Redefining multiple myeloma treatment: Advances, challenges, and future directions in immunotherapy

Abstract

Multiple myeloma (MM) is a hematological malignancy that poses significant treatment challenges due to its heterogeneity and propensity for relapse and progression. In the last two decades, the therapeutic landscape of MM has changed dramatically, but the disease remains largely incurable, with many patients facing treatment resistance. This review evaluates the current status of MM treatments, emphasizing the limitations of traditional therapies and the emerging role of immunotherapy in improving patient outcomes. It highlights the importance of achieving and maintaining minimal residual disease negativity and a balanced immune response as key treatment goals. Furthermore, it discusses the advancements in immunotherapies that are improving the prospects for patients, particularly those with relapsed or refractory disease. Innovative strategies, such as chimeric antigen receptor T-cell therapy, bispecific antibodies, and bispecific T cell engagers, have shown significant promise by targeting the malignant cells and the bone marrow microenvironment, which are essential for disease persistence and resistance to therapy. Future research should focus on refining MM treatment strategies, including the integration of immunotherapy into earlier treatment lines and the development of predictive biomarkers for personalized treatment approaches, ultimately enhancing patient outcomes.

Introduction

Multiple myeloma (MM), a hematological malignancy, has long posed significant treatment challenges due to its complex pathology and the diverse clinical manifestations, including bone destruction, renal failure, anemia, and immunodeficiency.^[1,2] MM accounts for a considerable portion of blood cancer cases globally,^[1,3,4,5] and the treatment landscape has experienced a transformative shift over the past two decades.^[6,7] Despite these advancements, the majority of patients still face relapse or treatment resistance.^[4,8] The impact of MM extends far beyond physical symptoms, deeply affecting patients’ emotional well-being and social functioning. From debilitating bone pain and fatigue to the emotional toll of constant vigilance against relapse, MM casts a long shadow over the lives of those affected.^[4,9,10] The need for more effective and less toxic treatments has become greater, as immunotherapy has developed. By harnessing the body’s immune system to attack cancer, innovative strategies such as chimeric antigen receptor T (CAR-T) cell therapy,^[11] bispecific T cell engagers (BiTEs), and immune checkpoint inhibitors are reshaping the treatment landscape, offering glimpses of deeper, more durable responses, and potentially providing a path toward a cure.^[12,13,14] While facing the challenge of curing MM, the medical community continues to grapple with the disease’s high heterogeneity and propensity for relapse and progression.^[2] Traditional therapies, which have made significant strides in improving patient outcomes, often see their efficacy wane over time, culminating in disease relapse due to the emergence of drug-resistant clones or the failure to eradicate minimal residual disease (MRD).^[15] The challenge of achieving a definitive cure is further complicated by the disease’s capacity to evolve within the bone marrow microenvironment (BMM), coupled with the immune system’s failure to effectively recognize and eradicate malignant cells.^[16,17] This study aims to elucidate the current status of MM treatment, including the efficacy and limitations of existing therapies; to elucidate the treatment goals of achieving MRD negativity and maintaining immune balance as essential targets for successful therapy; and to examine the progress in immunotherapies, particularly CAR-T cell, BiTEs, and other novel modalities, in altering the prognosis for MM patients.

Current Treatment Status in MM

Challenges in achieving long-term remission in MM

Addressing the significant challenge of curing MM involves navigating the widespread problem of disease relapse, which reveals the decreasing effectiveness of traditional treatments over time.^[18] This predicament is highlighted by the inherent complexities of MM, including clonal heterogeneity, immune tolerance and escape, and the intricate interplay between tumor cells and BMM.^[19,20] These factors not only complicate the disease trajectory, characterized by progressively shorter remission durations and worsening prognosis, but also raise significant concerns regarding the quality of life for those living with MM.^[21,22] Although considerable advancements in treatment options, such as chemotherapy, stem cell transplantation,^[23] and the introduction of new therapies like proteasome inhibitors (PIs) and immunomodulatory drugs (IMiDs) have emerged for patients with relapsed refractory multiple myeloma (RRMM), the quest for a definitive cure remains arduous. Traditional chemotherapy, once the cornerstone of MM treatment, exhibits a broad attack on rapidly dividing cells, leading to substantial toxicity and often affecting healthy cells as well.^[24,25] While chemotherapy is effective in reducing tumor burden, it rarely achieves lasting remission.^[26] The advent of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has provided a greater opportunity for deeper remission; however, the majority of patients ultimately experience relapse.^[27,28] The paradigm shift introduced by PIs and IMiDs has improved patient outcomes by targeting specific pathways crucial for myeloma cell survival. However, resistance development and the inability to achieve complete eradication of malignant clones result in disease progression for many patients.^[29,30] Comprehensive standard treatment regimens for newly diagnosed MM (NDMM) and RRMM are listed in Table 1.^{[31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50]}Table 2 lists the comparative analysis of clinical trial outcomes for RRMM.^{[33,35,36,38,44,51,52]}

Table 1.

Comprehensive standard treatment regimens for NDMM and RRMM.

Treatment regimes	Categories	Setting	Endpoints
Lenalidomide/dexamethasone/bortezomib (VRd)[31]	Preferred	NDMM	5-year PFS: 56% (95% CI, 48–64%); 5-year OS: 80% (95% CI, 75–87%); median PFS not reached; overall outcomes less favorable compared to KRd, particularly in high-risk patients.
Lenalidomide/dexamethasone/carfilzomib (KRd)[31]	Preferred	NDMM	5-year PFS: 67% (95% CI, 60–75%); 5-year OS: 90% (95% CI, 85–95%); median PFS: 70.9 months (58.2–NR); improved PFS and EFS compared to VRd, especially in high-risk patients.
Daratumumab/carfilzomib/dexamethasone[32,33,34]	Preferred	1–3 prior therapies	High ORR, improved PFS, FDA approved
Isatuximab-irfc/carfilzomib/dexamethasone[34,35]	Preferred	1–3 prior therapies	Significant improvement in PFS, high ORR
Carfilzomib/pomalidomide/dexamethasone[32,35]	Preferred	1–3 prior therapies	Effective for lenalidomide-refractory patients
Daratumumab/pomalidomide/dexamethasone[32]	Optional	1 prior therapy	High ORR, suitable for patients with at least 1 prior therapy
Isatuximab-irfc/pomalidomide/dexamethasone[35,36]	Preferred	After 2 prior therapies	Improved ORR and PFS, suitable after 2 prior therapies
Ixazomib/pomalidomide/dexamethasone[37]	Option	After 2 prior therapies	Promising preliminary response rates
Elotuzumab/pomalidomide/dexamethasone[38]	Option	≥2 prior therapies	A two-fold increase in PFS and ORR compared to pomalidomide/dexamethasone
BiTEs (e.g., elranatamab, talquetamab, teclistamab)[39]	Preferred	After ≥4 prior therapies	High efficacy, target BCMA, and CD3
CAR T cell therapies (e.g., idecabtagene vicleucel[ide-cel], ciltacabtagene autoleucel[cilta-cel])[40,41]	Preferred	After ≥4 prior therapies	High ORR, effective in heavily pretreated patients
Venetoclax/dexamethasone with or without daratumumab or PI[42,43]	Option	For t (11;14) patients	Effective in t(11;14) translocation MM
Pomalidomide/dexamethasone[36]	Option	After ≥2 prior therapies	Approved for lenalidomide and bortezomib-refractory MM
Selinexor/pomalidomide/dexamethasone[44]	Option	After ≥2 prior therapies	Effective in heavily pretreated MM
Daratumumab[45]	Option	After ≥3 prior therapies	Targets CD38, effective in heavily pretreated MM
Bendamustine-based regimens[46]	Option	Various settings	Effective in RRMM, manageable toxicity
High-dose or fractionated cyclophosphamide[47]	Option	RRMM	Effective in patients needing immediate disease control
Selinexor/dexamethasone[44]	Option	After ≥4 prior therapies	Effective for heavily pretreated MM, including those who are refractory to IMiDs, PIs, and anti-CD38 MoAb
Belantamab mafodotin-blmf[48]	Certain circumstances	After ≥4 prior therapies	BCMA-directed ADC, option for MM refractory to multiple agents
Supportive care	N/A	All stages	Includes bisphosphonates or denosumab for bone health, plasmapheresis for hyperviscosity, and erythropoietin for anemia
Bisphosphonates or denosumab[49]	Supportive	All patients	For bone disease management, including prevention of fractures and pain management
VTE prophylaxis[50]	Supportive	All stages	Important for all MM patients, especially those at high risk of VTE

ADC: Antibody–drug conjugate; BCMA: B-cell maturation antigen; BiTEs: Bispecific T cell engagers; CAR-T: Chimeric antigen receptor T; CI: Confidence interval; CD: Cluster of differentiation; FDA: Food and Drug Administration; IMiDs: Immunomodulatory drugs; MoAb: Monoclonal antibody; MM: Multiple myeloma; N/A: Not available; NDMM: Newly diagnosed MM; ORR: Overall response rate; OS: Overall survival; PFS: Progression-free survival; PIs: Proteasome inhibitors; RRMM: Relapsed/refractory MM; VTE: Venous thromboembolism.

Table 2.

Comparative analysis of clinical trial outcomes for RRMM.

Treatment regimens	Study	Number of patients enrolled	Median number of lines of therapy	Median follow-up time (months)	Objective response rate (%)	CR rate (%)	MRD negativity rate (%)	Median time to response (months)	Median PFS (months)
Sd	STORM[44]	122	7	8.3	26	2	NA	1	3.7
DPd	EQUULEUS/MMY1001[36]	103	4	13.1	60	17	NA	1	8.8
EPD	ELOQUENT-3[38]	60	3	9.1	53	8	NA	2	10.3
IsaPd	ICARIA-MM[35]	154	3	11.6	60	5	NA	1	11.5
DKd	CANDOR[33]	312	2	16.9	84.3	29	NA	1	28.6
DVd	CASTOR[51]	251	2	19.4	83.8	28.8	11.6	–	16.7
PVd	OPTIMISMM[52]	281	2	15.9	82.2	15.7	NA	0.9	11.2

CR: Complete response; DKd: Daratumumab combined with carfilzomib and dexamethasone; DPd: Daratumumab combined with pomalidomide and dexamethasone; DVd: Daratumumab combined with bortezomib and dexamethasone; EPd: Elotuzumab combined with pomalidomide and dexamethasone; IsaPd: Isatuximab combined with pomalidomide and dexamethasone; NA: Not available; MM: Multiple myeloma; MRD: Minimal residual disease; PFS: Progression-free survival; Pvd: Pomalidomide combined with bortezomib and dexamethasone; RRMM: relapsed/refractory MM; Sd: Selinexor combined with dexamethasone; Vd: Bortezomib combined with dexamethasone.

