Edited by: Francesca Gay, University Hospital of the City of Health and Science of Turin, Italy
Reviewed by: Frederique Vegran, INSERM U1231 Lipides, Nutrition, Cancer (LNC), France; Kawaljit Kaur, University of California, Los Angeles, United States
This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Oncology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Immunotherapy has recently emerged as a promising treatment option for multiple myeloma (MM) patients. Profound immune dysfunction and evasion of immune surveillance are known to characterize MM evolution and disease progression. Along with genomic changes observed in malignant plasma cells, the bone marrow (BM) milieu creates a protective environment sustained by the complex interaction of BM stromal cells (BMSCs) and malignant cells that using bidirectional connections and cytokines released stimulate disease progression, drug resistance and enable immune escape. Local immune suppression and T-cell exhaustion are important mediating factors of clinical outcomes and responses to immune-based approaches. Thus, further characterization of the defects present in the immune system of MM patients is essential to develop novel therapies and to repurpose the existing ones. This review seeks to provide insights into the mechanisms that promote tumor escape, cause inadequate T-cell stimulation and impaired cytotoxicity in MM. Furthermore, it highlights current immunotherapies being used to restore adaptive T-cell immune responses in MM and describes strategies created to escape these multiple immune evasion mechanisms.
Multiple myeloma (MM), although a rare disease, is the second most common hematologic malignancy (
As such three major anti-MM immunotherapeutic approaches have been developed: (i) agents that remove the breaks of the immune system, such as immunomodulatory agents (IMiDs) and immune checkpoint inhibitors, (ii) agents that target highly selective antigens on the MM cells in the form of monoclonal antibodies (mAbs) and (iii) agents that stimulate immune cells to selectively kill the malignant cells, such as chimeric antigen receptor (CAR) T-cells, bispecific T-cell engagers (BiTE), and anti-MM vaccines. Those strategies have shown encouraging results in patients with relapsed refractory MM (RRMM) and hold the potential of targeting specifically the malignant cells and the stimulation of a continued response due to harnessing immune surveillance against MM. Nevertheless, the field still presents many challenges, such as the need for tailored therapeutic strategies and biomarkers, the difficulty of selecting the appropriate combination therapy, and resistance to currently available immune-based approaches. Here, we will review the mechanisms that lead to immunosuppression and reduce immune recognition in MM and highlight the strategies created to escape these multiple immune evasion mechanisms to provide long term disease control and better survival for MM patients.
Along with the genomic changes occurring in plasma cells (
Mechanisms leading to MM immune escape.
Lastly, an increase in the number of immunosuppressive cells such as Tregs, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) have been demonstrated in advanced MM. Tregs express CD25 and transcriptional factor forkhead box P3 (FOXP3) and are capable of inducing expression of co-inhibitory molecules on antigen presenting cells (APCs). They are also known to secrete IL-10 and TGF-β and have the capacity to kill APCs and cytotoxic T-cells by using the granzyme- and perforin-dependent pathways (
Tumor-induced impairment of cytotoxic T-cells repertoire at the site of tumor has been also linked to immune escape and failure of immunotherapy-based approaches. An extensively investigated form of T-cell dysfunction is the T-cell exhaustion. Initially described in chronic viral infection and later in cancers, it results from prolonged antigen stimulation and is characterized by gradual loss of T-cells effector activity and increased expression levels of inhibitory receptors (
Immunosuppression plays a critical role in MM pathogenesis, therefore reversing this suppression could potentially reinstate MM immune surveillance and improve disease control. IMiDs exhibit potent anti-MM activity (
Of note, the synergistic phenomena reported when anti-CD38 antibodies are combined with IMiDs seem to derive from their co-modulated effects on the host adaptive and innate immunity, suggesting that the acquired resistance to this combination may be mainly immune-mediated. These CD38 targeting antibodies have been reported by many groups (including ours) to exert multiple anti-tumoral immune effect such as complement dependent cytotoxicity (CDC), antibody mediated cellular phagocytosis (ADCP) as well as antibody driven cellular cytotoxicity (ADCC) (
Co-stimulatory and co-inhibitory immune checkpoints tightly regulate the immune response upon activation to defend the host from autoimmunity or harm due to inflammation (
Summary of combination trials with checkpoint inhibitors ongoing in MM.
PD-1 | Immune checkpoint blockade | Cemiplimab | Isatuximab | I-II | NCT03194867 |
PD-1 | Immune checkpoint blockade | Nivolumab | Pomalidomide and Dexamethasone | III | NCT02726581 |
PD-1 | Immune checkpoint blockade | Nivolumab | Lenalidomide | II | NCT03333746 |
PD-1 | Immune checkpoint blockade | Nivolumab | Daratumumab and Cyclophosphamide | II | NCT03184194 |
PD-1 | Immune checkpoint blockade | Nivolumab | Dexamethasone, Carfilzomib, Nivoluman, and Reovirus | I | NCT03605719 |
PD-1 | Immune checkpoint blockade | Pembrolizumab | Pomalidomide and Dexamethasone | I-II | NCT02289222 |
PD-1 | Immune checkpoint blockade | Pembrolizumab | Lenalidomide and Dexamethasone | I | NCT02036502 |
PDL-1 | Immune checkpoint blockade | Durvalumab | Daratumumab | I | NCT03000452 |
Furthermore, since epigenetic abnormalities have been observed in cancer cells and tumor infiltrating T-cells (
Monoclonal antibodies (mAbs) have recently emerged as active therapeutic agents for the management of MM patients. They target highly selective antigens expressed in malignant plasma cells and not in normal tissues, stimulating specific anti-tumor activity and preventing toxicity due to off target effects. They elicit anti-MM activity through multiple mechanisms, including a direct cytotoxic effect on MM cells via apoptosis and an immune-mediated cytotoxicity such as ADCC, CDC, and ADCP. They can also be used to directly target the malignant plasma cells while releasing an anti-cancer agents linked via a chemical linker, as it is the case for the antibody-drug conjugates (ADCs), or to engage and stimulate cytotoxic T-cells for lysis of MM cells with bispecific T-cell engagers (BiTEs).
Elotuzumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody that targets SLAMF7, also known as CS1, a glycoprotein greatly expressed in MM cells and NK cells (
Summary of combination trials with monoclonal antibodies ongoing in MM.
SLAMF7 | Monoclonal antibody | Elotuzumab | Lenalidomideand Dexamethasone | III | NCT01239797 | ELOQUENT-2 |
SLAMF7 | Monoclonal antibody | Elotuzumab | Pomalidomide and Dexamethasone | II | NCT02654132 | ELOQUENT-3 |
SLAMF7 | Monoclonal antibody | Elotuzumab | Bortezomib and Dexamethasone | II | NCT01478048 | |
SLAMF7 | Monoclonal antibody | Elotuzumab | Lenalidomide, Bortezomib, and Dexamethasone | II | NCT02375555 | |
SLAMF7 | Monoclonal antibody | Elotuzumab | Kyprolis, Lenalidomide, and Dexamethasone | II | NCT02969837 | |
SLAMF7 | Monoclonal antibody | Elotuzumab | Pomalidomide, Bortezomib, and Dexamethasone | II | NCT02718833 | |
CD38 | Monoclonal antibody | Daratumumab | Lenalidomide and dexamethasone | III | NCT02076009 | POLLUX |
CD38 | Monoclonal antibody | Daratumumab | Pomalidomide and Dexamethasone | II | NCT01998971 | EQUULEUS |
CD38 | Monoclonal antibody | Daratumumab | Pomalidomide and Dexamethasone | III | NCT03180736 | APOLLO |
CD38 | Monoclonal antibody | Daratumumab | Bortezomib and Dexamethasone | III | NCT02136134 | CASTOR |
CD38 | Monoclonal antibody | Daratumumab | Carfilzomib and Dexamethasone | III | NCT03158688 | CANDOR |
CD38 | Monoclonal antibody | Daratumumab | Bortezomib, Melphalan, and Prednisone | III | NCT02195479 | ALCYONE |
CD38 | Monoclonal antibody | Daratumumab | Lenalidomide and Dexamethasone | III | NCT02252172 | MAIA |
CD38 | Monoclonal antibody | Daratumumab | Bortezomib, Thalidomide, and Dexamethasone | III | NCT02541383 | CASSIOPEIA |
CD38 | Monoclonal antibody | Daratumumab | Bortezomib, Lenalidomide, and Dexamethasone | II | NCT02874742 | GRIFFIN |
CD38 | Monoclonal antibody | Isatuximab | Pomalidomide and Dexamethasone | III | NCT02990338 | ICARIA |
CD38 | Monoclonal antibody | Isatuximab | Kyprolis and Dexamethasone | III | NCT03275285 | IKEMA |
CD38 | Monoclonal antibody | MOR202 | I | NCT01421186 | ||
CD38 | Monoclonal antibody | TAK-079 | I | NCT03439280 |
CD38 is a transmembrane glycoprotein highly expressed in MM cells and at low level in plasma, myeloid, and lymphoid cells, and some non-hematopoietic tissues (
