Which Should be Pursued, Cumulative Dose or Dose Intensity: A Real-World Effectiveness Analysis of Bortezomib-Based First Line Treatment for Untreated Multiple Myeloma Patients
Authors: Yang Shenmiao , Liu Aijun , Zhong Yuping , Huang Xiaojun , Chen Wenming , Lu Jin 
Published: October 2019

Abstract
Background: The higher cumulative dose of bortezomib associated with better OS was demonstrated by some prospective studies of bortezomib continuing therapy. A cutoff of cumulative bortezomib dose of 39mg/m2 was found in the treatment of multiple myeloma (MM) with VISTA trial recently. However, dose reduction due to adverse events was common. Moreover, many Chinese patients accepted bortezomib injections at a fixed dose of 1.75mg, the half volume of a vial because of economic problems. To clarify if a reasonable cumulative bortezomib dose achieved by prolonged treatment duration with reduced dose intensity can do the same work, we conducted a multicenter retrospective analysis in previously untreated MM patients with the initial treatment of bortezomib-based regimens.
Method: From March 2005 to December 2014, 579 previously untreated MM patients received the bortezomib-based chemotherapy with informed consents in three hematologic centers of Beijing. Median age at the diagnosis was 59 years (range: 27~89). Initial chemotherapeutic regimens included BD, PAD, BCD and VMP. After median of 4 cycles (range: 0.25~13.00) of treatment, the median cumulative dose of bortezomib was 28mg (range: 1.75~124.80). The median follow-up of surviving patients was 26.0 months (2.0-123.0). Seventy nine patients recieved autologous hematopoietic cell transplantation (ASCT) according to the eligibility and patients' desire.
Results: To overcome confounding effects of early discontinuations/deaths on the cumulative dose, a landmark analysis was conducted at 6 months, eliminating patients who died before this time from the analysis. Among the patients survived the initial 6-month treatment, 450 treated with chemotherapy alone and 78 received ASCT.
ROC analysis showed the cumulative bortezomib dose predicted survival in chemotherapy group with the AUC of 0.617 (95%CI: 0.565~0.670, P<0.001). A cutoff value of cumulative bortezomib dose was 20.75mg with optimal sensitivity and specificity of 0.831 and 0.373, respectively. The patients' characteristics of both low (<20.75mg) and high (≥20.75mg) cumulative bortezomib dose groups were comparative. The high cumulative dose group had superior OS than the low cumulative dose group (median OS: 51.0 months (95%CI: 44.66-57.34) vs. 42.0 months (95%CI: 33.24-50.76), P=0.015). However, PFS was not significantly different between the two groups (P=0.994). Two hundred and forty eight (65.3%) patients initiated treatment of bortezomib with the fixed dose of 1.75mg, and 202 (34.7%) patients had the standard dose of 1.3 mg/m2. Bortezomib dose reduction occured in 50 patients. Twenty nine (11.7%) patients of the standard dose intensity group and 2(1.0%) of the fixed dose intensity group had the dose reduction due to adverse events. And the other 19 patients reduced bortezomib dose for other reasons. PFS and OS of the patients with reduced dose intensity were not significantly different from the patients with the standard dose intensity of 1.3 mg/m2 (P=0.183 and 0.482, respectively). However, in the patients with the cumulative bortezomib dose of ≥20.75mg and the standard dose intensity of 1.3mg/m2 was associated with superior survival (P=0.05). Median OS of these patients was 57.0 months (95%CI: 50.62-63.38), while median OS of other patients treated with the cumulative bortezomib dose of <20.75mg or reduced dose intensity was 45.0 months (95%CI: 41.45-48.55). In the ASCT group, we could not find any association between bortezomib dose and the survival.
Conclusion: For previously untreated MM patients intend to be treated with chemotherapy alone, we suppose cumulative bortezomib dose ≥20.75mg in the first line treatment should be administered for better OS. Despite reasonable cumulative bortezomib dose, any reduction of the dose intensity from 1.3mg/m2 is associated with inferior OS. For patients treated with ASCT, the association between the bortezomib dose and the survival needs to be elucidated with a long term follow-up.

Disclosures
No relevant conflicts of interest to declare.