2012-02 Total Therapy 5B: A Phase II Trial for High-risk Myeloma Evaluating Accelerating and Sustaining Complete Remission (AS-CR) By Applying Non-Host-Exhausting and Timely Dose-Reduced MEL-80-CFZ-TD-PACE Transplant(s) with Interspersed MEL-20-CFZ-TD-PACE with CFZ-RD and CFZ-D Maintenance
Principal Investigator: Dr. van Rhee
TT5B will attempt to accelerate and sustain, at 2 years from starting therapy, the proportion of subjects in complete remission (AS-CR-2) by reducing host-imposed toxicity and thus facilitating timely completion of highly synergistic 8-drug combination therapy, including the next generation proteasome inhibitor, Carfilzomib (CFZ). This will result in avoiding MM re-growth that, we postulate, ensued in TT3 during recovery phases from severe de-conditioning. Furthermore, we speculate that the incidence of positive minimal residual disease (MRD) will be reduced with the addition of one cycle of consolidation therapy. Toward this goal, the following approach will be implemented:
To perform, 48hr after CFZ 20 mg/m2 followed by 48 hour post melphalan 10 mg/m2, gene expression profiling (GEP) examinations of CD138-purified MM plasma cells (PC) and of bone marrow biopsy (BX) samples, and determine whether “response” and “resistance” GEP signatures can be identified via short-term GEP alterations in PC and BX, analogous to observations in TT3 with bortezomib1.
A sub-aim examines whether CFZ or melphalan-induced changes are tumor cell specific or might be genetically predetermined; toward this aim, we will compare and contrast GEP in peripheral blood (PB) mononuclear cells and MM tumor cells prior to and following drug(s) test dosing.
To perform such GEP examinations plus proteomic analyses on PC and BX procured from randomly sampled (RS) iliac crest bone marrow sites and from MRI-defined focal lesions (FL) under CT-guidance during defined phases of TT5B from the time of diagnosis to remission and on to relapse.
Patients with newly diagnosed, active, high-risk myeloma requiring treatment; patients with a history of smoldering myeloma if there is evidence of progressive disease requiring chemotherapy
2008-03 Total Therapy 6: Phase II Trial for Patients Not Qualifying for TT4 and TT5 Protocols Because of Prior Therapy (No Prior Transplant)
Principal Investigator: Dr. Barlogie
To determine the rate of complete and near-complete response at two years after initiation of therapy
To determine the frequency and duration of continued complete and near-complete response in relationship to: Duration of prior therapy (<6 months versus 6-12 months);.Prior response; Type of initial therapy, such as regimens containing Velcade or immunomodulatory agents (thalidomide, Revlimid) with or without melphalan
To determine duration of complete response and near-complete response
To determine event-free survival and overall survival
To apply separately bortezomib and low-dose Melphalan 10 mg/m2 and examine, via serial gene expression profiling (GEP) examinations of CD138-purified MM plasma cells (PC) and of un-separated bone marrow biopsy (BX) samples, whether “response” and “resistance” GEP signatures can be identified via short-term GEP alterations in PC and BX, analogous to observations in TT3 with Velcade
A sub-aim examines whether melphalan-induced changes are tumor cell specific or might be genetically predetermined; toward this aim, we will compare and contrast GEP in peripheral blood mononuclear cells and myeloma tumor cells prior to and following drug dosing
2010-35 A Phase II Study of Expanded Natural Killer Cell Therapy for Multiple Myeloma
Principal Investigator: Dr. van Rhee
To determine the therapeutic efficacy of the exp-NK cell therapy in research participants with relapsed high risk MM [defined as gene expression profile (GEP) 70 gene score ≥0.66 and/or GEP 80 gene score of ≥ 2.48 and/or metaphase chromosomal abnormalities and/or high LDH ≥ 360U/L] by establishing the (near) complete response rate. Response rate will be compared to case matched historical controls (patients who relapsed on Total Therapy 2 or 3 with high-risk MM defined as above). Disease-free survival and overall survival will be captured but are not primary or secondary endpoints.
To monitor the persistence of exp-NK cells by molecular methods in recipients of haploidentical exp-NK cells;
To determine whether escape from exp-NK cell recognition is the mechanism for relapse in those who fail the proposed therapy
Patients with high-risk disease; Previously-treated patients; Relapsed/Refractory patients