Thalidomide, Dexamethasone, Doxil and Velcade (ThaDD-V) Induction Therapy Followed by Consolidation/Maintenance Is Very Effective In Early Relapsed/Refractory MM
Authors: Offidani Massimo , Polloni Claudia , Corvatta Laura , Gentili Silvia , Mele Anna , Brunori Marino , Rizzi Rita , Catarini Massimo , Samori Arduino , Blasi Nicola , Ferranti Mario , Malerba Lara , Caraffa Patrizia , Leoni Pietro 
Published: October 2019

Abstract
Abstract 3020

Background.
In patients with newly diagnosed MM, three/four-drug combinations seem to be more effective compared with two-drug associations in terms of both rate and duration of remission. Moreover, there is an emergent body of evidences that consolidation/maintenance therapy improves quality of response and remission duration. However, the impact of these strategies in relapsed/refractory MM (r-rMM) are still unknown.

Methods.
This is a multicenter, phase II study including patients with r-rMM having measurable disease, no more than 4 prior lines of therapy, adequate performance status, cardiac and liver function. As induction therapy patients received 6 28-day cycles of oral thalidomide 100 mg/day continuously at bedtime, oral dexamethasone 20 mg on day 1–2, 4–5, 8–9, 11–12, pegylated Liposomal Doxorubicin (pLD) 30 mg/m2 iv on day 4 and bortezomib 1.3 mg/m2 iv on day 1, 4, 8, 11 (ThaDD-V). As consolidation patients underwent 6 28-day cycles of rotating bortezomib 1.3 mg/m2 iv on day 1, 4, 8, 11 plus oral dexamethasone 20 mg on day 1–2, 4–5, 8–9 (3 courses) or thalidomide 100 mg/day continuously at bedtime plus oral dexamethasone 20 mg on day 1–4 (3 courses). Patients eligible and having suitable stem cell storage underwent ASCT instead of standard consolidation at the discretion of attending physician. Maintenance therapy included thalidomide 100 mg/day until relapse or intolerable toxicity. Since in the first 20 patients we recognized an excess of peripheral neuropathy, protocol was amended as follow: bortezomib 1.3 mg/m2 on day 1, 4, 11 and thalidomide 50 mg/day in all therapeutic phases. The primary end-points of this study were best response and toxicity of the planned therapy.

Results.
Forty-six patients were enrolled. Median age was 63.5 years (range 31–80 years) and the median number of prior regimens was 1 (range 1–4). Twenty-four patients (52%) had undergone autologous stem cell transplantation, 30 (65%) had received anthracyclines, 27 (59%) thalidomide, 8 (17.5%) bortezomib and 16 (35%) were refractory to the last regimen. After induction 16 patients (34.5%) achieved CR (6=13% sCR), 15 (32.5%) VGPR and 4 (8.5%) PR with a ORR of 76.5%. Seven patients (15%) progressed. Out of 46 patients undergone induction, 26 (20 standard, 6 ASCT) received consolidation therapy since 1 patients died during induction, 8 had progressive disease, 1 had second neoplasm, 7 had severe toxicities and 3 undergone allogeneic stem cell transplantation. Excluding 6 patients who have obtained sCR before, 5 (25%) out of 20 patients had further improvement in response. Therefore, best response after induction and consolidation were: 25 CR (54%; 8 sCR=17.5%), 16 VGPR (34.5%) and 2 PR (4.5%). Maintenance therapy did not further improve response. Patients receiving ≤ 2 prior regimens had a CR rate significantly higher than those heavily treated (41% vs 0%; p= 0.010) whereas prior ASCT, thalidomide or bortezomib, refractory disease and bortezomib dose-intensity did not affect quality of response. After a median follow-up of 31 months (range 12–53), 28 patients relapsed and 20 died. Median TTP was 18.5 months, median PFS was 17.5 months and median survival was 40 months. Median TTP of patients achieving PR-VGPR was 16 months (3 years= 10%) whereas in those obtaining CR it was 32.5 months (3 years= 45%; p=0.032) vs not reached (3 years= 85%) in patients achieving sCR (p=0.003). Main toxicity was peripheral neuropathy (PN). Indeed, in the first 20 patients we observed 6 (30%) grade 2 and 3 (15%) grade 3 PN. After amendment, grade 2 and 3 PN occurred in 3 (11.5%) and 2 patients (7.5%), respectively. DVT occurred in 2 patients (4.5%) and severe infection in 7 (15%). Grade 3–4 neutropenia, anemia and thrombocytopenia occurred in 4 (8.5%), 2 (4%) and 7 patients (15%), respectively. Finally, only one patients died of myocardial infarction during induction. During consolidation therapy other 2 patients developed grade 3 peripheral neuropathy. During maintenance with thalidomide no patients developed severe neuropathy requiring discontinuation.

Conclusions.
Multi-drug combination namely ThaDD-V as induction followed by consolidation-maintenance therapy seems to be very effective in patients with r-rMM provided that this procedure is used early on relapse when very deep responses are still possible. A reduced dose-intensity of bortezomib significantly decreases PN without jeopardizing outcome.

Disclosures:
Offidani: Celcene, Janssen Cilag: Honoraria. Polloni:Celgene: Honoraria. Corvatta:Celgene: Honoraria. Gentili:Celgene: Honoraria. Brunori:Celgene, Janssen-Cilag: Honoraria. Catarini:Cerlgene, Janssen-Cilag: Honoraria. Malerba:celgene, Janssen-Cilag: Honoraria. Leoni:Celgene, Janssen-Cilag: Honoraria.