This phase I/II trial studies the side effects and best dose of melphalan and total marrow irradiation and how well they work with stem cell transplant in treating patients with high-risk multiple myeloma. Drugs used in chemotherapy, such as melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Total marrow irradiation is a type of radiation therapy and a form of total body irradiation that may deliver focused radiation to the major marrow sites where cancer cells reside. Giving chemotherapy and total-body irradiation before a peripheral blood stem cell transplant helps kill any cancer cells that are in the body and helps make room in the patient’s bone marrow for new blood-forming cells (stem cells) to grow. After treatment, stem cells are collected from the patient's blood and stored. More chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03100877.
PRIMARY OBJECTIVES:
I. To assess the safety and determine the maximum tolerated dose (MTD) of melphalan and fractionated total marrow irradiation (TMI) as conditioning for autologous stem cell transplantation (ASCT) patients with high-risk or treatment-insensitive multiple myeloma (MM). (Phase I)
II. Evaluate the safety of the regimen at each dose level by assessing adverse events: type, frequency, severity, attribution, time course, duration.
III. Evaluate the safety of the regimen at each dose level by assessing complications including: infection, delayed engraftment and secondary malignancy.
IV. To assess complete response (CR) and minimal residual disease (MRD) rates at 100 days post ASCT in a phase II expanded cohort of patients treated at the MTD. (Phase II)
SECONDARY OBJECTIVES:
I. To assess the predictive value of high risk features inclusive of fluorescent in situ hybridization (FISH), lactate dehydrogenase (LDH), International Staging System (ISS) stage, gene expression profiling (GEP) for CR and minimal residual disease (MRD) for relapse free survival/progression free survival/overall survival (RFS/PFS/OS) after melphalan TMI (mel/TMI).
II. To assess MRD by positron emission tomography (PET), next generation sequencing (NGS), and flow cytometry after mel/TMI, prior to maintenance and correlation with PFS and OS.
III. To assess in a descriptive fashion PFS and OS following mel/TMI and ASCT.
IV. Evaluate changes in fludeoxyglucose F-18 (FDG) PET pre and post TMI/melphalan.
TERTIARY OBJECTIVES:
I. Assessment of bone marrow residual damage.
II. Assessment of immune recovery dynamics.
III. To conduct genetic profiling of myeloma cells.
IV. Multimodal imaging for non-invasive assessment of treatment effect on bone and marrow.
OUTLINE: This is a phase I, dose-escalation study of melphalan and TMI followed by a phase II study.
MOBILIZATION AND APHERESIS: Patients receive cyclophosphamide intravenously (IV) over 2 hours. Beginning 24 hours after cyclophosphamide administration, patients receive filgrastim subcutaneously (SC) or IV. Patients also undergo apheresis over 4 hours on day 10.
CONDITIONING REGIMEN: Patients receive palifermin IV on days -8, to -6, undergo TMI on days -5 to -2, and receive melphalan IV over 30 minutes on day -1. Patients then undergo ASCT IV on day 0, receive palifermin IV on days 1-3, and receive filgrastim SC or IV on day 5.
MAINTENANCE THERAPY: Beginning 30 days after ASCT, patients receive lenalidomide orally (PO) daily.
Lead OrganizationCity of Hope Comprehensive Cancer Center
Principal InvestigatorGeorge Somlo
