Повышение эффективности лечения нескольких миелом: интеграция четырехкратной и двойной антигенной терапии CAR-T.

Introduction

Multiple myeloma (MM) is a malignant plasma cell disorder characterized by the uncontrolled proliferation of plasma cells in the bone marrow. 1 This further leads to complications such as bone pain, immune dysfunction, and deficiencies such as anemia and thrombocytopenia. 2 Globally, MM is the second most common hematologic malignancy and remains incurable mainly due to persisting factors such as disease relapse and antigen escape. 3

Initial treatment typically begins with quadruplet therapy to induce remission and lessen disease burden. Quadruplet therapy includes an anti-CD38 monoclonal antibody, immunomodulatory drug (iMiD), proteasome inhibitor (PI), and dexamethasone. 4 The addition of anti-CD38 monoclonal antibodies, such as daratumumab and isatuximab, to a traditional chemotherapy triplet backbone has further enhanced patient outcomes. However, many MM patients experience relapsed or refractory disease despite aggressive initial treatment. Thus, there is a need for novel therapeutics with deeper activity that can overcome resistance barriers and sustain remission in MM. 5 , 6 , 7 , 8

Chimeric antigen receptor (CAR-T) therapy has revolutionized cancer treatment. 9 During CAR-T therapy, a patient’s own T cells are collected and engineered ex vivo to express the CAR ( Figure 1 ). These genetically modified cells can then target a specific tumor-associated antigen. The persistence and efficacy of CAR-T cells depend on several factors, including the structure of the CAR, the quality of the T cells, and their differentiation status. 10 Reinfusing a patient’s own reprogrammed CAR-T cells back into the body stimulates a T cell-mediated response against the malignant cells that express the antigen for cancer. 11 Subsequently, upon T cell activation, CAR-T cells induce mitochondrial apoptosis in target cells, leading to tumor cell death. 12

Previous and current ongoing clinical trials for CAR-T therapy have demonstrated efficacy in treating several hematological malignancies which has resulted in various FDA approvals. 13 Common malignancies include diffuse B cell lymphoma (DLBCL), acute lymphoblastic leukemia (ALL), mantle cell lymphoma, follicular lymphoma, and more recently, autoimmune diseases such as lupus and myasthenia gravis. 14 Despite these therapeutic innovations, clinical trials have revealed challenges similar to previous cancer therapies. Many patients have shown relapse following CAR-T therapy as a major limitation frequently attributed to T cell exhaustion and antigen loss. 15 These limitations underscore the need for continued innovation and clinical trials to refine current therapies and overcome resistance mechanisms.

To overcome these limitations, dual-antigen CAR-T therapy has been introduced to enhance tumor response and reduce resistance. Dual-target CAR-T prevents antigen escape by simultaneously targeting the B cell mature antigen (BCMA) alongside alternative antigens such as CD19 and GPRC5D. 16 Preliminary clinical trials have demonstrated positive safety profiles and maintained cytotoxic activity, which suggests that dual-antigen CAR-T cell therapy may convey meaningful benefit across hematologic malignancies.

Tandem integration of quadruplet therapy with next-generation dual-target CAR-T therapy can offer a synergistic treatment model to maximize response durability and remission in patients with MM. 17 This review provides a comprehensive analysis of current FDA-approved CAR-T therapies, emerging dual-target rationale, and clinical studies supporting their potential use with quadruplet regimens. The goal is to analyze how the combination strategy can improve patient outcomes by improving progression-free survival and sustaining MRD negativity while providing a clear insight into functional MM treatment.

Evolving FDA-approved CAR-T therapies

Current FDA-approved CAR-T therapies have achieved remarkable efficacy in transforming the treatment of MM and other hematologic malignancies. Despite these advancements, barriers including antigen escape and relapse remain a challenge that requires implementation of next-generation designs.

