Treatment of multiple myeloma: What is the impact on T-cell function?

Abstract

Treatment of multiple myeloma (MM) has evolved remarkably over the past few decades. Autologous stem cell transplantation, as well as proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies, has substantially improved the prognosis of patients with MM. Novel therapies, including chimeric antigen receptor-T cells, bispecific T-cell engagers, antibody-drug conjugates, histone deacetylase inhibitors, and nuclear export inhibitors, have provided more options. However, MM remains incurable. T cells are the principal weapons of antitumor immunity, but T cells display a broad spectrum of dysfunctional states during MM. The promising clinical results of T-cell-directed immunotherapies emphasize the significance of enhancing T-cell function in antimyeloma treatment. This review summarizes the potential effects of these antimyeloma agents on T-cell function and discusses possible optimized strategies for MM management by boosting T-cell immunity.

Keywords

antimyeloma treatment CAR-T cell therapy effects on T cell multiple myeloma optimized strategies

Graphical abstract

Introduction

Multiple myeloma (MM) is one of the most common hematological malignancies characterized by dysregulated plasma cell growth.¹ Over the past two decades, substantial progress in the treatment of MM has been achieved and is comprehensively reviewed.^2,3 Despite these advances with improved outcomes for patients, MM remains largely incurable, and most patients eventually relapse.^4,5 Progressive immune dysfunction, notably in the T-cell repertoire, is a hallmark of the myeloma course.⁶

T cells are important components of the adaptive immune system and play a major role in tumor eradication and cure. The major players are CD8⁺ cytotoxic T and CD4⁺ helper T (Th) lymphocytes. CD8⁺ T cells specifically recognize and kill malignant cells directly and indirectly by releasing granzyme B, perforin, and other effector cytokines as well as triggering Fas/Fas ligand (FasL)-mediated apoptosis.⁷ CD4⁺ T cells are heterogeneous, with distinct subsets characterized by specific cytokine spectrums.⁸ Th1 subsets are involved in cellular immunity by producing interferon-gamma (IFN-γ) and interleukin (IL)-2. Th2 subsets promote humoral immunity by releasing IL-4. The Th1/Th2 balance plays an important role in the antimyeloma response.⁹ Th17 subsets sustain MM cell growth and osteoclasts-dependent bone damage by secreting IL-17.^10,11 Moreover, regulatory T cells (Tregs) represent a critical subset of CD4⁺ T cells, characterized by a CD4⁺CD25⁺Foxp3⁺/CD127^−/dim phenotype. Tregs inhibit CD8⁺ and CD4⁺ effector T cells (T_EFF) and the specific functions of antigen-presenting cells via direct cell-to-cell contact and by releasing IL-10 and transforming growth factor beta (TGF-β).¹² The imbalance of Th1/Th2/Th17/Treg cells contributes to the pathogenesis and underlying mechanisms of MM.¹³

MM has long been associated with quantitative and qualitative deficits in T cells, particularly in relapsed or refractory (RR) settings.^14–18 T-cell deficits include declined T-cell counts, inverted CD4⁺/CD8⁺ ratios, increased levels and functionality of Tregs, reduced expression of activation markers, loss of memory T (T_M) subsets, acquisition of an exhausted or senescent phenotype, and impaired effector function (Table 1).^6,14–18 Understanding the effects of the current treatment modalities on T cells will provide implications for the development and optimization of therapeutical strategies for MM. Chimeric antigen receptor (CAR)-T cell therapy and bispecific T-cell engager (BiTE) have been designed to directly redirect T cells to elicit antimyeloma responses and have shown promising clinical efficacy, further emphasizing the significance of T cells in MM management. This review focuses on the mainstay and novel therapeutic approaches toward MM and their potential influence on T cells (Figures 1 and 2) and further proposes a new therapeutic paradigm for MM integrating T-cell functional status.

Table 1.

T-cell deficits in MM and strategies for improvement.

T-cell deficits in MM	Agents for accelerating deterioration	Strategies to improve T-cell immunity	Agents and combination strategies for improvement
Declined T-cell counts	Bortezomib; elotuzumab; selinexor	Promoting T-cell proliferation	ASCT; lenalidomide; daratumumab; AMG 701; belantamab mafodotin; ACY241
Inverted CD4⁺/CD8⁺ T-cell ratios	Panobinostat	Increscent CD4⁺/CD8⁺ T-cell ratios	ASCT; daratumumab; AMG 701
Increased levels and functionality of Tregs	Bortezomib	Inhibition of Tregs	ASCT; lenalidomide; pomalidomide; daratumumab; isatuximab; elotuzumab; CTLA-4 inhibitors; ACY241
Reduced expression of activation markers	ASCT; bortezomib	Upregulated expression of activation markers	ASCT plus PD-1, LAG-3, TIGIT inhibitors; AMG 420; belantamab mafodotin; ACY241
Loss of Tm subsets	Bortezomib; panobinostat	Retention of Tm subsets	Lenalidomide; ASCT plus lenalidomide; daratumumab; PD-1 and CTLA-4 inhibitors; AMG 701; ACY241
Acquisition of an exhausted or senescent phenotype	ASCT; elotuzumab	Resisting to or reviving an exhausted or senescent phenotype	ASCT plus PD-1, LAG-3, TIGIT inhibitors; bortezomib; lenalidomide; ACY241
Impaired effector function	Selinexor	Improved effector function	ASCT; lenalidomide; pomalidomide; daratumumab; isatuximab; PD-1 and LAG-3 inhibitors; CD38 and PD-1 co-inhibition; TIGIT inhibitors; AMG 420; AMG 701; lenalidomide plus AMG 701; AMG 424; ACY241; ACY241 plus PD-1 inhibitors
Downregulated glycolysis	Bortezomib; lenalidomide; PD-1 and CTLA-4 signals	Upregulated glycolysis	ASCT; PD-1 and CTLA-4 inhibitors

ASCT, autologous stem cell transplantation; CLTA-4, cytotoxic T-lymphocyte associated antigen 4; LAG-3, lymphocyte-activation gene 3; MM, multiple myeloma; PD-1, programmed cell death protein 1; TIGIT, T-cell immunoreceptor with Ig and ITIM domains; Tm, memory T cell; Tregs, regulatory T cells.

Figure 1.

Effects of the mainstay drugs for MM on T cells. (a) The effects of ASCT on T cells. (b) The effects of the proteasome inhibitor (bortezomib) on T cells. (c) The effects of immunomodulatory drugs (lenalidomide and pomalidomide) on T cells. (d) The effects of monoclonal antibodies (daratumumab, isatuximab, and elotuzumab) on T cells.

Figure 2.

Effects of the novel therapies for MM on T cells. (a) The three major components of CAR and their effects on CAR-T cells; important cytokines for CAR-T expansion and their effects on CAR-T cells; the effects of endogenous T cells on CAR-T cells and their crosstalk. (b) The effects of bispecific T-cell engagers (AMG 420, AMG 701, and AMG 424) on T cells. (c) The effects of BCMA-targeted antibody-drug conjugate (belantamab mafodotin) on T cells. (d) The effects of histone deacetylase inhibitors (panobinostat and ACY241) on T cells. (e) The effects of the nuclear export inhibitor (selinexor) on T cells.

Effects of MM treatment on T cells

Autologous stem cell transplantation

Autologous stem cell transplantation (ASCT) following induction chemotherapy is regarded as the standard therapy for all eligible patients with MM, whereas allogeneic stem cell transplantation is controversial in MM and is currently not recommended outside clinical trials.^19,20