Challenges in MM treatment due to clonal heterogeneity and evolution and immune tolerance and escape

MM is characterized by the presence of various subpopulations of cancer cells within a single patient, each exhibiting distinct genetic and phenotypic traits.^[53] This heterogeneity is not static; it evolves over time, especially under the selective pressure exerted by therapeutic interventions.^[53] Treatments that effectively target one subclone may inadvertently leave behind or even select for resistant clones, setting the stage for relapse. The dynamic nature of clonal evolution in MM allows the disease to adapt to and circumvent therapeutic strategies, necessitating treatments that can target a broad spectrum of myeloma cells.^[54] MM cells have developed sophisticated immune evasion mechanisms. They can express immune checkpoint molecules, secrete immunosuppressive cytokines, and induce T-cell exhaustion, among other strategies.^[55] These mechanisms not only enable myeloma cells to survive and proliferate but also weaken the host’s immune response against the tumor,^[55] creating a vicious cycle of disease progression and immune system suppression that standard treatments often fail to disrupt.^[55,56] The BMM plays an important role in MM pathogenesis.^[57,58] It serves as a protective sanctuary for myeloma cells, promoting their growth, facilitating their evasion of therapeutic interventions, and fostering drug resistance.^[59] The interactions between myeloma cells and the bone marrow stroma activate signaling pathways essential for tumor survival, angiogenesis, and immune suppression. Disrupting these interactions is vital for effective MM treatment, as the microenvironment significantly contributes to the disease’s persistence and resistance to therapy [Figure 1].^[60,61]

Figure 1.

The dependence on and continuous evolution of the immune microenvironment in MM. MM cells develop clonal heterogeneity and continuous clonal evolution to adapt to the BMM, including the induction of immune tolerance. Treatment pressure and the immune-tolerant microenvironment induce residual myeloma cells to undergo persistent clonal evolution, further inducing an immunocompromised environment. These factors are mutually causal and promote the progression of MM. BMM: Bone marrow microenvironment; DC: Dendritic cell; MDSC: Myeloid derived suppressor cell; IL: Interleukin; MM: Multiple myeloma; MRD: Minimal residual disease; NK: Natural killer; pDC: Plasmacytoid dendritic cell; RRMM: Relapsed/refractory MM; TGF-β: Transforming growth factor-beta; TH: T helper cell; Treg: Regulatory T cell.

Treatment strategy for MM

The proposed therapeutic strategy for MM diverges from current protocols by prioritizing the achievement of high rates of MRD negativity and complete response (CR), particularly in cases of RRMM.^[62] The data indicate that existing treatments fall short of these objectives due to their limited efficacy in securing these endpoints [Table 2]. Traditional treatment regimens typically combine PIs, IMiDs, and monoclonal antibodies (MoAbs). These therapies work synergistically to target multiple disease pathways, aiming to eliminate the diverse subclones of myeloma cells within the complex BMM.^[29] While this approach attempts to decrease tumor burden and restore the immune balance, its capacity to sustain MRD negativity and support long-term immune competence is inadequate. In contrast, the strategies, which involve cutting-edge modalities like CAR-T cell therapies and BiTEs that aim to reignite the immune system’s intrinsic ability to discern and exterminate myeloma cells by overcoming immune escape and tolerance, not only directly combat the tumor but also fortify the patient’s immune system for ongoing disease surveillance.^[63,64]

Moreover, immunotherapies such as CAR-T cells and BiTEs represent a paradigm shift in MM treatment, emphasizing the reactivation of the immune system’s capacity to recognize and eliminate myeloma cells.^[65] These therapeutic strategies aim to overcome the mechanisms of immune tolerance and tumor escape by either administering engineered immune cells capable of specifically targeting myeloma cells or by bridging immune cells to cancer cells to facilitate direct cytotoxic activity. Targeting the BMM is also pivotal, as it involves disrupting the supportive structures and pathways that facilitate survival, drug resistance, and immune escape of myeloma cells. By intervening in this microenvironment, the sanctuary of myeloma cells is deprived, thereby increasing their susceptibility to treatments.^[63] Besides, this strategy is not only to attack the tumor directly but also to empower the patient’s immune system to maintain long-term surveillance against the disease.^[66] Furthermore, targeting the BMM is a critical aspect of contemporary MM treatment strategies. This involves disrupting the signaling pathways and interactions that enable myeloma cells to thrive, develop drug resistance, and evade the immune response.^[67,68] By targeting the microenvironment, these strategies aim to strip myeloma cells of their protective niche, making them more susceptible to therapeutic interventions. In summary, the treatment strategy for MM is based on a comprehensively understanding of the disease’s underlying causes and employing an arsenal of therapeutic agents and approaches that can target the disease on multiple principles, thus minimizing the tumor burden, restoring the balance of the immune microenvironment, achieving sustained remission, and improving patient outcomes.^[69]