Over the past decade, the therapeutic landscape of CAR-T cell therapies has undergone tremendous transformation, as illustrated in Figure 2 . Table 1 summarizes the current FDA-approved CAR-T therapies, including their target antigen, approval year and clinical indications. In August 2017, the first CAR-T cell therapy, tisangenleucel (Kymriah) was approved by the Food and Drug Administration (FDA) for the treatment of pediatric and young adult ALL. 18 Subsequently, three additional CD19 CAR-T therapies were FDA-approved between 2018 and 2021, including axicabtagene (Yescarta), brexucabtagene autoleucel (Tecartus), and lisocabtaegene masrleucel (Breyanzi). 19 Building upon the success from CD19-directed therapeutics, two BCMA-specific CAR-T cell therapies, idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carkvykti), were FDA-approved for the treatment of MM in April 2021 and February 2022, respectively. 20 Most recently, in November 2024, obecabtagene autoleucel (Aucatzyl) was FDA-approved to treat adults with relapsed or refractory CD-19-positive-B cell precursor ALL (B-ALL). 21 The prescribing information for all seven medications includes a boxed warning for cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and T cell malignancies. 22 Collectively, all seven FDA-approved CAR-T therapies in the US offer an effective treatment option for specific blood cancers such as leukemia, lymphoma and MM. These therapies have been demonstrated to achieve long-term responses in clinical trials.

Early-line approval of Abecma and Carvykti

The BCMA-directed CAR-T cell therapies Abecma (idecabtagene vicleucel) and Carvykti (ciltacabtagene autoleucel) have shown efficacy in treating relapsed and refractory MM (RRMM). These two CAR-T therapies have demonstrated significant efficacy in clinical trials, with improved progression-free survival and clinical benefit. 23 In 2024, the FDA expanded indications for both Abecma and Carvykti to be used simultaneously as an “early-line” treatment strategy for adults with relapsed or refractory MM. This personalized CAR-T cell therapy design reflects a shift in treatment. Incorporating CAR-T therapy earlier in the treatment of MM was associated with improved progression-free survival compared with conventional regimens for relapsed or refractory disease. 24

Ciltacabtagene autoleucel is now FDA-approved for the treatment of adult MM patients who have received at least one prior line of therapy. 22 Evidence from the CARTITUDE-4 trial, a randomized open-label phase III study, demonstrated statistically significant overall response rates (ORRs) and progression-free survival compared to standard of care regimens for MM. 25 In the CARTITUDE-4 trial, 419 patients were enrolled who had previously received one to three previous lines of prior treatment and were also refractory to lenalidomide. These patients were randomized to receive ciltacabtagene autoleucel or the physician’s choice standard of care for MM. 25 Primary endpoint results showed that ciltacabtagene autoleucel led to longer progression-free survival compared to standard care in lenalidomide-refractory patients (76.4% vs. 63.8%, respectively). Additionally, patients in the ciltacabtagene autoleucel arm demonstrated better rates of MRD negativity compared to the standard-of-care group (89% vs. 38%, respectively). These findings show CAR-T therapy may have a role in earlier lines of therapy, as it is more effective than traditional standard-of-care chemotherapy regimens.

Idecabtagene vicleucel’s expanded indication now includes patients who are refractory to at least two prior lines of therapy, including a PI, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. The phase III KarMMa trial ( NCT03651128 ) evaluated idecabtagene vicleucel in adults with RRMM who had received two to four regimens previously. 26 Idecabtagene vicleucel therapy significantly prolonged progression-free survival compared to the standard of care group (13.3 months vs. 4.4 months, respectively), emphasizing idecabtagene vicleucel’s ability to achieve durable responses in heavily pretreated patients.

Shifting CAR-T therapies into earlier lines of treatment may enhance long term therapeutic outcomes for MM patients. Ongoing research indicates that T cells collected earlier in patients’ disease courses tend to exhibit lower toxicity over time, making the patients more suitable for CAR-T products. This supports the rationale for implementing earlier interventions in CAR-T therapy by improving durability and reducing the risk of relapse.

