Achievement of Sustained Molecular Remission Induces Long-Term Freedom From Disease After Autologous-Allogeneic Tandem Transplantation in Patients with Multiple Myeloma
Authors: Kröger Nicolaus , Zabelina Tatjana , Ayuk Francis , Wolschke Christine , Alchalby Haefaa , Badbaran Anita , Atanackovic Djordje , Schilling Georgia , Sezer Orhan , Bacher Ulrike , Stübig Thomas , Fehse Boris , Zander Axel R. 
Published: October 2019

Abstract
Abstract 148
Multiple Myeloma (MM) is considered to be an incurable disease, but in some patient long-term survival can be achieved after high dose chemotherapy followed by autologous or allogeneic stem cell transplantation. Those patients, who achieved molecular remission, have a high probability of long-term disease-freedom and of cure. More recently the introduction of dose-reduced conditioning and the use of auto-allo tandem approach has broaden the use of allogeneic stem cell transplantation in MM, but the results of prospective trials are controversial. We here investigated within a prospective protocol the incidence and impact of molecular remission on long-term outcome obtained after auto-allo tandem approach in MM. (study registration NCT 00781170).
From 4/2000 to 10/2008, 73 patients with a median age of 50 years (r 29–64) and advanced stage II/III MM were included. The conditioning regimen for autologous transplantation consisted of melphalan 200 mg/m2 given divided over 2 days. After an interval of 2–3 months, the patients received a dose-reduced conditioning consisting of melphalan 140 mg/m2, fludarabine 180 mg/m2 and ATG Fresenius® (Fresenius, Bad Homburg, Germany) at a dose of 10 mg/kg for related and 20 mg/kg for unrelated donors on day -3, -2, and -1 followed by allogeneic stem cell transplantation.
Remission was defined according to modified EBMT criteria. In 46 patients with CR or nCR minimal residual disease could be monitored by myeloma-specific primers (allele specific oligonucleotides, ASO) targeting IgH gene rearrangements (n=20) or by highly sensitive plasma cell chimerism using real-time PCR after magnet-activated cell sorting of CD138+ cells (n=26). The sensitivity of plasma cell chimerism was 10−4 using real-time PCR and donor/patient specific polymorphisms and 10−5 in case of Y-PCR. Sensitivity for nested PCR with myeloma-specific primers was 10−5. In 5 patients only 1 MRD measurement was available and those patients were excluded from MRD sub-analysis. Molecular complete remission was defined as by least two negative PCR results with ASO primers or achievement of at least two times ≥99.9 % donor chimerism of plasma cells by real-time PCR from bone marrow samples. Sustained MRD negativity was defined by at least 4 negative molecular results either by ASO primer or plasma-cell chimerism. Mixed MRD was defined by negative molecular markers for at least two times, but intermittent positivity was defined by myeloma-specific primers or plasma cell chimerism.
Overall 44 patients (60 %) achieved a CR according to EBMT criteria with negative immunofixation. 8 % achieved a VGPR and 18 % a partial remission. 3 % had progressive disease and 11 % were not evaluable for determination of remission. Molecular remission was observed in 30 patients, in 15 patients the molecular markers were sustained negative while in 15 patients molecular markers were only intermittent negative, resulting in an overall complete molecular remission rate of 46 % and a stable sustained complete molecular remission rate of 23 %.
After a median follow-up at 7 years the 5 year progressive-free survival was 29 % (95% CI: 17–41%). Patients without del(13q14) had a significantly better PFS than those with del(13q14) (5 y: 56% vs. 17%, p=0.02). Patients who achieved CR after transplantation had improved PFS in comparison to non-CR patients (5 y: 41% vs. 28%, p=0.008). Patients with sustained negative molecular remission had a 5 year PFS of 85 % vs. 31 % for mixed molecular remission (p= 0.003).
The 5 year overall survival was 52 % (95% CI: 40–64%). Patients without del(13q14) had significantly improved 5 year survival (75% vs. 40%. p=0.02). Patients who achieved a sustained molecular remission had a 5 year OS of 91 % while those with mixed molecular remission resulted in a 5 year OS of 87 % (p=0.06).
The study underlines the importance of the depth of remission and shows that achieving molecular remission as determined by myeloma-specific IgH gene rearrangements and plasma cell chimerism is associated with long-term freedom from disease and potential cure of MM in an auto-/allo SCT approach.

Disclosures:
No relevant conflicts of interest to declare.