Treatment Goals for MM

Relationship between different depths of remission and prognosis

MRD in MM is vital for assessing patient outcomes, particularly regarding depths of remission such as CR. Achieving MRD negativity, defined as the undetectable presence of myeloma cells through sensitive techniques, is associated with enhanced progression-free survival (PFS) and overall survival (OS) rates.^[70,71,72] Patients who are negative for MRD exhibit prolonged PFS than those who are MRD-positive, indicating a more profound therapeutic response and a lower likelihood of disease progression. However, although MRD negativity serves as a strong prognostic indicator, it does not guarantee permanent disease control, underscoring the need for continuous monitoring and individualized treatment strategies.^[73] Therefore, incorporating MRD assessment into clinical practice and trial designs is essential for evaluating treatment efficacy in MM.

Importance of sustained MRD negativity and its impact on PFS

Sustained MRD negativity serves as a crucial prognostic indicator in MM, significantly influencing PFS. Maintaining MRD negativity for durations of 12–24 months correlates with improved PFS; patients who achieve this status for over a year exhibit notably higher 2-y PFS rates compared to those who do not (76.8% vs. 27.6%). Additionally, MRD negativity serves as a valuable surrogate endpoint in clinical trials, associated with the better PFS and OS across various treatment settings.^[71]

Moreover, MRD negativity is a critical prognostic marker at various treatment stages in MM. Studies consistently demonstrate that achieving MRD negativity, either before starting maintenance therapy or 12 months thereafter, correlates with improved PFS. Patients who attain MRD negativity 12 months after the onset of maintenance therapy experience notably better PFS, consistenting with previous findings that highlight enhanced long-term survival for those achieving MRD negativity prior to ASCT.^[70] Moreover, MRD negativity following ASCT is linked to similarly improve clinical outcomes during ongoing maintenance therapy.

Improvement in immune microenvironment with sustained MRD negativity

Sustaining MRD negativity in MM patients enhances the immunity and improves long-term survival outcomes.^[71] This encompasses the restoration of immune cell functions, suppression of immunosuppressive cells, and promotion of sustained disease control. IMiDs, such as lenalidomide and pomalidomide, along with MoAbs against CD38 like daratumumab, play pivotal roles in this immunological enhancement. IMiDs augment the activity of T and natural killer (NK) cells while concurrently suppressing regulatory T cells (Tregs), by the degradation of cereblon (CRBN, an E3 ligase adapter protein). This illustrates their dual role in directly targeting myeloma cells and modulating the immune environment to sustain MRD negativity. Researches had demonstrated that early restoration of humoral immunity is associated with longer disease control during lenalidomide maintenance therapy. MoAbs improve the microenvironment by inducing complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, while also suppressing Tregs and regulatory B cells (Bregs), thus maintaining an effective immune response.^[70] Moreover, lenalidomide maintenance therapy combined with sustained MRD negativity leads to an elevation in circulating helper T cells and a decrease in exhausted T cells and suppressive Tregs, suggesting enhanced immune surveillance. A significant decline in the frequency of circulating Tregs following one year of maintenance therapy, regardless of whether they had undergone transplantation treatment, underscores a common feature among patients who achieve a deep and durable response. Moreover, the identification of specific T-cell receptor (TCR) β sequences unique to patients exhibiting sustained MRD negativity indicates the role of specific T-cell clonotypes in maintaining response, possibly through the recognition of tumor-associated antigens.

Progress in Immunotherapy

CAR-T cell therapy and BiTEs

Target advantage in immunotherapy

CAR-T cell therapy and bispecific antibody (BsAb) therapy, often referred to as BiTEs, have emerged as leading treatments for MM.^[74] These therapies target B-cell maturation antigen (BCMA), which is crucial for the proliferation and survival of myeloma cells.^[14] BCMA’s exclusive expression on MM cells provides a unique therapeutic advantage, allowing for the targeted elimination of cancer cells while sparing healthy ones. However, the presence of soluble BCMA (sBCMA) complicates therapeutic efforts, as sBCMA can intercept BCMA-targeted treatments, impeding their ability to connect with their intended targets on MM cells. This competitive binding scenario underscores the adaptability of cancer in evading targeted treatment interventions. The complexity of MM and its varied response to current therapies necessitate the development of more universally applicable treatment strategies. Unlike idecabtagene vicleucel (ide-cel)^[75] and ciltacabtagene autoleucel (cilta-cel),^[76] along with dual antibodies and other BCMA-targeted approaches, equecabtagene autoleucel (eque-cel, CT103A)^[5] represents a significant advancement by circumventing the negative impact of sBCMA, ensuring that efficacy remains unaffected. This eque-cel is designed to mitigate the effects of sBCMA, thereby maintaining efficacy across a broader range of patients.

