The challenges of checkpoint inhibition in the treatment of multiple myeloma
Section snippets
Multiple myeloma
Multiple Myeloma (MM) is a malignancy that is characterized by the clonal proliferation of terminally differentiated plasma cells within the bone marrow. MM represents 1% of all malignancies and 18% of hematologic malignancies in the United States accounting for an estimated 30,770 new diagnoses and 12,770 deaths in 2018 alone [1]. Classically, MM results in the secretion of a non-functional monoclonal immunoglobulin (Ig) that is produced by the transformed plasma cells. Production of this
Overview of the human immune system
The human immune system consists of two main components: the innate immune system, and the adaptive immune system. Innate immunity serves as the initial defense mechanism against microbial invasion and is characterized by a rapid, nonspecific response to pathogens. The components of the innate immune system include natural anatomic barriers (skin and mucosa), soluble proteins, bioactive small molecules (cytokines and complement components), and several types of myeloid derived leukocytes which
Immune dysfunction in multiple myeloma
As shown in Fig. 1, patients with multiple myeloma show profound defects/dysfunction in both innate and adaptive immunity [56]. The human innate immune system includes natural killer (NK) cells, macrophages, monocytes, neutrophils, eosinophils, and basophils. NK cells recognize and kill myeloma cells by activating receptors including NKG2D, DNAX accessory molecule (DNAM-1 or CD226) and the natural cytotoxicity receptors (NCRs) Np46, Np30, Np44 [57], [58]. NK cells play an important role in
CTLA-4
CTLA-4 is an inhibitory receptor expressed on T cells. The biological role of CTLA-4 is regulation of T cell responses, predominantly during initial activation in the lymph node and the prevention of autoimmunity; this has previously been illustrated by the development of massive lethal lymphoproliferation in CTLA-4 knock-out mice [88], [89]. Recognizing the role of CTLA-4 as a negative regulator of immunity, investigators have shown that antibody blockade of CTLA-4 could result in antitumor
Preclinical studies targeting CTLA4/CD28 and PD-1/PD-L1 pathways
Immunosuppresion is an important characteristic of MM pathology. Reversing this suppression could potentially restore myeloma immunosurveillance and improve disease control. Immune checkpoints are negative immunologic regulators that downregulate the magnitude of immune responses in order to protect the host from autoimmunity or damage from inflammation. This mechanism is frequently subverted by malignant cells, which escape immune surveillance by increasing inhibitory immune checkpoint ligands
Single agent activity
To date, there are no published clinical trials looking at ipilimumab or tremelimumab exclusively in MM patients. Ipilimumab was tested in a phase I trial of 28 patients with relapsed hematologic malignancies after allogenic stem cell transplant. This trial included 1 MM patient who presented with pulmonary plasmacytomas. Overall, 5 of the 22 (23%) patients who received the maximum tolerated dose of ipilimumab (10 mg/kg) had a complete response while another 2 (9%) patients had a partial
Future directions in treatment with immune checkpoint inhibitors
As detailed above, checkpoint inhibitors have proven challenging in the treatment of multiple myeloma. Targeting the CTLA4 and/or PD-1/PD-L1 pathways can re-activate and boost anti-tumor immunity, resulting in disease regression and prolonged survival in solid tumors. However, checkpoint inhibitors have not been effective as a single agent in multiple myeloma patients. Furthermore, current combinations of checkpoint inhibitors with IMiDs have yielded disappointing results and were associated
Conclusions
Multiple myeloma remains an incurable disease. Immunotherapy using checkpoint inhibitors holds great promise in reversing the suppressive anti-myeloma immune response in MM patients. Thus far, the efficacy and safety profile of checkpoint inhibitors have been disappointing in MM. However, a full understanding of the immune defects present in the MM patient is required to appreciate the unique state of immune impairment that this disease entails. With this understanding, new combinations of
Acknowledgements
None.
Competing interests
The authors declare no competing conflicts of interest.
Funding
This work is supported by Duke Cancer Institute Fund, NIH R44CA199767, NIH R01CA197792, and NIH 5T32HL007057-42.
Authors’ contributions
All authors wrote, read, and approved the final manuscript.
References (169)
The pathogenesis of acute kidney impairment in patients with multiple myeloma
Adv. Chron. Kidney Dis.
(2012)Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial
Blood
(2008)High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA
Blood
(2005)Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma
Blood
(2007)Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma
Blood
(2016)Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b–2 dose-escalation study
Lancet Haematol.
(2015)Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial
Lancet Oncol.
(2010)- et al.
Cell surface signaling molecules in the control of immune responses: a tide model
Immunity
(2011) - et al.
Dynamic regulation of T cell activation and co-stimulation through TCR-microclusters
FEBS Lett.
