Facts and hopes in multiple myeloma immunotherapy

Abstract

Among the hallmarks of cancer is the ability of neoplastic cells to evade and suppress immune surveillance to allow their growth and evolution. Nowhere is this as apparent as in multiple myeloma, a cancer of antibody-producing plasma cells, where a complex interplay between neoplastic cells and the immune microenvironment is required for the development and progression of disease. Decades of research has led to the discovery of a number of therapeutic agents, from cytotoxic drugs to genetically engineered cells that mediate their anti-myeloma effects at least partially through altering these immune interactions. In this review we discuss the history of immunotherapy and current practices in multiple myeloma, as well as the advances that promise to one day offer a cure for this deadly disease.

Introduction

Targeting of the immune system in multiple myeloma has been a long-standing therapeutic goal with early approaches utilizing immune stimulants such as interferon(1) and allogeneic hematopoietic stem cell transplantation with its accompanying graft versus myeloma effects(2). While associated with significant toxicity, limited reports of long-term remissions have buoyed hopes that immune therapies could one day cure multiple myeloma. Over the past two decades these approaches have continued to evolve with the advent of immune modulatory agents, monoclonal antibodies, and engineered cellular therapies that have dramatically improved survival for multiple myeloma patients (Figure 1). In addition, our understanding of how even some cytotoxic agents, such as proteasome inhibitors, affect and may cooperate with immune targeted agents has created new synergistic avenues with which to explore combinatorial therapy.

Figure 1.

Schematic overview of immune therapies in multiple myeloma.

Monoclonal antibodies recognize tumor antigens leading to inhibition of normal signaling or function of receptors, direct induction of apoptosis, antibody-directed cellular phagocytosis, antibody directed cellular cytotoxicity, complement-dependent cytotoxicity, immune stimulation, and via direct delivery of toxic payloads to tumor cells in the case of antibody-drug conjugates (ADCs). Chemotherapeutics such as bortezomib can induce immunogenic cell death leading to release of damage-associated molecular patterns (DAMPs) and stimulation of dendritic cells (DCs). CAR, chimeric antigen receptor; NK, natural killer; Treg, regulatory T-cell. Created with BioRender.com.

Immune dysfunction and the niche in multiple myeloma

Normal plasma cells develop and grow within a supportive niche in the bone marrow surrounded by stromal and immune cells(3). Neoplastic plasma cells tend to retain many features of their normal progenitors, including a dependence on interactions with this bone marrow microenvironment, a complex network that includes endothelial cells, osteoblasts, osteoclasts, plasmacytoid dendritic cells, tumor associated macrophages, myeloid-derived suppressor cells, and bone marrow stromal cells, that supports both normal hematopoiesis and the neoplastic cells (Figure 2)(4). These cells secrete growth factors such as transforming growth factor β (TGFβ)(5) and vascular endothelial growth factor (VEGF)(6) that promote angiogenesis, and cytokines such as interleukin-6 (IL-6), IL-17, and tumor necrosis factor (TNF) that support adhesion and growth of plasma cells, as well as protect them from the effects of cytotoxic therapies(7). The ability of neoplastic plasma cells to grow outside this supportive environment is associated with the development of extramedullary disease and plasma cell leukemia and portends a more aggressive clinical course, often occurring in the later stages of disease evolution. This may also act as an escape mechanism from immune-targeted therapies, allowing malignant plasma cells to grow and proliferate in immune-privileged spaces or in large extramedullary tumors that restrict access to monoclonal antibodies and T-cell engagers.

Figure 2.

Myeloma cells grow and evolve within a supportive bone marrow microenvironment.

Mesenchymal stromal cells (MSCs) and tumor associated macrophages (TAMs) secrete supportive cytokines and growth factors that promote growth of myeloma cells. T-regulatory cells, myeloid-derived suppressor cells (MDSCs), and plasmacytoid dendritic cells (pDC) suppress natural immune targeting and protect malignant plasma cells from therapy. Myeloma cells suppress normal osteoblasts and promote osteoclast-mediated bone turnover to disrupt the normal microenvironment. Created with BioRender.com.

