Impact Of Consolidation With Bortezomib-Thalidomide-Dexamethasone (VTd) Upfront In Multiple Myeloma (MM) With Partial Response (PR) At Completion Of Induction With Vtd
Authors: Leleu Xavier , Fouquet Guillemette , Hebraud Benjamin , Garciaz Sylvain , Stoppa Anne-Marie , Roussel Murielle , Caillot Denis , Chretien Marie-Lorraine , Arnulf Bertrand , Szalat Raphael , Garderet Laurent , Benajiba Lina , Pegourie Brigitte , Regny Caroline , Royer Bruno , Caulier Alexis , Touzeau Cyrille , Tessoulin Benoit , Fermand Jean Paul , Facon Thierry , Attal Michel , Avet-Loiseau Herve , Moreau Philippe 
Published: October 2019

Abstract

Background
Several studies have demonstrated the impact of VTd on response rates and PFS either as induction or consolidation regimen. However, studies have also showed that VGPR and greater was associated with a better survival prognostic at completion of intensification regimen, and that these patients benefited most from consolidation. Questions remain as to the benefit of consolidation using VTd in patients that reached solely PR at completion of VTd induction, patients that display features of resistance to VTd partially.
We aimed to assess the efficacy and safety of VTd as consolidation therapy in the context of VTd as induction regimen followed by a single auto (VTd-auto-VTd regimen) in patients that reached PR at completion of Induction with VTd.

Method
This study has included a group of 121 newly diagnosed MM patients that underwent auto from 2009 to 2011 across 9 IFM centers. Patients were to be eligible for auto in first-line of treatment, aged less than 65 years old and treated with VTd-auto-VTd regimen. We then studied the 54 patients that reached PR (n=54) at completion of VTd induction.

Results
The median age was 57 years, the sex ratio was 1,25, 58% had ISS 2 and 3, 25% had adverse FISH, including t(4;14) and/or del17p (similar in the 2 groups).
Overall, 37 (68%) responded (at least VGPR) at completion of consolidation, including 33% and 35% that reached VGPR and CR, respectively. 55% and 37.5% of patients improved response rate after auto and consolidation, respectively. We then studied the role of consolidation whether or not patients responded to auto. Out of the 15 patients that remained on PR after auto (no benefit from auto), 35% responded at completion of consolidation. Out of the 31 patients that improved response rate to auto (at least VGPR), 32% further improved to CR at completion of consolidation. The median duration of response was prolonged from 10 (CI95% 10-14) months to 16 (13-20) months for patients in PR at completion of induction with VTd that further responded to consolidation VTd (p=0.24).
With a median follow-up of 36 months, 30% and 11% had relapsed and died, respectively. The incidence rate of relapse was greater in patients that did not benefit from consolidation, 86% versus 14%, (p=0.27). The median TTP was 26 (95%CI 13-38) months in patients that did not benefit from consolidation versus not reached yet for the second group (p=0.012); the 3-year TTP was 18% and 87%. The 3-year PFS was 18% and 58%, respectively (p=0.03). The median OS was not reached in either group, and the 2-years OS was 75%. In univariate analysis, the variables that shortened TTP were high serum beta2m greater than 5mg/L (p=0.014), adverse FISH (p=0.05), elevated serum LDH (p<0.0001), absence of response following auto (p=0.022) and absence of response following consolidation (p=0.012). We have then sought for independent variables that impacted TTP in multivariate analysis after exclusion of LDH, beta2m and FISH known to be the most powerful predicators of short TTP and OS. The response to consolidation was then the most important marker to predict shorten median TTP [OR = 4.4, 95%CI = 1-21; p = 0.039].
The safety profile of VTd consolidation in this population was similar to reports in patients that reached VGPR and greater at completion of induction with no excess toxicity. The incidence rate of hematological EIs of grade 3 and 4 was 2% with no excess and non hematological EIs related to consolidation. The incidence rate of neuropathy all grades was 7%, but only 2% occurred during the consolidation. We have also observed 9 (9%) thromboembolic events (TE), with none occurring during the consolidation phase.

Conclusion
This study showed an improved response rate in relation to the VTd consolidation phase in two-third of patients that only partially responded to the induction VTd regimen. This improved quality of responses translated into a lower relapse rate with a prolonged PFS. This study demonstrates that VTd consolidation in the context of a the VTd-auto-VTd regimen upfront should be recommended to all responders to the induction phase, including patients in PR characterized with a lower sensitivity to the VTd regimen.

Disclosures:
Leleu: Amgen: Honoraria; Millennium : Honoraria; Leopharma: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Honoraria. Roussel:CELGENE: Honoraria; JANSSEN: Honoraria. Facon:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Attal:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Moreau:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau.