Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Induction Therapy For Newly Diagnosed Light Chain Amyloidosis
Authors: Reece Donna E. , Phillips Madeline , Chung Beryl , Chen Christine I. , Masih-Khan Esther , Tiedemann Rodger E. , Trudel Suzanne , Jimenez-Zepeda Victor H , Kukreti Vishal 
Published: October 2019

Abstract
Previously, most younger and fit patients (pts) with light chain amyloidosis (AL) received upfront autologous stem cell transplantation (ASCT) -- without any preceding induction therapy-while older pts and/or those with significant organ dysfunction were given definitive therapy with oral melphalan + dexamethasone (mel + dex). Recently, bortezomib (btz) was shown to be effective in relapsed AL, and has increasingly been used earlier in the disease course. The CyBorD combination (weekly cyclophosphamide + btz + dex) is a highly effective induction regimen for newly diagnosed multiple myeloma pts, and has shown encouraging preliminary outcomes in AL. Over the last 2 years, we have been offering CyBorD induction to all newly diagnosed AL pts. CyBorD was either administered for: 1) 2-4 cycles to try to reduce the monoclonal plasma cell population while allowing time to arrange stem cell (SC) collection/transplant admission in eligible pts, or 2) 8 cycles to serve as primary therapy for transplant-ineligible pts; it was also hoped that some of these pts who responded to CyBorD might experience improved organ function over time and eventually be able to undergo SC collection and/or ASCT. In order to assess this approach, we retrospectively examined the relative efficacy of induction therapy with CyBorD compared to other btz-containing regimens and to mel + dex in AL pts.

Methods
Between 01/2009 and 06/2013, 43 pts with biopsy-confirmed AL were referred to Princess Margaret Cancer Centre and received induction therapy with ≥1 cycle of CyBorD (n=15), other btz therapies (n=10; btz alone in 2, btz + steroids in 6 and btz + mel + prednisone in 2), or mel + dex (n=18). CyBorD doses were individualized and consisted of weekly oral cyclophosphamide 300 mg/m2, bortezomib IV/SQ 1.3-1.5 mg/m2and dex 12-20 mg. Thirty-four pts are evaluable for hematologic (heme) responses; 4 had insufficient data, while 5 are too early to evaluate. Organ responses were assessed in 44 organ systems in 26 pts.

Results
Median age was 55 yrs (range 44-85). Organ involvement included cardiac in 65%, renal in 49% and ≥ 2 organs in 58%. Median troponin I level was <0.07 (range <0.07-1.57) and BNP 305.6 (range 212-1625.3). After induction, 22 pts (64.7%) achieved a heme response (≥ PR): 67%, 44%, and 75% in the CyBorD, btz-other, and mel + dex groups, respectively. Treatment with CyBorD yielded the highest percentage of ≥ VGPR (55.5%, compared with 22% in the btz-other and 31% in the mel + dex arms); corresponding CR rates were 11%, 22% and 6%, respectively. Median times to first/best heme responses for the 3 groups were 1.2/4.0 mos for CyBorD, 1.3/2.1 mos for btz-other, and 2.1/5.5 mos for mel + dex.
Pts treated with CyBorD also experienced the highest percentage of organ improvement: 29% improvement in 21 evaluable organs, compared with 12.5% of 8 organs btz-other and 0% of 15 organs in the mel + dex group at the time of this analysis. The median time to first organ response was 3 mos for CyBorD and 0.9 mos for btz-other.
Toxicities included peripheral neuropathy in 30% of those treated with CyBorD (gr 1/2 in 4 and gr 3 in 1 pt) vs 20% in those receiving btz-other (gr 1/2 in 1 and gr 3 in 1 pt) vs 0 with mel + dex. Among the mel + dex pts, 17% experienced gr 3/4 thrombocytopenia and 6% developed gr 3/4 neutropenia; 1 case of secondary AML was observed in this group.
SCs have been collected in 15 pts (34.8%), including 9 who received CyBorD, 3 treated with btz-other and 3 treated with mel + dex. To date, 8 pts (18.6%) have undergone ASCT (5 after CyBorD and 3 after btz-other regimens). Twelve of 15 (80%) CyBorD pts are alive at a median of 10 mos (range 1-22), while 5/10 (50%) btz-other pts are surviving at a median of 7 mos (range 5-47) and 14/18 (77.7%) mel + dex pts are alive at a median of 25 mos (range 2-50) after starting induction therapy.

Conclusions
Treatment with CyBorD produced a high rate of ≥ VGPR, with a median time to first heme response of only 1.2 months; improvements in organ function, which typically occur later, were observed in a significant proportion of pts as well. CyBorD therefore compares favorably with mel + dex, and has the advantage of less myelosuppression and reliable SC collection. Longer follow-up is needed to determine the durability of remissions induced by CyBorD alone or followed by ASCT, as well as the number of initially transplant-ineligible pts who can eventually undergo this procedure if needed.

Disclosures:
Reece: Otsuka: Honoraria, Research Funding; BMS: Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Millennium Pharmaceuticals: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Onyx: Consultancy. Off Label Use: Use of bortezomib in light chain amyloidosis. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Tiedemann:Janssen: Honoraria; Celgene: Honoraria. Trudel:Celgene: Honoraria; GSK: Research Funding; Sanofi: Honoraria.