BCMA has been recognized as a crucial target in the treatment of MM, but recent studies have highlighted G protein-coupled receptor, class C group 5 member D (GPRC5D) as a potential new target. Preclinical research indicates that GPRC5D-targeted CAR-T cells can combat myeloma, even in cases where BCMA expression is lost.^[77] BiTEs targeting BCMA-CD3 or GPRC5D-CD3 have also shown efficacy in heavily pretreated, RRMM patients. This has led to the approval of teclistamab, elranatamab, and talquetamab.^[78] However, challenges remain in optimizing dosing, determining treatment sequencing, and overcoming immune escape. Combining GPRC5D-targeted therapies with existing treatments may offer a strategy to address the complexity of MM.^[77,78]

Structural design differences between CAR-T cell therapy and BiTEs

The structural design differences between CAR-T therapy and BiTEs underscore the innovations and specificity in targeting MM through immunotherapy [Table 3]. Each approach is tailored to exploit the immune system’s capabilities against cancer cells, albeit through distinct mechanisms and structural compositions.

Table 3.

Comparative analysis of CAR-T therapy and BiTEs therapy in MM treatment.

Features	CAR-T therapy	BiTEs therapy
Basis of design	Genetically modified T cells with CAR receptors	Engineered antibodies with dual specificity
Targeting mechanism	Directly targets tumor-associated antigens	Bridges T cells to cancer cells by simultaneously targeting CD3 on T cells and an antigen on cancer cells
Manufacturing complexity	High (requires cell extraction, genetic modification, and reinfusion)	Relatively low (manufactured as an off-the-shelf drug)
Treatment personalization	Highly personalized, using the patient’s own cells	Not personalized, can be used for any eligible patient
Therapy persistence ADA	Potential for long-term persistence in the bodyReduced risk of ADA (anti-drug antibodies) induction in fully human CAR-T therapies	Lacks long-term persistence; repeated dosing necessaryRepeated doses with high risk of inducing ADA
Side effect management	Requires careful monitoring and management of potential severe side effects	Generally manageable with standard care protocols
Administration	Complex, involving leukapheresis, lymphodepleting conditioning, and one time infusion	Simpler, administered directly without prior patient-specific preparation, but repeated administering
Applicability and accessibility	Limited by manufacturing time and capacity; not immediately available	Widely applicable and immediately available to patients
Activation of T cells	Regulate immune functions of host cells, inducing T cell expansion	Activate host T cells without inducing expansion
Immune system regulation	Modulate immune function of both converted and non-converted host immune cells	Limited capability; can only activate T cells directly engaged by the therapyBiTEs carry the risk of inducing T cell exhaustion
Antigen targeting	Target tumor antigens through engineered receptors, capable of broader immune system engagement	Direct targeting of tumor cells and activation of T cells through dual specificity
Immune escape	Lower risk of immune escape due to the ability to modulate broader immune responses	Higher risk of antigen-mediated immune escape due to reliance on a single target for activation
Cost	High initial cost due to the complexity of manufacturingPotentially reduced long-term healthcare costs due to durability	Potentially lower upfront costsMay increase over time with the need for continuous treatment
Efficacy and safety	CAR-T involves a single infusionHigh efficacy with the potential for durable remission, but associated with a risk of severe immune-related adverse events	Less effective, with a mild and transient responseRequire repeated infusionsSlower immune reconstitution with BiTEsRisk of worse infection outcomes

ADA: Anti-drug antibodies; BiTEs: Bispecific T cell engagers; CAR-T: Chimeric antigen receptor T; CD: Cluster of differentiation; MM: Multiple myeloma.

CAR-T therapy: Structural complexity and personalization

CAR-T therapy represents a groundbreaking approach in the treatment of MM, harnessing the power of genetic engineering to reprogram a patient’s T cells.^[79] These engineered cells are equipped with a CAR designed to target tumor-associated antigens, such as BCMA, which are prevalent on the surface of MM cells. The efficacy of this therapy hinges on the sophisticated architecture of the CAR itself, composed of several critical elements. The CAR’s architecture is vital to the therapy’s success. The outermost part, known as the extracellular domain, is typically derived from the single-chain variable fragment (scFv) of an antibody. The design of this domain, particularly its affinity for the antigen, plays a significant role in the therapy’s success. Achieving optimal affinity is critical; moderate affinity is ideal to ensure that the dissociation time between the CAR-T cell and target cells closely aligns with that of the TCR, approximately 5–7 min. This balance allows CAR-T cells to function as “serial killers”, engaging and eliminating multiple target cells in a sustained manner, in contrast to the more limited “1v1” killing mechanism of BiTEs.^[79] The diversity in CAR designs, ranging from fully human to murine and camelid sources, underscores the therapy’s adaptability. Different sources can target various antigen epitopes, influencing the CAR-T cells’ interactions with target antigens and the potential for immune responses against the therapy itself.^[79] For instance, cilta-cel, derived from camelid antibodies characterized by their unique heavy-chain-only structure, exemplifies a nuanced approach to optimizing CAR-T cell efficacy. However, the use of single heavy chain variable domains might lead to diminished efficacy, highlighting the intricate balance required in CAR design. Linked to the extracellular domain by a hinge region, the CAR allows for the necessary flexibility to ensure optimal engagement with the antigen. It is embedded in the T cell membrane through a transmembrane domain, which provides essential structural stability to the receptor. The core of the CAR’s functionality lies the intracellular domain, crafted from a fusion of costimulatory domains such as CD28 or 4-1BB with the CD3ζ chain.^[79] Upon antigen recognition, this domain activates the T cell, triggering a cascade of events that result in T cell proliferation, cytokine secretion, and a potent cytotoxic attack on cancer cells. This intricate design allows the CAR-T cells to operate as autonomous entities, capable of seeking out and destroying cancer cells with remarkable efficiency.

