Major Tumor Shrinking and Persistent Molecular Remissions After Consolidation With Bortezomib, Thalidomide, and Dexamethasone in Patients With Autografted Myeloma

Abstract

PURPOSE We investigated the effect on minimal residual disease, by qualitative and real-time quantitative polymerase chain reaction (RQ-PCR), of a consolidation regimen that included bortezomib, thalidomide, and dexamethasone (VTD) in patients with multiple myeloma (MM) responding to autologous stem-cell transplantation (auto-SCT). PATIENTS AND METHODS Patients achieving at least very good partial response who had an available molecular marker based on the immunoglobulin heavy-chain rearrangement received four courses of treatment every month: four infusions per month of bortezomib at 1.6 mg/m(2), thalidomide at 200 mg/d, and dexamethasone at 20 mg/d on days 1 to 4, 8 to 11, and 15 to 18. Patients were studied with tumor-clone-specific primers by qualitative nested PCR and RQ-PCR. Results Of 39 patients enrolled, 31 received the four VTD courses. Immunofixation complete responses increased from 15% after auto-SCT to 49% after VTD. Molecular remissions (MRs) were 3% after auto-SCT and 18% after VTD. Median time to maximum response was 3.5 months. So far, no patient in MR has relapsed (median follow-up, 42 months). VTD consolidation induced an additional depletion of 4.14 natural logarithms of tumor burden by RQ-PCR. Patients with a tumor load less than the median value after VTD had outcomes better than those who had tumor loads above the median value after VTD (at median follow-up: progression-free survival, 100% v 57%; P < .001). CONCLUSION To the best of our knowledge, this study is the first to document the occurrence of persistent MRs in a proportion of MM patients treated without allogeneic transplantation. Moreover, the major reduction in tumor load recorded by RQ-PCR after VTD suggests that unprecedented levels of tumor cell reduction can be achieved in MM thanks to the new nonchemotherapeutic drugs.

Minimal residual disease testing after stem cell transplantation for multiple myeloma

“…38 As an alternative, ASO realtime quantitative PCR provides an accurate quantification of residual disease, thus overcoming the problem. Several reports using this technique have been published, showing effective outcome discrimination in the transplant setting 29,[39][40][41][42][43] (Table 5). …”

Consolidation and maintenance therapy for multiple myeloma after autologous transplantation: where do we stand?

“…Similarly, Ladetto et al 23 treated patients who had achieved at least a very good partial response following ASCT with four cycles of VTD consolidation and observed not only an increase in CR rates, but also in molecular remissions, which were found to be persistent as no patient with molecular remissions had relapsed at a median follow-up of 42 months. A retrospective study reported by Leleu et al 24 also showed the benefit of VTd (bortezomib-thalidomide-low dose dexamethasone) consolidation (with dexamethasone administered at 40 mg weekly) after a single ASCT following VTd induction.…”

Can multiple myeloma become a curable disease?

“…As already mentioned, the definition of CR is far from optimal, and sensitive techniques will contribute to the evaluation of minimal residual disease both at bone marrow (BM) level (by using molecular techniques, quantitative PCR, and immunophenotyping techniques such as flow cytometry) 13,18,19 and outside the BM (using imaging techniques such as MRI and PET-CT). [20][21][22] If myeloma continues to be evaluated by the M-component and morphology it will remain the Cinderella of hematologic malignancies in terms of the resources invested in monitoring treatment efficacy.…”

“…Thus, the benefit of treatment intensification in low-risk patients was recently demonstrated in a cohort who, although they were already in more than VGPR after ASCT, received intensification with VTD, and none of those who achieved a molecular remission has so far relapsed. 13 Accordingly, the risk of undertreating low-risk patients by concluding that they are already in conventional CR could be a serious error if cure is the goal. Clinical investigation based on large phase III randomized trials that integrate comprehensive genetic studies upfront and sensitive tools for monitoring treatment efficacy will be the best way to find appropriate answers to these questions.…”