Daratumumab is the first anti-CD38 targeting antibody approved as monotherapy and in combination with numerous anti-MM standard regiments in MM. It is a fully humanized IgG1κappa monoclonal antibody that targets the cyclic ADP ribose hydrolase CD38. It mediates the killing of MM cells via CDC, ADCC, ADCP, and direct apoptosis via FcR-mediated cross-linking, and modulation of CD38 enzyme activities (
In combination with Lenalidomide and Dexamethasone, Daratumumab (Dara-Rd) demonstrated significant efficacy in the phase III POLLUX trial. The ORR was 92.9% in Dara-Rd patients vs. 72.9 in Rd group, with a mPFS not reached vs. 17.5 months in the Dara-Rd vs. Rd arm and higher rate of patients achieving deep response with a minimal residual disease (MRD) negativity of 26% in the DRd group vs. 6% in the Rd group (
Daratumumab has been also combined with PIs. The phase III CASTOR trial revealed that adding Daratumumab to Bortezomib and Dexamethasone (Dara-Bd) resulted in higher ORR (83 vs. 63%), extended PFS (median 16.7 vs. 7.1 months) and higher MRD negativity rate (12 vs. 2%) (
Isatuximab is a chimeric IgG1−κ anti-CD38 mAb which selectively targets a unique epitope on human CD38 receptor and induces anti-MM activity by direct apoptosis, CDC, ADCC, and ADCP (
Of note, others anti-CD38 antibodies currently being evaluated include MOR202 (fully human from Morphosys), and TAK-079 (fully human from Takeda). Clinical activities in RRMM patients have been reported in combination with IMiDs (
In recent years, the development of therapeutic agents able to induce the autologous immune cells to mediate tumor cell killing and to overcome the immunosuppressive mechanisms of the tumor microenvironment has revolutionized the treatment of cancers. In this setting adaptive cell therapy using chimeric antigen receptor (CAR)-T cell therapy has been developed to eliminate cancer cells in many hematological malignancies including MM. CARs are artificial fusion proteins that consist of the extracellular antigen recognition part of an antibody from a single-chain variable fragment (scFv) fused with the CD3ξ chain for the intracellular signaling, and a T cell costimulatory domains (CD28 or 4-1BBB) (
Different antigen have been tested as targets for CAR-T cell therapy against MM. These include CD44v6, CD70, CD38, CD138, SLAMF7, and class C group 5 member D (GPRC5D) (
BCMA, a transmembrane signaling protein member of the tumor necrosis factor superfamily member 17 (TNFRSF17 or CD269), is expressed in mature B lymphocytes, and is important in maintaining the long-lived plasma cell homeostasis (
The first in-human trial using an anti-BCMA CAR-T cells was completed at the National Cancer Institute (NCI) by Brudno et al. (
Following bb2121, the phase I trial of the next generation of anti-BCMA CAR-T therapy bb21217 has been also reported. The use of the phosphoinositide 3 kinase (PI3K) inhibitor bb007, to increase of memory-like CAR-T cells the final product, indicated similar ORR and toxicity profile to what was observed with bb2121. A longer follow-up and clinical data from patients receiving higher doses of cells are now required to understand if the
To improve the effects of anti-BCMA CAR-T therapy, a CAR-T cell therapy targeting two different BCMA epitopes (VHH1 and VHH2) was recently developed (LCAR-B38M). It showed a high response rate, with an ORR of 88%, an MRD negativity of 63% and a median PFS of 15 months in RRMM patients (
Additional CAR-T clinical trials targeting BCMA also include the JCARH125, MCARH171, and FCARH143 studies. They use three new CAR-T cell products composed of a human-derived scFv, a 4-1BB costimulatory domain, and a truncated human epidermal growth factor receptor (tEGFR), respectively, and are currently being evaluated in phase I clinical trials. A summary of combination trials with anti-BCMA CAR-T cell therapies ongoing in MM is presented in
Summary of combination trials with anti-BCMA T-cell therapies ongoing in MM.