BiTEs therapy

BiTEs therapy stands out for its innovative approach to mobilizing the body’s immune system against cancer. Unlike the cell-based intricacies of CAR-T therapy, BiTEs employ a unique dual-targeting mechanism that harnesses the body’s T cells in the fight against cancer.^[74] These molecules are engineered with two distinct binding sites: one that specifically binds to a tumor antigen, such as BCMA on MM cells, and another that engages with CD3 on T cells. By simultaneously binding to these two targets, BiTEs act as a bridge, bringing T cells into close proximity with cancer cells. This interaction triggers a targeted immune assault on the tumor, leveraging the natural cytotoxic capabilities of T cells.^[74] The versatility of BiTE therapy is further demonstrated by its structural diversity. Developers can tailor these therapies to include full-length antibodies with Fc regions, which not only preserve the antibody’s ability to recruit additional immune effector functions but also potentially extend their half-life in circulation. Alternatively, therapy can utilize smaller, more streamlined antibody constructs that eschew the Fc region. This design choice aims to mitigate potential off-target effects and enhance the therapeutic’s ability to penetrate the tumor microenvironment more effectively.^[74]

Differences in immunotherapy mechanisms: BiTEs vs. CAR-T therapy

The advancement of immunotherapy in treating MM has been marked by notable advancements in the development of BiTEs and CAR-T cell therapy.^[79] Each approach represents a unique strategy in leveraging the immune system to combat cancer, with distinct mechanisms of action that offer advantages and face challenges in clinical application. This dual binding enables the direct interaction between T cells and cancer cells, thereby enhancing T cell activation and directing its cytotoxic activity against the tumor. The precision of BiTEs in activating T cells directly against tumor cells minimizes off-target effects and collateral damage to healthy tissues, representing a significant advantage over less discriminative therapies.

In contrast, autologous CAR-T cell therapy entails genetically modifying a patient’s T cells to express CARs that specifically target tumor antigens. Unlike BiTEs, CAR-T therapy combines the advantages of both humoral and cellular immunity. Upon reintroduction into the patient, these engineered T cells not only identify and eradicate cancer cells through antigen recognition but also proliferate, ensuring a long-term presence and surveillance against the cancer. The key advantage of CAR-T therapy lies in its ability to regulate the immune function of both the converted CAR T cells and host immune cells not modified by CAR [Figure 2 and Table 3].^[12]

Figure 2.

Differences in immunotherapy mechanisms: BiTEs vs. CAR-T therapy. CAR-T cells rapidly activate and expand, and then kill myeloma cells upon recognizing antigens. After the clearance of myeloma cells, they transition into memory cells that, together with restored normal immune cells, play a role in immune surveillance. TCE (BiTE) links host T cells to recognize myeloma cells, inducing the killing of some myeloma cells. However, residual myeloma cells require repeated infusions of BiTE, which simultaneously induces T cell exhaustion in the host. In an environment of ongoing immune compromise, myeloma cells continuously undergo clonal evolution. BCMA: B-cell maturation antigen; BiTE: Bispecific T cell engager; CAR-T: Chimeric antigen receptor T; CD: Cluster of differentiation; FcRL5: Fc receptor like 5; GPRC5D: G protein-coupled receptor, class C group 5 member D; IFN: Interferon; IL: Interleukin; MM: Multiple myeloma; TNF: Tumor necrosis factor.

Comparative efficacy of CAR-T vs. BiTEs in achieving and sustaining MRD negativity in MM

In the treatment of MM, achieving and sustaining MRD negativity is critical for improving patient outcomes. MRD negativity serves as a powerful prognostic marker, closely correlating with enhanced survival rates.^[70] CAR-T therapies, BiTEs, and antibody–drug conjugates (ADCs) like belantamab mafodotin represent innovative immunotherapeutic strategies. Studies like KarMMa^[41] and CARTITUDE-1^[80] have provided strong evidence that CAR-T therapies can induce sustained MRD negativity even in heavily pretreated or high-risk genetic populations. Moreover, CT103A, as showcased in the FUMANBA-1 study,^[4] demonstrated an impressive sustainability rate for MRD negativity, indicating a stronger and more durable response in treating heavily pretreated RRMM patients. MAIC analyses^[81] indicate that ide-cel provides clinically significant increases in PFS and OS compared to therapies like selinexor plus dexamethasone and belantamab mafodotin. Moreover, cilta-cel has shown improved outcomes in comparison to ide-cel across various efficacy measures, including overall response rate (ORR), CR, and duration of response (DoR).^[82] CAR-T therapies, represented by ide-cel^[40] and cilta-cel, have shown promise in patients with RRMM who have failed conventional therapies. MAIC analyses^[80] suggest that these CAR-T cell therapies can lead to superior MRD negativity rates compared to BiTEs and even some ADCs. This advantage is partly attributed to the CAR-T cells’ mechanism of action, which involves the genetic modification of the patient’s T cells to more effectively target cancer cells, allowing not only for tumor eradication but also for the possibility of long-term immune surveillance. The data indicate that CAR-T therapies can extend both PFS and OS compared to other treatments, offering the potential for durable remission in heavily pretreated patient populations.^[12,77] Indirect comparisons of PFS and OS benefit between different CAR-Ts and BiTEs are shown in Table 4, particularly in the absence of direct head-to-head trial data.^{[39,83,84,85]}

Table 4.

