaly, 62% vs 17%). Median percentage changes in individual symptom scores are presented in the Table. Mean changes from baseline at Week 32 on the 5 items of the PSIS indicated that the severity of pruritus and its interference on daily life improved with RUX (range, −1.5 to −2.2) and was unchanged/worsened with BAT (range, −0.1 to 0.3). Treatment with RUX vs BAT was associated with improved mean changes from baseline at Week 32 on EORTC QLQ-C30 symptom subscales, functional subscales, and Global Health Status/QOL (Table); 46% of RUX patients versus 10% of BAT patients achieved an MID in Global Health Status/QOL (Figure). At Week 32, RUX patients were more likely to rate their global impression of symptom changes as “very much improved” or “much improved” (67%) vs BAT patients (13%). Conclusion : In patients with PV who were resistant to or intolerant of HU, treatment with RUX was associated with greater and clinically meaningful improvements in PV-related symptom burden and QoL measures compared with BAT. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Mesa: Incyte Corporation: Research Funding; CTI: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Eli Lilly: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Sanofi: Research Funding; Celgene: Research Funding. Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Verstovsek:Incyte Corporation: Research Funding. Kiladjian:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Masszi:Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Durrant:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. He:Incyte Corporation: Employment, Equity Ownership. Jones:Incyte Corporation: Employment, Equity Ownership. Parasuraman:Incyte Corporation: Employment, Equity Ownership. Li:Novartis Pharmaceuticals: Employment, Equity Ownership. Côté:Novartis Pharmaceuticals: Employment, Equity Ownership. Habr:Novartis Pharmaceuticals: Employment, Equity Ownership. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.