Antibodies in Development for Multiple Myeloma: A Systematic Review
Authors: Fraz Muhammad Asad , Tariq Muhammad Junaid , Usman Muhammad , Nunes Cavalcante Parr Nadia Carenina , Ijaz Awais , Ahmad Malik Qistas , Yasir Muhammad , Durer Seren , Khalil Muhammad Jahanzeb , Durer Ceren , Samuel Sharoon , Amin Saher Nasir , Safdar Ahmad , Anwer Faiz 
Published: October 2019

Abstract
Introduction
Immunotherapy using monoclonal antibodies (mAbs) have been gaining significance in the treatment of multiple myeloma (MM). These include naked antibodies, checkpoint inhibitors (CPIs), novel bispecific mAbs targeting two epitopes and antibody-drug conjugates (ADCs) having a mAb conjugated to a cytotoxic drug. This review aims to summarize phase I and I/II clinical trials using mABs for the treatment of MM.
Methods
A comprehensive literature search using data from PubMed, Embase, AdisInsight and Clinicaltrials.gov was performed for identification of early phase (I and I/II) trials of mAbs in MM treatment (January 2008 to December 2017). Studies involving mAbs including targeting antibodies, ADCs, CPIs and bispecific mAbs were included, without considering the geo-location, age, sex or specific eligibility criteria. Drugs already approved by FDA were excluded.
Results
Total of 2537 phase I and phase I/II studies were identified. After screening by two reviewers and categorization by their mechanism of action, 74 clinical trials (CTs) that involved mAbs as monotherapy or in combination with other chemotherapeutic drugs for the treatment of newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM). 41 CTs are active, completed or discontinued (Table 1) and 33 CTs are recruiting, approved for recruitment or planned. Most explored mechanism of action in these trials was mAb therapy directed against CD38, IL-6, huCD40, PD-L1 and PD-1.
Isatuximab (Anti-CD38) has shown objective response rate (ORR) of >50% in combination with lenalidomide (R) or pomalidomide (P) plus dexamethasone (d) in ongoing phase I trials NCT01749969 (n=57) and NCT02283775 (n=89) respectively. According to Vij et al. (2016) and Mikhael et al. (2018), 54% ORR (n=31) and 62% ORR (n=28) was shown by combination of isatuximab with Rd and Pd in 57 and 45 evaluable RRMM patients, respectively. In Vij et al. (2016) study, stringent complete response (sCR) in 2 (3%) patients, very good partial response (VGPR) in 13 (23%) and partial response (PR) in 16 (28%) patients was observed. In Mikhael et al. (2018) study, sCR in 1 (2%) patient, CR in 1 (2%), VGPR in 10 (21%) and PR in 16 (34%) patients was observed. In comparison, Martin et al. (2014) mentioned ORR of only 24% with isatuximab monotherapy in 34 RRMM patients. Grade (G) ≥3 pneumonia (n=4) was the most common high-grade adverse events (AEs) being reported (Table 2).
Siltuximab (Anti-IL-6) has shown clinical efficacy in combination with bortezomib (V) + d and RVd in phase I and I/II CTs. Shah et al. (2016) and Suzuki et al. (2015) found ORR to be 90.9% and 67% in 11 (NDMM) and 9 (RRMM) patients when siltuximab was given combined with RVd and Vd, respectively. Clinical benefit response (CBR) i.e. ≥ minimal response (MR) was 100% with siltuximab + RVd in NDMM patients. In comparison, siltuximab monotherapy in 13 RRMM patients yielded an ORR of 15% (2 CR) as reported by Kurzrock et al. (2012). G≥3 neutropenia (n=9), G≥3 thrombocytopenia (n=6) and G≥3 lymphopenia (n=8) were most common reported high-grade AEs.
Checkpoint inhibitors including pembrolizumab (anti-PD-1) and pidilizumab (anti-PD-L1) are being investigated in RRMM treatment. According to Otero et al. (2017) and Ribrag et al. (2017), 50% ORR was obtained with pembrolizumab combined with Rd compared to 0% with monotherapy, respectively. However, combination therapy was associated with G≥3 neutropenia (n=17), thrombocytopenia (n=9) and anemia (n=6) while no high-grade AEs were observed with monotherapy.
Antibody-Drug conjugates including lorvotuzumab mertansine and indatuximab ravtansine have been investigated in CTs for MM treatment. Lorvotuzumab mertansine has shown clinical efficacy in combination with Rd in a phase I trial (NCT00991562). Berdeja et al. (2012) reported an ORR of 59% (1 sCR, 1 CR, 8 VGPR, 9 PR) in 32 RRMM patients. In a phase I/II trial (NCT01638936) of indatuximab ravtansine combined with either Rd or Pd, Kelly et al. (2016) showed ORR of 77% with Rd (n=43) including at least 1 CR and 4 VGPR and 79% with Pd (n=14) including 4 VGPR in total 57 RRMM patients.
Conclusion
Combination regimens including monoclonal antibodies, CPIs and ADCs have shown clinically significant response in RRMM and NDMM patients. The mAbs caused hematological and nonhematological AEs like cytopenias and infections which needs to be monitored closely.

Disclosures
No relevant conflicts of interest to declare.