Indirect comparison of PFS and OS benefit between different CAR-Ts and BiTEs for MM.

Study	Treatment	Comparison	Patients	Outcomes (e.g., ORR, PFS, OS)
RODRIGUEZ-OTERO P et al[83]	Idecabtagene vicleucel (ide-cel)	Conventional care in RWS	RRMM with prior triple-class exposure	Improved PFS and OS with ide-cel
CHO S F et al[39]	Ciltacabtagene autoleucel (cilta-cel)	Ide-cel	Triple-class exposed RRMM	Statistically significant improvement in ORR, DoR, PFS, OS
Martin T et al[84]	Cilta-cel	Ide-cel	Triple-class exposed RRMM	Statistically significant improvement in ORR, ≥CR rate, DoR, PFS; OS in favor of cilta-cel but CI overlaps one
Mol I et al[85]	Elranatamab	PCT	TCE/R MM	Higher ORR and ≥CR, longer PFS and OS compared to PCT
Mol I et al[85]	Elranatamab	Teclistamab	TCE/R MM	Better ORR and PFS, numerically better CR, DoR, and OS

CI: Confidence interval; CR: Complete response; DoR: Duration of response; MM: Multiple myeloma; MRD: Minimal residual disease; ORR: Overall response rate; OS: Overall survival; PCT: Physician’s choice of treatment; PFS: Progression-free survival; RRMM: Relapsed/refractory MM; RWS: Real world study.

CAR-T Therapy in MM

Immune modulation and recovery of immune surveillance by CAR-T

In the rapidly evolving landscape of immunotherapy for MM, CAR-T therapy stands out for its potential to induce sustained MRD negativity, particularly in patients with high-risk prognostic factors [Table 5]. CAR-T cell therapy represents a significant leap forward in personalized oncology for treating MM. Targeting BCMA with therapies like eque-cel^[5] and others such as cilta-cel and ide-cel,^[40] has demonstrated profound efficacy in clinical trials, achieving impressive rates of MRD negativity and CR. The FUMANBA-1 study underscores the profound and sustained responses of eque-cel, demonstrating a 94.2% MRD negativity rate, with 80.8% of patients maintaining this status for 12 months post-infusion.^[5] Additionally, at the 12-month, 50.0% of patients exhibited CAR-T cell levels above the lower limit of quantitation (LLOQ), with 40.0% showing persistence at 24 months. A pivotal aspect of CAR-T therapy’s success is its dual role in directly eradicating cancer cells and modulating the patient’s immune system. This immune modulation is crucial for recovering immune surveillance mechanisms, allowing for the continuous monitoring and elimination of residual MM cells. Importantly, sustained MRD negativity, a hallmark of successful CAR-T treatment, is often linked to the long-term persistence of CAR-T cells. Such persistence is not merely a by-product of therapy but a necessary condition for maintaining disease control over time, particularly in patients with high-risk prognostic factors. The relationship between CAR-T cell persistence and sustained MRD negativity is further emphasized in patients with high-risk MM.^[14] The study further revealed that patients with high-risk cytogenetics, elevated BCMA expression, and those who underwent bridging therapy had a significantly higher hazard ratio for sustaining MRD negativity.^[13]

Table 5.

Comparative analysis of BCMA CAR-T cell therapies in clinical trials.

Items	CT103A (IASO)	Cilta-cel (legend)	Cilta-cel (legend)	CT053 (Shanghai KECHOW Pharma)	Ide-cel (BMS)
Clinical trial phase (Country)	1b/2 (China)	2 (China)	1b/2 (USA)	2 (China)	2 (USA)
Number of patients enrolled	103 (91 without prior CAR-T)	48	97	102	100
Dosage	1 × 106 CAR-T cells/kg	0.75 × 106 CAR-T cells/kg	0.5–1.0 × 106 CAR-T cells/kg	1.5 × 108 CAR-T cells	300–460 × 106 CAR-T cells
Median follow-up time (months)	18.07	26	18	20.3	13.3
Best objective response rate (%)	98.9	89.6	97.9	92.2	73
Best CR rate (CR/sCR) (%)	82.4	77.1	82.5	71.6	33
MRD negativity rate	97.8%	NA	NA	NA	26%
Median time to response	16 days	0.95 month	1 month	29 days	1 month
12-month PFS rate	85.5%	77%	77%	76.8%	NA
12-month sustained MRD negativity rate	81.7%	NA	53.1%	NA	19.5%
Median CAR persistence time	24-month persistence rate: 40% Median persistence duration: 419 days	Median persistence duration: 69 days	6-month persistence rate: undetectable in most	Median duration: 140 days	12-month persistence rate: 36%
≥Grade 3 cytokine release syndrome (%)	1	35.4	5	6.9	5
≥Grade 3 ICANS	0	0	5%	0	3%

BCMA: B-cell maturation antigen; CAR-T: Chimeric antigen receptor T; CR: Complete response; DoR: Duration of response; ICANS: Immune effector cell-associated neurotoxicity syndrome; NA: Not available; MM: Multiple myeloma; MRD: Minimal residual disease; ORR: Overall response rate; OS: Overall survival; PCT: Physician’s choice of treatment; PFS: Progression-free survival; RRMM: Relapsed/refractory MM; sCR: Stringent complete response.