Myeloma cells growing in the bone marrow are also surrounded by a matrix of T-, B- and NK-cells that have the potential to recognize and eliminate tumor cells(8). A complex interplay exists in which these components of the immune system are rendered inactive, or exhausted(9). This occurs via direct mechanisms such as upregulation of immune checkpoint proteins such as PD-L1(10), CD155 (the ligand for TIGIT) and GAL-3 (the ligand for LAG3), as well as via dysregulation of bone marrow stromal cells, which in turn suppress T- and B- lymphocytes(11). This evasion of surveillance by the innate and adaptive immune system is crucial to disease development, and may also contribute to the immunocompromised states seen in patients with multiple myeloma(12). Strategies to reverse this immune tolerance and restore anti-myeloma immunity are a major research focus.

Immunogenic cell death

Most classical chemotherapeutic agents cause DNA damage and/or cell cycle arrest, eventually leading to apoptosis. In contrast, during immunogenic cell killing, cell death is preceded by upregulation of damage-associated molecular patterns (DAMPs), including signaling proteins such as Calreticulin and HMGB1 and release of ATP, which can stimulate macrophages and dendritic cells to take up and present tumor neoantigens (Figure 3)(13,14). These dendritic cells, in turn, promote activation of T- and B-cells, leading to improved recognition of tumor cells and immune-mediated clearance. It remains unclear exactly why some agents trigger immunogenic cell death, but activation of the unfolded protein response (UPR) and increased ER stress are major determinants(15). Proteasome inhibitors such as bortezomib(16) are potent inhibitors of protein turnover, activators of the UPR, and a mainstay of multiple myeloma therapy. They have previously been shown to increase dendritic cell exposure to tumor antigens(16), and more recently been demonstrated to induce immunogenic cell death(17). Thus, even some anti-myeloma drugs without a direct link to immune cell function can potentially stimulate immunogenic mechanisms of cancer therapy and provide a scientific rationale for combining proteasome inhibitors with other immune-modulating agents.

Figure 3.

Schematic of immunogenic cell death.

XRT, X-ray therapy; UPR, unfolded protein response; DAMP, damage-associated molecular pattern; DC, dendritic cell. Created with BioRender.com.

Thalidomide analogs

Thalidomide and its analogs, lenalidomide and pomalidomide, are a cornerstone of multiple myeloma therapy. At least two additional thalidomide analogs, iberdomide(18) and CC-92480(19), are in clinical development. These agents function via a novel mechanism in which they recruit neosubstrates to the E3 ubiquitin ligase substrate adaptor CRBN, leading to their eventual polyubiquitylation and proteasomal degradation(20). In multiple myeloma cells, degradation of the core lymphoid transcription factors IKZF1 and IKZF3 promotes apoptosis. Degradation of IKZF3 in T-cells leads to upregulation of IL-2 and inhibition of TNFα production in activated monocytes, which gave rise to the moniker immunomodulatory imides (IMiDs®)(21). Newer agents appear to overcome resistance at least partly by inducing deeper and more robust degradation of IKZF1 and IKZF3(22,23). Thalidomide analogs have also been proposed to inhibit angiogenesis and alter the bone marrow niche(24), and may have additional targets and functions(25). While there are good correlative and model system data supporting all of these immune modulatory effects, it remains unclear to what extent this is important in mediating their therapeutic efficacy, as there are no malignancies in which thalidomide analogs are active but do not also have direct cytolytic activity.

Data supporting combinatorial synergy with other anti-myeloma agents are more robust. While the combination of lenalidomide and bortezomib has been proposed to act synergistically(26), these agents are actually predicted to have opposing functions as bortezomib inhibits the proteasome, a key mediator of lenalidomide-induced neosubstrate degradation(20,27). Their combinatorial efficacy could be due to independent actions as they are dosed on very different schedules, or due to enhanced immune functions in the context of immunogenic cell death.

