Cyclophosphamide, Bortezomib and Dexamethasone (CyBorD) Induction Therapy For Newly Diagnosed Light Chain Amyloidosis

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.

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