BIOLOGIC EFFECTS OF ANTI-INTERLEUKIN-6 MURINE MONOCLONAL-ANTIBODY IN ADVANCED MULTIPLE-MYELOMA

In patients with advanced multiple myeloma (MM) there is an excess of production of interleukin-6 (IL-6) in vivo, and elevated serum levels are associated with plasmablastic proliferative activity and short sur vival. These data prompted us to perform a clinical trial with a murin e anti-IL-6 monoclonal antibody (MoAb) to neutralize the excess of thi s putatively deleterious factor in these patients. Ten MM patients wit h extramedullary involvement frequently were treated with anti-IL-6 Mo Ab. The MoAb was administered intravenously to 9 patients; 1 patient w ith malignant pleural effusion received intrapleural therapy. Of the 3 patients who succumbed to progressive MM after less than 1 week of tr eatment (including the only 1 treated locally), 2 with evaluable data exhibited marked inhibition of plasmablastic proliferation. Among the 7 patients remaining more homogeneous receiving the anti-IL-6 MoAb for more than 1 week, 3 had objective antiproliferative effect marked by a significant reduction of the myeloma cell labelling index within the bone marrow. One of these 3 patients achieved a 30% regression of tum or mass. However, none of the patients studied achieved remission or i mproved outcome as judged by standard clinical criteria. Of major inte rest, objective antiproliferative effects were associated with complet e inhibition of C-reactive protein (CRP) synthesis and low daily IL-6 production in vivo. On the other hand, the lack of effect in 4 patient s was associated with a higher IL-6 production and inability of the Mo Ab to neutralize it. Anti-IL-6 was also associated with resolution of low-grade fever in all the patients and with worsening thrombocytopeni a and mild neutropenia. The generation of human antibodies to Fc fragm ent of the murine anti-IL-6 MoAb observed in 1 patient was associated with dramatic progression. These data show that anti-IL-6 MoAb can sup press the proliferation of myeloma cells and underscore the biologic r ole of IL-6 for myeloma growth in vivo. Furthermore, suppression of CR P and worsening of neutropenia/thrombocytopenia both indicate that IL- 6 is critically involved in acute-phase responses and granulopoiesis/t hrombopoiesis. (C) 1995 by The American Society of Hematology.