Bortezomib-Based Induction Therapy Followed by Autologous Stem Cell Transplantation and Maintenance Therapy with Bortezomib Improves Outcome In Myeloma Patients with Gain 1q21 and t(4;14) - a Subgroup Analysis of the HOVON-65/GMMG-HD4 Trial
Authors: Goldschmidt Hartmut , Neben Kai , Bertsch Uta , Hielscher Thomas , van der Holt Bronno , Hose Dirk , Jarari Laila el , Salwender Hans , Blau Igor Wolfgang , Pfreundschuh Michael , Duehrsen Ulrich , Weisel Katja , Martin Hans , Lindemann Walter , Teschendorf Christian , Haenel Mathias , Scheid Christof , van de Velde Helgi , Derigs Hans Guenter , Hoffmann Martin , Peter Norma , Kaufmann Martin , Schmidt-Wolf Ingo , Jauch Anna , Lokhorst Henk M , Sonneveld Pieter 
Published: October 2019

Abstract
Abstract 305
Chromosomal aberrations are important prognostic parameters in multiple myeloma (MM). By using interphase fluorescent in situ hybridization (FISH) on CD138-enriched plasma cells, specific changes in interphase cells can be detected, overcoming the lack of dividing cells required for conventional cytogenetics. We evaluated the association of FISH results and outcome of a subgroup of patients (pts) within the HOVON-65/GMMG-HD4 trial, a prospective, randomized phase III trial for pts with newly diagnosed MM stage II or III according to Salmon & Durie up to 65 years. Pts were randomized to receive three cycles of VAD (arm A; vincristine, adriamycin, dexamethasone) or PAD (arm B; bortezomib, adriamycin, dexamethasone). Hematopoietic stem cells were mobilized using the CAD regimen and G-CSF. All pts received one or two cycles of high dose melphalan (200 mg/m2) with autologous stem cell transplantation followed by maintenance therapy with thalidomide 50 mg daily (arm A) or bortezomib 1.3 mg/m2 once every 2 weeks (arm B), respectively, for a maximum of 2 years. Sites in Germany, the Netherlands and Belgium participated in this trial (n=833 pts). For the German pts (GMMG, n=399) FISH was performed in a single laboratory prior to start of treatment. Cytospins of CD138 purified plasma cells were subjected to FISH with two-color probe sets for the detection of numerical changes for the following chromosome regions: 1q21/8p21, 6q21/15q22, 9q34/22q11, 11q23/13q14, and 17p13/19q13, as well as for the translocations t(4;14)(p16;q32), t(11;14)(q13;q32), and t(14;16) (q32;q23).
As of July 2010 data from the first consecutively enrolled 626 patients of the trial have been analyzed, including 284 GMMG pts. For this analysis, FISH results from 258 (91%) GMMG pts were available (n=131 in arm A; n=127 in arm B). Patient characteristics in the GMMG subgroup are comparable to the analyzed trial population of 626 pts.
For all pts the median follow-up time from randomization was 40.3 months (mo.). The most pronounced impact on prognosis was seen for t(4;14), del17p13, and gain1q21, each significantly associated with poor prognosis with respect to progression free survival (PFS) and overall survival (OS). The strongest prognostic impact was found for del17p13. FISH analysis detected del17p13 in 9.4% of pts (A: 12.3% vs. B: 6.4%), t(4;14) in 14.8 % (16.3% vs. 13.4%), and gain 1q21 in 33.7% of pts (33.1% vs. 34.4%).
When comparing pts in the two arms for PFS, we found a borderline significance for the interaction between t(4;14) and treatment arm (p=0.06), indicating that the effect of t(4;14) depends on the treatment. Pts with t(4;14) in arm A show a very poor prognosis with a median PFS time only half as long compared to patients without translocation (18 vs. 36 mo.; p=0.003). No such negative effect was observed for patients in arm B with t(4;14) (36 vs. 40 mo.; p=0.97). PAD resulted in improved 3yr-OS rates for pts with t(4;14) (A:39% vs B:76%), while 3yr-OS was 79% and 87% in pts without t(4;14).
Median PFS for pts with gain 1q21 was 22 mo. (arm A) vs. 30 mo. (arm B) compared to 41 mo. in both arms for patients without gain 1q21. Pts with gain 1q21 showed a significantly better OS when treated with bortezomib (3yr-OS rates: A: 59%, B: 83%, p=0.016). Del17p13 was significantly associated with poor prognosis in both arms for OS (A: p<0.0001, B:p=0.01) and PFS (A: p=0.0008, B: 0.07), with pts with del 17p13 in arm B showing higher PFS rates (median PFS of 26 mo.) compared to pts in arm A (median PFS of 13 mo., p=0.35), but based on low pts numbers.
In conclusion our analysis confirms the significant negative prognostic impact of del17p13 and gain 1q21 on PFS and OS for pts with newly diagnosed MM. In our analysis, the negative impact of t(4;14) on PFS could almost completely be overcome by the bortezomib-based treatment. Pts with t(4;14) also showed improved OS when treated with bortezomib, but still had an inferior prognosis compared to pts without this cytogenetic aberration. Similarly, bortezomib significantly prolonged OS in patients with gain 1q21 but did only partially overcome the adverse effect of this aberration.
The HOVON65/GMMG-HD4 trial (EudraCT nr 2004-000944-26) was supported by the Dutch Cancer Foundation, the German Federal Ministry of Education and Research and a grant from Janssen Cilag. The GMMG also received grants for this trial by Novartis, AMGEN, Chugai, Roche and the Tumorzentrum Heidelberg/Mannheim.

Disclosures:
Goldschmidt: Ortho Biotech: Honoraria, Research Funding; Amgen: Research Funding; Novartis: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Off Label Use: bortezomib in newly diagnosed myeloma. Neben:Ortho Biotech: Honoraria; Celgene: Honoraria. Pfreundschuh:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Duehrsen:Ortho Biotech: Honoraria. Weisel:Ortho Biotech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Scheid:Ortho Biotech: Honoraria. Velde:Johnson & Johnson: Employment. Schmidt-Wolf:Janssen Cilag: financial support (symposium); Celgene: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees.