A Phase II Study Of V-BEAM (Bortezomib, Carmustine, Etoposide, Cytarabine, and Melphalan) As Conditioning Regimen Prior To Second Autologous Stem Cell Transplantation For Multiple Myeloma
Authors: Wang Tzu-Fei , Fiala Mark A. , Wu Ningying , Fletcher Theresa , Abboud Camille N. , Cashen Amanda F. , Dipersio John F. , Uy Geoffrey L. , Westervelt Peter , Stockerl-Goldstein Keith E. , Vij Ravi 
Published: October 2019

Abstract

Background
High-dose melphalan (HDM) has been the standard conditioning regimen for autologous stem cell transplantation (ASCT) in multiple myeloma (MM) for decades. Second ASCT is often offered as salvage therapy for patients who relapse after a first ASCT, but while response rates are similar, the progression free survival (PFS) is rarely comparable with that of the first ASCT when HDM conditioning is used for both. BEAM (carmustine, etoposide, cytarabine, and melphalan) is one of the most commonly used conditioning regimens for lymphoma patients undergoing ASCT and all of the components have been shown to be effective in refractory MM, but it has not been tested as a conditioning regimen for ASCT in MM. Bortezomib has been incorporated with HDM as a conditioning regimen for initial ASCT, with promising outcomes and limited toxicities. Based on these findings, we proposed a new conditioning regimen, V-BEAM (bortezomib-BEAM), administered prior to a second ASCT for relapsed/progressive MM, aiming to improve the response rates and PFS of the second ASCT.

Objectives
To evaluate the safety and efficacy of a new conditioning regimen, V-BEAM, prior to a second ASCT in patients with relapsed/progressive MM after a first ASCT with HDM conditioning.

Patient/Methods
Patients with relapsed/progressive MM after a previous ASCT with HDM conditioning were enrolled after 2 to 6 cycles of induction chemotherapy with a bortezomib or carfilzomib based regimen. Patients who had progressive disease on induction chemotherapy were excluded. V-BEAM was administered as the following: Bortezomib 1.3 mg/m2 on days -6, -3, +1, and +4, carmustine 300 mg/m2 on day -7, etoposide 100 mg/m2 and cytarabine 100 mg/m2 each twice daily on days -6 through -3, and melphalan 140 mg/m2 on day -2. On day 0, autologous stem cells (> 2.0x106/kg) were infused. No maintenance or consolidation therapy was given post-transplant.

Results
A total of 10 patients were enrolled from October 2012 to May 2013 at the Siteman Cancer Center. The median age was 64.5 years old (range, 48-68) and 50% were male. Seventy percent of patients were Durie-Salmon stage IIIA at diagnosis, while the remaining 30% were stage IIA. The median time to progression following previous autologous stem cell transplant was 29 months (range, 17-97). The median number of prior therapies (including first ASCT) was 4 (range, 3-6).
At the time of abstract submission, one patient has not reached day +100 and two patients expired within 30 days of transplant. For the remaining seven patients, the day +100 response rates include five complete responses (CR) and two very good partial responses (VGPR). To date, no patients have had subsequent disease progression after a median follow-up of 5.0 months (range, 2.3-9.3).
Two patients suffered from treatment related mortality (one from neutropenic colitis [Day +18] and the other from sepsis [Day +2]). Serious complications included: neutropenic fevers (100%), diarrhea (grade 3-4, 100%), oral mucositis (all grade, 100%; grade 3-4, 20%), sepsis (30%), Clostridium difficile colitis (30%), and neutropenic colitis without Clostridium difficile (30%). Two patients (20%) had new or worsening peripheral neuropathy, both of which were grade 2 and easily controlled. The median duration of hospitalization was 23 days (range, 19-29). The median duration of neutrophil engraftment and platelet engraftment (>20x109/L) were 10 days (range, 9-11) and 22.5 days (range, 17-36), respectively. The median duration of intravenous antibiotics was 14 days (range, 2-23). Two patients were readmitted shortly following discharge for neutropenic fevers and candida esophagitis, respectively. In June 2013, eight months after study initiation, the decision was made to terminate the study due to excessive toxicity.

Conclusion
While the new conditioning regimen V-BEAM prior to a second ASCT produced promising response rates for relapsed/progressive MM, it resulted in unexpected treatment related mortality and should not be investigated further without modifications.

Disclosures:
Off Label Use: BEAM regimen as a conditioning regimen for relapsed multiple myeloma. Abboud:Ariad, Alexion, Novartis, Teva: Honoraria, Speakers Bureau. Stockerl-Goldstein:Millennium: Speakers Bureau; Celgene : Speakers Bureau. Vij:Celgene : Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau.