Suppression Of Uninvolved Immunoglobulin Has Significant Clinical Implication Including Predicting Relapse In Multiple Myeloma

In multiple myeloma, immunoparesis, defined as suppression of uninvolved immunoglobulins (UIg), is one of the most common indicators of immune dysfunction. UIgs are known to improve following therapy but its clinical significance remains under studied. Here, we have looked at frequency and significance of suppressed UIG and its recover following therapy as well as its recurrence at relapse.

We analyzed the data from the APEX trial to assess the frequency of UIg suppression in multiple myeloma and its impact on outcome. The APEX (Assessment of Proteosome Inhibition of Extending Remissions) trial was a randomized, international, Phase 3 trial in relapsed multiple myeloma comparing bortezomib 1.3 mg/m² and dexamethasone 40 mg, as described in Richardson et al(NEJM 2005 Jun 16;352(24):2487-98). All patients previously received between 1 and 3 prior therapies. Immunoparesis was defined as one or two suppressed, UIgs.

Of the 639 patients with measured immunoglobulins, 561 (88%) had suppression of at least one UIG. IgA was most commonly suppressed at 82% (n=390) of patients, followed by IgG at 76% (n=182), and IgM at 74% (n=468). Patients with suppressed UIg, as compared to patients with normal UIg were more likely have a higher ISS Stage (Stage 3 was 30% vs. 12%), and received more therapies (>2 therapies in 64% vs. 50%). Eight-seven % (n=270) and 88% (n=267) of patients receiving bortezomib or dexamethasone, respectively, had suppressed UIg. In the bortezomib arm, patients with and without suppressed UIgs had similar ORR (44% vs. 38%, p=.568). However, patients with normal baseline uninvolved Ig had longer median TTP (276 vs. 169 days, p=0.023) and trend towards longer median OS (NR vs. 836 days, p=0.0832) compared to suppressed UIg. Fifty-three patients (19%) that received bortezomib had normalization of uninvolved Ig. Compared to those with persistently suppressed UIgs, patients with normalized Ig had longer median TTP (HR=0.40, p=0.0003) and OS (HR 0.47, p=0.006). In the dexamethasone arm, patients without suppressed UIgs had a trend toward higher ORR (44% vs 38%, p=.145). Patients with normal baseline uninvolved Ig had longer median TTP (191 vs. 106 days, p=0.012) and trend towards longer median OS (956 vs. 640 days, p=0.066). Thirty-two patients (11%) receiving dexamethasone had normalization of uninvolved Ig. Compared to those with persistently suppressed UIg, patients with normalized Ig had longer median TTP (HR=0.52, p=0.0123) and OS (HR 0.43, p=0.0184). Interstingly in both arms, recurrence of suppression of UIg preceded clinical disease progression by 64 days (range, 1-227) suggesting suppressed UIg as one of the early indicator or impending relapse.

In summary, patients with normal baseline uninvolved Ig have better TTP, and OS; that improvement in UIg correlates with improved TTP and OS and importantly UIg suppression can occur 2 months prior to disease progression, confirming a benefit to monitoring uninvolved immunoglobulins in myeloma.

Neuwirth:Millennium: The Takeda Oncology Company: Employment. Esseltine:Millenium: The Takeda Oncology Company: Employment. Anderson:celgene: Consultancy; onyx: Consultancy; gilead: Consultancy; sanofi aventis: Consultancy; oncopep: Equity Ownership; acetylon: Equity Ownership. Richardson:Millennium: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees.