Efficacy and Safety Profile of Novel Alkylators in Combination Regimens for Patients with Multiple Myeloma: A Review of Literature
Authors: Aslam Shehroz , Riaz Rida , Rafae Abdul , Malik Mustafa Nadeem , Jose Jemin Aby , Shah Zunairah , Abu Zar Muhammad , Qureshi Anum , Kamal Ahmad , Ijaz Awais , Khan Ali Younas , Malik Saad Ullah , Anwer Faiz 
Published: October 2019

Abstract
Introduction
Bendamustine (B) and Melflufen (Mel) are Non-Food and Drug Administration (FDA) approved novel alkylators that exert their cytotoxic effects by cross-linking of DNA strands via alkylation, resulting in the inhibition of mitotic checkpoints leading to cell death. We report published literature on efficacy and safety of combination regimens of novel alkylators in patients (pts) with multiple myeloma.
Methods
We performed a comprehensive literature search on articles published after 2012 using following search engines (Pubmed, Embase, Cochrane, Web of Science and Clinical Trials.gov). We included both phase II, III studies and summarized our data using absolute values and percentages.
Results
Bendamustine: We included four phase II studies of B involving 217 pts. One hundred seventy-six pts had relapsed and refractory multiple myeloma (RRMM) while 41 pts had newly diagnosed multiple myeloma (NDMM). The overall response rate (ORR) was 71.75 % and 92% in RRMM and NDMM pts respectively. In a phase II trial (n=41), NDMM pts who were not eligible for autologous stem cell transplant (ASCT) were included. B (80 mg/m2 on days 1 and 2), bortezomib (V) (1.3 mg/m2 on days 1, 8 and 15) and dexamethasone (D) (20 mg on days 1, 2, 8, 9, 15 and 16) were given for every 28 days for 8 cycles. In 39 evaluable pts, the ORR was 92% with complete response (CR) in 17% pts, very good partial response (VGPR) in 59% pts, and partial response (PR) in 21% pts. The most common grade 3 and 4 adverse effects (AEs) were leukopenia (12%), thrombocytopenia (7%), neutropenia (15%), and fatigue (12%). In a phase II trial (n=50), pts with RRMM were included. B (75mg/m2 on days 1 and 2), Lenalidomide (R) (25mg on 1-21 days) and D (40mg/20mg on days 1, 8, 15, 22) were given in a 4-weekly cycle for 6 cycles. In 45 evaluable pts, the ORR was 88.9% with CR in 15.5% pts, VGPR in 40% pts, and PR in 33.3% pts. The 2-year progression-free survival (PFS) and the overall survival (OS) were 42% and 76% respectively. The most common grade 3 and 4 AEs were neutropenia (74%), leukopenia (70%), thrombocytopenia (38%), anemia (20%), and infections (14%). In another phase II trial (n=94) pts with RRMM were included. B (60 mg/m2 versus 100 mg/m2 on days 1-8 of 28 day cycle), thalidomide (T) (100 mg on days 1-21) and D (20 mg on days 1,8,15 and 22 of 28 day cycle) were given. The dose of 100 mg/m2 was later discontinued due to cytopenias. In 54 evaluable pts, the ORR was 46.3% with CR in 1.9% pts, VGPR in 3.7% pts, and PR in 40.7% pts. The PFS and OS at 12 months were 18.7% (95% CI= 9.1- 31.0) and 56% (95% CI= 39.7-69.5) respectively. The common grade 3 and 4 dose-dependent (60mg/m2 vs. 100mg/m2) AEs were neutropenia (33% vs. 64%), thrombocytopenia (31% vs. 43%), and anemia (22% vs. 36%). In another Phase II trial (n=32), pts with RRMM undergoing tandem ASCT were included. Before the first ASCT, melphalan (M) (200 mg/m2) alone was given as a conditioning regimen while before the second ASCT, M (140 mg/m2) in combination with B (200mg/m2) was given. High dose cyclophosphamide (CY) (3-4 g/m2) and granulocyte colony stimulating factor (G-CSF) were used to mobilize peripheral blood stem cells (PBSC). The ORR and CR after the first ASCT were 81.2% and 46.8% respectively while the ORR and CR after second ASCT were 90.6% and 62.5% respectively. No phase III studies were found.
Melflufen: In a phase II trial (n=55), pts with RRMM were included. Melflufen (Mel) (40 mg every 3 weeks) in combination with D was given to 31 pts. The median number of prior lines of therapies was 4 (2-9). In 23 evaluable patients, the ORR was 48% with VGPR in 4.34% pts and PR in 43.47% pts. The median PFS was 7.6 months. An ORR of 43% in proteasome inhibitors (PI) refractory pts, 40% in immunomodulator (IMiD) refractory pts, 62% in alkylator refractory pts, 38% in double refractory (IMid and PI) pts and 50% in triple refractory (IMid, PI, and alkylators) pts was demonstrated. The most common grade 3 and 4 AEs were thrombocytopenia (68%), neutropenia (55%), anemia (42%), and leukopenia (32%).
Conclusion
Our study demonstrated that combination regimen (BVD) has shown superior efficacy with an ORR of >90% when compared to other combination regimens. Furthermore, BVD was well tolerated in patients with grade 3 and 4 toxicities < 20%. Moreover, the combination of B with M when used as conditioning regimen for ASCT showed superior efficacy than M alone (90.6% vs. 81.2%). However, there is a paucity of data regarding this and future randomized prospective trials are needed.

Disclosures
No relevant conflicts of interest to declare.