Real Life, Retrospective Analysis of Bortezomib Re-Use As Second Treatment for Relapsed Multiple Myeloma Patients Previously Exposed to Bortezomib-Based Therapies As First Line: The Rebound Study
Authors: Musto Pellegrino , Simeon Vittorio , Cascavilla Nicola , Falcone Antonietta , Petrucci Maria Teresa , Cesini Laura , Di Raimondo Francesco , Conticello Concetta , Ria Roberto , Catalano Lucio , Salvatore Dalila , Mastrullo Lucia , Gagliardi Alfredo , Villani Oreste , Pietrantuono Giuseppe , D'Arena Giovanni , Mansueto Giovanna , Patriarca Andrea , Bringhen Sara , Genuardi Mariella , Di Renzo Nicola , Reddiconto Giovanni , Fragasso Alberto , Caravita Tommaso , Mangiacavalli Silvia , Palumbo Antonio , Corso Alessandro 
Published: October 2019

Abstract
Background: Several trials and analysis have explored the efficacy of bortezomib re-use in relapsed patients with multiple myeloma (MM), notably in those who have experienced good response and late relapse after the end of frontline treatments including the same drug. However, very few specific evidences on bortezomib re-challenge at first relapse are available.
Patients and methods: This observational, retrospective study enrolled 135 MM patients treated from January 2002 to May 2015 in 12 Italian centres with bortezomib-based regimens as first line therapy (both in daily practice or clinical trials) and who had received again a salvage treatment containing bortezomib at first relapse, according to current clinical practice and/or guidelines recommendations.
Results: Median age was 61 years (range 28-95) and 60% of patients were males. At diagnosis, ISS was 30% stage I, 30% stage II and 40% stage III; r-ISS (available in 45 cases) was 25% stage I, 44% stage II and 31% stage III. Two patients presented as primary plasma cell leukemia (PCL). First line induction treatments included VD (27%), VTD (25%), VMP (23%), PAD (10%), and further combinations of bortezomib with cyclophosphamide (11%) or other drugs (4%). Eighty-two percent of patients received a twice-week schedule and 18% once-a-week administration of bortezomib, which was initially given i.v. in 71% and s.c. in 29% of patients, respectively. Seventy-five patients (56%) underwent single (72%) or double (28%) autologous stem cell transplantation (AuSCT) as part of their frontline therapy. Consolidation or maintenance with borteomib were performed in 17 and 4 patients, respectively. As per inclusion criteria, all patients achieved PR or better response (according to IMWG criteria), including at least VGPR in 36%, CR in 20% and sCR in 1% of cases. Median duration of PFS1 was 33 months (95% CI 28-36), while median treatment free-interval (TFI) was 23 months (95% CI 22-28). Median PFS1 was 35 months (95% CI 31-43) and 27 months (95% CI 20-33) for patients undergoing or not AuSCT, respectively (p n.s.).
At first relapse (clinical 65%, only biochemical 35%), anemia, neutropenia and thrombocytopenia were present in 42%, 5% and 9% of patients, respectively. Median bone marrow plasma cell infiltration was 40% (range 2-99). Bone lesions were present in 74%, hypercalcemia in 7%, high LDH values in 15% of patients. Serum beta2-microglobulin levels were increased in 48%, while albumin was decreased in 17%. Renal failure was observed in 14%, with a median value of serum creatinine of 2.2 mg/dl (range 1.4-7). PCL occurred in 3 patients. Second line regimens included VD (44%), VCD (11%), PAD (9%), VTD (7%), BVD (7%), VMP (7%), VRD (4%), VRCD (2%), or other combinations (9%). Six patients had maintenance therapy with bortezomib. Twenty-one patients (16%) received AuSCT as part of their salvage therapy, while 4 patients (3%) underwent allogeneic transplantation (AlloSCT) and 5 (4%) a tandem sequence of AuSCT followed by AlloSCT. Seventy-four percent of patients received bortezomib once-a-week, 26% twice-weekly, 35% i.v. and 65% s.c. A total of 782 cycles (median 6, range 1-13) were given. Grade 3-4 hematological and non-hematological toxicities occurred in 27% and 10% of patients, respectively. No patient reported grade 3-4 neuropathy. Bortezomib dose reductions were needed in 12%. SPM occurred in 1 patient. Overall response rate was 70%, with 24% at least VGPR and 7% CR (sCR/nCR 1.5%). Improvement of renal failure (13 cases) was complete in 4 and partial in 6 patients. Bone disease improved in 31% of patients with osteolytic lesions. Median duration of second PFS was 19 months (95% CI 13-23), while that of second TFI was 14 months (95% CI 8-17). Median PFS2 was 56 months (95% CI 50-70); it was 60 months (95% CI 54-78) for patients who underwent AuSCT and 50 months (95% CI 45-68) for those who did not (p n.s.). Median OS was 94 months (95% CI 80-121) for the entire cohort, 94 months (95% CI 75-107) for patients undergoing AuSCT, and 86 months (95% CI 76-92) for those who did not receive AuSCT. After a median follow up of 56 months, 85 patients (63%) are alive, with 41 of them in response after second line therapies containing bortezomib.
Conclusions: This real-life survey indicates that re-treatments including bortezomib as first salvage therapy should be considered for selected MM patients achieving prolonged response after initial exposure to first line, bortezomib-based regimens.

Disclosures
Musto: Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cascavilla:Janssen-Cilag: Honoraria. Falcone:Janssen-Cilag: Honoraria. Petrucci:Janssen-Cilag: Honoraria. Di Raimondo:Janssen-Cilag: Honoraria. Ria:Binding Site: Speakers Bureau; BMS: Speakers Bureau; BMS: Speakers Bureau; Italfarmaco: Consultancy, Speakers Bureau; Janssen-Cilag: Other: Advisory Board, Speakers Bureau; CSL Behring: Consultancy, Research Funding, Speakers Bureau. Mastrullo:Janssen-Cilag: Honoraria. D'Arena:Janssen-Cilag: Honoraria. Bringhen:Janssen-Cilag: Honoraria; Celgene: Honoraria; BMS: Honoraria; Amgen: Other: ADVISORY BOARD; Mundipharma: Other: ADVISORY BOARD; Karyopharm: Other: ADVISORY BOARD. Di Renzo:Janssen-Cilag: Honoraria. Caravita:Janssen-Cilag: Honoraria. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Corso:Janssen-Cilag: Honoraria.