Lenalidomide has also been proposed to have synergistic effects in combination with dexamethasone(28), histone deacetylase inhibitors(29), JAK/STAT inhibitors suchs as ruxolitinib(30), and monoclonal antibodies(31). Lenalidomide is known to enhance NK-cell function(32), likely via upregulation of IL-2, which may be important for its activity in combination with the monoclonal antibodies elotuzumab(33) and daratumumab(31), and which are discussed further below.

Antigenic targets in multiple myeloma

Most novel immune based therapies take advantage of tumor specific antigens that can be directly targeted. Ideal therapeutic targets would be easily accessible (the cell surface is preferred), expressed at a high level or only in malignant plasma cells to allow for specificity, and required for cell viability, such that deletion or downregulation of the target leading to drug resistance cannot readily occur. Finally, an ideal target would be expressed on all malignant cells, including disease initiating stem cells. Significant work has gone into identifying targets that meet some, but not all, of these criteria, which include CD38, CS1, BCMA, GPRC5D, FCRL5, CD138, immunoglobulin light chain, and ICAM1, among many others (Table 1). Efforts are ongoing to identify additional antigens that specifically mark myeloma cells and thus might provide targets either alone, or in combination, that will allow for increased selectivity while minimizing immune and off-target toxicity.

Table 1.

Antigenic targets in multiple myeloma. SLAMF7, SLAM family member 7; BCMA, B-cell maturation antigen; APRIL, a proliferation-inducing ligand; BAFF, B-cell activation factor; GPRC5D, G protein-coupled receptor, class C group 5 member D; FCRL5, Fc receptor-like 5; ICAM1, Intercellular adhesion molecule 1.

Antigen:	Normal function:	Expression:
CD38	Ecto-enzyme (converts NAD+ to adenosine)(103) Modulates local immune function(104) Response to bacterial infections(104) Marker of immune activation(105)	Mature B-cells Plasma cells T-cells NK cells HSCs Erythrocytes(106)
CS (SLAMF7)	Homophilic interactions leading to activation of NK-cell cytotoxicity(107) Aberrantly expressed on malignant plasma cells	NK cells Malignant plasma cells(51) CD8+ cells Dendritic cells Activated monocytes
BCMA	Member of TNF receptor superfamily Binding to APRIL or BAFF leads to activation of NF-κB pathway(108) Promotes plasma cell survival and proliferation(109) Cleaved into soluble form by γ-secretase(110)	Mature B-cells Plasma cells Plasmacytoid dendritic cells
GPRC5D	Unknown	Malignant plasma cells(111) Hair follicle
FCRL5	Transmembrane protein homologous to Fc receptor(112) Binds IgG and stimulates B-cells(113) Located on chromosome 1q21 (often amplified in myeloma)(114)	Malignant plasma cells(115)
CD138	Cell surface protein involved in interactions with microenvironment Expression required for myeloma cell growth and survival(116)	Plasma cells(117)
Ig κ	Immunoglobulin light chain Expressed on cell surface	Mature B-cells Plasma cells(118)
ICAM1	Leukocyte interactions with endothelial cells and transmigration(119) Overexpressed in myeloma cells due to hyperactivation of NF-κB pathway(120,121)	Endothelial cells B-cells Plasma cells

Monoclonal antibodies

Monoclonal antibodies have been a mainstay of the treatment of other B-cell malignancies such as non-Hodgkin lymphoma since the development of rituximab, but have only made their way to multiple myeloma in the last decade. These agents target cell surface proteins expressed at high levels or exclusively on malignant plasma cells and exert their cytotoxic effects through a variety of mechanisms (Figure 1).