Clinical impact on patient outcomes

CAR-T cell therapies have significantly transformed the management of hematologic malignancies such as MM by offering personalized, single-infusion treatments that can induce durable remission. Multiple studies have shown that CAR-T therapy in relapsed or refractory MM can significantly improve patients’ overall response rate, with a median duration of response often exceeding 12 months 27 Over the past decade, the CAR-T receptor, in conjunction with T cell engineering, has shown many advancements in patient safety and efficacy. Despite these advancements, CRS and ICANS remain the most prominent adversities. In most cases, they are manageable and can be mitigated when recognized and treated early before disease progression. 28 Although CAR-T therapy has shown many improvements, there are high chances of disease relapse due to antigen escape, T cell exhaustion, and limited persistence. These challenges underscore the need for additional clinical trials to further evaluate dual-target CAR-T constructs in combination with combinatorial approaches to achieve durable remission in MM.

Quadruplet therapy in MM

Quadruplet induction has significantly impacted the treatment of MM patients by combining PIs, immunomodulatory agents, corticosteroids, and anti-CD38 monoclonal antibodies. 29 When used alone, however, resistance is still prevalent and relapse remains a primary concern. Optimizing quadruplet regimens alongside CAR-T therapy can provide valuable insights into improving long-term disease control.

Rationale and clinical significance

Quadruplet therapy regimens combining an anti-CD38 monoclonal antibody with a PI, an iMiD, and dexamethasone ( Figure 3 ) have become a powerful treatment option for patients with MM. Adding an anti-CD38 monoclonal antibody, such as daratumumab or isatuximab, to existing molecular backbones such as bortezomib, lenalidomide, and dexamethasone (VRd) or carfilzomib, lenalidomide, and dexamethasone (KRd) has shown to improve clinical outcomes. 30 The addition improves the depth of response to treatment, including increased MRD negativity and improved PFS. 31 Mechanistically, anti-CD38 mediates direct tumor killing and antibody-dependent cellular toxicity, enhancing T cell and NK-cell activation. 32 Multiple phase II and III clinical trials have validated that quadruplet therapy regimens represent a new standard of care, demonstrating increased safety and efficacy in transplant-eligible and transplant-ineligible MM patients. A systematic review and meta-analysis of quadruplets containing dexamethasone, a PI, an iMiD, and an anti-CD38 monoclonal antibody have demonstrated superior efficacy compared to triplet regimens for the treatment of patients with MM. Based on their synergistic mechanism of action, quadruplet regimens should continually be considered for these patients in both a transplant-eligible (TE) and transplant-ineligible (TI) MM patients. 33

Overview of clinical trials

Multiple phase II and III clinical trials have been conducted to evaluate how the incorporation of quadruplet regimens, which include anti-CD38 monoclonal antibodies with PIs, iMiDs, and corticosteroids, influences the treatment response in MM patients. Studies have collectively demonstrated that adding daratumumab or isatuximab significantly deepens treatment response, improving MRD negativity and prolonging progression-free survival compared to triplet regimens. Table 2 summarizes key ongoing and completed clinical trials that are being investigated in both transplant-eligible (TE) and transplant-ineligible (TI) MM patients.

The PERSEUS trial ( NCT03710603 ) is a phase III randomized study evaluating the addition of subcutaneous daratumumab to a standard triple backbone therapy containing bortezomib, lenalidomide, and dexamethasone (VRd) versus VRd alone in patients with newly diagnosed MM who are transplantation-eligible. Importantly, this study did not involve CAR-T therapy; however, it assessed the effectiveness and safety of quadruplet therapy. Overall, the PERSEUS trial demonstrated a clinically meaningful benefit with respect to depth of response and progression-free survival in the daratumumab-containing arm. These findings support the incorporation of daratumumab-based quadruplet regimens to have a more favorable benefit-risk profile in transplant-eligible patients with newly diagnosed MM.

