Abstract: To provide an update on recent advances in the management of patients with multiple myeloma who are not eligible for autologous stem-cell transplantation. Methods A comprehensive review of the literature on diagnostic criteria is provided, and treatment options and management of adverse events are summarized. Results Patients with symptomatic disease and organ damage (ie, hypercalcemia, renal failure, anemia, or bone lesions) require immediate treatment. The International Staging System and chromosomal abnormalities identify high- and standard-risk patients. Proteasome inhibitors, immunomodulatory drugs, corticosteroids, and alkylating agents are the most active agents. The presence of concomitant diseases, frailty, or disability should be assessed and, if present, treated with reduced-dose approaches. Bone disease, renal damage, hematologic toxicities, infections, thromboembolism, and peripheral neuropathy are the most frequent disabling events requiring prompt and active supportive care. Conclusion These recommendations will help clinicians ensure the most appropriate care for patients with myeloma in everyday clinical practice.

Abstract: e19505 Background: CFZ combined with dexamethasone is approved to treat pts with RRMM, with CFZ given once-weekly at 70 mg/m 2 (Kd70 QW) or twice-weekly at 56 mg/m 2 (Kd56 BIW). No randomized trials have directly compared Kd70 QW with Kd56 BIW. We performed a post hoc comparison between pts who received Kd56 BIW in the ENDEAVOR trial and pts who received Kd70 QW in the A.R.R.O.W. or CHAMPION-1 trials. Methods: Data were analyzed from 3 trials of CFZ in RRMM: A.R.R.O.W. (240 pts in Kd70 QW arm; 2–3 prior therapies and refractory to most recent therapy), CHAMPION-1 (104 pts received Kd70 QW; 1–3 prior therapies), and ENDEAVOR (464 pts in Kd56 BIW arm; 1–3 prior therapies). Pts who received Kd70 QW in A.R.R.O.W. and CHAMPION-1 were pooled and compared with pts who received Kd56 BIW in ENDEAVOR. As study populations slightly varied among the 3 trials, an analysis of safety and efficacy was performed in a subgroup of pts who received 2–3 prior therapy lines and were not refractory to bortezomib (BTZ). Also, we performed regression analyses (controlling for age, ISS stage, BTZ and lenalidomide refractory status, and number of prior regimens) among all pts in the trials who received Kd70 QW or Kd56 BIW. Results: Among BTZ non-refractory pts with 2–3 lines of prior therapy, median progression-free survival (PFS) was 12.1 months (95% CI 8.4–14.3) for Kd70 QW (n = 146) and 14.5 months (95% CI 10.2–NE) for Kd56 BIW (n = 217), and the overall response rate (ORR) was 69.9% (95% CI 61.7–77.2) for Kd70 QW and 72.4% (95% CI 65.9–78.2) for Kd56 BIW. The rate of grade ≥3 adverse events (Kd70 QW vs Kd56 BIW) was 67.6% and 85.3%; among adverse events of interest, the grade ≥3 rate was 1.4% and 5.1% for cardiac failure, 3.4% and 6.0% for renal failure, and 5.5% and 15.7% for hypertension. Kd70 QW represents a convenient and well-tolerated treatment modality for pts with RRMM. In a Cox proportional hazards model, the hazard ratio for PFS (Kd70 QW vs Kd56 BIW) was 0.91 (95% CI 0.69–1.19), and in a logistic regression model the odds ratio for ORR (Kd70 QW vs Kd56 BIW) was 1.12 (95% CI 0.74–1.69). Conclusions: This post hoc analysis suggests that once-weekly Kd70 has a comparable benefit-risk profile to twice-weekly Kd56. Clinical trial information: NCT02412878, NCT01677858, NCT01568866.

Abstract: Panobinostat in combination with bortezomib and dexamethasone demonstrated a significant and clinically meaningful progression‐free survival benefit compared with placebo, bortezomib and dexamethasone in the phase 3 PANORAMA 1 (Panobinostat Oral in Multiple Myeloma 1) trial. Despite this benefit, patients in the panobinostat arm experienced higher rates of adverse events ( AE s) and higher rates of discontinuation due to AE s. This PANORAMA 1 subanalysis examined AE s between 2 treatment phases of the study ( TP 1 and TP 2), in which administration frequency of bortezomib and dexamethasone differed per protocol. The incidences of several key AE s were lower in both arms following the planned reduction of bortezomib dosing frequency in TP 2. In the panobinostat arm, rates of thrombocytopenia (grade 3/4: TP 1, 56·7%; TP 2, 6·0%), diarrhoea (grade 3/4: TP 1, 24·1%; TP 2, 7·1%), and fatigue (grade 3/4: TP 1, 16·3%; TP 2, 1·8%) were lower in TP 2 compared with TP 1. Dose intensity analysis of panobinostat and bortezomib by cycle in the panobinostat arm showed reductions of both agent doses during cycles 1–4 due to dose adjustments for AE s. Exposure‐adjusted analysis demonstrated a reduction in thrombocytopenia frequency in TP 1 following dose adjustment. These results suggest that optimization of dosing with this regimen could improve tolerability, potentially leading to improved patient outcomes.

Abstract: Introduction: Panobinostat is a potent pan-deacetylase inhibitor (pan-DACi) that targets key aberrations in multiple myeloma (MM) cell biology, including epigenetics and protein metabolism. In the phase 3 clinical trial PANORAMA 1, panobinostat in combination with bortezomib and dexamethasone (PAN-BTZ-Dex) led to a statistically significant and clinically relevant increase in progression-free survival of approximately 4 months compared with that with placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex). Further analyses of patient outcomes by prior treatment demonstrated that the magnitude of PFS benefit was greatest among patients who received at least 2 prior regimens, including bortezomib and an immunomodulatory drug (IMiD; PAN-BTZ-Dex [n = 73]: 12.5 months [95% CI, 7.3-14.0 months] ; Pbo-BTZ-Dex [n = 74]: 4.7 months (95% CI, 3.7-6.1 mo; HR 0.47 [95% CI, 0.32-0.72] ). These data supported the regulatory approvals of PAN-BTZ-Dex for the treatment of patients with multiple myeloma who received at least 2 prior regimens, including bortezomib and an IMiD. Here we present the final analysis of overall survival (OS) for the entire patient population and among patients who received at least 2 prior regimens, including bortezomib and an IMiD. Methods: The study design for the PANORAMA 1 trial was described previously (San-Miguel. Lancet Oncol. 2014;15:1195-206). The key secondary endpoint was OS. As of June 29, 2015, the 415 events required to conduct the final analysis of OS had been observed. Kaplan-Meier estimation was utilized for OS analyses for the entire population (N = 768), the pre-specified subgroup of patients who received prior bortezomib and IMiD (n = 193), and patients who received at least 2 prior regimens including bortezomib and an IMiD (n = 147). Results: The median OS of patients who received PAN-BTZ-Dex in the overall population was 40.3 months (95% CI, 35.0-44.8 months) vs 35.8 months (95% CI, 29.0-40.6 months) for the Pbo-BTZ-Dex arm with HR 0.94 [95% CI, 0.78-1.14], P = .5435 (Fig 1A). The percentage of patients in each arm who received post-study therapy was 37.7% in the PAN-BTZ-Dex arm and 48.8% in the Pbo-BTZ-Dex arm. The median OS of patients who received at least 2 prior lines, including bortezomib and an IMiD, was 25.5 months (95% CI, 19.6-34.3 months) in the PAN-BTZ-Dex arm vs 19.5 months (95% CI, 14.1-32.5 months) in the Pbo-BTZ-Dex arm (Fig. 1B). The proportion of patients in this subgroup who received post-study therapy was 35.6% in the PAN-BTZ-Dex arm and 66.2% in the Pbo-BTZ-Dex arm. Conclusion: For the overall PANORAMA 1 study population, patients in the PAN-BTZ-Dex arm demonstrated an increase in median OS of 4.5 months vs patients in the Pbo-BTZ-Dex arm, but this result was not statistically significant (P = .5435). Median OS was also slightly longer for the PAN-BTZ-Dex arm among the more heavily pretreated subgroup of patients who received at least 2 prior regimens, including bortezomib and an IMiD. A higher percentage of patients on the Pbo-BTZ-Dex arm received post-study therapy vs the PAN-BTZ-Dex arm, which may have confounded the OS results. In summary, PAN-BTZ-Dex demonstrates statistically significant increases in PFS vs Pbo-BTZ-Dex in patients with relapsed or relapsed and refractory MM; however, this did not translate to a statistically significant increase in OS. Future trials will plan to focus on further optimization of dose and schedule of panobinostat and bortezomib to improve outcome, as well as novel combinations with other agents, including IMiDs and next-generation proteasome inhibitors. Figure 2. Figure 2. Disclosures Beksac: Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: 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; Janssen-Cilag: Consultancy, Speakers Bureau. Dimopoulos:Janssen: Honoraria; Janssen-Cilag: Honoraria; Onyx: Honoraria; Amgen: Honoraria; Genesis: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Jedrzejczak:Onconova: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Siritanaratkul:Pfizer: Research Funding; Roche: Research Funding; Novartis: Research Funding; Janssen-Cilag: Research Funding. Schlossman:Millennium: Consultancy. Hou:Novartis: Membership on an entity's Board of Directors or advisory committees. Moreau:Novartis: 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; Celgene: 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. Lonial:Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Sopala:Novartis Pharma: Employment, Equity Ownership. Bengoudifa:Novartis: Employment. Corrado:Novartis: Employment, Equity Ownership. Richardson:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees.

Abstract: Background: In the phase 3 ENDEAVOR trial, treatment with carfilzomib administered at 56 mg/m2 twice weekly in combination with dexamethasone (Kd56) significantly improved progression-free survival (PFS) compared to treatment with bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (RRMM) (Dimopoulos MA, et al. Lancet Oncol . 2016;17:27-38). In this substudy of ENDEAVOR, we used whole transcriptome RNA sequencing (RNA-seq) to identify genes whose baseline expression levels in CD138+ cells were predictive of PFS in patients treated with Kd56 or Vd. The objective of this study was to develop a genomic classifier that could be used to stratify patients for benefit with Kd56 or Vd therapy. Methods: Patients were randomized to receive Kd56 or Vd at a 1:1 ratio. Patients who consented for this biomarker study and provided samples (Kd56, n = 155; Vd, n = 148) were included. CD138+ cells were isolated from bone marrow aspirate collected at baseline. Sequencing libraries for isolated RNA samples were prepared using an Illumina TruSeq RNA library construction kit and sequenced on an Illumina HiSeq 2500 platform. Sequencing reads were aligned against the human reference genome GRCh38 using STAR RNA-seq aligner and annotated with GENCODE v24 at the gene level. Expression counts were estimated using RSEM software and converted to counts per million for subsequent analyses using the edgeR package. Cox proportional hazard regression analysis with LASSO was used to model the relationship between patients' baseline gene expression and PFS. A classifier was established and its predictive performance was assessed using the cross-validation scheme outlined by Simon et al (Brief Bioinform . 2011;12:203-214). The statistical significance of the cross-validated Kaplan-Meier curves and corresponding log-rank statistic was estimated by generating an approximate null distribution of the cross-validated log-rank statistic through 500 random permutations. For each permutation, the patients' baseline gene expression profiles and treatment assignments were randomly re-shuffled against patients' survival times and event indicators, and the same cross-validation procedures used in the model performance assessment were repeated to compute the cross-validated log-rank statistic for the permuted data. Results: Among the 303 Kd56 or Vd patients included in this biomarker study, patients in the Kd56 arm had a 58% reduced risk of progression or death compared with patients in the Vd arm (hazard ratio [HR]: 0.42; 95% confidence interval [CI] : 0.30-0.59; P= 4.5 x 10-7). We developed a linearized classifier using patients' baseline gene expression (n = 303) to stratify patients for PFS benefit from Kd56 or Vd therapy. The cross-validated Kaplan-Meier curves and log-rank statistic for the classifier were statistically significant at P & lt; 0.001. A 13-gene classifier derived from the whole data set could separate patients from the Kd56 arm (n = 155) into two distinct subgroups, in which one with 113 (73%) patients had a PFS benefit over the other with 42 (27%) patients (HR: 0.13; 95% CI: 0.06-0.26; P= 3.3 x 10-13). When these 42 patients were excluded from the Kd56 arm, the PFS benefit for the Kd56 arm (n = 113) over the Vd arm (n = 148) was improved by 52% (HR: 0.20; 95% CI: 0.12-0.31; P= 2.0 x 10-14). The classifier was unable to stratify patients in the Vd arm for high or low PFS benefit. The 13 genes included in the classifier were ACOXL, CLEC2B, CLIP4, COCH, FRK, IGHD, ITPRIPL2, NAP1L5, RNASE6, SH3RF3, SHROOM3, TCF7, and UGT3A2 . Several genes in this classifier, including CLIP4, IGHD, and SH3RF3, have been previously implicated in myeloma biology and in vitroresistance to proteasome inhibitors. Individually, each gene showed similar ability to stratify patients from the Kd56 arm, but the cross-validated Kaplan-Meier curves for the individual genes were not significant at P & lt; 0.05. Conclusions: We identified a classifier with a set of genes whose baseline expression could potentially be used to stratify RRMM patients for greater treatment benefit with Kd56. As only one patient cohort was used for this study, the classifier identified here should be validated in prospective studies and with independent sets of patient cohorts. Further study of this group of genes may provide additional insights into the biology of multiple myeloma and how mechanism of action differs between carfilzomib and bortezomib. Disclosures Pelham: Amgen: Employment, Equity Ownership. Hu: Amgen: Employment, Equity Ownership. Moreau: Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Janssen: Consultancy, Honoraria; Celgene, Janssen, Takeda, Novartis, Amgen, Roche: Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceutical: Consultancy, Honoraria. Oriol: Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau; Celgene: Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau. Quach: Novartis: 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, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria; Takeda: Honoraria. Kovacsovics: Seattle Genetics: Research Funding; Celgene: Consultancy; Flexus: Research Funding. Keats: Amgen: Research Funding. Feng: Amgen: Employment, Equity Ownership. Kimball: Amgen: Employment, Equity Ownership. 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.

Abstract: Background Melphalan, prednisone and thalidomide (MPT) is a standard therapy for NDMM recognized worldwide based on a statistically significant advantage in overall survival (OS) and progression-free survival (PFS) vs. MP (Facon Lancet 2007; Fayers Blood 2011; NCCN 2013). The combination of lenalidomide and low-dose dexamethasone (Rd) increased OS with fewer adverse events (AEs) than treatment with lenalidomide and high-dose dexamethasone in NDMM pts (ECOG E4A03) (Rajkumar Lancet Oncol 2010). The FIRST trial is a multicenter, open-label, phase III trial comparing the efficacy and safety of Rd versus MPT in transplant-ineligible NDMM pts. Methods NDMM pts either ≥ 65 years of age, or not candidates for SCT were randomized to one of three arms: Rd in 28-day cycles until disease progression (Arm A), Rd in 28-day cycles for 72 weeks (18 cycles, Arm B), or MPT in 42-day cycles for 72 weeks (12 cycles, Arm C). Assessments by International Myeloma Working Group criteria were done after each cycle. Pts with renal impairment were enrolled; however, pts on dialysis were excluded. Starting doses of lenalidomide and dexamethasone were adjusted based