Anti-CD38 monoclonal antibodies

There are two FDA-approved monoclonal antibodies targeting CD38, daratumumab and isatuximab. Daratumumab is a humanized immunoglobulin G1 (IgG1) antibody(34) with potent activity in multiple myeloma. In relapsed/refractory patients it demonstrated a 29% overall response rate as a single agent(35), and its addition to either lenalidomide or bortezomib in combination with dexamethasone lead to significant improvements in progression free survival in two large randomized phase 3 trials(36,37). Mechanistic synergy between lenalidomide and daratumumab has also been proposed(31), although the combination of daratumumab with either lenalidomide or bortezomib result in similar response rates, suggesting that potential mechanistic synergy observed in the lab could arise from different mechanisms (amplification of immunogenic cell death for instance) or may not translate into significant clinical advantages. More recently, daratumumab has been introduced into the newly diagnosed setting where its combination with lenalidomide and dexamethasone has shown excellent activity and tolerability and is thus a preferred option for older or unfit patients(38). Finally, quadruplet induction regimens with daratumumab, lenalidomide, a proteasome inhibitor and dexamethasone have demonstrated extraordinary rates of MRD negativity (51% versus 20% with RVd alone) and may soon become established as a standard of care for fit newly diagnosed patients(39).

Isatuximab differs from daratumumab in that it is a chimeric IgG1 antibody that targets a unique epitope on CD38 and similar to daratumumab induces cell death through a variety of mechanisms including direct apoptosis(40), antibody directed cellular cytotoxicity (ADCC), and complement activation(41). Isatuximab also inhibits the enzymatic activities of CD38(42) and thus may alter the microenvironment to inhibit tumor growth(43). As a single agent, it has activity in relapsed/refractory multiple myeloma (ORR of 23%)(44) that is similar to daratumumab, and it was recently FDA-approved for use in combination with pomalidomide and dexamethasone, where it demonstrated a near doubling in median PFS as compared to pomalidomide and dexamethasone alone (11.5 vs 6.5 months)(45).

Mechanisms of resistance to these agents have not been fully worked out, but appear to involve downregulation or loss of the CD38 epitope from myeloma cells(46,47). There are ongoing efforts to identify strategies to upregulate or induce re-expression of CD38. Signaling through the JAK-STAT pathway downregulates CD38, something that can be reversed following treatment with the pan-JAK inhibitor ruxolitinib(48). Retinoids such as all-trans retinoic acid(49) and histone deacetylase inhibitors(50) have been shown to increase CD38 expression in cell line models and clinical trials are ongoing to explore these agents in patients.

Anti-CS1 monoclonal antibodies

Elotuzumab is a humanized IgG1 antibody that targets CS1 and showed no single agent anti-myeloma activity despite high expression on neoplastic plasma cells(51,52). However, when combined with lenalidomide and dexamethasone it demonstrated an increased ORR (79% vs 66%) and a PFS (median of 19.4 vs 14.9 months) and OS (4-year OS of 50% vs 43%) advantage when compared to lenalidomide and dexamethasone alone(53,54). When combined with pomalidomide and dexamethasone the ORR (53% vs 26%) and median PFS (10.3 vs 4.7 months) were significantly increased as compared to pomalidomide and dexamethasone alone(55). The synergy with thalidomide analogs has been proposed to be mediated by elotuzumab-induced upregulation of IL-2 in T-cells and stimulation of NK-cell mediated cellular cytotoxicity(56,57). Thalidomide analogs also enhance T- and NK-cell functions, likely by degradation of IKZF3 and subsequent upregulation of IL-2. Other combinations, such as with bortezomib and dexamethasone also appear to have activity, possibly mediated by enhancement of immunogenic cell killing(58).

Anti-BCMA monoclonal antibodies

Anti-BCMA antibodies are rapidly making their way into the clinic with the FDA-approval of the antibody-drug conjugate (ADC) balantamab mafadotin(59). In a highly refractory patient setting it demonstrated a 34% ORR, but with significant toxicity, primarily cytopenias and keratopathy related to the toxin conjugate monomethyl auristatin F (MMAF)(60). This toxicity may limit its widespread use, as it requires every 3-week ophthalmologic evaluation. Studies are ongoing to assess its safety and efficacy in combination with a number of other anti-myeloma agents. MEDI2228 is another anti-BCMA antibody fused to the toxin pyrrolobenzodiazepine with promising pre-clinical activity(61), and it is in early stage clinical trials(62). Interestingly, ophthalmic toxicity, albeit through a different mechanism than with belantamab mafadotin, was common.