BCMA | CAR-T cell | Bb2121 | I | NCT02658929 | |
BCMA | CAR-T cell | Bb2121 | II | NCT03361748 | |
BCMA | CAR-T cell | Bb21217 | I | NCT03274219 | |
BCMA | CAR-T cell | LCAR-B38M | I | NCT03090659 | |
BCMA | CAR-T cell | LCAR-B38M | Ib-II | NCT03548207 | |
BCMA | CAR-T cell | JCARH125 | I-II | NCT03430011 | |
BCMA | CAR-T cell | MCARH171 | I | NCT03070327 | |
BCMA | CAR-T cell | FCARH143 | I | NCT03338972 | |
BCMA | ADCs | GSK2857916 | Pembrolizumab | II | NCT03848845 |
BCMA | ADCs | GSK2857916 | Pomalidomide | I-II | NCT03715478 |
BCMA | ADCs | GSK2857916 | Lenalidomide/ Borthezomib and Dexamethasone | II | NCT03544281 |
BCMA | BiTE | AMG 420 | I | NCT02514239 | |
BCMA | BiTE | AMG 701 | I | NCT03287908 |
In addition to CAR-T therapy BCMA is also a perfect target for antibody-drug conjugates (ADCs) and for bispecific T-cell engagers (BiTEs). ADCs are immunoconjugates composed of a monoclonal antibody conjugated to a cytotoxic drug via a chemical linker. They precisely target cells expressing the target antigen and are then internalized to release the cytotoxic component and lead to cell death (
BiTEs are engineered molecules able to direct the host's immune system, more precisely the T-cells, against cancer cells. They are recombinant bispecific proteins with two linked scFvs. from two different antibodies, one targeting a cell-surface molecule on T cells (e.g., CD3ε) and the other targeting antigens on the surface of malignant cells. By binding to tumor antigens and T-cells simultaneously, BiTEs mediate T-cell responses and killing of tumor cells (
In MM, among potential targets, BCMA, CD38, SMALF7, FcRH5, and G protein-coupled receptor (GPCR) GPRC5D, have been selected to develop anti-MM BiTEs, with BCMA representing the most promising target. As such, AMG 420 is the first anti-BCMA BiTE currently being evaluated in MM. It contains the scFv targeting BCMA in its N-terminal and CD3ξ in its C-terminal followed by a hexa-histidine (His6-tag) (
Research investigating tri-specific antibodies is also emerging. As such, HPN217 is the first in this category. It is designed to recognize human BCMA to target MM cells, serum albumin to extend its half-life, and CD3ε for the engagement of T cells. Preclinical studies have demonstrated BCMA- and T cell-dependent anti-tumor activity
Anti-cancer vaccines are based on the use of tumor antigens to stimulate the immune system and produce an antitumor response. To date, several therapeutic vaccine strategies have been established. These include the use of whole tumor cell, gene-modified tumor cells, or tumor-cell lysates, peptide or protein-based vaccines, RNA- and DNA- based vaccines, viral vector modified to express tumor antigen and DC-based vaccines containing DNA, RNA, or peptides (
Numerous preclinical studies and clinical trials using these diverse therapeutic strategies have been completed and reported to be promising for the treatment of indolent metastatic disease (
In MM these approaches have been used in disease stages with lower tumor burden including stem cell transplantation (SCT), precursor disease such as smoldering myeloma (SMM), and MRD settings (
Among the cell-based vaccines, therapeutic strategies based on the use of autologous DCs pulsed with tumor antigens have been tested. As such, in a phase II trial, a fusion vaccine generated by combining autologous MM and DCs was administrated to MM patients following ASCT (
Overall, anti-MM vaccination therapy appears to be well tolerated and largely considered to have the greatest activity when used in combination with other therapies that have immunomodulatory properties. In this context, vaccines could increase the probability of clinical response or improve its duration making this approach a promising adjuvant strategy against MM.
The treatment of MM patients has improved significantly over the past few years (
IMiDs with their pleiotropic anti-MM properties have showed ability to enhance the effects of mAb treatments, checkpoint inhibitors and ADCs (
Further research is now required to define the most active and safe combination and the most appropriate time point of drugs administration throughout the course of the disease. Although most of the immune-based studies were completed in RRMM patients, it is expected that patients benefit the most when it is used earlier in their disease course. The optimal sequence of the different type of immune therapies is also unspecified and in need of further studies.