on renal function and age, respectively. Melphalan starting dose was adjusted based on age, absolute neutrophil count, platelet count, and renal function; and thalidomide was adjusted for age. Dose adjustments were permitted for AEs. All pts were required to receive anti-thrombotic prophylaxis. Stratification factors included age, International Stage System, and country. The primary endpoint was a comparison of PFS in Arm A vs. Arm C. Secondary endpoints included OS, overall response rate (ORR), time to response, duration of response (DOR), safety, and quality of life (QOL). A preplanned additional analysis included time from randomization to second progression event or death (PFS2). The final preplanned analysis of independently adjudicated progressive disease (PD) events in Arm A vs. Arm C conducted after 960 events of death or PD, and an interim of OS in 64% of survival events (574/896 events) are presented in this abstract. Comparisons of PFS and all secondary endpoints, including OS for all three arms, will be presented at the meeting. Results A total of 1,623 pts were randomized 1:1:1 in three arms. As of today, 121 pts continue to receive lenalidomide on study (Arm A). The median age was 73 (40.0–92.0) years; 35% pts were aged ≥ 75 years; and 41% of pts had ISS stage 3 disease. After a median follow-up of 37 months, the trial met its primary endpoint (PFS), demonstrating a 28% reduction in risk of progression or death (HR=0.72; p= 0.00006). The preplanned interim analysis of OS demonstrated a 22% reduction in risk of death in favor of Arm A vs. Arm C (HR=0.78, p=0.01685); however, the pre-specified boundary (p 〈 0.0096) was not crossed. All other secondary endpoints consistently showed improvement in favor of Arm A vs. Arm C; ORR (PR or better) 75% vs. 62% (p 〈 0.00001), DOR (HR=0.63; p 〈 0.00001), and PFS2 (HR=0.78, p=0.0051). Relevant Grade 3/4 adverse events in Arm A vs. Arm C were neutropenia (28% vs. 45%), thrombocytopenia (8% vs. 11%), febrile neutropenia (1% vs. 3%), infection (29% vs. 17%), neuropathy (5% vs. 15%), and deep-vein thrombosis (5% vs. 3%). The incidence of secondary primary malignancies (SPM) was evaluated. Hematologic malignancies were 0.4% in Arm A vs. 2.2% in Arm C; the overall incidence of solid tumors was identical (2.8%). Conclusion Continuous treatment with the all oral doublet Rd significantly improved the primary endpoint of PFS compared with the standard triplet, MPT. All secondary endpoints support the clinical benefit of continuous Rd treatment. The safety profile of Rd was manageable, with reduced hematologic SPM compared to MPT. Disclosures: Facon: Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Lenalidomide as treatment for NDMM. Dimopoulos:Celgene, Orthobiotech: Honoraria. Dispenzieri:Celgene, Millenium, Jansenn, Pfizer: Research Funding. Catalano:Celgene, Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Hulin:Janssen: Honoraria; Celgene: Honoraria. Cavo:Celgene, Janssen, Millennium, Onyx, Brystol Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Pinto:Mundipharma: Consultancy, Honoraria; Roche: Honoraria; Celgene: Consultancy, Honoraria. Weisel:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Ludwig:Celgene: Honoraria, Research Funding, Speakers Bureau. Bahlis:Celgene: Consultancy, Honoraria. Delforge:Celgene: Honoraria. Chen:Celgene: Consultancy, Research Funding; Lundbeck: Consultancy; Johnson & Johnson: Consultancy, Research Funding; Roche: Honoraria; GlaxoSmithKline: Research Funding. Oriol:Celgen: Consultancy. White:Celgene: Honoraria, Research Funding. Binder:Celgene: Research Funding. Anderson:Acetylon, OncoPep: Equity Ownership; Celgene, Onyx, Sanofi Aventis, Gileod: Consultancy. Moreau:Celgene Corporation: Honoraria, Speakers Bureau. Attal:Janssen: Lectures, Lectures Other, Membership on an entity’s Board of Directors or advisory committees; Celgene Corporation: Lectures Other, Membership on an entity’s Board of Directors or advisory committees. Knight:Celgene: Employment, Equity Ownership. Chen:Celgene: Employment. Van Oostendorp:Celgene: Employment. Jacques:Celgene: Employment. Ervin-Haynes:Celgene: Employment, Patents & Royalties. Benboubker:Celgene: Consultancy.