Anti-ICAM1 monoclonal antibodies

Naked anti-ICAM1 antibodies have demonstrated minimal activity in multiple myeloma, with the best response seen being stable disease(63). However, recent development of an antibody conjugated to MMAF has shown promise in pre-clinical models, and is now entering clinical trials(64).

Anti-CD138 monoclonal antibodies

The anti-CD138 antibody VIS832 is capable of inducing direct cytotoxicity to multiple myeloma cells in vitro and produces synergistic activity when combined with thalidomide analogs or bortezomib(65). Whether CD138 targeted agents are safe and effective in patients has not yet been tested.

Cellular therapies

Cellular therapies harness and re-direct the patient’s adaptive cellular immune system to attack and treat the cancer.

T-cell engagers

Bispecific antibodies or bispecific T-cell engagers (BiTEs) are recombinant antibody fragments containing the Fab variable regions of two separate antigen recognition motifs fused together in one of a variety of conformations (Figure 4). These variations can produce differences in half-life and function(66). They act to bring into close proximity the two targets of the cognate halves of the molecule, and in so doing produce their therapeutic action. The most common pairing is a CD3 binding domain fused to a domain that binds a tumor antigen such as CD19 or BCMA. In so doing they function to recruit αβT-cells into close proximity with tumor cells, activating the TCR and leading to cellular cytotoxicity. Molecules can be designed that target other immune cells such as NK-cells(67) or γδT-cells(68) to induce different modes of cell killing, or even to bring together soluble extracellular proteins such as in the case of emicizumab. Thus, these are highly flexible modular drugs capable of a number of therapeutic functions.

Figure 4.

Schematic of T-cell engagers and chimeric antigen receptors.

Bispecific T-cell engagers (BiTEs) have a CD3 binding moiety that can interact with the native T-cell receptor (TCR) fused to an antigen binding moiety that can target tumor antigens such as B-cell maturation antigen (BCMA) bringing T-cells into proximity of the tumor and inducing immune synapse and cytotoxicity. Chimeric antigen receptor (CAR) T-cells contain are genetically engineered to express a chimeric protein that includes an extracellular scFv domain capable of binding tumor antigens such as BCMA fused to a transmembrane (TM) domain, the CD3ζ stimulatory domain and a costimulatory (costim) domain, typically 4-1BB or CD28. Binding of the CAR to antigen leads to immune synapse formation and cytotoxicity. Created with BioRender.com.

In myeloma, the greatest experience has been reported with BCMA-targeted CD3 engagers. Early studies of AMG420 in patients with relapsed or refractory multiple myeloma demonstrated a 70% response rate at the maximally tolerated dose of 400ug/day, with five of ten patients achieving an MRD-negative complete response(69). The immune toxicity profile demonstrated mostly grade 2 CRS at this dose with increased rates of infection including two deaths. Despite these promising results, further development of this agent was abandoned due a short half-life that required continuous intravenous dosing. Studies are ongoing with modified agents, such as AMG701, that have a longer half-life and allow for every 3-week dosing. Multiple other T-cell engagers targeting BCMA are now in clinical trials(70,71).

Studies with bispecific antibodies targeting CD38, FCRL5 and GPRC5D among other targets are all ongoing, and are expected to report initial results in the coming year(66,72). Additional data will be needed in order to know how these agents compare to other molecularly-targeted drugs including ADCs and CAR T-cells and whether, and in what contexts, they can be safely and effectively combined with other anti-myeloma agents(73).