Dual-target CAR-T therapy

Although BCMA-directed CAR-T therapy has transformed into MM therapy, relapse commonly occurs because of antigen escape, downregulation of BCMA, or heterogeneous expression. 38 Certain pooled dual-targeting strategies permit sequential delivery of CAR-T cells, an approach associated with reduced risk of severe CRS in earlier clinical studies. To overcome limitations such as relapse, dual CAR-T therapy engineered with advanced strategy designs provides broader coverage for the patient and enhances tumor recognition ( Figure 4 ). Recent reviews demonstrate a high response rate among patients with hematological malignancies undergoing CAR T cell therapy. 39 Costimulatory domains, including CD28 and 4-1BB, play a central role in determining the function and persistence of CAR-T cells. 40 These cells provide rapid and robust cytotoxicity, whereas 4-1BB promotes sustained T cell persistence. In response to these limitations, several BCMA combination pairings, including BCMA/CD19, BCMA/CD38, BCMA/GPRC5D, and BCMA/CS1 (also known as SLAMF7), can be targeted using this mechanism, allowing T cells to remain active even when one target antigen is downregulated. 41

CAR-T cell therapy targeting BCMA has demonstrated success in targeting MM, relapse remains a major barrier during the treatment process, driven by decreased antigen expression. In response to this, identifying novel CAR-T cell targets has shown promise, including antigens such as GPRC5D, CD38, CS1 (SLAMF7), and CD19. Recent studies have shown promising alternative approaches to CAR-T therapy for relapsed/refractory (r/r) MM. These studies demonstrated impressive efficacy and high safety. In a study evaluating the use of BCMA/CD19 dual-targeting fast CAR-T GC012F, the overall and complete response rates were 93.1% and 82.8%, respectively, demonstrating the potential efficacy of dual-target approaches. 42 The present data support that relapse remains a major therapeutic challenge in patients with r/r MM, and further investigation of dual-target options is required.

Mechanistically, integrating quadruplet induction therapy with CAR-T therapy is supported by immunological processes that enhance CAR-T efficacy. Anti-CD38 antibodies such as daratumumab and isatuximab enable T cells to function more effectively by repressing glycolytic metabolism, thereby creating a pro-immunogenic environment that enhances the anti-tumor response. Historically, immunomodulators have stimulated our immune system to function more effectively by regulating immune responses, thereby enhancing CAR-T activity and reducing toxicities. 34 When administered with CAR-T therapy, iMiDs such as lenalidomide and pomalidomide can lead to optimal persistence without making cells overactive. In addition, PIs further support CAR-T expansion by increasing tumor antigen expression and sensitize myeloma cells, thereby improving CAR-T cell-mediated tumor killing. Collectively, these mechanisms can synergistically prime the immune microenvironment prior to CAR-T cell therapy. Furthermore, this can lead to sustained persistence and a deeper clinical response, supporting the mechanistic rationale for quadruplet induction strategies with CAR-T-based therapies in MM.

Early clinical trials in relapsed MM patients have achieved dual-target BCMA/CD19 CAR-T therapy using two pools of single CAR transduced T cells ( NCT03706547 , NCT03767725 ). To minimize the potential for exacerbated CRS, patients received CAR-T cells in a sequential manner, rather than simultaneously. As a result, both groups experienced tolerable CRS without any neurological damage, indicating that the sequential combination of BCMA and CD19 CAR-T cells could enhance therapeutic outcomes and safety profiles. 43

Design of strategies

To improve response durability, several engineering designs have been developed to enhance T cell functionality. Currently, there are three common CAR configurations, including tandem, bicistronic and pooled constructs. 35 Collectively, they aim to improve response rates and minimize antigen escape.

Tandem CARs (TanCARs) comprise two single-chain variable fragments (scFvs) linked within a single CAR molecule, enabling simultaneous antigen recognition on the same T cells. This synergistic mechanism enhances cytolytic signaling for targeted T cells. Bicistronic CARs contain two independent CAR constructs within a single vector. Expression of both receptors on the same T cell allows activating signaling pathways while simultaneously sharing costimulatory domains. Finally, pooled CAR-T products are a newer domain in which two separately engineered T cell populations, each specific to one target, are combined. “CAR pooling” is a screening platform that enables independent in vivo expansion of CAR-T cells. By testing a library of CAR designs simultaneously, researchers can identify optimal signaling patterns to target the tumor while reducing the risk of antigen escape. 36 Together, these specific design configurations can provide durable, adaptive, and evolutionary next-generation CAR-T therapy.

Antigen pairs under investigation

Targeting combination therapies including B cell maturation antigen (BCMA) alongside other therapeutic targets in MM offer properties to overcome BCMA-specific treatment resistance. Disease relapse after anti-BCMA CAR T cell therapy is very common and requires further investigation. Other viable antigen targets include G protein-coupled receptor class C group 5 member D (GPRC5D), signaling lymphocytic activation molecule family member 7 (SLAMF7), along with cell surface proteins such as CD19, CD24, and CD38. 38 Targeting these antigens in combination with other anti-BCMA approaches has shown successful results, leading research studies to progress from preclinical studies to early-phase clinical trials ( Table 3 ). Several dual-target CAR-T targets such as GPRC5D, SLAMF7, and CD38 are highly expressed on the surface of malignant plasma cells, making them potential targets in the immunotherapy of MM.

GPRC5D

GPRC5D was initially introduced as a novel target on malignant plasma cells located on human chromosome 12p13. 37 Its short extracellular domains enable it to facilitate tighter immunological synapses, driving greater cytotoxic effects. GPRC5D is highly expressed in MM cells, with elevated levels in the bone marrow of MM patients. This increased expression suggests that GPRC5D is highly specific to multiple cell types, including skin cells, making it a potentially ideal target for immune effector cell-mediated therapy to treat MM. Preclinical approaches under investigation to improve the efficacy of anti-GPRC5D CAR T cell therapy include lysophosphatidic acid receptor modulation.

Utilizing GPRC5D-directed CAR-T therapy has shown promising results, especially when used early in the treatment of MM. In a phase I study evaluating MCARH109 in heavily pretreated patients with relapsed or refractory disease, treatment led to an overall response rate (ORR) of approximately 71%; however, the complete response rate should be stated more carefully, as six of 17 patients achieved a complete response rather than 71%. 44 The safety profile of GPRC5D has been consistent with other CAR-T therapies, including the majority of patients (∼88%) experiencing low-grade (grade 1 or 2) CRS as an adverse event. ICANS was also observed in a minority of patients (∼6%), and others had grade 3 or 4 severe side effects. Notably, a unique side effect associated with GPRC5D included cerebellar toxicity, which occurred in most patients at higher doses. Aside from balance issues, these led to dermatologic effects, including skin and nail changes, reflecting GPRC5D expression in the skin. These findings support GPRC5D as a promising alternative pathway that can be targeted in patients who relapse following BCMA-directed therapies.

SLAMF7 (CS1/CD319)

SLAMF7, also known as CS1 or CD319, is a glycoprotein cell surface receptor that is highly expressed on malignant plasma cells to promote their survival. 45 Elotuzumab, an anti-SLAMF7 antibody, is FDA-approved for treating relapsed/refractory (R/R) MM when used with lenalidomide and dexamethasone. 46 Anti-SLAMF7 CAR T cells in clinical trials showed promising preclinical results with no reported ICANS, but there have been significant cytopenias. Therefore, ongoing trials are under review to assess the safety and efficacy of this therapy.

CD38 and other antigens

CD38 is another protein that is highly and uniformly expressed on the surface of MM cells. CD38 plays a role in the adhesion, migration, and survival of MM cells. 47 Anti-CD38 antibodies such as isatuximab and daratumumab are now part of first-line treatment for both transplant and ineligible MM patients. Often combined with dexamethasone and either carfilzomib or pomalidomide, the use of anti-CD38 regimens has been particularly effective as a T cell based treatment by depleting regulatory T cells to enhance the immune system’s response to therapy. Earlier preclinical studies suggest that BCMA/CD38 dual-target CAR-T therapy can increase cytotoxicity, which also reduces the chances of antigen escape.

