Effect of Dosing Bortezomib According to Adjusted Body Surface Area in Multiple Myeloma

Introduction:

Multiple myeloma (MM) is the second most common hematologic malignancy in the U.S., accounting for 15% of hematologic malignancies. MM five-year survival rates have improved from 25.8% in 1980 to their current rate of 49.6% (SEER Stat Fact Sheets: Myeloma). Grade 2 or higher peripheral neuropathy (PN) has been reportedin up to 39% of patients on bortezomib, with 31% of patients requiring a dose reduction and 9% requiring discontinuation (Velcade [bortezomib] injection prescribing information; Blood 2008 112:1593-99). Although dosing recommendations are available to help limit PN in patients at high risk of developingPN, there is limited evidenceon how these dose adjustments relate toobese patients receiving bortezomib therapy. The American Society of Clinical Oncology (ASCO) guidelines recommend avoiding unnecessary dose reductions in obese patients, especially when the goal of treatment is cure (J Clin Oncol 30: 1553-61). To date, no studies have evaluated dosing bortezomib according to an adjusted body surface area (BSA) in MM, a difficult-to-cure disease, mainly affecting older people with other co-morbidities.

Objectives:

To evaluate the effect of an adjusted bortezomib dosing scheme utilized at the University of Iowa in MM patients post-autologous hematopoietic stem cell transplant (HSCT). The primary objectivewas the incidence of neuropathy requiring MM therapy dosage adjustment or discontinuation including the following: adjustment in bortezomib therapy due to neuropathy, adjustment in any MM regimen due to neuropathy, discontinuation of thalidomide, and discontinuation of thalidomide due to neuropathy. Secondary objectives included the percentage of patients with disease progression while on bortezomib therapy and percentage of patients deceased due to MM at data collection.

Methods:

This is a single-center, retrospective chart review of MM patients with a BSA >2.0 and/or weight >60 kg treated with bortezomib post-autologous HSCT between 01/01/14 and 01/31/16. Two dosing schemes were evaluated, a dose-adjusted and a non-adjusted version (referred to as protocol vs. non-protocol dosing, respectively). Protocol dosing was defined as bortezomib 1 mg/m2 intravenously on days 1, 4, 15 and 18 q 4 weeks with a maximum dose of 2 mg or BSA capped at 2.0 m2 while using an adjusted body weight when weight is >60 kg. Patients that received non-protocol dosing received bortezomib 1 mg/m2 intravenously. Statistical analysis of baseline characteristics was performed using Fisher's exact test for nominal data and T-test for continuous data. Primary and secondary objectives were evaluated using a multiple regression analysis.

Results:

71 patients were identified, of which 33 received non-protocol dosing, 31 received protocol dosing, and 7 were excluded due to the inability to verify outside infusion center dosing. Baseline characteristics between the non-protocol and protocol dosing group were well matched and no statistically significant difference was seen in age at bortezomib initiation, mean BSA, gender, current enrollment in a HCCC clinical trial, time of bortezomib therapy, or HSCT history. No statistically significant difference was seen between patients receiving non-protocol versus protocol dosing in primary or secondary study objectives, including the following outcomes: change in bortezomib therapy due to neuropathy (18.2% vs. 12.9%, p>0.05), change in regimen due to neuropathy (33.3% vs. 32.3%, p>0.05), discontinuation of thalidomide (36.4% vs. 35.5%, p>0.05), discontinuation of thalidomide due to neuropathy (21.2% vs. 22.6%, p>0.05), disease progression while on bortezomib (12.1% vs. 6.5%, p>0.05), deceased due to MM at data collection and disease progression while on bortezomib therapy or death at data collection (21.2% vs. 16.1%, p>0.05).

Conclusion:

The use of a weight adjusted dosing protocol for bortezomib in obese patients did not appear to decrease the incidence of neuropathy, specifically neuropathy leading to alterations in MM therapy. Although this was a relatively small study and further evaluation would be beneficial, the percentage of patients with disease progression or death while on bortezomib therapy was not found to be affected by the weight adjusted protocol. These results are in line with the 2012 ASCO statement that recommends avoiding unnecessary dose reductions while treating obese patients with cancer.