Factors Influencing Responsiveness to Bortezomib in Patients with Multiple Myeloma Suggest a Possible Role for Host Immunocompetency.

Patients with multiple myeloma (MM) are often severely immunocompromised. Unfortunately, current therapies, e.g. glucocorticoids and cytotoxic drugs, augment these immune defects. Recently, several novel therapeutic agents have been found to exert a positive immunomodulatory effect in preclinical studies, e.g. thalidomide (Thal) induces CD8 T and natural killer (NK) cells; zoledronic acid (ZOL) induces gamma delta T cells; and bortezomib (Velcade) induces CD4 T and NK cells. In this study, we analyzed the factors that influenced the responsiveness of 20 previously-treated Asian patients with MM to bortezomib, to determine whether host immunocompetency could play a role. Response to bortezomib was defined as a 50% reduction in the paraprotein level; and responsiveness was arbitrarily defined as rapid, if response occurred after 2 cycles; average, after 4 cycles; and slow, after more than 4 cycles of bortezomib. Half (50%) of patients recorded rapid responses, supporting prior anecdotal reports that bortezomib is a highly-effective drug in Asian patients with MM. Approximately, 20% of patients demonstrated average responses, whilst another 20% showed slow responses. There were 2 (10%) non-responders. Among the rapid responders, 70% received no prior chemotherapy. Instead, they were treated using low-dose Thal/dexamethasone (Dex) regimens. Two (20%) patients received up to 2 cycles of melphalan and prednisolone, followed by low doses of Thal/Dex; and 1 (10%) patient received an autologous hematopoietic stem cell transplant (AHSCT), followed by a mini allogeneic transplant, and then followed by 2 donor lymphocyte infusions. In fact, this patient with a mini-transplant went on to achieve complete remission, as well as full donor chimerism after bortezomib. These data suggest that rapid responders were relatively immunocompetent at the time they received bortezomib. Interestingly, all rapid responders were treated predominantly with ZOL. In contrast, slow responders were heavily-pretreated with immunosuppressive therapy, either chemotherapy (2 out of 4) or high-doses of Thal/Dex (2 out of 4). All slow responders also received pamidronate (PAM), instead of ZOL. Three of 4 average responders underwent conventional chemotherapy followed by AHSCT; whilst the last average responder failed to complete conventional chemotherapy because of severe cytopenias. All average responders were also treated predominantly with PAM. These data further suggest that unresponsiveness to bortezomib could be related to a poorly preserved immune system, and that attempts to reconstitute immune function, e.g. using AHSCT, could improve responsiveness. Moreover, these data also suggest that ZOL, but not PAM, could positively influence responsiveness to bortezomib. Whether this is related to gamma delta T cell activation is currently being investigated. In conclusion, our study demonstrates that a relatively immunocompetent host (whether by omission of prior immunotoxic therapy or by reconstitution of host immunity) could boost responsiveness to bortezomib. Moreover, ZOL (but not PAM) may contribute to this responsiveness. It therefore may be argued that bortezomib should then be used as first-line therapy in MM, especially when combined with ZOL. In addition, we speculate that the pro-osteoblastic effect of bortezomib combined with the anti-osteoclastic effect of ZOL would make this combination even more advantageous.