Early high-quality T cell collection and cryopreservation are essential

The isolation of peripheral blood mononuclear cells (PBMCs) represents the initial step in the process of autologous CAR-T therapy. Obtaining enough viable PBMCs from peripheral blood can ensure the successful production of CAR-T cells with a high yield of quality T cells. Key factors influencing T cell quality include a high CD4/CD8 ratio, a high proportion of poorly differentiated T cells, and a low number of Tregs.^[86] A higher ratio of CD4/CD8 and low-differentiated T-cell proportion correlate with improved T-cell quality and enhanced clinical remission. Meanwhile, evidence from a clinical study suggests that early harvesting PBMC preserves T-cell quality and maximizes the quality of the CAR-T cell product. Patients who underwent early single harvesting demonstrated significantly higher CD4⁺/CD8⁺ ratios and greater proportions of naïve T-cells compared to those in the standard harvesting group.^[14]

Exploring CAR-T therapy as a potential treatment in early line for MM

The exploration of CAR-T therapy in the treatment of MM is at the forefront of personalized medicine, heralding a paradigm shift in the management of high-risk NDMM.^[14] With high-risk genetic abnormalities identified in 25–30% of NDMM patients who have an OS of less than 3 years, the need for innovative therapies has never been greater. Promising results from trials such as KarMMa-4^[87] and CARTITUDE-2^[88] have paved the way for exploring CAR-T therapy in high-risk NDMM and early line treatment scenarios. Furthermore, CAR-T therapy has evolved from its initial approval for third-line treatment to now being approved for both second- and third-line therapies. Recent studies, including CARTITUDE-4^[76] and KARMMA-3,^[83] have further validated this progression by demonstrating the efficacy of CAR-T therapy in later treatment lines. Additionally, ongoing investigations are exploring CAR-T therapy as a first-line treatment for high-risk patients, with preliminary data indicating significantly improved efficacy compared to standard treatments. Notably, eque-cel has shown promising efficacy and safety in treating patients with high-risk NDMM, as indicated by new data from the FUMANBA-2 study (NCT05181501). In addition to CAR-T cell and BiTEs, ASCT has remained a standard treatment for NDMM for over two decades, consistently achieving higher CR rates and improving event-free survival and OS compared to conventional chemotherapy.^[79]

ASCT, particularly after successful induction therapy, shows a CR rate ranging from 30% to 50% and a low toxic death rate (<5%). This prompts ongoing evaluation of its role in combination with new therapies. Conversely, ASCT offers the potential graft-versus-myeloma effect, but its effectiveness is tempered by complications such as graft-versus-host disease and inconsistent survival benefits. Ongoing clinical trials are essential for determining the optimal treatment paradigm for MM in the context of evolving therapies.

Limitations and Downsides of Innovative Treatment Strategies for MM

CAR-T cell therapy and BiTEs show promise in treating RRMM, but both face significant challenges.^[14] CAR-T therapy, particularly those targeting BCMA, is limited by issues such as antigen escape, poor cell persistence, and the immunosuppressive tumor microenvironment. Additionally, the high costs and lengthy manufacturing processes further restrict patient access.^[14] BsAbs, while achieving ORR ranging from 25% to 100%, show inconsistent effectiveness and pose risks such as cytokine release syndrome and other toxicities.^[74] Therefore, research into combination therapies is crucial for enhancing the safety, efficacy, and accessibility of both CAR-T and BsAbs for MM.^[14,74]

Conclusions and Future Directions

In this comprehensive review, we have delved into the transformative impact of immunotherapy on the treatment landscape of MM, highlighting its role in advancing the search for more effective, targeted interventions. The advent of CAR-T therapy and BiTEs, particularly those targeting the BCMA, marks a pivotal advancement, demonstrating substantial efficacy in not only reducing tumor burden but also achieving and sustaining MRD negativity. However, treatment resistance remains a formidable challenge, as the dynamic nature of MM and its microenvironment can lead to the emergence of antigen-negative variants, thereby diminishing the effectiveness of targeted therapies. Moreover, the potent activation of the immune system by CAR-T therapy and BiTEs can result in severe side effects, necessitating vigilant management and limiting treatment tolerance.

Despite these advancements, challenges persist, including optimization of treatment efficacy, management of associated toxicities, and the accessibility of drugs. Future research is pivotal in investigating early line treatments, identifying new targets beyond BCMA, and refining CAR-T structure designs.

Conflicts of interest

None.