Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis Version Date: 29JAN2019 Principal Investigator: Catherine J. Lee, MD Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis Lead Org. ID: HCI98381/IRB# 98381 CTO#HCI-17-HEME-07 ClinicalTrials.gov ID – NCT03303950 Principal Investigator Catherine J. Lee, MD Blood & Marrow Transplant Program University of Utah 2000 Circle of Hope, Rm 2152 Salt Lake City, UT 84132 Phone: (801) 587-0231 Email: [email protected] Sub-investigator(s) Douglas Sborov, MD Clinical Instructor, Department of Medicine Phone: (801) 581-8394 Email: [email protected] Vedran Radojcic, MD Assistant Professor, Department of Medicine Phone: (801) 213-6109 Email: [email protected] Daniel R. Couriel, MD, MS Director, Blood & Marrow Transplant Program Professor, Department of Medicine Phone: (801) 587-4056 Email: [email protected] Jo-Anna Reems, PhD (Laboratory) Scientific Director, Cell Therapy & Regenerative Medicine Research Professor, Department of Medicine Phone: (801) 585-6262 Email: [email protected] Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis Version Date: 29JAN2019 Principal Investigator: Catherine J. Lee, MD Michael Boyer, MD Associate Professor, Department of Medicine Phone: (801) 585-3229 Email: [email protected] Josef Prchal, MD Professor, Department of Medicine Phone: (801) 585-3229 Email: [email protected] Tibor Kovacsovics, MD Associate Professor, Department of Medicine Phone: (801) 213-5621 Email: [email protected] Janet Weidner, PA-C Physician Assistant, Division of Hematology Phone: (801) 587-0236 Email: [email protected] Mary Steinbach, DNP, APRN Nurse Practitioner, Division of Hematology Phone: (801) 587-1604 Email: [email protected] Sam Shewan, PA Physician Assistant, Division of Hematology Phone: (801) 213-2069 Email: [email protected] Statistician(s) Ken Boucher University of Utah Huntsman Cancer Institute 2000 Circle of Hope Salt Lake City, UT 84112 801-585-9544 [email protected] IND Number Exempt Historical Protocol Versions Version 1:26APR2017 Version 2:27OCT2017 Version 3: 02JUL2018 Version 4: 29JAN2019 Page 2 of 51 Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis Version Date: 29JAN2019 Principal Investigator: Catherine J. Lee, MD TABLE OF CONTENTS Page LIST OF ABBREVIATIONS ............................................................................................. 5 PROTOCOL SIGNATURE ................................................................................................ 9 STUDY SUMMARY........................................................................................................ 10 OBJECTIVES ................................................................................................................... 12 1.1 Primary Objectives and Endpoint ...................................................................... 13 1.2 Secondary Objectives and Endpoint .................................................................. 13 BACKGROUND .............................................................................................................. 13 2.1 Allogeneic in Stem Cell Transplantation in Multiple Myeloma ........................ 13 2.2 Allogeneic Stem Cell Transplant in Myelofibrosis ............................................ 13 2.3 Post allograft Cyclophosphamide....................................................................... 14 2.4 Detection of minimal residual disease (MRD) following transplantation in MM and MF .......................................................................................................................... 14 DRUG INFORMATION .................................................................................................. 14 3.1 Busulfan ............................................................................................................. 14 3.2 Fludarabine ......................................................................................................... 15 3.3 Cyclophosphamide ............................................................................................. 15 STUDY DESIGN.............................................................................................................. 16 4.1 Number of Patients ............................................................................................. 16 4.2 Number of Study Centers ................................................................................... 16 4.3 Study Duration ................................................................................................... 16 ELIGIBILITY CRITERIA................................................................................................ 17 5.1 Inclusion Criteria ................................................................................................ 17 5.2 Exclusion Criteria ............................................................................................... 18 5.3 Donor Inclusion Criteria..................................................................................... 18 TREATMENT PLAN ....................................................................................................... 20 6.1 Administration Schedule .................................................................................... 20 6.2 Treatment Administration .................................................................................. 21 6.3 Accountability and Compliance ......................................................................... 22 6.4 Prohibited Concomitant Medications ................................................................. 22 6.5 Duration of Therapy ........................................................................................... 22 TOXICITIES AND DOSEAGE MODIFICATION ......................................................... 22 7.1 Supportive Care .................................................................................................. 23 7.2 Diagnosis and Treatment of Acute GVHD ........................................................ 23 7.3 Diagnosis and Treatment of Chronic GVHD ..................................................... 24 STUDY CALENDAR ........................................................................................................ 25 CRITERIA FOR EVALUATION AND ENDPOINT ...................................................... 27 9.1 Non-relapse mortality (NRM) up to day +365 ................................................... 27 9.2 Rate of acute GVHD grade II-IV at Day +100 post-transplant.......................... 27 9.3 Cumulative chronic GVHD rates ....................................................................... 27 9.4 Response (clinical and molecular, disease free survival) ................................... 28 9.5 Safety .................................................................................................................. 30 9.6 Stopping Rules ................................................................................................... 31 STATISTICAL CONSIDERATIONS.............................................................................. 31 Page 3 of 51 Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis Version Date: 29JAN2019 Principal Investigator: Catherine J. Lee, MD REGISTRATION GUIDELINES ..................................................................................... 31 DATA SUBMISSION SCHEDULE ................................................................................ 31 ETHICAL AND REGULATORY CONSIDERATIONS ................................................ 32 13.1 Informed consent ............................................................................................ 32 13.2 Institutional Review ........................................................................................ 32 13.3 Data and Safety Monitoring Plan ................................................................... 32 13.4 Adverse Events / Serious Adverse Events ...................................................... 32 13.5 SAE Reporting Requirements ........................................................................ 35 13.6 Reporting of Pregnancy .................................................................................. 37 13.7 Protocol Amendments .................................................................................... 37 13.8 Protocol Deviations ........................................................................................ 37 13.9 FDA Annual Reporting .................................................................................. 38 13.10 Clinical Trials Data Bank ............................................................................... 38 13.11 Record Keeping .............................................................................................. 38 REFERENCES ................................................................................................................. 38 Appendices ........................................................................................................................ 43 Page 4 of 51 Protocol name: Allogeneic Stem Cell Transplantation for Multiple Myeloma and Myelofibrosis Version Date: 29JAN2019 Principal Investigator: Catherine J. Lee, MD LIST OF ABBREVIATIONS Abbreviation or Term1