Abstract
Bortezomib is a first-in-class proteasome inhibitor approved for the treatment of MM patients who have received at least one prior therapy. Classically, patients receive bortezomib 1.3 or 1.0 mg/m2 by IV bolus on days 1, 4, 8, and 11 of a 21-day cycle, associated or not to dexamethasone, for a total number of 8 cycles. Such administration schema is associated with a remarkable anti-tumor activity and response. However, a significant number of patients who are initially responders to bortezomib, will progress after drug discontinuation, raising the question of long term or maintenance treatment with bortezomib. The objective of this analysis was to evaluate the tolerance and safety profiles of long term treatment with bortezomib in a cohort of 16 patients with relapsed and/or refractory MM treated in a single institution. Eligible patients for this analysis are those who had relapsed MM, and who continued to receive bortezomib (1.3 or 1.0 mg/m2) as a long term therapy beyond the classical 8 cycles. All medical charts were uniformly reviewed in detail for assessment of toxicity, safety and response. The median age was 53 (range, 27–74) years. The majority of patients had already received at least one prior autologous or allogeneic stem cell transplantation (n=12; 75%). Also, 12 patients (75%) had received prior treatment with thalidomide at a median dose of 200 mg/day, for a median duration of 7 months. Before treatment with bortezomib, 7 patients (44%) already had some form of peripheral neuropathy (PN). With a median follow-up of 16 months from bortezomib initiation, patients from this series received a median of 10 (range, 9–16) cycles of bortezomib administered over a median period of 11 (range, 7–35) months. Overall, 6 patients had evidence of bortezomib-associated PN (38%; 4 grade 1, 1 grade 2 and 1 grade 3; sensory symptoms in all cases). Other bortezomib-related toxicities included thromobopenia (n=8; 50%; 1 grade 1, 5 grade 2, and 2 grade 3–4). General fatigue was also common and was encountered in 5 (31%) patients. Overall, bortezomib-associated toxicities led to dose reduction or increase of treatment cycle duration in 9 patients (56%), but none of the patients had to definitively discontinue treatment because of unacceptable toxicity. At last follow-up, 6 patients are still receiving bortezomib, 4 patients died from disease progression, no patient died from treatment-related causes, and the remaining 12 patients are still alive. Long term treatment with bortezomib was associated with an objective disease response rate in 87% (95%CI, 60–98%) of patients (n=14; 3 CR, 8 VGPR, 3 PR). The Kaplan-Meier estimate for overall survival is shown in the figure below. Though relatively small, results from this series suggest that long term treatment with bortezomib is feasible. Toxicity, tolerance and safety profiles of long term treatment are comparable to those observed with the standard schedule and manageable after dose reduction. Therefore, prospective studies aiming to optimize bortezomib administration schedule and duration (beyond the classical 8 cycles) are warranted, since such long term treatment can yield major objective disease response.
Figure Figure
Refractory Acute Interstitial Nephritis in the Setting of Nivolumab Therapy