After the high-dose melphalan-induced lymphodepletion, newly transplanted T cells have a high availability of cytokines without endogenous cellular competition and thus get a better proliferation and effector function.²¹ T-cell reconstruction after ASCT manifests as the recovery and expansion of CD8⁺ T cells, with markedly elevated ratios of CD8⁺/CD4⁺ T cells and T_EFF/Tregs.¹⁵ Metabolic activation was more pronounced in T cells with upregulated glycolysis and fatty acid oxidation during engraftment after ASCT.²² ASCT also alters the molecular signatures of T cells and downregulates expression of the co-stimulatory receptors CD27 and CD28 and upregulates expression of immune checkpoints, programmed cell death protein 1 (PD-1), lymphocyte-activation gene 3 (LAG-3), and T-cell immunoreceptor with Ig and ITIM domains (TIGIT).²³ However, T-cell exhaustion and senescence characterize the immune impairment and relapse after ASCT.^15,23,24 PD-1 and TIGIT inhibitors could revive the expansion and cytokine secretion of exhausted CD8⁺ T cells in vitro.^15,24

Proteasome inhibitors

Proteasome inhibitors (PIs) are one of the most important classes of agents used for MM treatment over the past two decades. In MM, the ubiquitin-proteasome system (UPS) is dysfunctional, and PIs are designed to target the 26S proteasome, a critical component of the UPS. PIs control the dysregulated UPS, leading to the accumulation of misfolded and unfolded proteins, provoking endoplasmic reticulum stress and ultimately promoting MM cell death.²⁵ Bortezomib is a first-in-class PI and is widely used in clinical settings.

Bortezomib selectively induces T-cell apoptosis, which is related to caspase activation and cleavage of the anti-apoptotic protein BCL-2, by upregulating nuclear factor kappa B (NF-κB) expression.²⁶ Moreover, bortezomib suppresses activation, proliferation, and survival of CD4⁺ T cells, leading to a transient drop of CD4⁺ T cells in MM patients.^27,28 However, Tregs are resistant to the pro-apoptotic effects of bortezomib, which promotes the emergence of a distinct Tregs population.²⁹ Proteasome activity strongly influences the fate of CD8⁺ T cells. Inhibition of proteasome activity leads T cells to a terminal effector status, whereas enhancement results in the acquisition of memory characteristics in the early stages of T-cell differentiation.³⁰ Transcriptomic and proteomic analyses have revealed that the modulation of proteasome activity in CD8⁺ T cells affects glycolysis and metabolic reprogramming in a Myc-dependent manner.³⁰ In addition, bortezomib alleviates PD-1-mediated exhaustion in activated CD8⁺ T cells for the potential mechanism that bortezomib induces microRNA-155-dependent downregulation of suppressor of cytokine signaling 1 and inositol polyphosphate-5-phosphatase.³¹ In vitro and in an MM mouse model, bortezomib makes MM cells more sensitive to T-cell-mediated killing via the Fas/FasL pathway but does not promote the intrinsic cytotoxic activity of T cells.^32,33

Immunomodulatory drugs

Immunomodulatory drugs (IMiDs) exert pleiotropic anti-MM effects, including anti-angiogenic, anti-proliferative, and immunomodulatory effects. Notably, IMiDs mediate pleiotropic immunomodulation in a wide range of immune cells, particularly T cells. Lenalidomide is a second-generation IMiD, whereas pomalidomide is a novel one.

Lenalidomide significantly amplifies the stimulation from CD3 ligation and dendritic cells, resulting in striking T-cell proliferation.³⁴ Furthermore, lenalidomide and pomalidomide induce enhanced ubiquitination and degradation of T-cell transcriptional repressors IKAROS and AIOLOS, subsequently triggering robust T-cell activation and effector functions.³⁵ Lenalidomide decreases CD45RA expression on T cells in MM patients,³⁶ induces an increasement in central memory T (T_CM) and effector memory T (T_EM) cells, and decreases T_EFF cells in vitro and in transplanted patients.³⁷ A possible explanation for the arrested T_EFF differentiation is that lenalidomide inhibits T-cell glycolysis³⁸ or induces Wnt signaling activation.^39,40 Lenalidomide polarizes T-cell responses toward a Th1 phenotype, decreases Treg levels, and downregulates PD-1 expression.⁴¹ Lenalidomide and pomalidomide also strongly inhibit the proliferation and immunosuppressive function of Tregs via downregulating Foxp3 expression and inhibiting STAT5 phosphorylation.^41,42 In addition, natural killer T cells exert enhanced antigen-specific expansion in response to CD1d-mediated presentation of glycolipid antigens and have a greater ability to secrete IFN-γ in the presence of lenalidomide.⁴³

Monoclonal antibodies

Monoclonal antibodies (mAbs) act via multiple mechanisms, including antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity, and immunomodulatory effects. Currently, two CD38-targeted mAbs (daratumumab and isatuximab) and one signaling lymphocyte-activation molecule family member 7 (SLAMF7)-targeted mAb (elotuzumab) have been approved for the treatment of MM.