(2010) Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation
Immunity
(2010)
B7–H1 is a ubiquitous antiapoptotic receptor on cancer cells
Blood
HLA class I, NKG2D, and natural cytotoxicity receptors regulate multiple myeloma cell recognition by natural killer cells
Blood
The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody
Blood
Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug-induced apoptosis
Blood
In vivo peripheral expansion of naive CD4+CD25high FoxP3+ regulatory T cells in patients with multiple myeloma
Blood
A novel role of IL-17-producing lymphocytes in mediating lytic bone disease in multiple myeloma
Blood
Elevated IL-17 produced by TH17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma
Blood
Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies
Blood
Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6
Blood
Dendritic cells from patients with myeloma are numerically normal but functionally defective as they fail to up-regulate CD80 (B7–1) expression after huCD40LT stimulation because of inhibition by transforming growth factor-beta1 and interleukin-10
Blood
Tumor-promoting immune-suppressive myeloid-derived suppressor cells in the multiple myeloma microenvironment in humans
Blood
Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication
Blood
Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4
Immunity
Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120)
Blood
Immunosuppressive effects of multiple myeloma are overcome by PD-L1 blockade
Biol. Blood Marrow Trans.
Plasma cells from multiple myeloma patients express B7–H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway
Blood
Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-gamma-induced upregulation of B7–H1 (CD274)
FEBS Lett.
Pathogenesis and therapy of neuropathies associated with monoclonal gammopathies
Ann. Neurol.
Light chain multiple myeloma, clinic features, responses to therapy and survival in a long-term study
World J. Surg. Oncol.
Clinical course and prognosis of non-secretory multiple myeloma
Eur. J. Haematol.
High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma
N. Engl. J. Med.
A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome
N. Engl. J. Med.
Single versus double autologous stem-cell transplantation for multiple myeloma
N. Engl. J. Med.
A phase 2 study of bortezomib in relapsed, refractory myeloma
N. Engl. J. Med.
Bortezomib or high-dose dexamethasone for relapsed multiple myeloma
N. Engl. J. Med.
Survival and years of life lost in different age cohorts of patients with multiple myeloma
J. Clin. Oncol.
Daratumumab, bortezomib, and dexamethasone for multiple myeloma
N. Engl. J. Med.
Daratumumab, lenalidomide, and dexamethasone for multiple myeloma
N. Engl. J. Med.
Targeting CD38 with daratumumab monotherapy in multiple myeloma
N. Engl. J. Med.
Elotuzumab therapy for relapsed or refractory multiple myeloma
N. Engl. J. Med.
Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3
Br. J. Haematol.
Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed multiple myeloma: high response rates in a phase II clinical trial
Leukemia
Bortezomib, IV cyclophosphamide, and dexamethasone (VelCD) as induction therapy in newly diagnosed multiple myeloma: results of an interim analysis of the German DSMM Xia trial
J. Clin. Oncol.
Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients
J. Clin. Oncol.
Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer
Nat. Rev. Clin. Oncol.
Advances in cancer immunotherapy in solid tumors
Cancers
Cited by (15)
Interplay between fat cells and immune cells in bone: Impact on malignant progression and therapeutic response
2022, Pharmacology and TherapeuticsCitation Excerpt :The limited efficacy of checkpoint inhibition has been particularly apparent in metastatic prostate cancer, a malignancy exhibiting reduced immunogenicity and low mutational tumor burden (Stultz & Fong, 2021). Single-target immunotherapies have also been failing in metastatic breast cancers, multiple myelomas and other bone trophic-cancers (Paul, Kang, Zheng, & Kang, 2018; Topalian et al., 2019; Vonderheide, Domchek, & Clark, 2017). However, growing understanding of the complexity of the bone microenvironment and the role of the immune system in bone homeostasis and anti-tumor response is opening some potentially promising therapeutic avenues that give hope to patients with skeletal cancers, although there are still many roadblocks in the journey ahead (Fig. 2).
Oncolytic virotherapy – Forging its place in the immunomodulatory paradigm for Multiple Myeloma
2021, Cancer Treatment and Research CommunicationsThe promise of chimeric antigen receptor (CAR) T cell therapy in multiple myeloma
2019, Cellular ImmunologyCitation Excerpt :Using intravital imaging they tracked CD19 CAR T cells in B cell lymphoma-bearing mice and found that many of these cells were trapped in the lungs in the form of large cell aggregates and never reached their target destination [100]. Myeloma cells in particular have developed specific abilities to evade immune detection, such as upregulation of immune suppressive molecules (reviewed in [101]), increased Tregs and myeloid derived suppressor cells (MDSCs) [102,103], and secretion of VEGF, HGF, fibroblast growth factor (FGF), and stromal-cell-derived factor (SDF)-1α by bone marrow stromal cells [104] to avoid the killing of CAR T cells. Insufficient persistence of the CAR T cells has been postulated as a probable cause of loss of efficacy, and ultimately relapse of myeloma in response to CAR T therapy.
Contemporary patient-tailored treatment strategies against high risk and relapsed or refractory multiple myeloma
2019, EBioMedicineCitation Excerpt :Unfortunately, excessive and unpredictable toxicity has raised serious safety concerns about anti-PD1 MoAb, as reflected by several advanced clinical trials in R/R MM as well as newly diagnosed high-risk MM having been suspended by the FDA (e.g. NCT02579863, NCT02576977, NCT02906332) [52]. Further investigation and randomized trials are needed to further evaluate the safety and effectiveness of the ICI targeting the PD-1/PD-L1 axis [52,53]. MM is characterized by a heterogeneous mutational landscape [2–4].