Lastly, the detection of prognostic factors or biomarkers able to predict clinical responses and/or toxicity in patients will enable more active tailored treatments and better survival for MM patients. As such interrogation at single cell level of the BM immune repertoire of patients treated with immunotherapies can identify cellular mediators of sensitivity or resistance to those therapies and define potential means to reinstate sensitivity. Along with the improvement of existing therapeutic strategies and the development of new approaches, a better understanding of the role of immune system in MM pathogenesis is essential.
NL, RM, FH, and PN analyzed the data and wrote the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Antibody driven cellular cytotoxicity
Antibody mediated cellular phagocytosis
Antibody-drug conjugates
Adverse events
Acute lymphoblastic leukemia
Antigen presenting cells
A proliferation inducing ligand
Arginase
Autologous stem cell transplant
American Society of Hematology
B-Cell Activating Factor
B-cell maturation antigen
Bispecific T-cell engagers
Bone marrow
Bone marrow stromal cells
Chimeric antigen receptor
Complement dependent cytotoxicity
Casein kinase 1α
Cyclooxygenase-2
Complete response
Cereblon
Cytokine release syndrome
Cytotoxic T lymphocyte
Cytotoxic T-lymphocyte-associated antigen 4
Dendritic cell
European Medicines Agency
Food and Drug Administration
Forkhead box P3
G protein-coupled receptor
Class C group 5 member D
Hexa-histidine
Indoleamine 2,3-dioxygenase
Interferon gamma
Immunoglobulin
IKAROS Family Zinc Finger 1
AIOLOS
Interleukin
Immunomodulatory agents
Inducible nitric oxygen synthase
Interferon regulatory factor 4
Immunoreceptor tyrosine based-inhibition motif
c-Jun N-terminal kinase
Lymphocyte-activation gene 3
Monoclonal antibodies
Mitogen-Activated Protein Kinase 8
Myeloid-derived suppressor cells
Monoclonal Gammopathy of Undetermined Significance
Major histocompatibility complex
Multiple myeloma
Median overall survival
Median progression-free survival
Minimal Residual Disease
Maximum tolerated dose
National Cancer Institute
Near complete response
Natural killer
Newly diagnosed multiple myeloma
Nitric oxide synthase
Overall response rates
Overall survival
Programmed death-ligand 1
Programmed death 1
Plasmacytoid dendritic cells
Progression-free survival
Phosphoinositide 3 kinase
Proteasome inhibitors
Partial response
Receptor activator of nuclear factor kappa-B ligand
Reactive species of oxygen
Relapsed refractory multiple myeloma
Single-chain variable fragment
Stringent complete remission
Stem cell transplantation
Signaling lymphocytic activation molecule F7
smoldering multiple myeloma
Soluble MHC class I chain-related protein A
Tumor-associated macrophages
T-cell receptor
Truncated epidermal growth factor receptor
Transforming growth factor- β
T helper
T-cell immunoglobulin and ITIM domains
Tumor necrosis factor superfamily member 17
Regulatory T cells
Vascular endothelial growth factors
Heavy chain variable domain
Light chain variable domain
X-box binding protein 1
Elotuzumab with Lenalidomide and Dexamethasone
Lenalidomide and Dexamethasone
Elotuzumab plus Pomalidomide and Dexamethasone
Pomalidomine and Dexamethasone
Elotuzumab plus Bortezomib and Dexamethasone
Bortezomib and Dexamethasone
Elotuzumab plus Lenalidomide (Revlimid), Bortezomib (Velcade), and Dexamethasone
Elotuzumab plus Kyprolis (Carfilzomib), Lenalidomide, and Dexamethasone
Elotuzumab plus Pomalidomide, Bortezomib, and Dexamethasone
Daratumumab with Lenalidomide and Dexamethasone
Daratumumab with Pomalidomide and Dexamethasone
Daratumumab with Bortezomib and Dexamethasone
Daratumumab with Carfilzomib and Dexamethasone
Carfilzomib and Dexamethasone
Daratumumab with Bortezomib, Melphalan and Prednisone
Bortezomib, Melphalan and Prednisone
Daratumumab with Bortezomib plus Thalidomide and Dexamethasone
Bortezomib plus Thalidomide and Dexamethasone
Daratumumab with Bortezomib plus Lenalidomide and Dexamethasone
Bortezomib plus Lenalidomide and Dexamethasone
Isatuximab with Pomalidomide and Dexamethasone.