Efficacy and Safety of Newer Targeted Immunotherapy for Multiple Myeloma
Authors: Aslam Shehroz , Riaz Rida , Malik Mustafa Nadeem , Rafae Abdul , Faridi Warda , Malik Saad Ullah , Selene Insija Ilyas , Shah Zunairah , Sohail Chaudhry Saad , Mahfooz Faisal , Samuel Sharoon , Yasir Muhammad , Anwer Faiz 
Published: October 2019

Abstract
Introduction:
Targeted immunotherapy includes monoclonal antibodies, antibody-drug conjugates and chimeric antigen receptor T-cells (CAR-T cells). With recent advancements, the study of novel agents that target various cellular receptors involved on myeloma cells, have been actively pursued. The main aim of our study is to review and summarize published literature on the efficacy and safety of these targeted immunotherapies in patients (pts) with multiple myeloma (MM).
Methods:
We performed a comprehensive literature search on articles published after 2012 using the following databases (Pubmed, Embase, Cochrane, Web of Science and Clinicaltrials.gov). We included 6 completed and 16 ongoing phase II, III trials involving both newly diagnosed MM (NDMM) as well as relapsed/refractory MM (RRMM) pts.
Results:
Siltuximab: We included 3 phase II trials of Siltuximab (S) involving 243 pts. One hundred ninety-one pts had RRMM while 52 pts had NDMM. The overall response rate (ORR) was 45.50 % and 88% in RRMM and NDMM pts respectively. In a phase II trial involving 52 transplant ineligible NDMM pts, S (11mg/kg) in combination with bortezomib (V), melphalan (M) and prednisolone was given. In 49 evaluable pts, the ORR was 88% with complete response (CR) in 27% pts, very good partial response (VGPR) in 71% pts, and partial response (PR) in 61% pts. The median progression-free survival (mPFS) was 17 months (mo) while the overall survival (OS) at 1 year (y) was 88%. The most common grade 3 and 4 adverse effects (AEs) were neutropenia (62%), thrombocytopenia (44%), pneumonia (17%), and anemia (13%). In a phase II trial involving 142 pts with RRMM, S (6mg/kg) in combination with V was given. The number (no.) of prior therapies were 1-3. In 131 evaluable pts, ORR was 55% with CR in 11% pts and PR in 44% pts. The mPFS was 8 mo (p=0.345) while the OS at 1 y was 81%. The most common grade 3 and 4 AEs were neutropenia (49%), and thrombocytopenia (48%). In another phase II trial involving 49 pts with RRMM, S (6mg/kg) in combination with dexamethasone (D) was given. The median no. of prior therapies was 4. In 47 evaluable pts, the ORR was 19% while the mPFS and OS were 3.7 mo (95% CI= 2.8-4.9) and 20.4 mo (95% CI= 11.4-32.3) respectively. The most common grade 3 and 4 AEs were neutropenia (36.7%), thrombocytopenia (53%), anemia (32.6%), leukopenia (8%), and fatigue (16.3%). Only one ongoing phase II study was found (Table 2). No phase III studies were found.
Isatuximab (SAR650984): In a phase II trial involving 97 pts with RRMM, escalating doses of isatuximab (3-20 mg/kg) were given. The median age of pts was 62.5 y. The median no. of prior therapies was 5. At dose ≥10 mg/kg, maximum ORR of 24% was observed. The most common AEs were nausea (33%), fatigue (30%), dyspnea (26%), and cough (24%). Two ongoing phase II studies and 3 ongoing phase III studies were found (Table 2).
Pembrolizumab and nivolumab: In a phase II study involving 48 pts with RRMM, pembrolizumab (200mg) in combination with pomalidomide and D was given. The median no. of prior therapies was 3. The ORR was 60% with CR in 8.33% pts, VGPR in 19% pts, and PR in 33% pts. The mPFS was 17.4 mo. The most common grade 3 and 4 AEs were neutropenia (42%), thrombocytopenia (13%), anemia (21%), and lymphopenia (15%). Two ongoing phase II/III studies each was found for Pembrolizumab. One ongoing phase II and III study each was found for nivolumab (Table 2).
Tabalumab: In a phase II trial involving 148 pts with RRMM, tabalumab (100-300mg) in combination with D and V was given. The ORR was 58.1-59.5%. The mPFS was 6.6-7.5 mo. The most common grade 3 and 4 AEs were thrombocytopenia (15.6%), anemia (10.9%), and fatigue (7.5%). No phase III studies were found.
Conclusion:
Our study demonstrated that siltuximab combination regimens have shown excellent efficacy in NDMM pts compared to RRMM pts with an ORR of 88% vs. 46%. Similarly, better OS (88% vs. 81%) and mPFS (17 months vs. 8 months) were found in NDMM pts compared to RRMM pts. Neutropenia and thrombocytopenia were the major side effects reported with siltuximab. Pembrolizumab and tabalumab have shown moderate efficacy in RRMM pts with an ORR of 60%. However, isatuximab has shown mild efficacy in RRMM pts with an ORR of 24%. These drugs are well tolerated compared to siltuximab. Significant data in the literature are lacking and data from larger study population are needed.

Disclosures
No relevant conflicts of interest to declare.