Byrne, Catriona

Abstract Background There is increasing evidence for the clinical benefit of long-term, continuous therapy for NDMM pts. Proteasome inhibitors (PIs) form a backbone of therapy in MM; however, long-term therapy with some PIs may be limited due to toxicity and the need for regular parenteral administration, increasing the treatment burden. Ixazomib, the first oral PI, has been studied in NDMM pts in 4 phase 1/2 studies in which approximately 1 year of induction therapy with once- or twice-weekly ixazomib plus lenalidomide-dexamethasone (IRd), melphalan-prednisone (IMP), or cyclophosphamide-dexamethasone (ICd) was followed by single-agent ixazomib maintenance. Here we report an integrated analysis of pts from these studies who did not undergo autologous stem cell transplant (ASCT) and received ixazomib maintenance therapy. Methods Pts from 4 studies were included: 1) weekly IRd, 12x28-d cycles IRd (weekly ixazomib 1.68-3.95 mg/m² in phase 1, recommended phase 2 dose [RP2D] 4.0 mg; C16005, NCT01217957; ASCT-eligible/-ineligible pts); 2) twice-weekly IRd, 16x21-d cycles IRd (twice-weekly ixazomib 3.0-3.7 mg in phase 1, RP2D 3.0 mg; C16008, NCT01383928; ASCT-eligible/-ineligible pts); 3) IMP, 9x42-d or 13x28-d cycles IMP (weekly/twice-weekly ixazomib 3.0-5.5/3.0-3.7 mg in phase 1, RP2D of weekly ixazomib 4.0 mg; C16006, NCT01335685; ASCT-ineligible pts); 4) ICd, 13x28-d cycles ICd (weekly ixazomib 4.0 mg; C16020, NCT02046070; ASCT-ineligible pts). In all 4 studies, pts completing induction without progressive disease (PD) and, in the IRd studies, not withdrawn for ASCT, could receive single-agent ixazomib maintenance at the last tolerated dose during induction until PD or unacceptable toxicity. Results 121 pts received ixazomib maintenance (25, 18, 35, and 43 in weekly IRd, twice-weekly IRd, IMP, and ICd studies, respectively). Median age was 72 yrs (range 34-90 yrs; 83% aged ≥65 yrs), 62% had IgG myeloma, 47/34/19% had ISS disease stage I/II/III, 40/49% had Eastern Cooperative Oncology Group performance status 0/1. Combined median progression-free survival (PFS) was 33.8 months from time of study entry and 21.4 months from start of maintenance (Figure). Median PFS from the start of maintenance seemed to be longer for the two IRd studies than for IMP, while median PFS for ICd had not yet been reached. 4-yr OS from time of study entry/3-yr OS from the start of maintenance was 82%. Overall response rate was 93% after induction and 94% after maintenance. Best response rate of CR+VGPR after induction was 57% (22% CR), which increased to 63% (35% CR/sCR) after maintenance; 24 pts (20%) improved their response during maintenance (4 pts with CR improved to sCR; 14 VGPR to CR/sCR; 5 partial response [PR] to VGPR/CR; 1 stable disease to PR). Combined mean dose intensity during maintenance was 89.1%. At time of analysis, median duration of maintenance therapy was 2.2 yrs for weekly IRd, 1.0 yr for twice-weekly IRd, and 0.9 yr for IMP and ICd; maximum duration was 4.8, 3.8, 3.9, and 1.6 yrs respectively. 78% of pts had discontinued maintenance, primarily due to PD (55%), and only 7% due to adverse events (AEs). 15% of pts had ixazomib dose reductions during maintenance. Grade ≥3 AEs (48% vs 74%), drug-related grade ≥3 AEs (24% vs 62%), serious AEs (SAEs; 21% vs 43%), and drug-related SAEs (5% vs 19%) were less common during maintenance than during induction. Common grade ≥3 AEs are shown in the Table. Other AEs of clinical interest were also generally similar or less common during maintenance than during induction, including cardiac arrhythmias (13% vs 21%), pneumonia (12% vs 17%), acute renal failure (7% vs 8%), hypotension (4% vs 7%), myocardial infarction (0 vs <1%), and heart failure (2% vs 2%). Only 6 pts (5%) reported a new primary malignancy. There was only 1 on-study death during maintenance, which was not considered related to ixazomib; due to pulmonary edema in an 81-yr old pt with a history of cardiovascular co-morbidities. Conclusions In this integrated analysis, single-agent ixazomib maintenance therapy following an ixazomib-based induction regimen was associated with deepening of responses and good long-term outcomes in NDMM pts not undergoing ASCT. Single-agent ixazomib is feasible for long-term administration, with limited new-onset grade ≥3 AEs. These outcomes appear similar to other studies involving maintenance approaches in NDMM and support the ongoing phase 3 investigation of ixazomib maintenance therapy. Disclosures Dimopoulos: Novartis: Consultancy, Honoraria; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology; Genesis Pharma: Research Funding. Laubach: Novartis, Takeda, Celgene, Onyx: Research Funding; Novartis, Takeda, Celgene: Consultancy. Hofmeister: Thrassos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Roche: Research Funding; Karyopharm: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Janssen: Research Funding; Celgene: Research Funding. San Miguel: Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kumar: Celgene, Millennium/Takeda, Onyx, AbbVie, Janssen, Sanofi, Novartis, Amgen, Genentech, Merck, Oncopeptides, Roche, Skyline Diagnostics: Research Funding; Celgene, Millennium, BMS, Onyx, Janssen, Noxxon, AbbVie, Amgen, Merck, Oncopeptides, Skyline Diagnostics, Takeda: Consultancy; Skyline: Honoraria. Lu: Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Teng: Array Pharmaceuticals: Equity Ownership; AMAG Pharmaceuticals: Equity Ownership; Gilead Science: Equity Ownership; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Liu: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Byrne: Oncopeptides AB: Consultancy; Takeda: Consultancy. Berg: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. van de Velde: Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Richardson: Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Oncopeptides AB: Membership on an entity's Board of Directors or advisory committees.

Abstract Prompted by the activity of lenalidomide (Revlimid®) in pts with chronic idiopathic myelofibrosis (CIMF), we sought to evaluate the safety and efficacy of the combination of lenalidomide and prednisone in a phase II study for pts with CIMF. The rationale for this combination is that the anti-angiogenic and anti-TNFa effects of lenalidomide may be potentiated by the effects of prednisone to reduce marrow fibrosis and improve hematopoiesis in CIMF. Initial therapy consisted of lenalidomide 10 mg/d (dose level [DL] 0) on days 1–21 of a 28–day cycle for 6 cycles, in combination with prednisone 30 mg/d orally during cycle 1, 15 mg/d orally during cycle 2, and 15 mg/d every other day during cycle 3. The lenalidomide dose could be reduced to 5 mg/d (DL -1) or to 5 mg/d every other day (DL -2), or increased to 15 mg/d (DL +1) or 20 mg/d (DL +2) depending upon toxicity or lack of response, respectively. A total of 40 pts (23 male, 17 female) have been enrolled. The median age was 62 years (range, 41–86), time from CIMF diagnosis to the study treatment 10 months (range, 0–269), WBC count 87x109/L (range, 1.1–89), hemoglobin 9.8 g/dL (range, 7.8–17.3), platelets 137x109/L (range, 8–1183). Pts had received a median of 1 prior therapy (range 0–4): hydroxyurea (HU; n=14), anagrelide (AG; n=4), azacitidine (n=6), steroids (n=5), thalidomide (n=4), and interferon (n=3). Ten (25%) pts had not received any prior therapy. JAK2 V617F mutation was detected in 18 (50%) of 36 tested pts and 20 (50%) of 40 had abnormal cytogenetics. A total of 260 cycles have been administered. All 40 pts are evaluable for response and toxicity. Responses have been observed in 12 (30%) pts, including complete response (CR) in 2 (normal blood counts and <5% bone marrow blasts, off HU, AG, growth factors, and no transfusions); partial response (PR) in 7 (at least 2 of the following: Hb increase by ≥2 g/dL, 50% increase in platelets, decrease of bone marrow blasts or organomegaly by ≥50%, normalization of WBC count without blasts, or reduction in bone marrow fibrosis; off HU, AG, growth factors, and transfusion independence); and hematologic improvement (HI) in 3 (at least 2 of the following: decrease by ≥25% of pretreatment leukocytosis, splenomegaly, or marrow blasts, or increase of Hb by ≥1g/dl without growth factor or transfusion support or platelets by ≥25%; off HU, AG, growth factors). Median time to response was 12 weeks (range, 2–32). Responses have been sustained for a median of 15 wks (range, 5–36) and are ongoing in all 12 responders. Overall, 21 (53%) pts experienced grade 3–4 toxicity, being the most frequent neutropenia, anemia, musculoskeletal pain, and fatigue. Twenty-four (60%) pts have required dose reduction to DL -1, of which 5 (12.5%) further reduced to DL -2. One (2.5%) pt dose-escalated to DL +1, while 15 (25%) remained at DL 0. Twenty-one (53%) pts discontinued lenalidomide due to: lack of response (n=8), pt’s decision (n=7), grade 3–4 toxicity (n=5), and poor compliance (n=1). No deaths or transformation to acute myeloid leukemia occurred. In summary, the combination of lenalidomide and prednisone is an active and generally well-tolerated regimen for pts with CIMF. Longer follow-up is warranted to evaluate the durability of ongoing responses. Updated results will be presented at the meeting.