Chimeric antigen receptor T-cells

Adoptive cell transfer utilizing genetically engineered T-cells has been a highly successful approach inducing cures in multiple B-cell malignancies such as acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). These strategies have utilized autologous T-cells transduced with a chimeric T-cell receptor containing an extracellular domain targeting the tumor antigen fused to intracellular signaling domains (typically CD3ζ combined with either CD28 or 4-1BB costimulatory domains) that promote robust T-cell activation following antigen binding (Figure 4). Therapy involves apheresis of autologous T-cells, transduction with the engineered chimeric antigen receptor (CAR), followed by ex vivo growth and expansion. Following administration of lymphodepleting chemotherapy, typically a combination of fludarabine and cyclophosphamide, the cells are re-infused. For most currently available CARs, the process takes approximately 4-6 weeks from vein to vein. CD19 targeted CAR T-cells have produced durable remissions in up to half of patients with relapsed or refractory ALL and DLBCL and are now a mainstay of therapy for these patients. CD19 is not expressed on the majority of multiple myeloma cells, but it may be expressed on myeloma initiating cells, and there have been limited reports demonstrating efficacy of CD19-targeted CAR T-cells in this setting(74).

A far more promising target is anti-BCMA targeted CARs. Idecabtagene vicleucel (ide-cel, bb2121) is a BCMA-targeting CAR that is currently in phase 3 clinical trials, and is expected to obtain FDA-approval in 2021. Ide-cel has produced objective responses in 85% of patients, with complete response or better in 45% of patients(75). The median progression free survival was 11.8 months in this heavily pre-treated population, without any maintenance therapy. Grade 3 or higher hematologic toxicities occurred in the majority of patients. In addition, three quarters of patients developed CRS, although most was grade one or two. Severe neurologic toxicity was uncommon. Data for at least three other products have also been presented. These CARs all have similar structures and clinical profiles, although differences in the valency of the antigen binding domain (ciltacabtagene autoleucel, cilta-cel)(76) or humanization of the chimeric construct (CT053) may produce subtle differences in the activity, persistence, and toxicity profile of these different agents. What the specific differences are, and whether there are certain patient populations that may benefit more from one or another of these products, remains to be seen.

Unlike in other B-cell malignancies, multiple myeloma uniformly relapses following treatment with anti-BCMA CAR T-cells. The reasons for this are unclear, and mechanisms of resistance and relapse have not been well characterized, although it does appear that at least in some cases biallelic loss of BCMA may occur(77). The quality and makeup of the T-cell input and the effects multiple lines of prior therapy have on T-cell function may also be an important determinant of response and persistence(78). Whether T-cells should be banked early in disease is an important question in the field. Strategies are ongoing to develop approaches to improve outcomes with these therapies including upregulation of surface BCMA using γsecretase inhibitors(79), designing new CAR constructs that allow for more rapid manufacturing and improved persistence, introduction into other immune subsets such as γδT-cells(80) and NK cells(81), and the development of allogeneic “off the shelf” CARs. Future studies will likely involve novel combinations of CARs with standard therapies or other immune targeted agents to augment activity. Multi-targeting constructs to help decrease the chance for antigen escape and modified CARs to help overcome T-cell exhaustion are also being developed(82). These new approaches may at some point finally achieve the ultimate goal of curing patients with multiple myeloma.

Tumor vaccines and other cellular therapies

Somatic mutations in multiple myeloma cells can generate neoantigens capable of inducing anti-tumor immune responses, which may be associated with clinical responses(83) and are potential targets for cellular therapies. A variety of other cellular therapy approaches including tumor antigen vaccines, cytolytic T-lymphocytes, and allogeneic or autologous NK T-cell infusions have been tested or are in various states of clinical investigation(84,85). So far, these therapies have shown limited effectiveness, but they may have utility in selected disease states such as preventing progression from precursor states(86), in the setting of immune reconstitution following bone marrow transplantation or in combination with other immune modulatory drugs, immune checkpoint inhibitors, T-cell engagers or CARs.

