Unremitting Presence of Marrow Immunoglobulin Heavy Chain Gene Rearrangement (IGH-GR) 3 Months Following Autotransplant Is Associated with Poor Outcome in Disease Control in Patients with Multiple Myeloma (MM).
Authors: Lee Choon Kee , Wei Qi , Lovell Mark , Swisshelm Karen , Ryder John , Myint Han , Kolhouse J. Fred , Robinson William 
Published: October 2019

Abstract
Abstract 1807
Poster Board I-833
In the study, we sought to determine the role of serial monitoring of immunoglobulin heavy chain monoclonality by IGH-GR tests in symptomatic MM patients who have been uniformly treated with induction chemotherapy, autotransplant following high-dose melphalan-based ablative therapy and post-transplant maintenance. Between September 2006 and April 2009, 51 patients (median age 60, range 37 – 77 years) were evaluated for conventional cytogenetics, myeloma FISH panel and IGH-GR on bone marrow samples prospectively every 3 months (mo) starting before initiation of therapy. The myeloma FISH panel included probes for chromosomes 1, 4, 11, 13, 14, and 17. IGH-GR test was performed by the InVivoScribe Technologies IGH Gene Rearrangement Assay using PCR primers targeting the conserved framework within the V-J region and J regions. A segment of the HLA-DQA1 gene was amplified as a control for patient DNA quality. 22 patients had IgG, 12 IgA, 13 light chain only and 4 nonsecretory MM. 30 patients (59%) were previously treated before and 16 (31%) had prior relapse. 23 patients (45%) received a tandem transplant and all patients received a maintenance regimen that included bortezomib and lenalidomide. Of the 51 patients, 11 (22%) had pre-therapy cytogenetic abnormalities (CA), 22 (43%) FISH abnormalities (FA) and 22 (43%) positive IGH-GR for monoclonality. Detection of positive IGH-GR was not associated with either CA (Fisher's exact test, p = 0.32) or FA (p = 0.14). The 3-year overall survival was 92% with 4 deaths. Relapse occurred in 10 with a 3-year cumulative index (CI) of 20%. In 3 to 12 mo following the first transplant, CA were seen in 7 (14% - 3 mo), 4 (8% - 6 mo) and 3 patients (6% - 12 mo); for FA, 9 (18%), 5 (10%) and 4 (8%); for IGH-GR, 10 (20%), 6 (12%) and 8 (17%). Findings before therapy were prognostic in survival and disease control. The 3-yr Kaplan-Meier survival was 80% for 11 patients (22%) with pre-therapy CA compared to 96% for those (n = 40) without CA (Logrank p = 0.02), 83% for 22 patients with FA (43%) compared to 100% for those (n = 29) without FA (p = 0.03), and 87% for 22 positive for IGH-GR (43%) versus 96% for those (n = 29) negative for IGH-GR (p = 0.03). Pre-therapy CA but not FA nor IGH-GR was significant for the CI of relapse: 33% vs. 15%, p = 0.06. Of the post-transplant follow-up on the CI of relapse, only the 3-mo evaluation was prognostically significant (Table). Although the current findings require further study for confirmation, the data suggests a potential role of IGH-GR tests in monitoring treatment responses in patients with MM. Additional primers such as the ones used in the BIOMED-2 may increase the sensitivity of test.
Cumulative Index of Relapse Pre-therapy 3-mo post-transplant 6-mo post-transplant 12-mo post-transplant CA + vs. - 33% vs. 15% P=0.06 43% vs. 18% P = 0.02 50% vs. 23% P = 0.03 33% vs. 13% P = 0.7 FA + vs. - 17% vs. 17% P = 0.52 33% vs. 16% P = 0.02 40% vs. 19% P = 0.67 25% vs. 15% P = 0.16 IGH-GR + vs. - 28% vs. 9% P = 0.57 30% vs. 19% P = 0.001 29% vs. 17% P = 0.3 25% vs. 19% P = 0.37

Disclosures
Myint: Seattle Genetics, Inc.: Research Funding.