Abstract: The aim of the International Myeloma Working Group was to develop practical recommendations for the diagnosis and management of multiple myeloma–related renal impairment (RI). Methods Recommendations were based on published data through December 2015, and were developed using the system developed by the Grading of Recommendation, Assessment, Development, and Evaluation Working Group. Recommendations All patients with myeloma at diagnosis and at disease assessment should have serum creatinine, estimated glomerular filtration rate, and electrolytes measurements as well as free light chain, if available, and urine electrophoresis of a sample from a 24-hour urine collection (grade A). The Chronic Kidney Disease Epidemiology Collaboration, preferably, or the Modification of Diet in Renal Disease formula should be used for the evaluation of estimated glomerular filtration rate in patients with stabilized serum creatinine (grade A). International Myeloma Working Group criteria for renal reversibility should be used (grade B). For the management of RI in patients with multiple myeloma, high fluid intake is indicated along with antimyeloma therapy (grade B). The use of high-cutoff hemodialysis membranes in combination with antimyeloma therapy can be considered (grade B). Bortezomib-based regimens remain the cornerstone of the management of myeloma-related RI (grade A). High-dose dexamethasone should be administered at least for the first month of therapy (grade B). Thalidomide is effective in patients with myeloma with RI, and no dose modifications are needed (grade B). Lenalidomide is effective and safe, mainly in patients with mild to moderate RI (grade B); for patients with severe RI or on dialysis, lenalidomide should be given with close monitoring for hematologic toxicity (grade B) with dose reduction as needed. High-dose therapy with autologous stem cell transplantation (with melphalan 100 mg/m 2 to 140 mg/m 2 ) is feasible in patients with RI (grade C). Carfilzomib can be safely administered to patients with creatinine clearance 〉 15 mL/min, whereas ixazomib in combination with lenalidomide and dexamethasone can be safely administered to patients with creatinine clearance 〉 30 mL/min (grade A).

Abstract: Introduction: In the randomized placebo controlled phase 3 trial PANORAMA 1 the pan-deacetylase inhibitor (pan-DACi) panobinostat combined with bortezomib and dexamethasone (PAN-BTZ-Dex) led to a statistically significant and clinically relevant increase in progression free survival in patients (pts) with relapsed or relapsed and refractory multiple myeloma (Pbo-BTZ-Dex; 12.0 vs 8.1 months; hazard ratio 0.63, P 〈 0.0001). Gastrointestinal (GI) toxicity, particularly diarrhea, a known class-effect of pan-DACi and BTZ, was the most common non-hematologic adverse event (AE) observed in both treatment arms, occurring at a higher incidence in the PAN-BTZ-Dex arm. Optimal management of GI toxicity, especially diarrhea-related AEs, in pts who receive PAN-BTZ-Dex could help maximize treatment outcomes. Here we present a detailed analysis of pts with diarrhea on the PANORAMA 1 study to inform strategies to reduce the effects of diarrhea and improve efficacy. Methods: The PANORAMA 1 trial included 12 cycles of treatment with two treatment phases (TP1: eight 3-week cycles; TP2: four 6-week cycles). In TP1, pts were randomized to receive oral PAN (20 mg) or Pbo administered thrice weekly for the first 2 weeks, with intravenous BTZ (1.3 mg/m2) administered on days 1, 4, 8, and 11 and Dex (20 mg) administered orally on the days of and after BTZ. In TP2 (for pts demonstrating clinical benefit), PAN or Pbo were administered similarly but BTZ was administered once-weekly (days 1, 8, 22 and 29) with Dex on the day of and after BTZ. For each cycle, prevalence and incidence for diarrhea AEs were determined; these were characterized by grade, improvement in grade, worsening of grade, and resolution of diarrhea. Results: In the PANORAMA 1 trial, a total of 260/381 (68.2%) pts treated with PAN-BTZ-Dex and 157/377 (41.6%) pts treated with Pbo-BTZ-Dex reported AEs of diarrhea; most were grade 1 or 2 (PAN-BTZ-Dex: 42.8% vs Pbo-BTZ-Dex: 33.7%). Grade 4 diarrhea was rare (PAN-BTZ-Dex: 1.3%; Pbo-BTZ-Dex: 0.5%). Dose adjustments/interruptions for diarrhea occurred in 26% on the PAN-BTZ-Dex arm and 9% on the Pbo-BTZ-Dex arm. Treatment discontinuation due to diarrhea occurred in 4.5% on the PAN-BTZ-Dex arm and 1.6% on the Pbo-BTZ-Dex arm. Serious AEs of diarrhea occurred in 11.3% on PAN-BTZ-Dex arm and 2.4% on Pbo-BTZ-Dex arm. There was no hemorrhagic diarrhea on the PAN-BTZ-Dex arm and in 1 pt in the Pbo-BTZ-Dex arm. In the majority of pts (56.2%) in the PAN-BTZ-Dex arm, diarrhea occurred for the first time in cycles 1-4 and was primarily grade 1/2; first onset occurred rarely in TP2 (Figure). Cumulative incidence of diarrhea on the PAN-BTZ-Dex arm plateaued by cycle 6 (61.9% by cycle 6; 68.2% overall). The cumulative number of pts with complete resolution of diarrhea (defined as resolved diarrhea that did not recur on treatment) increased over the course of the study. During treatment, 67.7% (258/381) in PAN-BTZ-Dex arm had either no diarrhea or complete resolution of their diarrhea. Analysis of diarrhea management by grade and treatment phase revealed that most pts received medication to manage the diarrhea. Antidiarrheal medications were administered to 70.8% (184/260) pts with diarrhea across all grades; loperamide was used most commonly. However, many pts with grade 1/2 diarrhea had no action taken in TP1: grade 1 - 58% (115/198); grade 2 - 26% (33/127), suggesting suboptimal management of diarrhea. Conclusions: These data demonstrate that diarrhea in pts who received PAN-BTZ-Dex occurs primarily in the first 1-4 cycles of treatment with cumulative incidence reaching a plateau around cycle 6. Majority of pts with diarrhea had complete resolution during treatment. Although diarrhea was commonly observed in pts who received PAN-BTZ-Dex in the PANORAMA 1 trial, it was manageable and seldom led to treatment discontinuation; however, some pts with grade 1/2 diarrhea did not receive proactive management. Optimal management of diarrhea with prompt intervention including antidiarrheal medication and dose holds/adjustments of BTZ and PAN at the first sign of loose stools may help to maintain pts on therapy and thus improve outcomes with PAN-BTZ-Dex. Future trials should seek to employ these strategies for pts who experience GI toxicity, and should consider subcutaneous administration of BTZ. In addition, studies using combinatorial agents with less overlapping GI toxicity with PAN may further improve safety in this setting. Figure 1 Figure 1. Disclosures Richardson: Takeda: Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Celgene: Consultancy, Honoraria. Jedrzejczak:Amgen, Novartis: Consultancy, Research Funding. Guenther:Novartis: Consultancy, Research Funding. Siritanaratkul:Novartis: Research Funding; Roche: Research Funding; Janssen: Research Funding. Schlossman:Millennium: Consultancy. Hou:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Sanofi: Consultancy. Sopala:Novartis Pharma AG: Employment. Panneerselvam:Novartis: Employment, Equity Ownership. Redhu:Novartis: Employment. Corrado:Novartis Pharma AG: Employment. Binlich:Novartis Pharma SAS: Employment.