Subcutaneous Bortezomib, Thalidomide and Dexamethasone As Induction Therapy Prior to Autologous Peripheral Blood Stem Cell Transplantation in Young Patients Diagnosed of Multiple Myeloma. a Retrospective Analysis from Two Centers
Authors: Jiménez Ruiz De La Torre David , Ibarra Gladys , Encuentra Maite , Abril Laura , Oriol Albert , Ribera Josep-Maria , Sureda Anna 
Published: November 2019

INTRODUCTION
The combination of intravenous bortezomib, thalidomide and dexamethasone (VTD) is a well described induction treatment for young patients with multiple myeloma (MM) that are candidates to be consolidated with an autologous stem cell transplantation (auto-HCT) as first line strategy. Peripheral neuropathy (PN), mostly sensory but also motor, is a common side effect of intravenous bortezomib. The subcutaneous (sc) formulation of bortezomib has been more recently introduced in the market and has demonstrated a similar efficacy but a significantly lower toxicity profile, mostly represented with a reduction in the incidence and severity of PN. Herein, we describe our clinical experience with sc VTD as induction therapy before auto-HCT in a series of 80 consecutive patients with the novo MM.
PATIENTS AND METHODS
Consecutive patients with de novo MM younger than 65 years and candidates for auto-HCT diagnosed between January/2016 and December/2018 and treated during this period of time with scVTD at the Catalan Institute of Oncology (Hospitalet and Badalona) were included. Six cycles of scVTD (bortezomib at a dose of 1.3 mg/m2 sc days 1,4,8 and 11, thalidomide 50 mg po daily with progressive increasing dosage up to 200 mg if adequate tolerance and dexamethasone 40 mg po days 1, 4, and 12) every 28 days were given. Disease response was evaluated after the first three cycles and at the end of induction and before auto-HCT. Hematological and extra-hematological toxicity was evaluated following standard CTCAE criteria. Peripheral blood progenitor cells were collected after single drug G-CSF (10 ug/kg/day sc x 4-5 days) and a minimum number of 2.5 x 106 CD34+ cells/kg was required to proceed to auto-HCT. All patients were conditioned with high dose melphalan (200 mg/m2 iv). Disease response was evaluated at 3 months after auto-HCT following standard criteria.
RESULTS
80 patients were included, 38 (47.5%) males and 42 (52.5%) females with a median (range) age at the time of diagnosis of 61 (29-70) years. In 48 cases, heavy chain was IgG (60%) and in 11 (14%), IgA. Light chain was kappa in 48 patients (60%) and lambda, in 29 (36%). ISS was 1 in 35 patients (44%), 2 in 27 patients (34%) and 3 in 18 patients (22%). 53 patients received 6 cycles of sc VTD (66%), being the main reason for not completing induction, treatment toxicity (67% of the cases). 45 patients (56%) developed PN (grade ≥2 - 36%), 11 patients (14%), gastrointestinal toxicity (grade ≥ 2 - 3%) and 13 patients (16%) cutaneous toxicity (grade ≥2 8%). Two patients presented a thromboembolic episode. Thalidomide dosage was reduced / stopped in 31 patients (39%), bortezomib in 27 patients (33%) and dexamethasone, in 29 (36%). 33 patients achieved a complete remission after treatment (41%), 27 a very good partial remission (33%), 14 (18%) partial remission and 6 (8%), progressive disease at the end of therapy. 65 patients (79% of the series) underwent the auto-HCT procedure; 24 patients (37%) did relapse after transplant, 7 of them in the first 12 months after transplantation. With a median follow up of 16 months, progression free survival and overall survival at 1 year of the whole series are 43% (95%CI 23% - 64%) and 71% (95%CI 56% - 85%), retrospectively.
CONCLUSION
In spite of the use of sc bortezomib, PN was a significant side effect that lead to the reduction / stopping of the drug in 34% of the patients from our series. The association between bortezomib and thalidomide might have been a major factor contributing to it.

Disclosures
Oriol: Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy; Takeda: Consultancy, Speakers Bureau. Sureda:Gilead: Consultancy; Sanofi: Consultancy, Honoraria; Roche: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.