General MM

Overview of new immunotherapies in myeloma treatment

During the Myeloma and Plasma Cell Disorders Meeting, held at the University College London (UCL) on the 30th of October 2019, our Steering Committee Member Professor Shaji Kumar, Mayo Clinic, Rochester, US presented an overview of the immunotherapies in myeloma treatment.

The myeloma treatment paradigm foresees an induction phase followed by autologous stem cell transplantation (ASCT), maintenance therapy and treatment of relapsed disease. Transplant ineligible patients are usually subject to induction plus continuous therapy. Immunotherapy with the introduction of novel drugs represents one of the major advances in multiple myeloma (MM) treatment and in this article, we aim to answer the question: how can we harness the immune system for the purpose of anticancer therapy?

There are two different strategies:

  1. Direct targeting strategy with monoclonal antibodies and toxin-conjugated monoclonal antibodies
  2. Enhancing T cell function with immunomodulatory drugs, checkpoint inhibition, chimeric antigen receptor (CAR) T-cell therapy Bi-specific T-cell engagers (BiTEs) and vaccination

Direct targeting strategy:

  • Monoclonal antibodies
    • Anti-CD38
      • Daratumumab is active as a single agent and its efficacy was reported by Saad Z. Usmani and colleagues in 2016 (Overall Response Rate [ORR]= 31.1%).1 After this study, daratumumab has been tested in other clinical trials: the CASSIOPEIA study, the ALCYONE trial,2 the MAIA trial); the POLLUX trial, the CASTOR In all of these study Daratumumab demonstrated good efficacy in combination with other drugs. A phase III trial (EAA173) is testing whether daratumumab is able to enhance the therapeutic effectiveness of lenalidomide (LEN) and dexamethasone (d) in a population of patients with smoldering MM (SMM).
      • Isatuximab (Isa) has better activity in combination with immunomodulatory drugs, as demonstrated by a phase Ib study evaluating Isa in combination with standard doses of LEN and d in patients with RRMM.3 The only phase III study is the ICARIA study that compared Isa, pomalidomide (P) and low-dose d (Isa-Pd) with P and Pd only, in relapsed/refractory MM (RRMM). Results showed a better ORR and better progression-free survival (PFS) in the Isa-Pd arm vs the Pd arm (ORR= 60.4% vs 35.3%; PFS= 11.53 months vs 6.47 months)
    • Anti-SLAMF7 (SLAMF7 is a glycoprotein highly expressed on myeloma and natural killer cells)
      • Elotuzumab has little activity as a single agent and is used in combination with LEN and d; bortezomib (B) and d; P and d
    • Anti- B-cell maturation antigen (BCMA), (BCMA is a cell surface receptor specifically expressed on plasma cells and myeloma cells and its expression increases as the disease progresses from MGUS to advanced myeloma)
      • Belantamab mafodotin is an anti-BCMA antibody-drug conjugate that has demonstrated good clinical activity

Enhancing T cell function:

  • Checkpoint inhibition
    • Pembrolizumab is an anti- Programmed Death receptor 1 (PD1) antibody that in combination with P and Pd showed a higher response rate than P and Pd alone
  • CAR T cell approach
    • bb2121 is a second-generation CAR construct with an anti-BCMA targeting domain. The response rate is dose-related and independent of BCMA expression. Unfortunately, patients experienced adverse events such as cytokine release syndrome, neurotoxicity, neutropenia, thrombocytopenia, anemia, and infection
    • Other MM target antigen candidates for CAR T-cell therapy are represented by: CD44v6, CD70, CD56, CD38, CD138, CD19, immunoglobulin κ light chain, and SLAMF7

Multiple mechanisms occur in patients that relapse after CAR T-cell therapy, such as the loss of expansion and persistence of vector copies, and the development of resistance. Strategies to overcome resistance are represented by dual targeting of different antigens (e.g. anti-BCMA/anti-CD38 CAR T cells) or the use of gamma-secretase inhibitors to enhance BCMA expression. Other limiting factors are represented by neurological toxicity, insertional mutagenesis, cytokine release syndrome, “on-target, off-tumor” toxicity, and anaphylaxis/allergy.

  • BiTE
    • AMG 420 targets BCMA on tumor cells and CD3 on T cells, allowing T cells to be closer to the tumor cells and leading to a T cell-mediated lysis of BCMA-expressing cells. Problems related to AMG 420 are the continuous infusion and some toxicity
  • Vaccination approaches
    • PVX-410 vaccine was tested in a population of patients with SMM as monotherapy or in combination with LEN. Combination treatment was more effective in enhancing the immune response
    • Dendritic cell vaccination. An ongoing trial (NCT02728102) is testing vaccination with dendritic cell/myeloma fusions plus LEN maintenance therapy vs maintenance therapy alone following ASCT

Summary

  • Immune approaches will have a major role in the future, with multiple approaches such as CAR T, BiTE, vaccination showing good therapeutic potential. However, these approaches need further elucidation
  • In order to make these approaches more successful, it is important to understand the mechanisms leading to resistance
  • The timing and combination of different approaches needs more investigation
References
  1. Usmani S.Z. et al., Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016 Jul 7;128(1):37-44. DOI: 10.1182/blood-2016-03-705210
  2. Mateos M.V. et al., Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. N Engl J Med. 2018 Feb 8;378(6):518-528. DOI: 10.1056/NEJMoa1714678
  3. Martin T. et al., A phase 1b study of isatuximab plus lenalidomide and dexamethasone for relapsed/refractory multiple myeloma. Blood. 2017 Jun 22; 129(25): 3294–3303. DOI: 10.1182/blood-2016-09-740787
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