Novel Therapies for the Treatment of Patients with Relapsed/Refractory Multiple Myeloma: A Review of Clinical Trials
Authors: Iftikhar Ahmad , Ahmad Muhammad , Pachika Pranali , Razzaq Faryal , Ali Muhammad Ashar Ashar , Farrukh Hizra , Latif Azka , Anwer Faiz 
Published: November 2020

Introduction:
Multiple myeloma (MM) is a neoplastic proliferation of plasma cells. It is the second most common hematological malignancy in the US. Although it is associated with poor prognosis, newer therapies have improved outcomes in MM patients. This review aims to describe novel therapies used for the treatment of relapsed/refractory multiple myeloma (RRMM).
Methods:
A literature search was performed on Embase and clinicaltrials.gov using the keyword "Multiple Myeloma" from 1/1/2016 to 6/25/2020 for identifying ongoing clinical trials in the treatment of RRMM. After detailed scrutiny, we included 23 ongoing clinical trials (N=4362). We excluded case reports, case series, review articles, meta-analysis, and observational studies.
Results:
We summarized the interim results from ongoing clinical trials evaluating treatment of RRMM under following newer categories of drugs: Immunomodulatory drugs
In a phase 1b/IIa trial (NCT02773030, N=51) evaluating the efficacy of a novel immunomodulators, iberdomide CC-220 + dexamethasone (Dex) yielded an overall response rate (ORR) of 31%, clinical benefit (CB) was seen in 51% of the patients, and disease control (DC) in 88% of the patients and it was well tolerated by RRMM patients. There are other ongoing clinical trials evaluating the efficacy of Avadomide (CC-122), CC-92480 in RRMM. Alkylating agents
In a phase I/II trial (NCT01897714, N=45), melphalan-flufenamide (melflufan) + Dex yielded an ORR of 31%, it was well tolerated with 49% CB. Phase III OCEAN trial (NCT03151811, N=450) is currently ongoing to compare melflufen + Dex vs. pomalidomide (Pom) + Dex. Apoptotic agents
A phase 3 trial BELLINI (NCT02755597, N=291) evaluated the efficacy of veneteclox (Ven, Bcl-2 inhibitor) by randomizing patients to either Ven or Placebo arm. With a median follow up of 28.6 months (m), progression free survival (PFS) was 23.2m in the Ven arm vs. 11.4m in placebo. The interim results from a phase I/II trial (NCT03314181, N=104) of Ven + daratumumab (Dara) + Dex showed ORR of 96% with ≥ very good partial response (VGPR) of 96%. The addition of Bortezomib (Bor) to VenDaraDex had a slightly low ORR of 92%, with ≥VGPR of 79%. Another phase I/II trial (NCT01794520, N=117) is in progress to assess the efficacy and safety of Ven as monotherapy. Monoclonal Antibodies (MoAb)
A phase I/II trial (NCT01421186, N=91) evaluated the efficacy of MOR202, which is a novel MoAb. MOR202 was evaluated in three arms; MOR202 + Dex, MOR202 + Lenalidomide (Len) + Dex and MOR202 + Pom + Dex. The interim analysis showed the ORR of 65% with MOR202 + Len + Dex which was better than ORR of 48% with MOR202 + Pom + Dex, while the use of MOR202 + Dex yielded only 28% ORR. Antibody-drug conjugate (ADC)
Four ongoing trials are evaluating the efficacy of ADC (belantamab mafodotin), and the interim results are available for two trials. In phase II DREAMM-2 trial (NCT03525678, N=221) evaluating 2 doses of GSK2857916, 2.5mg/kg dose yielded ORR of 31% while 3.4mg/kg showed ORR of 34%. Another phase I trial (NCT02064387, N=79) evaluated belantamab mafodotin in RRMM and other hematologic malignancies expressing B-cell maturation antigen (BCMA). The results were promising with ORR of 60%. Bispecific T-cell engagers (BiTE)
Phase I trial of BiTE AMG 420 (NCT02514239, N=43) showed favorable results with ORR 70%, and CR 12%. The interim results from another phase I trial (NCT03486067, N=115) which evaluated the efficacy of BiTE CC-93269 showed 43% ORR and CR 17%. CAR-T Cell therapy
CAR-T cell therapy is also being studied in RRMM with JNJ-68284528 directed against BCMA in a phase Ib trial (NCT03548207, N=118). The interim analysis of 29 response evaluable patients out of 118 reported 100% ORR with stringent CR 76%. PK13 Inhibitors
In a phase I/II study (NCT00401011, N=84) evaluating perifosine + Bor +/- Dex, ORR of 41% was observed in Bor RR patients, and therapy was well tolerated with PFS of 6.4m and mOS of 25m.
Conclusion:
This review demonstrates novel and promising therapies which are currently in early phase clinical trials for the treatment of RRMM. Based on interim results, Iberdomide, melflufan, Ven, MoAb MOR202, ADC belantamab mafodotin, BiTE Molecule AMG 420, BCMA CAR-T cell therapy and perifosine have shown promising early activity and safety data in RRMM patients. Additional exploratory clinical trials are needed to confirm the efficacy and safety of these agents.

Disclosures
Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.