Abstract Background Ixazomib, the first oral proteasome inhibitor (PI), is approved by the US FDA, in combination with lenalidomide-dexamethasone (Rd), for the treatment of pts who have received at least 1 prior therapy. Lenalidomide is a common partner agent in regimens for RRMM; however, due to increasing use of lenalidomide treatment to progression as a standard of care in the first-line setting, novel PI-based combinations without lenalidomide are needed for RRMM. Combinations of a PI, an alkylating agent, and dexamethasone have been shown to be active, with manageable side effects, in RRMM patients (e.g. VCD - bortezomib, cyclophosphamide, dexamethasone), but require SC or IV administration of the PI. The all-oral combination of ICd may offer activity, tolerability, and more convenient administration. This open-label, multicenter phase 2 study (NCT02046070) assessed the safety and efficacy of ICd in pts with RRMM. Methods Adult pts with RRMM after 1-3 prior lines of therapy, who had ECOG performance status 0-2, were not PI-refractory, had adequate hematologic, renal, cardiac, and hepatic function, and did not have grade ≥2 peripheral neuropathy (PN) or grade 1 PN with pain, were eligible. Pts received oral ixazomib 4.0 mg and oral cyclophosphamide 300 mg/m2 on days 1, 8, and 15, plus oral dexamethasone 40 mg (20 mg for pts aged &gt;75 yrs) on days 1, 8, 15, and 22, in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR; ≥partial response [PR]); secondary endpoints included safety, pharmacokinetics (PK), complete response (CR) plus very good PR (VGPR) rate, CR rate, time to response (TTR), duration of response (DOR), and progression-free survival (PFS). Results 78 pts were enrolled; median age was 64 yrs (40% aged &gt;65 yrs), 53% were male, median time from initial diagnosis was 53.4 months (range, 12.9-142.7), and 24%/27% had ISS stage II/III disease at diagnosis. Median number of prior therapies was 2, including prior bortezomib, lenalidomide, and stem cell transplant (SCT) in 45 (58%), 38 (49%), and 50 (64%) pts, respectively; 17% were immunomodulatory-drug-naive. At data cut-off (June 20, 2016), pts had received a median of 12 treatment cycles (range, 1-22). A total of 51 (65%) pts had discontinued treatment, primarily due to disease progression (26 pts, 33%) and AEs (13 pts, 17%). Overall, 92% of pts reported AEs, including 59% with grade ≥3 AEs (51%/71% in pts aged ≤65/&gt;65 yrs), and 29% with serious AEs (30%/29%). Common AEs are listed in Table 1. AEs resulted in dose reductions of any study drug in 28 (36%) pts (28%/48% of pts aged ≤65/&gt;65 yrs) and treatment discontinuation in 11 (14%) pts (15%/13% aged ≤65/&gt;65 yrs). Ixazomib, cyclophosphamide, and dexamethasone were dose modified in 83%, 85%, and 87% of pts, respectively. Median ixazomib relative dose intensity was 96%. There were 3 on-study deaths: cardiac arrest, severe pulmonary edema, and cerebral hemorrhage secondary to thrombocytopenia, with the latter considered treatment-related. PK data showed that ixazomib exposures were comparable to those in pts treated with IRd in the TOURMALINE-MM1 study, suggesting no PK interaction with Cd. ORR was 49%, including 16% CR+VGPR (Table 2); in pts with/without prior SCT, ORR was 41%/61% (15%/18% CR+VGPR). Median TTR in responding pts was 2.14 months; median DOR was not reached, with response durations of up to 17 months. After a median follow-up of 12.5 months, median PFS was not reached; 12-month PFS rate estimate was 57.5%. Subgroup analysis showed a higher ORR (68% vs 35%), a higher CR+VGPR rate (23% vs 12%), and a significant PFS improvement in pts aged &gt;65 yrs vs pts aged ≤65 yrs (12-month PFS rate estimate 67.2% vs 50.7%; HR=0.43, p=0.028) (Figure). Although pts aged &gt;65 yrs were less likely to have had prior SCT than those aged ≤65 yrs (22% vs 78%), this did not appear to account fully for the difference in outcomes (PFS in pts without vs with prior SCT, HR=0.82, p=0.6). Conclusions All-oral triplet therapy with ICd appears to have activity in RRMM pts, with a toxicity profile consistent with that seen with ixazomib in combination with Rd (Moreau, et al; N Engl J Med 2016). Preliminary best response and PFS data suggest there may be preferential benefit in elderly pts compared to younger patients (possibly related in part to more limited use of prior high-dose alkylator [melphalan] exposure associated with SCT in elderly pts) albeit with additional toxicity. Disclosures Kumar: Glycomimetics: Consultancy; Onyx: Consultancy, Research Funding; Kesios: Consultancy; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; BMS: Consultancy; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Noxxon Pharma: Consultancy, Research Funding. Grzasko:Celgene: Honoraria; Munipharma: Honoraria; Janssen: Honoraria. Jędrzejczak:Novartis: Consultancy, Research Funding; BMS: Research Funding; Janssen-Cilag: Consultancy; Celgene: Consultancy; Angelini: Consultancy; Roche: Consultancy, Research Funding; Amgen: Research Funding; Sandoz: Consultancy. Kyrtsonis:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genesis: 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. Gupta:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Teng:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; AMAG Pharmaceuticals: Equity Ownership; Gilead Science: Equity Ownership; Array: Equity Ownership. Byrne:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dimopoulos:Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

AbstractObjectivesTo evaluate the safety and efficacy of maintenance therapy with the oral proteasome inhibitor ixazomib in patients with newly diagnosed multiple myeloma (NDMM) not undergoing transplantation.MethodsData were pooled from four NDMM phase I/II studies; patients received induction therapy with once‐ or twice‐weekly ixazomib plus lenalidomide‐dexamethasone (IRd), melphalan‐prednisone (IMP), or cyclophosphamide‐dexamethasone (ICd), followed by single‐agent ixazomib maintenance, given at the last tolerated dose during induction, until disease progression, death, or unacceptable toxicity.ResultsA total of 121 patients achieved stable disease or better after induction (weekly IRd, n = 25; twice‐weekly IRd, n = 18; weekly or twice‐weekly IMP, n = 35; weekly ICd, n = 43) and received ≥ 1 dose of ixazomib maintenance. Grade ≥ 3 drug‐related adverse events occurred in 24% of patients during maintenance; each event was reported in ≤2% of patients. Rates of complete response were 22% after induction and 35% after maintenance. A total of 28 patients (23%) improved their response during maintenance.ConclusionsIxazomib maintenance following ixazomib‐based induction is associated with deepening of responses and a positive safety profile with no cumulative toxicity in patients with NDMM not undergoing transplantation, suggesting that ixazomib is feasible for long‐term administration. Phase III investigation of ixazomib maintenance is ongoing.

SummaryThere is a need for efficacious, convenient treatments with long‐term tolerability for patients with relapsed/refractory multiple myeloma (RRMM). This phase 2 study evaluated the all‐oral combination of ixazomib, cyclophosphamide and dexamethasone (ICd). Patients with RRMM received ixazomib 4 mg and cyclophosphamide 300 mg/m2 on days 1, 8 and 15, and dexamethasone 40 mg on days 1, 8, 15 and 22 in 28‐day cycles. The primary endpoint was overall response rate (ORR). Seventy‐eight patients were enrolled (median age 63·5 years). At data cut‐off, patients had received a median of 12 treatment cycles; 31% remained on treatment. ORR was 48% [16% very good partial response or better (≥VGPR)]. ORR was 64% and 32% in patients aged ≥65 and <65 years (25% and 16% ≥VGPR), respectively. At a median follow‐up of 15·2 months, median progression‐free survival (PFS) was 14·2 months, with a trend towards better PFS in patients aged ≥65 years vs. <65 years (median 18·7 months vs. 12·0 months; hazard ratio 0·62, P = 0·14). ICd was well tolerated. The most common treatment‐emergent adverse events were diarrhoea (33%), nausea (24%), upper respiratory tract infection (24%), and thrombocytopenia (22%); 10 patients (13%) had peripheral neuropathy (one grade 3). This study is registered at ClinicalTrials.gov (NCT02046070).

AbstractWe present results of 2 similarly designed but separate phase 2 studies involving single-agent lenalidomide (CC-5013, Revlimid) in a total of 68 patients with symptomatic myelofibrosis with myeloid metaplasia (MMM). Protocol treatment consisted of oral lenalidomide at 10 mg/d (5 mg/d if baseline platelet count < 100 × 109/L) for 3 to 4 months with a plan to continue treatment for either 3 or 24 additional months, in case of response. Overall response rates were 22% for anemia, 33% for splenomegaly, and 50% for thrombocytopenia. Response in anemia was deemed impressive in 8 patients whose hemoglobin level normalized from a baseline of either transfusion dependency or hemoglobin level lower than 100 g/L. Additional treatment effects in these patients included resolution of leukoerythroblastosis (4 patients), a decrease in medullary fibrosis and angiogenesis (2 patients), and del(5)(q13q33) cytogenetic remission accompanied by a reduction in JAK2V617F mutation burden (1 patient). Grade 3 or 4 adverse events included neutropenia (31%) and thrombocytopenia (19%). We conclude that lenalidomide engenders an intriguing treatment activity in a subset of patients with MMM that includes an unprecedented effect on peripheral blood and bone marrow abnormalities.