Bortezomib (Velcade) When Given Pretransplant and Once Weekly as Consolidation Therapy Following High Dose Chemotherapy (HDCT) Leads to High Rates of Reactivation of Varicella Zoster Virus (VZV).

Bortezomib is a selective inhibitor of the 26S proteasome with proven efficacy in relapsed multiple myeloma (MM). Current trials are evaluating bortezomib both as single agent and combination therapy in a variety of clinical settings. No data exists on the tolerability of bortezomib in the immediate post transplant setting. We conducted a prospective pilot study of bortezomib administered to MM patients both prior to, and as consolidation therapy following HDCT. Patients received 2 cycles of bortezomib 1.3mg/m² on days 1, 4, 8 and 11 of every 21 days, beginning 42 days prior to stem cell collection. HDCT comprised melphalan 100mg/m²/day x 2 days followed by reinfusion of peripheral blood stem cells 48 hours later. All patients received six cycles of consolidation bortezomib 1.3mg/m² given once weekly (for ease of administration) for 4 of every 5 weeks, 90–120 days following transplantation. To date, 40 patients have been enrolled. 3 patients did not receive HDCT (medical complications unrelated to therapy 1, failure to mobilize sufficient stem cells 1, disease progression 1). 4 patients did not proceed to consolidation therapy after HDCT (disease progression 1, grade 3/4 neuropathy 3). 33 patients have received at least one post transplantation cycle of consolidation bortezomib. Patient and disease characteristics at diagnosis were as follows (no. of patients): male (22), female (11), median age 56 years (range 39–70), Stage II (9), Stage III (24), IgG (22), IgA (9), free light chain (2). Median paraprotein at initiation of consolidation was 0 (range 0–3.6)(n=33), Day 1 cycle 4 was 0.1 (range 0–2.1)(n=23) and at end of study was 0.35 (range 0–3.4)(n=20). With a median follow up of 14 months 5 patients have had disease progression and 1 has died from progressive disease. 13 of 33 patients (39%) experienced reactivation of varicella zoster virus (VZV), 2 patients had human herpes virus 6 reactivation and 1 patient had oral herpes simplex virus reactivation, all requiring therapy. The median absolute lymphocyte count (ALC) at the onset of viral reactivation was 1336/mcl (range=600–4800/mcl). No significant difference was seen in the median ALC at initiation of consolidation therapy between the study population (1400/mcl, range 700–3500/mcl) and those patients with viral reactivation (1300/mcl, range 800–3700/mcl). The median time from enrollment to VZV reactivation was 189 days (range 25–375). 10 of 33 patients had grade 1/2 and none had grade 3/4 neuropathy at study enrollment. At initiation of post transplant bortezomib 21 of 33 (64%) had grade 1/2 neuropathy and 1 of 33 (3%) had grade 3/4 neuropathy. Treatment emergent neuropathy on once weekly bortezomib was seen in only 3 of 33 (9%) patients, necessitating dose reduction in 1 and discontinuation of therapy in the other 2 individuals. No grade 3/4 thrombocytopenia or neutropenia was observed with once weekly bortezomib. In conclusion, we observed a very high rate of VZV reactivation in this prospective study. Elsewhere we report that bortezomib therapy results in a decrease in circulating CD8 T cell and CD56 natural killer cell counts. Alterations in proportions of T cell subsets may therefore explain this finding which has major implications for future clinical trials of bortezomib in the peritransplant setting.