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Background: Panobinostat (pano) is a pan histone deacetylase inhibitor (HDAC-i) FDA-approved for use with bortezomib (btz) and dexamethasone (dex) for patients with multiple myeloma (MM) who have had ≥2 prior lines of therapy, including both btz and an immunomodulatory agent (IMiD). This retrospective study evaluates efficacy and safety of pano combined with other FDA-approved agents used in relapsed/refractory (RR) MM. Methods: From February 2015-July 2017, 47 consecutive patients with RRMM treated with commercial pano identified in the EMR were reviewed. Results: Median age was 58.7 (27-78) years with 55% men. 41 (87%) were Durie-Salmon Stage 3. 12 (26%) had high-risk FISH: t(14;16), t(4;14), del 17p, and gain 1q21. Median number of prior lines was 6 (2-14). 38 (81%) were RR to the last line of therapy. 29 (62%) were btz-refractory, 36 (77%) lenalidomide-refractory, 36 (77%) pomalidomide-refractory, and 36 (77%) carfilzomib-refractory. 33 (70%) were refractory to carfilzomib with an IMiD. 15 (32%) had prior daratumumab and 7 (15%) had prior HDAC-i therapy. Median pano cycles was 3 (0.25-18). ORR (≥PR) was 25.0% and clinical benefit rate (≥MR) was 38.6%. Median duration of response (≥SD) was 4.3 months. Median PFS was 2.4 months (95% CI: [1.61,4.01]). Median OS from initiation of pano through 1/16/19 was 6.25 months (95% CI: [5.10,12.95]). Three patients discontinued pano due to toxicity. Grade 3-4 non-hematologic toxicities were diarrhea (N=1), and respiratory failure (N=2). Grade 3-4 hematologic adverse events (AEs) occurred in 19 (40%) patients, 12 (26%) with anemia,15 (32%) with neutropenia, and 13 (28%) with thrombocytopenia. Serious AEs included acute kidney injury, GI bleed, febrile neutropenia, heart failure exacerbation, and dyspnea in 4 patients, respectively. PFS is negatively associated with a greater number of lines of treatment prior to initiating pano (HR 1.21: 95% CI 1.02-1.4). High-risk FISH (HR 0.71: 95% CI 0.31-1.60) and being refractory to the last prior line of therapy (HR 0.51: 95% CI 0.17-1.60) show no significant association with PFS. Conclusion: Use of pano outside of the FDA indication, in combination with PI and IMiD-based regimens, has activity and is well tolerated in heavily pretreated RRMM patients.

Thalidomide and lenalidomide, in combination with dexamethasone, provide response rates ranging from 63%-79% after 4 cycles of therapy. Because of toxicities such as neuropathy and myelosuppression for thalidomide and lenalidomide, respectively, dose escalation has not been pursued. We evaluated a syncopated regimen of alternating weeks of thalidomide and lenalidomide to determine if a modified schedule allows for fewer dose reductions and, subsequently, superior efficacy. Although well tolerated, this phase II trial did not show superior efficacy compared with conventional dosing and scheduling of these agents.Over the past decade, the novel agents thalidomide, lenalidomide, and bortezomib have emerged as effective treatment in patients with multiple myeloma (MM). Initially used in the relapse setting, these agents have been incorporated into frontline treatment algorithms. They have been combined in doublets with corticosteroids, in triplets with alkylators, or with each other. Because thalidomide and lenalidomide have different clinical activity and toxicity profiles, we designed a trial to evaluate a syncopated schedule of thalidomide and lenalidomide with weekly dexamethasone in patients with newly diagnosed MM to determine response and toxicity.Twenty-two patients with newly diagnosed MM were treated with syncopated thalidomide (200 mg on days 1-7 and 15-21), lenalidomide (25 mg on days 8-14 and 22-28 for the first cycle and 50 mg on the same schedule for subsequent cycles) with weekly dexamethasone (40 mg). Each cycle lasted 28 days. MM parameters were assessed at the end of each cycle. It was intended that the patients proceed to stem cell mobilization and autologous transplantation after 4 cycles of therapy.The median number of cycles administered was 3.5. The overall response was 68%. The regimen was well tolerated by the majority of the patients; only patient discontinued treatment because of toxicity.We conclude that a syncopated schedule of thalidomide and lenalidomide with weekly dexamethasone was tolerated well, with no unexpected toxicities. However the response rate, even using lenalidomide at 50 mg, was not superior to standard dosing of thalidomide or lenalidomide plus dexamethasone.

G-alone G-cyclo P-value No. of patients 112 (81%) 26 (19%) Median age (years; range) 61 (36-72) 55 (35-65) Male/female 65(58%)/47(42%) 17(65%)/9(35%) P1⁄40.47 Prior radiotherapy exposure 17 (15%) 5 (19%) P1⁄40.61 Median no. of bortezomib doses 16 (11-24) 16 (15-20) Median cumulative bortezomib dose (mg/m) 20.8 (14.3 e 31.2) 20.8 (16.0-22.1) Cyclophosphamide mobilisation dose 1.5 g/m NA 7 (24%) 2 g/m NA 19 (76%) G-CSF dose for mobilisation 5mg/kg daily 0 7 (27%) 10mg/kg daily 96 (86%) 18 (69%) 10mg/kg twice daily 16 (14%) 0 NA 0 1 (4%) PB CD34+ day of planned collection (10/L; median; range) 52 (8-326) 69 (0-227) P1⁄40.87 >100 26 (23%) 8 (31%) >50-100 31 (28%) 7 (27%) 20-50 39 (35%) 8 (31%) 4-6 49 (44%) 11 (44%) >6 44 (40%) 12 (48%) Median CD34+ yield in radiotherapy patients (10/kg; range) 5.8 (2.2-17.3) 4.5 (3.8-6.9) Outcomes of collection Success without intervention 38 (34%) 13 (50%) P1⁄40.49 Success with extra days of G-CSF 62 (55%) 11 (42%) Success with plerixafor rescue 7 (6%) 1 (4%) Failed first collection; no other attempts 1 (1%) 0 Failed first collection with subsequent successful collection 3 (3%) 1 (4%) Target yield not reached but deemed sufficient 1 (1%) 0

Background:Carfilzomib (CFZ) is a novel irreversible proteasome inhibitor (PI) approved for relapsed/refractory multiple myeloma, but its safety and efficacy in AL amyloidosis is not known. We report updated results of an investigator-initiated, multi-center, Phase I/II study of CFZ in AL (NCT01789242), including additional patients (pts) treated in the expansion cohort. Methods: Eligible pts (relapsed or refractory AL after ≥1 prior therapy; Mayo cardiac stage I or II; LVEF ≥40%; CrCl≥30; CFZ-naive) received CFZ over 30 minutes on days 1, 2, 8, 9, 15, 16 every 28 days, for 8 cycles, given at 20 mg/m2 on days 1, 2 of cycle 1, then at 27, 36, or 45 mg/m2 (depending on cohort) thereafter. Pre-CFZ hydration was recommended during cycle 1, but could be modified or omitted at investigator discretion. Responding pts could continue on a day 1, 2, 15, 16 schedule at investigator discretion. Dexamethasone 20mg with each CFZ dose was added if no VGPR after cycle 4. Primary objectives were safety and determination of MTD. A 3+3 dose escalation design was used, with a planned expansion cohort at MTD. Responses were based on updated AL consensus guidelines. Pts completing ≥2 cycles (or progressing before 2 cycles) were evaluable for response; all treated pts were evaluated for safety. Cardiac function was monitored in all pts by serial NT-proBNP and echocardiograms. Data cutoff was 6/23/16. Results: From June 2013 - June 2016, 28 eligible pts were enrolled and treated. Median age was 64 (range 43 - 81); 64% were male. Median time from diagnosis was 31 mos., with median of 2 prior regimens (range 1-5), including bortezomib (96%), IMiDs (43%) and stem cell transplant (46%). Thirteen (46%) were refractory to last therapy, and 10 (36%) were PI-refractory (9 bortezomib, 1 ixazomib). Involved organs included kidney (64%), heart (50%), nerve (25%), GI tract (21%), soft tissue (14%), and liver (11%); 13 pts had ≥2 major organs involved. Median baseline NT-proBNP was 542 pg/ml (range 20 - 13571), and median baseline difference in free light chains (dFLC) was 138 mg/L (range 44 - 4709). There were no DLTs at 20/27 and 20/36 mg/m2. At 20/45 mg/m2, there were 2 first-cycle DLTs of grade 3 fatigue ≥7 days, making 20/36 mg/m2 the MTD. Eighteen more pts have enrolled at MTD. Median number of cycles is 6 (range 1-25+), with 10 pts completing the planned 8 cycles (7 continuing on maintenance), 3 ongoing before cycle 8, and 15 stopping early (9 for AE’s, 4 for no response, 2 other). Most common drug-related AE’s to date are fatigue (36%), increased creatinine (29%), nausea (25%), dyspnea (18%), anemia (18%), diarrhea (14%), pyrexia, chills, and hypertension (11% each). Grade 3/4 AEs (all-cause) occurred in 20 (71%) pts, including several grade 3/4 cardiac or pulmonary AEs: hypoxia (n=1), lung infection (n=2), chest pain (n=1), hypotension (n=1), hypertension (n=3), decreased ejection fraction/CHF (n=3), and symptomatic ventricular tachycardia (n=2, 1 with cardiac arrest requiring defibrillation). There have been no grade 5 AEs. Of 24 response-evaluable pts, 15 (63%) have responded hematologically (3 CR, 8 VGPR, 4 PR), including 6 of 8 evaluable PI-refractory pts (1 CR, 2 VGPR, 3 PR). Responses have occurred at all dose levels (Table). Dex was added in 5 pts, with 3 response upgrades. Five (21%) pts have had organ responses (3 kidney, 1 GI, 1 liver) to date. With median follow-up of 16 mos. (range 0.5 - 32), 9 pts have had hematologic progression, and 2 have died. To date, 11 pts have had NTproBNP increases of ≥30% and ≥300 pg/ml on CFZ. For 5 this correlated with progressive clinical and/or echocardiographic signs of cardiac dysfunction; the other 6 lacked objective signs of worsening cardiac function, with either no symptoms (n=4) or progressive fatigue (n=2). Conclusions: CFZ monotherapy is feasible and effective in relapsed/refractory AL amyloidosis, with MTD identified as 20/36 mg/m2 as a 30-minute infusion. Hematologic response rates are promising in this bortezomib-exposed population, including in PI-refractory pts. Cardiac, pulmonary, and renal toxicities were common, warranting close monitoring and dose reductions as appropriate. Similar to IMiDs, NT-proBNP can increase in pts receiving CFZ, without always correlating with progressive cardiac dysfunction, potentially confounding its use as a marker of cardiac response/progression in this setting. Download : Download high-res image (125KB) Download : Download full-size image Disclosures Cohen: Bristol-Meyers Squibb: Consultancy, Research Funding; Janssen: Consultancy. Landau: Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx/Amgen: Research Funding; Janssen: Consultancy. Scott: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees. Kaufman: Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Consultancy; Incyte: Consultancy. Vesole: Janssen: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau; Amgen: Speakers Bureau. Lentzsch: BMS: Consultancy; Celgene: Consultancy, Honoraria. Gomes: Criterium, Inc: Employment. Comenzo: Karyopharm: Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Durie: Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy.