The cancer-testis antigens (CTA) are immunogenic antigens expressed in numerous tumor types, making them attractive targets for cancer immunotherapy. Expression of CTAs such as MAGE-A3, MAGE-C1 (CT7), MAGE-C2 (CT10), NY-ESO1 and the SSX antigens has been reported in multiple myeloma (MM); however, these reports have included a heterogeneous group of newly diagnosed and relapsed/refractory patients, all receiving different treatments. The true extent and prognostic significance of expression and de novo immune responses against CTA in newly-diagnosed MM is not known. From 8/00-11/04, we treated 67 newly-diagnosed patients (46% ISS II/III, 14% with del13q by FISH, 24% with soft tissue involvement) with a thalidomide, doxorubicin, and dexamethasone-based induction regimen, with 54 (81%) then getting up-front autologous SCT. Cryopreserved pre-treatment bone marrow plasma cells were used to assess CTA expression by RT-PCR. Pre- and post-treatment sera were tested for antibody (Ab) responses by ELISA. At least 1 CTA was expressed in 77% of cases, including MAGE-A3 (52%), SSX1 (40%), CT7 (29%), CT10 (25%), NY-ESO1 (21%), and SSX5 (17%). Three or more CTA were expressed in 29% of cases. At a median follow-up of 65 months, MAGE-A3 or NY-ESO1 expression at diagnosis was associated with worse overall survival (MAGE-A3: median OS 66 mos. vs. not reached, p=0.02 by log-rank; NY-ESO1: median OS 65 mos. vs. not reached, p=0.09). These poorer outcomes were independent of ISS stage, presence of del 13q, or response to induction therapy. No other CTA was associated with an OS difference, nor was the number of CTA expressed prognostically significant. Baseline Ab responses were noted to NY-ESO1 in 6/46 (13%) patients with available sera, all at titers > 1:1600. Ab responses were also noted to CT7 (n=2), CT10 (n=1) and SSX4 (n=1) but not MAGE-A3. No consistent effect of induction therapy on antibody titers was seen. Interestingly, 2 of the 6 NY-ESO1 Ab+ patients had no NY-ESO1 expression in bone marrow plasma cells. Both, however, had extensive soft tissue (ST) plasmacytomas, suggesting another source of NY-ESO1 antigen. Presence of NY-ESO1 Ab correlated significantly with baseline ST involvement, with 67% of Ab+ patients having ST disease compared with 20% of Ab- patients (p=0.05). NY-ESO1 Ab+ patients also had significantly poorer OS (med 21 mos. vs. not reached, p=0.009), independent of other prognostic factors. In sum, CTA expression is frequent in newly diagnosed MM patients, and expression of MAGE-A3 or NY-ESO1 is associated with worse long-term survival. Spontaneous antibody responses against NY-ESO1 are seen in untreated patients, and are associated with ST involvement and poorer survival. Immunotherapeutic targeting of CTA, as well as further investigation of biologic differences between CTA+ and CTA- MM, is warranted.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4173.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO