Efficacy of Bortezomib Based Regimens and Disease Monitoring in Light Chain Multiple Myeloma: A Review of Literature
Authors: Malik Mustafa Nadeem , Rafae Abdul , Aslam Shehroz , Riaz Rida , Durer Seren , Durer Ceren , Abu Zar Muhammad , Shah Zunairah , Kamal Ahmad , Qureshi Anum , Jose Jemin Aby , Selene Insija Ilyas , Jamil Faiza , Shafqat Madeeha , Anwer Faiz 
Published: October 2019

Abstract
Introduction
Light chain multiple myeloma (LCMM) constitutes approximately 15% of patients with multiple myeloma (MM). It has an earlier average age of onset (54 years) and appears to have a poorer prognosis when compared to IgG or IgA variant. The main aim of our analysis is to study the published literature on the efficacy of bortezomib (V) based regimens and disease monitoring in patients with LCMM.
Methods
We performed a literature search of articles published after 2012 using following four databases (PubMed, Embase, Cochrane Library and Web of Science). We included only English language studies and summarized our data using medians, absolute values, and percentages.
Results
The literature search identified a total of 390 articles on LCMM. After detailed scrutiny, 6 studies involving a total of 1054 LCMM patients (pts) were included. In a study by Zhang et al. (2014) including 96 pts, 66 pts received 4 cycles of V (1 mg/m2) with dexamethasone (D) (20 mg) while 30 pts received non-V regimens. In bortezomib group, the overall response rate (ORR) was 95.5%. Complete response (CR) was seen in 56.1% pts while 39.4% pts showed partial response (PR). In non-bortezomib group, the ORR was 60%. CR was seen in 10% pts while 50% pts showed PR. The overall survival (OS) at 3 and 5 years in bortezomib group was 33% and 24% respectively while the OS in non-bortezomib group was 28% and 9% respectively (p=0.335). The progression free survival (PFS) at 1, 2 and 3 years in bortezomib group was 37%, 25% and 8% respectively while the PFS at 1 and 2 years in non-bortezomib group was 27% and 9% respectively (p=0.036) (Table 1). In two different studies by Mrachacz et al. (2015) and Tessenow et al. (2017), a total of 45 pts were treated with V (1.3 mg/m2) in combination with bendamustine (B) (60 mg/m2) and prednisone (P) (100 mg). ORR was 95.5% including 37.7% pts with CR, 22.2% pts with very good partial response (VGPR) and 35.5% pts with PR. Median OS at 24 and 30 months was 95% and 96 % respectively while PFS at 24 and 30 months was 90% and 68% respectively. In another study by Heaney et al. (2017) including 576 pts, 567 (98.4%) pts were identified by serum free light chain (sFLC) level compared to 460 (79.8%) pts which were identified by urine free light chain (uFLC) level. Hundred thirty-two pts were evaluated at maximum response to therapy with V. ORR was 98.4% including 43.1% pts with CR, 44.6% pts with VGPR, 10.6% pts with PR and 1.5 % pts had stable disease (SD).
In a study by Dejoie et al. PFS (2016) including 113 pts, Urine Protein Electrophoresis (UPEP) was positive in 87 (78.3%) out of 111 evaluable pts while serum involved free light chain (iFLC) was positive in all (113) pts. Seventy eight %, 37% and 18% pts showed abnormal UPEP at baseline (diagnosis), treatment cycle 1 and treatment cycle 3 respectively while 100%, 71% and 46% of pts showed abnormal iFLC at baseline, treatment cycle 1 and treatment cycle 3 respectively, indicating sFLC as more sensitive indicator of the disease than UPEP. Abnormal iFLC level at the end of consolidation therapy showed a statistically significant shorter PFS than pts with normal iFLC level [p= 0.004; Hazard ratio (HR) = 2.7; 95% CI = 1.4-5.4]. UPEP did not reach any statistical significance in determining PFS [p = 0.178; HR= 1.6; 95% CI= 0.8-3.3]. No statistically significant data was found for abnormal iFLC and abnormal UPEP in determining OS [(p= 0.164; HR= 2.2; 95% CI= 0.7-6.6) and (p= 0.891; HR= 0.9; 95% CI= 0.2-4.0) respectively]. However, abnormal sFLC ratio at the end of consolidation therapy showed a statistically significant shorter PFS (p= 0.006; HR= 3.1; 95% CI= 1.4-6.8) as well as OS (p=0.047; HR=7.8; 95% CI= 1.0-58.5). In a similiar study by Bradwell et al. including 224 pts, 82 pts were evaluated at follow up after chemotherapy with vincristine, doxorubicin and melphalan. CR was seen in 26 (31.7%) pts as indicated by normal uFLC levels compared with only 9 (10.9%) pts by their normal sFLC levels, indicating false negative results with uFLC compared to sFLC.
Conclusion
There is a paucity of data on LCMM in the literature. V has shown superior efficacy in LCMM patients over non-V regimens with ORR > 95%. Moreover, V showed better PFS at 2 years when used with bendamustin compared to VD (95% vs. 25%). Similarly, V with B showed better OS i.e. 90% at 2 years. Moreover, sFLC levels were more sensitive in indicating the disease and predicting PFS and OS compared to uFLC levels, hence monitoring of LCMM patients should include serum assays.

Disclosures
No relevant conflicts of interest to declare.