Recovery of Gonadal Hormone Level Is a Potential Marker for the Response and Prognosis in POEMS Syndrome Patients Treated with Bortezomib Based Combined Chemotherapy

Background：There is no standard treatment recommendation for POMES syndrome, a rare clonal plasm cell disease. Although autologous hematopoietic stem cell transplantation (ASCT) has been considered to have advantage in remission rate and long-term survival, but in most newly diagnosed cases, it is not applicable to conduct ASCT directly because of the severity of patients' conditions. Combined chemotherapy, applied in other plasm cell disorder, is a choice for POEMS syndrome. Both melphalan and lenalidomide have been proved to be effective in POEMS syndrome, but the long-term administration of these agents might damage hematopoietic stem cells and result in failure of stem cell mobilization. Proteasome inhibitor, bortezomib based regimen is also the first-line treatment in other plasm cell dyscrasia. In this study, we investigated and evaluated the effect and safety of the bortezomib-based combined chemotherapy in newly diagnosed POEMS syndrome patients. Method: POEMS syndrome patients newly diagnosed from July 2013 to August 2020 in Xuanwu hospital, Capital Medical University, were enrolled. Informed consent was obtained. Four cycles of Bortezomib-based 28-day BCD regimen (bortezomib 1.3mg/m 2 sc d1,8,15,22, cyclophosphamide iv 0.4g/m 2 d1,15, dexamethasone 40mg iv d1,8,15,22) were used as induction therapy. After the induction, ASCT or another two cycles of BCD therapy were conducted as consolidation therapy. Patients diagnosed in the same period but refusing bortezomib were treated with CD/CTD regimen (the same as BCD without bortezomib), and thalidomide 50-100mg once daily was suggested if it was well-tolerated. (Figure A) Results: There were totally 22 newly diagnosed POEMS syndrome patients accepted BCD regimen, and 16 patients CD/CTD regimen. First of all, the response rate in BCD group was superior to CD/CTD group, no matter the VEGF remission rate or hematologic complete remission rate (Figure B1-B4). The median time to achieve VEGF CR was 133 days in BCD group and 214 days in CD/CTD group. The median time to achieve hematologic remission was 218 days in BCD group and 415 days in CD/CTD group. Secondly, the improvement of neurologic symptoms in BCD group was not inferior to CD/CTD group. Bortezomib was well tolerated and didn't deteriorate the polyneuropathy (Figure C1-C3). Thirdly, during the median 35 months follow-up, the overall 5-year OS of 31 patients was 93.55%, 3-year and 5-year PFS were 83.47% and 76.51% respectively (Figure D1-D2). The 5-year-OS and 3-year and 5-year PFS of BCD group were superior to CD/CTD group (Figure D3-D4). In the consideration of ASCT significantly improve OS and PFS in POEMS syndrome patients, the long-term survival results were analyzed among ASCT group and cheotherapy only groups. The BCD+ASCT group achieved a best 5-year OS and 3-year and 5-year PFS (Figure D5-D6). Fourthly, about 54% of male patients had a subnormal testosterone at diagnosis, with normal or slightly elevated LH. After treatment, testosterone returned to normal level in male patients with the VEGF CR and VEGF PR (Figure E1). And the median remission time of testosterone was 76 days, which was earlier than that of VEGF remission was 143 days. The testosterone returned to normal after two cycle treatment predicted a better PFS. (Figure E2). About 86% of men at diagnosis had elevated estradiol which is the most common gonadal hormone abnormalities. After treatment, patients with better treatment response would have lower estradiol level (Figure E3-E4). Estradiol less than 58pg/ml after two cycle treatment and estradiol less than 48pg/ml after four cycle treatment predicted a better 5-year PFS (FigureE5-E6). After four cycle treatment, slightly elevated estradiol (48-79pg/ml) may be at risk for later recurrence and significant elevated estradiol tended to progress early (Figure E5). In women, low LH was frequently observed. Two patients with persistent low LH died within 1 year of diagnosis. Persistent low LH level in female patients may be an important predictor for poor prognosis. Conclusion: Bortezomib-based BCD regimen in newly diagnosed POEMS syndrome patients seems improve the response rate and survival, especially in patients with sequential ASCT. Recovery of gonadal hormone level might be a potential marker for response and prognosis. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.