Impact of Early Consolidation with Bortezomib, Thalidomide and Dexamethasone on Molecularly-Detectable Disease in MM Patients in CR or VGPR Following Autologous Transplantation: Uncommon Achievement of Molecular Remission Despite Evidence of Tumor Load Reduction by Real Time PCR.
Authors: Ladetto Marco , Astolfi Monica , Santo Loredana , Avonto Ilaria , Cavallo Federica , Pagliano Gloria , Pregno Patrizia , Grasso Mariella , Liberati Anna Marina , Caravita Tommaso , Pisani Francesco , Guglielmelli Tommasina , Genuardi Elisa , Crivelli Rossana , Cristiano Carmen , Drandi Daniela , Boccadoro Mario , Palumbo Antonio 
Published: October 2019

Background. autologous transplantation (ASCT) is unable to induce molecular remission (MR) in MM as opposed to allogeneic transplantation. It is unknown whether the use of new non-chemotherapeutic agents following ASCT might ensure further cytoreduction allowing patients to enter this status which seems associated with a reduced risk of relapse. In this study patients achieving CR or VGPR following an ASCT-containing regimen were treated with an early consolidation regimen including Bortezomib, Thalidomide and Dexamethsone (VTD). This abstract is an initial report of the molecular results associated to this treatment.

Patients and Methods. Patients were eligible if they had the following:

a molecular marker based on the IgH rearrangment; a documented CR or VGPR following ASCT. The VDT had to be started within 6 months from ASCT.

Each cycle consisted of:

Bortezomib at the dose of 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 to acceptable tolerance (maximum 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.

Bone marrow samples for molecular analysis were taken at study entry, after 50% of treatment, at the end of treatment and then at three months intervals. Minimal residual disease (MRD) has been evaluated using clone-specific primers by nested PCR and real time PCR as published elsewhere (Voena et al, Leukemia 1997 and Ladetto et al Biol Bone Marrow Transpl 2000).

Results. 19 Patients have entered the study. One was already PCR negative after ASCT, one is not evaluable due to early toxicity. One patient still has no post consolidation samples available. 16 patients have been evaluated only after 50% of therapy and seven also at the end of the whole program. For five patients also follow-up samples taken at three and six months from the end of treatment are available. Nested PCR was always PCR positive with the exception of three patients. One had a PCR-negative sample after 50% of consolidation therapy but reverted to PCR positivity at the end of treatment and remained PCR-positive at three months from the end. One patient is PCR-negative after 50% of therapy but we still do not have subsequent follow-up samples. Only one patient achieved PCR negativity following two VTD courses and mantained MR for the two subsequent follow-up examinations. Real time quantitative PCR is currently available in four patients. In three a clear reduction of tumor burden was observed following VTD treatment (median reduction 0.87 log).

Discussion. Consolidation with VTD has some activity on MRD as documented by the reduction of the clonal cell burden assessed by real time PCR. However in most patients, the present approach seems unable to reduce the tumor load below the sensitivity threshold of the most sensitive PCR-based approaches.