Toxicities related to cellular therapies

Because cellular therapies lead to hyperactivation of the immune system, they tend to share a common set of toxicities. The most well characterized of these is hyperactivation of αβT-cells leading to the cytokine release syndrome (CRS)(87). This is mediated by release of high levels of inflammatory cytokines including IL-1(88) and IL-6(89), often associated with rapid T-cell expansion. A systemic inflammatory state akin to sepsis follows, marked by high fevers and capillary leak leading to hypoxemia and hypotension. The severity of symptoms can range from mild flu-like symptoms to fatal HLH-like macrophage activation syndrome(90). Treatment is focused on anti-cytokine agents such as IL-6 and IL-1 blockade, as well as T-cytolytic therapies including corticosteroids and chemotherapeutics(91). This immune hyper-inflammation can also produce neurotoxicity (ICANS, immune-effector cell associated neurotoxicity syndrome)(92), via a less well understood process but thought to be mediated by endothelial dysfunction. Almost all cellular therapies have the capability of producing some degree of CRS and/or ICANS, but the degree to which they do this can be quite variable, even with the same antigenic target and disease indication. There has also been limited correlation between the degree of inflammatory toxicities and clinical efficacy, and anti-inflammatory mitigation of CRS and ICANS does not appear to impair clinical efficacy.

Checkpoint blockade

Cells express a number of molecules on their surface to prevent immune-mediated destruction including PD-L1, GAL-3, and CD47 that are often upregulated in cancer. Inhibition of these immune checkpoints has been a highly successful therapeutic strategy in a variety of solid and hematologic malignancies(93). In multiple myeloma, despite elevated expression of PD-L1(10) and the importance of the immune microenvironment, checkpoint inhibitors have shown limited activity as single agents(94,95). More concerningly, early trials testing pembrolizumab, a PD1 inhibitor, in combination with lenalidomide and pomalidomide had to be stopped early due to increased mortality, possibly related to increased immune-related toxicity(96). Whether there is a role for PD1-targeted or other immune checkpoint therapies in specific clinical contexts such as after CAR T-cell therapy or in combination with other agents, especially those like bortezomib that induce immunogenic cell death, is an unanswered question in the field.

Immune therapies in the COVID era

The COVID-19 pandemic has created new challenges for cancer patients receiving therapy(97). Initial data has been reassuring that patients with hematologic malignancies undergoing therapy are not at higher risk of adverse outcomes from infection with the novel coronavirus as compared to those not receiving therapy(98) and that myeloma patients are capable of mounting an immune response(99). Among cancer patients in general there have been reports of worse outcomes among those receiving immune checkpoint targeted therapy as compared to conventional chemotherapy(100). Whether this extends to other immune based therapies is unclear, and most myeloma patients being treated with immune and cellular based therapies have few options for additional therapy. Their primary risk is morbidity and mortality related to disease progression(101); therefore the most efficacious possible therapy should be pursued without significant modification, aside from efforts to avoid infection(102). Whether the recently approved COVID-19 vaccines will have any unexpected toxicity and will be effective in this patient population also remains unknown, but we recommend that patients with multiple myeloma receive the vaccine as per CDC guidelines.

Conclusions

In summary, while the history of immune therapies in multiple myeloma is long, there remains significant work to be done in order to achieve their true promise. Thalidomide analogs, proteasome inhibitors, and CD38-targeted monoclonal antibodies make up the backbone of modern myeloma therapy, all of which have important immune-mediated mechanisms of action and have dramatically improved outcomes for patients. An increasing number of new monoclonal antibodies, T-cell engagers, and cellular therapies are rapidly making their way to the clinic. They have great potential to overcome constitutive genomic heterogeneity as well as ongoing DNA damage and clonal evolution underlying relapse of disease by achieving minimal residual disease negativity and restoring host anti-myeloma immunity. The optimal timing and sequencing of these agents to maximize efficacy with the overarching goal being cure is a key issue that will define the next decade in myeloma research.