Consolidation with Bortezomib, Thalidomide and Dexamethasone Induces Molecular Remissions in Autografted Multiple Myeloma Patients.
Authors: Ladetto Marco , Pagliano Gloria , Avonto Ilaria , Santo Loredana , Ferrero Simone , Cavallo Federica , Astolfi Monica , Pregno Patrizia , Crippa Claudia , Liberati Anna Marina , Callea Vincenzo , De Rosa Luca , Falcone Antonietta , Grasso Mariella , Drandi Daniela , Boccadoro Mario , Palumbo Antonio 
Published: October 2019

Abstract
Background and aims: Persistence of molecularly detectable minimal residual disease (MRD) is a nearly constant finding in MM following autologous transplantation (ASCT). On the other hand, molecular remission (MR) can be obtained in MM in the allogeneic setting and is a basic requisite for long-term disease control (Corradini et al, Blood 2003). In this study a consolidation treatment, including Bortezomib/Thalidomide/Dexamethasone (VTD), was employed in the post-ASCT setting in patients (pts) undergoing strict molecular monitoring by qualitative and quantitative PCR to induce further cytoreduction and to verify if a proportion of them could enter MR.
Patients and methods: Inclusion criteria were:
a documented complete or very good partial remission (CR or VGPR) following ASCT delivered as first line treatment; no previous treatment with thalidomide and bortezomib; presence of a molecular marker based on the IgH rearrangment. Primary endpoint of the study was to obtain MR in > 20% of pts.
Methods: VTD had to be started within 6 months from ASCT. Each cycle consisted of:
Bortezomib 1.6 mg/m2 as an IV injection once weekly (on days 1, 8, 15, 22) followed by a 13-day rest period (days 23–35); Thalidomide at the initial dose of 50 mg/day PO once daily, with increments of 50 mg every 7 days up to 200 mg; Dexamethasone 20 mg/day PO once daily, on days 1 to 4, 8 to 11 and 15 to 18 followed by a 17-day rest period (days 19–35).
A total of 4 cycles were delivered. MRD was assessed on bone marrow (BM) samples at study entry, after two VTD courses, at the end of treatment and then at six months intervals. Qualitative and quantitative PCR analysis were carried out using IgH-derived patient-specific primers as already described (Voena et al, Leukemia 1997; Ladetto et al, Biol Bone Marrow Transpl 2000).
Results: Forty pts were enrolled and are evaluable at study entry. As expected 94% of pts were PCR-positive following ASCT. 18% did not receive the whole planned treatment, including one toxic death. The six pts requiring treatment reduction/discontinuation were nevertheless included in the MRD analysis. 35 PCR-positive pts at study entry are evaluable after 2 VTD courses and 17% converted to PCR negativity. 27 pts are evaluable at the end of the program with a PCR-negativity rate of 22%. Subsequent follow-up samples are available in 22 pts. All PCR-negative pts assessed at 6 months (four cases) and at 6 and 12 months (two cases) persisted in MR. Seven relapses/progressions occurred and were all among PCR-positive pts. Real-time PCR has been so far performed in ten persistently PCR-positive pts with a >0.5 log tumor reduction in eight of them (median 1.2 log; range 0.2–2.1).
Conclusions: VTD consolidation allows a proportion of CR/VGPR MM pts to enter MR and has a measurable anti-tumor effect also in persistently PCR-positive pts. This study is the first demonstration that new non chemotherapeutic agents have activity on MRD persisting following ASCT and indicate that MR is an achievable goal also outside the allogeneic transplantation setting.