ThaDD Regimen for Patients with Multiple Myeloma Aged ≥ 65 Years: An Update of the First 50 Patients Enrolled
Authors: Offidani Massimo , Corvatta Laura , Polloni Claudia , Piersantelli Maria-Novella , Gentili Silvia , Galieni Piero , Visani Giuseppe , Alesiani Francesco , Catarini Massimo , Brunori Marino , Samori Arduino , Burattini Maurizio , Centurioni Riccardo , Ferranti Mario , Giuliodori Luciano , Candela Marco , Mele Anna , Marconi Monica , Olivieri Attilio , Leoni Pietro 
Published: April 2020

Abstract
Previously we reported the outcome of 50 patients treated with an induction ThaDD regimen followed by a randomized maintenance therapy with a-Interferon or thalidomide and low-dose dexamethasone. At present, 88 patients with newly diagnosed MM have been enrolled in the ThaDD protocol. Here we present the updated results of the first 50 enrolled patients after a 42 months median follow-up (range 27–60). Baseline characteristics of the 50 patients were previously reported. Briefly, median age 72 years (range 65–78; 14% ≥ 75 years), more than three quarter of patients scored ISS 2–3, 60% presented abnormal serum levels of C-reactive protein (sC-RP) and 24% had unfavourable cytogenetics. Post-randomization best response included 34% CR, 14% nCR, 14% VGPR, 28% PR and 6% MR. One patient was diagnosed with progressive disease and two (4%) died early before response assessment. Median and 3-years TTP was 32 months and 40%, respectively. Median and 3-years PPF was 24 months and 38%, respectively. Factors negatively affecting PFS in univariate analysis were age &gt; 70 years (p=0.054), abnormal sC-RP level (p=0.023), randomization to Interferon (p=0.046) and response to induction &lt; VGPR (p=0.031) whereas high ISS score, high b2-microglobulin level and unfavourable cytogenetics did not. Multivariate stepwise analysis select abnormal sC-RP (p=0.021; HR=4.1) and response &lt; VGPR (p=0.022; HR=3.8) as adverse features for PFS. Subgroups analysis shows that thalidomide maintenance therapy offered a significantly better PFS (42.5 vs 23.5 months; p=0.015) particularly in non VGPR patients; moreover, consolidation with high-dose therapy and autologous stem cells transplant seems to overcome the adverse impact of abnormal sC-RP albeit it did not significantly prolong PFS in the whole transplanted population vs no-transplant population. First line salvage therapy of relapsed patients was bortezomib-chemotherapy based therapy (Offidani et al, EHA 2008). Three-years OS was 64% and it seems not adversely affected by long-term thalidomide maintenance therapy since response rate and post-relapse PFS were similar between in those patients randomized for Interferon or thalidomide. ThaDD was fairly well tolerated but DVT/PE occurred in 7 patients undergoing prophylaxis with fixed dose warfarin and severe infection in 20% (7% after antibiotic prophylaxis). Grade 3–4 neutropenia occurred in 5 patients whereas no patients presented &gt; grade 2 thrombocytopenia. Only 2 patients dropped out due to toxicity (1 EP, 1 severe infection). During thalidomide maintenance severe peripheral neuropathy was observed in 2 patients and 2 other patients died for myocardial infarction. In conclusion, patients treated with ThaDD showed similar TTP, PFS, OS and non-hematological toxicity but less hematological toxicity and better compliance compared to that reported in patients treated with MPT (Palumbo et al, Blood 2008; Facon et al, Lancet 2006) or VMP (Mateos et al, Haematologica 2008; San Miguel et al, EHA 2008). Patients with normal sC-RP level and achieving at least VGPR after ThaDD gained a very long PFS. However, even patients with abnormal sC-RP level or who didn’t achieve VGPR could have a long-term PFS if transplanted or maintained with thalidomide after induction, respectively. Outcome of salvage therapy with bortezomib, dexamethasone and chemotherapy seems to be not affected by time on thalidomide treatment.