CD38 is widely expressed in the lymphoid and myeloid lineages. Daratumumab induces significant T-cell growth with incremental CD8⁺/CD4⁺ and CD8⁺/Treg ratios, increases T_M cells, and decreases naïve T (T_N) cells in MM patients.⁴⁴ Daratumumab also improves T-cell functional response and T cell receptor (TCR) clone diversity, possibly due to the depletion of CD38⁺ regulatory cells, including myeloid-derived suppressor cells, regulatory B cells, and a subpopulation of Tregs.⁴⁴ A shift toward cytolytic granzyme B⁺ T cells was also observed in MM patients treated with daratumumab, suggesting an increased killing capacity of CD8⁺ T cells.⁴⁵ Daratumumab combined with IMiDs and dexamethasone has been approved in the treatment of RRMM. Daratumumab plus lenalidomide and dexamethasone resulted in preferential expansion of CD8⁺ T cells and a high proportion of T_EM cells as well as reduced immunosuppressive CD38⁺ Tregs.⁴⁶ Daratumumab plus pomalidomide and low-dose dexamethasone prominently increased activated and proliferating CD8⁺ T cells and T_EM cells but did not raise exhausted T cells or Tregs.⁴⁷

Isatuximab preferentially decreases Tregs, reduces Foxp3 expression and IL-10 production of Tregs, and augments the cytotoxicity of CD8⁺ T cells.⁴⁸ The immunomodulatory effects of CD38-targeted mAbs may contribute to deeper and more durable clinical responses in MM patients. The extracellular domain of CD38 acts as an ectoenzyme involved in the catabolism of nicotinamide adenine dinucleotide (NAD⁺) and NAD⁺ phosphate-generating calcium-signaling molecules. CD38 downregulation results in intrinsically higher NAD⁺, higher glutaminolysis, enhanced oxidative phosphorylation, and altered mitochondrial dynamics of T cells, which vastly improves tumor control.⁴⁹ Blockade of the CD38 ectoenzyme reduces adenosine production and mitigates its inhibitory effect on CD8⁺ T cells.⁵⁰ Moreover, osteoclasts protect MM cells against T-cell-mediated cytotoxicity by directly inhibiting T-cell proliferation. CD38 is significantly upregulated during osteoclast formation, and CD38-targeted mAbs can alleviate the suppressive effects of osteoclasts on T cells by inhibiting adenosine production.⁵¹

SLAMF7, also known as CS1 or CD319, is a target for MM immunotherapy. However, SLAMF7 is also expressed in a fraction of normal lymphocytes, and anti-SLAMF7 therapy poses a theoretical risk of lymphopenia.⁵² Transient reduction of lymphocytes has been observed after elotuzumab therapy, which is attributed to chemokine- and cytokines-mediated lymphocyte trafficking instead of elotuzumab-mediated depletion of SLAMF7⁺ lymphocytes.⁵³ Activation of the SLAMF7 self-ligand receptor on T cells induces STAT1 and STAT3 phosphorylation and the expression of multiple inhibitory receptors and exhaustion-associated transcriptional factors.⁵⁴ Interestingly, SLAMF7 is highly expressed on CD8⁺CD57⁺ Tregs in MM patients, and elotuzumab can specifically deplete SLAMF7⁺ Tregs via ADCP, suggesting that SLAMF7-targeted mAbs can relieve the immunosuppressive effects of Tregs in MM.⁵⁵

CAR-T cell therapy

CAR-T cell therapy, a novel genetically modified cellular immunotherapy, has transformed the cancer treatment landscape. Gratifying success has been achieved in patients with RRMM.

CARs are synthetic fusion proteins with at least three major components: an extracellular antigen-binding portion, hinge and transmembrane domain (HTD), and intracellular signaling module. The extracellular portion has high specificity for targeting surface molecular signals in malignant cells. The CAR targets for MM include B-cell maturation antigen (BCMA), the orphan G protein-coupled receptor, class C group 5 member D, CD38, CD138, and SLAMF7. SLAMF7- and CD38-targeted CAR-T cells may experience fratricide during early culture and spare the fraction with dim or absent antigen expression and stable functionalities.^52,56 Notably, optimizing antigen-binding affinity is a potential approach to dampen fratricide.^57,58 HTDs are also critical for certain functions of CAR-T cells such as immune synapse formation, cytokine production, activation-induced cell death (AICD), and cytotoxicity under low antigen density.⁵⁹ The hinge domain regulates the CAR signaling threshold, whereas the transmembrane domain regulates CAR signaling by affecting CAR expression levels.⁶⁰ The incorporation of a hinge domain can promote in vitro expansion and migration of CAR-T cells and enhance the antitumor activity of specific CAR-T cells.⁶¹ Compared with T cells expressing CARs with CD28 HTDs, T cells expressing CARs with CD8α HTDs exert similar antitumor potency but less cytokine production and AICD.⁶² Furthermore, the alterations of CD8α HTDs can make a safe and potent CAR-T cell therapy, with comparable cytolytic activity, less cytokines release, higher expression of anti-apoptotic molecules, and slower proliferation.⁶³ Intracellular signaling modules were designed to mimic natural T-cell signal transduction. The first-generation CARs only include CD3ε, the second-generation CARs contain CD3ε and one co-stimulatory domain (either CD28 or 4-1BB), and the third-generation CARs fuse two co-stimulatory domains to CD3ε. CD28-costimulated CAR-T cells display a faster response, and 4-1BB-costimulated CAR-T cells demonstrate longer persistence and higher peak expansion.⁶⁴ In addition, 4-1BB co-stimulation results in a higher proportion of T_CM cells, whereas CD28 co-stimulation enriches T_EM subsets, which may be explained by their shifted metabolisms toward different preferences to T_M subsets.⁶⁵ 4-1BB also attenuates CAR-T cell exhaustion mediated by tonic signaling, characterized by the decreased expression of exhausted hallmarks and enhanced cytokine production.⁶⁶ Other potential co-stimulatory molecules include OX40, ICOS, CD27, and CD40L. Notably, OX40 can decrease activation levels of Tregs via downregulating negative regulatory molecules such as cytotoxic T-lymphocyte-associated protein 4, TGF-β, and FOXP3,⁶⁷ and inducible co-stimulator (ICOS) augments the polarization of Th1/Th17.⁶⁸ Innovative strategies for exploring the third-generation CAR are ongoing.^69–71

Some cytokines are necessary for the survival and expansion of CAR-T cells both in vitro and in vivo. IL-2 is typically used during CAR-T cell manufacturing. However, IL-2 also accelerates the terminal differentiation and exhaustion of CAR-T cells.⁷² IL-15 is considered a promising surrogate for IL-2 because it promotes T-cell proliferation without affecting T-cell exhaustion.⁷³ Besides, IL-15 induces a retention of the T memory stem cell (T_SCM) subset among CAR-T cells via reducing the mechanistic target of rapamycin (mTOR) complex 1 activity.^74,75 IL-7 modulates homeostasis of CD8⁺ T_N and T_M subsets.⁷⁶ The IL-7/IL-15 combination triggers in vitro expansion of CAR-T cells with higher T_SCM subtypes.⁷⁷ Interestingly, some studies have indicated that IL-15 alone is much better than the IL-7/IL-15 combination in CAR-T culture for antitumor activity.⁷³ Further studies are needed to clarify the functions of different cytokines during CAR-T cell production.

Persistent exposure to antigens and tonic signaling results in CAR-T cell exhaustion.⁷⁸ Some regulatory genes and transcriptional factors such as TOX, the AP-1 family, Nr4a, c-Jun, basic leukine zipper ATF-like transcription factor, and mTOR are known to induce resistance to CAR-T cell exhaustion.^79,80 Endeavors have been made to mitigate exhaustion and revive exhausted CAR-T cells.

CAR-T cells are generally generated from autologous T cells. A higher pre-manufacturing CD4⁺/CD8⁺ ratio and CD45RO⁻CD27⁺CD8⁺ T cells have demonstrated better clinical outcomes in a BCMA-specific CAR-T trial.⁸¹ T cells from patients with early-stage MM exhibit better fitness for CAR-T cell manufacturing and efficacy than those from patients with RRMM.⁸² Moreover, single-cell RNA sequencing has revealed that endogenous T cells change dynamically after infusion and have a regulatory relationship with transplanted anti-BCMA CAR-T cells via ligand-receptor pairs. The first group of pairs is mainly involved in the immune response, T-cell activation, and cell-cell adhesion, whereas the second group of genes is enriched in tumour necrosis factor (TNF)-related pathways and the NF-κB signaling pathway.⁸³

Bispecific T-cell engagers

BiTEs act as linkers that direct T cells to tumor cells by simultaneously recognizing CD3 and tumor-specific antigens, further mediate polyclonal T-cell expansion independent of TCR specificity, and trigger T-cell-mediated lysis of malignant cells. BCMA-targeted BiTEs (AMG 420 and AMG 701) and CD38-targeted BiTE (AMG 424) are currently under clinical investigation.

AMG 420 upregulates the activation markers CD69 and CD25 and increases the cytokines release of T cells in the presence of BCMA⁺ cells.⁸⁴ AMG 701 has a longer serum half-life than AMG 420 because of the optimization of the Fc domain. AMG 701 induces T-cell proliferation to a greater extent in CD8⁺ T cells, resulting in an elevated CD8⁺/CD4⁺ ratio.^85,86 In addition, AMG 701 drives the differentiation of T_N cells toward memory phenotypes.⁸⁵ Notably, AMG 701 promotes CD107a expression and IFN-γ and TNF-α production more significantly in CD8⁺ T cells than in CD4⁺ T cells.⁸⁵ Lenalidomide and pomalidomide further enhance T-cell modulation by acting synergistically with AMG 701 to prevent myeloma relapse.^85,86 AMG 424 induces T-cell activation and enhances antitumor activities without evoking excessive cytokine release via CD3ε affinity adjustment. CD38-mediated T-cell fratricide is observed shortly after AMG 424 administration but has negligible effects on its activity.⁸⁷

Antibody-drug conjugates

Antibody-drug conjugates (ADCs) are a series of mAbs that bind to cytotoxic molecules to selectively kill target cells. Belantamab mafodotin, a BCMA-targeted ADC, has been approved for the treatment of RRMM. Other ADCs, such as CD56-targeted lorvotuzumab mertansine, CD74-directed milatuzumab doxorubicin, and CD138-targeted indatuximab ravtansine, are currently under clinical investigation.⁸⁸

Belantamab mafodotin promotes the proliferation of CD4⁺ T cells and intratumoral Tregs, significantly increases the infiltration of CD8⁺ and CD4⁺ T cells as well as upregulates the activation markers CD25 and CD69 and the T-cell co-stimulator ICOS on CD8⁺ T cells.⁸⁹ CD56 is also expressed on natural killer cells and a subset of T cells; however, its influence on T cells remains largely unknown.^90,91 CD74 plays a significant role in the antigen-presenting function and is involved in T-cell response.⁸⁸ CD74-targeted ADCs may affect T-cell immunity, but the mechanisms require further exploration.

Histone deacetylase inhibitors

Histone deacetylase inhibitors (HDACis) have pleiotropic effects, including epigenetic remodeling, cell-cycle arrest, induction of apoptosis and autophagy, mitosis perturbation, disruption of chaperone function, inhibition of aggresome formation, and anti-angiogenic effects. Several HDACis utilized alone or in combination with other anti-MM agents have shown promising efficacy.⁹²

Panobinostat, a pan-deacetylase inhibitor used in combination with bortezomib and dexamethasone, has been approved for the treatment of MM patients after at least two prior lines of therapy.⁹³ Panobinostat significantly increases T-cell histone acetylation in responders and reduces the frequency of T_M cells and the CD8⁺/CD4⁺ ratio in non-responders after ASCT.⁹⁴ ACY241 is an oral HDAC6 selective inhibitor. ACY241 promotes T-cell proliferation and decreases the frequency of Tregs.⁹⁵ ACY241 upregulates the co-stimulatory molecules CD28, 4-1BB, CD40L, and OX40, and the activation molecule CD38 on CD8⁺ T cells in a dose- and time-dependent manner, while inhibiting PD-1 expression on CD8⁺ T cells.⁹⁵ In addition, ACY241 promotes the formation of antigen-specific T_CM cells by activating the Akt/mTOR/p65 pathways and upregulating transcriptional factors, including Bcl-6, Eomesodermin, hypoxia-inducible factor 1, and T-Bet.⁹⁵ ACY241 also triggers more robust anti-MM activities characterized by incremental CD107a degranulation and cytokine production, which can be further enhanced by PD-L1 blockade.⁹⁶

Nuclear export inhibitors

Nuclear exportin 1 (XPO1) serves as a delivery tool for tumor repressor proteins, tumor-related messenger RNA, and cell-cycle regulatory proteins from the nucleus to the cytoplasm.⁹⁷ However, MM cells acquire a pervasive overexpression of XPO1, largely associated with a poor prognosis. Selinexor is the most classic selective XPO1 inhibitor and has been approved for the treatment of RRMM.⁹⁸

Selinexor transiently inhibits proliferation, TCR signaling, and the subsequent activation and effector function of CD8⁺ T cells in MM mouse models, whereas optimizing the dosage interval and frequency allows for normal CD8⁺ T-cell function.⁹⁹ Selinexor also hampers the export of STAT3 and NFATc1, which are significantly involved in PD-1 expression upon T-cell activation.^100,101 Nuclear export is a sophisticated process associated with T-cell development and function, which merits further studies to unveil the relevant effects and mechanisms of selinexor on T cells.

Implications for MM management

With novel agents in the pipeline, the landscape of MM treatment is rapidly changing. New questions have then arisen: do prior treatments influence the efficacy of subsequent lines of therapy? How can these agents be sequenced to provide the greatest benefits to patients? T cells are the main force in antitumor immunity, and progressive impairment of T-cell immunity is observed during MM and correlates with poor prognosis.^6,14–18 Drugs show diverse effects on T cells (Table 1). Optimizing the overall therapeutic schedule to maximize T-cell immunity is a potential strategy for MM management.

Implications for newly diagnosed MM

Current recommended management approaches for newly diagnosed (ND) MM are guided by eligibility for ASCT and risk stratification into standard- or high-risk MM (Figure 3).¹⁰² High-risk factors include t(4;14), t(14;16), t(14;20), del 17p, TP53 mutations, and gain of 1q. For candidates for ASCT, after four to six cycles of induction followed by stem cell harvest, patients can proceed to ASCT or resume induction therapy, shift to maintenance, and reserve ASCT for first relapse. Induction therapy with bortezomib, lenalidomide, and dexamethasone (VRd) remains the standard care for standard-risk patients, while mAb-based quadruplets are preferred for high-risk patients. For transplant-ineligible patients, daratumumab, lenalidomide, and dexamethasone are recommended as induction therapies for standard-risk subjects and bortezomib-containing regimens are administrated to patients with high-risk MM. Finally, standard-risk patients should receive lenalidomide maintenance after induction or ASCT, whereas PI plus lenalidomide should be used for high-risk patients. T-cell exhaustion and senescence contribute to myeloma escape after ASCT, supporting early administration of PD-1, LAG-3, and TIGIT inhibitors to revive and augment T-cell immunity after ASCT.^23,24

Figure 3.

Recommended MM therapeutic paradigm integrating T-cell function.

T-cells maintain antigen-specific memory and survival for several years in vivo. CAR-T cells have lasted over 10 years and maintained functional activation, proliferation, and cytotoxicity in two patients with sustained remission.¹⁰³ Although both CAR-T cells and BiTEs are T-cell-dependent immunotherapies, CAR-T cells have the advantages of a single administration and long-term immune memory. Therefore, CAR-T cell therapy holds promise for curing cancer and provides significant benefits as the first-line therapy when the patients’ autologous T cells have not been weakened by other treatments. However, immunotherapy has primarily been used for advanced or relapsed diseases, and two BCMA-targeted CAR-T cell therapies, idecabtagene vicleucel and ciltacabtagene autoleucel, have been approved for MM patients after at least four prior lines of treatment.^104,105 However, there is still a lack of evidence to support this assumption. Encouragingly, large multicenter clinical trials are being launched to test CAR-T cells as the frontline treatment for MM. KarMMa-4 is a phase I study evaluating idecabtagene vicleucel in high-risk patients with NDMM after induction treatment.¹⁰⁶ CARTITUDE-5 is a phase III trial assessing ciltacabtagene autoleucel in transplant-ineligible patients with NDMM after induction treatment with VRd.¹⁰⁷ Axicabtagene ciloleucel, a CD19-targeted CAR-T cell therapy, is highly effective as part of the first-line therapy for high-risk large B-cell lymphoma, with a manageable safety profile.¹⁰⁸ Long-term follow-up results of CAR-T cell therapies for NDMM are worth awaiting.

Implications for RRMM

Novel regimens provide plentiful options for patients with RRMM, but the choice is complicated. Response to prior treatment, timing of relapse, aggressiveness of the disease, performance status, affordability, and patient preferences should be comprehensively considered in the final decision-making. In this review, we recommend that the functional status of autologous T cells be included in subsequent management consideration (Figure 3).

If the patient has normal T-cell counts and function, T-cell-directed therapies, such as CAR-T and BiTEs, are preferred. Transplantation is firstly recommended if the patient has significantly dysfunctional T cells.¹⁰⁹ If the patient is not suitable for transplantation, CD38-targeted mAb/PI/IMiD combination and AMG701-containing regimens are recommended under the condition of declined T-cell counts and inverted CD4⁺/CD8⁺ ratios; mAb/IMiD combination and ACY241 containing regimens are recommended when Tregs play a predominant role or other CD4⁺ and CD8⁺ T cells lose memory phenotype; ADCs containing drugs are recommended to promote T-cell proliferation and activation; PD-1 inhibitors play synergistic effects with multiple regimes, including ASCT, ACY421, and anti-CD38 therapies in the context of cancer immunotherapy (Table 1). Nevertheless, the recommended strategy is mainly dependent on preclinical mechanisms. Further clinical studies and long-term follow-up are required to verify these theories.

Conclusion

As more options have been approved, and more agents have made their way through clinical trials, MM treatment has shifted to a promising paradigm. With an increasing understanding of the mechanisms underlying MM, the optimal application and sequencing of existing therapies and their integration into MM management depend on the underlying immune status to some extent.¹¹⁰ In this overview, we summarize the effects of the mainstay drugs and novel therapies for MM on T cells (Figures 1 and 2; Table 1) and propose a new therapeutic paradigm integrating the functional status of T cells (Figure 3). However, T-cell dysfunction is not the only reason for MM escape and treatment failure. Suppressive immune microenvironments and intrinsic tumor mechanisms are also important. CAR-T cell therapy has shown promise for achieving long-term remission with a single infusion and holds the potential to play a vital therapeutic role as ASCT in the future. Therefore, long-term follow-up and more studies are warranted. In addition, the potential synergies and combination strategies among these agents are not detailed in the review, and further research is required.

Footnotes

Appendix

Acknowledgements

None.

Declarations

ORCID iD

Chenggong Li

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