Bortezomib (BOR)-Thalidomide-Dexamethasone (VTD) and High-Dose Melphalan (HDM) As First Line Treatment for Multiple Myeloma (MM) Is Associated with a Lower Rate of Second Primary Malignancies (SPMs) Compared to TD Plus HDM
Authors: Brioli Annamaria , Pezzi Annalisa , Derudas Daniele , Petti Maria Concetta , Zannetti Beatrice Anna , Ferrara Felicetto , Rocchi Serena , Nobile Francesco , Baraldi Anna , Musto Pellegrino , Lanza Francesco , Mancuso Katia , Canepa Letizia , Catalano Lucio , Lazzaro Antonio , Pinotti Graziella , Boccadoro Mario , Cavo Michele 
Published: October 2019

Abstract
The availability of novel drugs such as immunomodulatory drugs, IMiDs, and proteasome inhibitors, PI, for the front line treatment of Multiple Myeloma (MM) has dramatically changed patients’ outcomes, significantly prolonging progression free survival (PFS) and translating into an extended overall survival (OS). Despite these impressive results, concerns have been raised regarding the possibility that IMiDs (lenalidomide and thalidomide) might increase the risk of developing SPMs, especially when associated with alkylating agents such as melphalan (MEL). It has long been known that the use of MEL can result in an increased incidence of SPMs, and this risk seems to be increased by the association with IMiDs. By the opposite, the use of PI in newly diagnosed MM (NDMM) patients (pts) was not associated with an increased risk of SPMs in a phase III study aimed at comparing BOR, MEL and prednisone (MP) vs MP.[1] Despite these results, the full impact of an upfront treatment containing both a PI and an IMiD in association with high dose MEL still has to be investigated.
To address this issue, we have evaluated the incidence of SPMs in pts enrolled in the GIMEMA 26866138-MMY-3006 multicentre phase III study aimed at comparing BOR, thalidomide and dexamethasone (VTD) versus TD as induction before, and consolidation after, a double course of high dose MEL.
The trial, conducted in Italy from 2006 to 2008, enrolled 480 transplant eligible NDMM, of which 474 received assigned treatment. Data on the incidence of SPMs are available for 299 pts (63%, 148 VTD and 151 TD).
With a median follow up of 73 months, 25/299 pts (8%) developed a SPM: 7 (2%) SPMs were hematologic and 18 (6%) were non hematologic. The median time from trial entry to development of the SPM was 36 months (range 8.4-69.0). The number of pts developing a SPM was lower in VTD arm (5%) compared to TD arm (11%, p=0.068). Among pts developing a SPM, the proportion of solid malignancies was similar between treatment arms (75% and 71% in VTD and TD, respectively). Similarly, the percentages of hematologic SPMs was 25% for VTD pts and 29% for TD. On the overall population, the incidence rate (IR) of developing a SPM was 1% at 1 year and 9.9% at 6 years (yrs). This incidence was significantly lower for patients randomised to VTD compared with patients receiving TD (6% vs 13% at 6 yrs, p=0.037). When looking at the IR of solid tumours we noticed that only 5% of VTD-treated patients developed a solid SPM, as compared to 9.6% in TD; similarly, less hematologic SPMs were observed in the BOR arm (1% vs 4% at 6 yrs for VTD and TD, respectively). When the analysis was performed according to SPMs type, no statistical significance could be demonstrated.
Our data compare favourably with data previously reported on the incidence of developing SPMs in NDMM treated with BOR frontline in association with MEL. With a follow up of 6 years, we were able to confirm that treatment with PI is associated with a low risk of developing SPM. Interestingly our data suggest that treatment with PI might decrease the risk of developing a SPM compared to IMiDs based treatment. Randomised trials with PI and IMiDs treatment should prospectively evaluate this issue.
References
1. San Miguel, J.F., et al., Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with previously untreated multiple myeloma. J Clin Oncol, 2013. 31(4): p. 448-55.

Disclosures
Musto: Janssen: Honoraria; Celgene: Honoraria. Cavo:Onyx: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Millenium Pharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau.