An Expanded Treatment Protocol of Panobinostat Plus Bortezomib and Dexamethasone in Patients With Previously Treated Myeloma  Vincent L. Hansen, Morton Coleman, Stephanie Elkins, Jeffrey P. Letzer, Moshe Yair Levy, Lasika Seneviratne, Jessica Rine, Marina White, Emil T. Kuriakose  Clinical Lymphoma, Myeloma and Leukemia  Volume 18, Issue 6, Pages 400-407.e1 (June 2018) DOI: 10.1016/j.clml.2018.03.002 Copyright © 2018 The Authors Terms and Conditions

Figure 1 PANEX (Panobinostat Expansion) Treatment Schedule. Panobinostat (20 mg) Was Given 3 Times per Week During Weeks 1 and 2 of Each 3-Week Cycle During Both Treatment Phases. Bortezomib (1.3 mg/m2 Subcutaneously or Intravenously) Was Administered Twice Weekly for the First 2 Weeks of Each 3-Week Cycle in Treatment Phase 1 and Was Reduced to Once Weekly in Treatment Phase 2, With Dexamethasone (20 mg) Always Administered on the Day of and the Day After Bortezomib Administration Clinical Lymphoma, Myeloma and Leukemia 2018 18, 400-407.e1DOI: (10.1016/j.clml.2018.03.002) Copyright © 2018 The Authors Terms and Conditions

Figure 2 Diarrhea Management Algorithm. Guideline for Management of Diarrhea During Treatment in the PANEX (Panobinostat Expansion) Trial. Patients Presenting With Grade 1 Diarrhea at Screening Were Advised to Begin Antidiarrheal Prophylaxis With Standard-Dose Loperamide (4 mg, Followed by 2 mg Every 4 Hours or After Each Loose Stool). Patients Were Allowed to Begin Treatment With Panobinostat (PAN) if Already Receiving Loperamide. During the Study, Patients Experiencing Grade 1 Diarrhea Were Given Standard-Dose Loperamide and Allowed to Continue Treatment. In Patients Experiencing Grade 2 Diarrhea, PAN Treatment Was Interrupted and High-Dose Loperamide (4 mg, Followed by 4 mg Every 4 Hours or After Each Loose Stool) Was Administered. On Recovery to Grade ≤ 1, Patients Could Restart PAN at the Same Dose. In the Event of Persistent Grade 2 Diarrhea, Diphenoxylate/Atropine (5 mg Every 6 Hours) Was Added to High-Dose Loperamide. On Improvement to Grade ≤ 1, PAN Was Restarted at the Same Dose With a Reduced Dose of Bortezomib (BTZ). In the Event of Grade 3/4 Diarrhea, PAN Treatment Was Interrupted, and Patients Started High-Dose Loperamide and Diphenoxylate/Atropine. If Diarrhea Improved to Grade ≤ 1, Patients Could Resume PAN at a 1-Dose Level Reduction. In the Case of Persistent Diarrhea, BTZ Was Reduced 1 Dose Level. On Improvement to Grade ≤ 1, Patients Could Resume PAN at a 1-Dose Level Reduction With a Reduced Dose of BTZ. aFour Milligrams Followed by 2 mg Every 4 Hours or After Each Loose Stool (Maximum, 16 mg/d). bFour Milligrams Followed by 2 mg Every 2 Hours or 4 mg Every 4 Hours (Maximum, 16 mg/d). cFive Milligrams Every 6 Hours. dOn Resolution to Grade ≤ 1. eFor Further Episodes of Grade 3/4 Diarrhea, PAN Dose Reduced To Not < 10 mg/d and/or BTZ Dose Reduced to 0.7 mg/m2 at Investigator’s Discretion Clinical Lymphoma, Myeloma and Leukemia 2018 18, 400-407.e1DOI: (10.1016/j.clml.2018.03.002) Copyright © 2018 The Authors Terms and Conditions

Figure 3 Analysis of Platelet Kinetics Stratified by Route of BTZ Administration. Analysis of Median Platelet Values Stratified by Visit for Patients Receiving Intravenous (IV; Blue Line) or Subcutaneous (SC; Red Line) BTZ. Note the Characteristic Platelet Rebound Regardless of Route of BTZ Administration in Off-Treatment Week of Each Cycle. aThe final patient in the intravenous BTZ cohort discontinued after visit 22 because of progressive disease; laboratory assessments were not collected during the week 4 visit Abbreviations: BTZ = bortezomib; Dex = dexamethasone; EOT = end of treatment; IV = intravenous; PAN = panobinostat; SC = subcutaneous. Clinical Lymphoma, Myeloma and Leukemia 2018 18, 400-407.e1DOI: (10.1016/j.clml.2018.03.002) Copyright © 2018 The Authors Terms and Conditions