High Frequency of Molecular Remissions (m-CR) in Multiple Myeloma Patients Achieving a Hematologic Complete Remission (CR) on Total Therapy II (TT-2).
Authors: Tricot Guido , Carrabba Matteo , Barlogie Bart , Epstein Joshua , Shaughnessy John , Corradini Paolo 
Published: October 2019

Abstract
TT-2 represents a very intensive treatment approach for newly diagnosed myeloma patients consisting of hematopoietic growth factor-dependent induction therapy (VAD, DCEP, CAD, DCEP); followed by melphalan 200 mg/m2-based tandem autotransplant; 4 quarterly consolidation chemotherapy cycles with D-PACE; and interferon alpha maintenance with added dexamethasone pulsing during the first year. A stringently defined hematologic CR (immunofixation negative, normal bone marrow aspirate and biopsy, and absence of a light-chain restricted aneuploid population of bone marrow plasma cells by DNA/cIg flow cytometry) was obtained in 48% of the first 446 patients enrolled on TT-2. A CR defined as such probably reflects a detection threshold of 108–109 tumor cells. CDR3-PCR to evaluate minimal residual disease (MRD) in myeloma has revealed m-CR in 50% of 40 reported allotransplant cases compared to approximately 15% among 75 reported autotransplants myeloma. We evaluated the frequency of m-CR in 20 TT-2 patients with a qualitative PCR for CDR3, which can detect 1 myeloma cell in 105–106 normal bone marrow cells (Corradini et al. J Clin Oncol 1999, 17: 208). CDR3 probes were generated from RNA of CD138 immunogenetic bead-purified plasma cells obtained at diagnosis. Light-density (<1.077 g/cm3) bone marrow cells served as the source of DNA post-therapy to assess MRD. The quality of DNA was determined by amplification of the p53 exon 6 sequence on all CDR3-PCR negative cases. At the time of CDR3-PCR analysis, 13 patients were in hematologic CR, 1 in near CR (immunofixation positivity as the only evidence of disease), 4 in partial remission (PR) (bone marrow < 5% plasma cells, decrease in serum M protein ≥ 75% and in urine M protein ≥ 90%) and two had less than a PR. Four patients were tested for MRD prior to the first transplant (2 < PR, 1 PR, 1 CR), two prior to the second transplant (2 PR) and 14 at a median of 21 months (range 6 months to 2 years) after the second transplant (12 CR, 1 near CR, 1 PR). Six of the 13 CR patients had abnormal metaphase cytogenetics at diagnosis, including 5 with deletion of chromosome 13. A m-CR was observed in 10/13 (77%) hematologic CR patients, including 4/6 with abnormal cytogenetics and 6/7 with normal cytogenetics. P53 exon 6 amplification was seen in all patients who were CDR3-PCR negative. Not unexpectedly, all seven patients failing to achieve a stringently defined hematologic CR had persistent disease as assessed by CDR3-PCR. Our results suggest that high intensity therapy as applied in TT-2 can indeed achieve a more marked tumor cytoreduction as reflected by a higher m-CR rate than previously reported with autotransplantation also in patients with baseline abnormal metaphase cytogenetics, and that the m-CR rate appears to be at least equivalent to that observed after allotransplantation. It remains to be shown whether achieving a m-CR will result in prolonged survival and a potential of cure in myeloma as has been shown convincingly for other hematologic malignancies. An additional 35 hematologic CR patients have samples available for CDR3-PCR analysis so that, at the time of presentation, a more definitive assessment of TT-2’s potential to effect a m-CR can be presented.