Other potential antigen pairings under study include BCMA/CD19 and BCMA/CD24. Both bispecific CAR-T cell therapies aim for more effective treatment by targeting two different antigens to induce durable responses. 48 The majority of malignant plasma cells are BCMA positive, and more aggressive B cells include CD19-positive and CD24-positive cells. Utilizing this strategy allows for more effective killing and can prevent relapse with prolonged response to duration. A dual-target BCMA and surface protein combination exhibits improved efficacy compared to monospecific BCMA-CAR-T cell therapy.

Safety and toxicity profile

Dual CAR-T therapy has demonstrated improved clinical efficacy in hematologic and autoimmune diseases. Although dual CAR-T therapy showed modest responses in targeting solid tumors, it also has the capacity to increase circulating toxicity levels. Toxicities remain a concern for patients and can potentially lead to unexpected outcomes; CRS and immune effector-cell associated neurotoxicity (ICANS) are the most common and most severe adverse effects. 49 Aside from these severe adverse effects, CAR-T can also cause hypogammaglobulinemia and cytopenias which can increase risk of infection. As a result, patients may require treatment with monthly intravenous immunoglobulin to maintain optimal levels of immunoglobulin for immune response. It is also not uncommon for CAR-T patients to develop pancytopenia after therapy. Patients may be at risk for developing opportunistic infections, such as Pneumocystis jiroveci pneumonia, and should be treated prophylactically until blood cell counts normalize and infection risk is mitigated. 50 Preventing and controlling CAR-T related toxicities have become a critical step for successful completion of therapy for patients with MM.

Cytokine release syndrome

CRS is a disorder caused by the release of cytokines from immune and nonimmune cells. Symptoms may be progressive, but must include fever at onset, and may include hypotension, capillary leak, and, in severe cases, end-organ dysfunction. 51 The onset of CRS is variable but generally presents days to weeks after CAR-T infusions. Consensus grading and management criteria were developed by the American Society of Transplantation and Cellular Therapy in 2019. 52 CRS is graded on a scale of 1–4, with a score ≤2 indicating mild disease and >3 indicating life-threatening disease. 53 Various therapeutic measures are used to manage CRS depending on its severity and manifestation. Lower-grade CRS (grades 1 and 2) is managed with fluids, supplemental oxygen, and tocilizumab, whereas higher-grade CRS (grades 3 and 4) is treated with the same recommendation as grades 1 and 2, with the addition of corticosteroids and vasopressors. However, early steroid use may reduce the rate of CAR-T related CRS, and is recommended for axicabtagene ciloleucel and brexucabtagene autoleucel. Severe CRS should be managed in a high-acuity inpatient setting, such as an intensive care unit, due to the significant resources required for care.

Immune-effector cell-associated neurotoxicity syndrome

ICANS in MM patients can lead to symptoms such as confusion, tremor, aphasia, and dysphagia. 54 Onset of symptoms can occur about 5 days following CAR-T infusion, and in >10% of patients can persist for more than 3 weeks after CAR-T infusion. 55 Patients at higher risk include those with a higher disease burden and older age. The effects of ICANS can be mitigated with supportive care and early corticosteroid interventions. All patients undergoing CAR-T treatment should be proactively monitored for ICANS twice daily using the 10-point immune effector cell encephalopathy (ICE) score, to ensure overall assessment of neurological function. The higher the ICE score is, the lower the ICANS grade and vice versa. A score of less than 2 with seizures is classified as severe and should be transferred to intensive care. Based on severity, grade 1 ICANS involves supportive care; patients with grades 2–3 can receive 10–20 mg intravenous dexamethasone every 6 h, and patients with grade 4 ICANS can receive 1 g IV methylprednisolone for at least 3 days, until symptoms improve. In summary, although dual CAR-T therapy demonstrates therapeutic potential in MM patients, proactive toxicity mitigation is crucial to monitor to ensure patient safety and clinical efficacy.

Integration of quadruplet and CAR-T therapy

Mechanism of integration of both therapy strategies

The integration of quadruplet therapy with CAR-T regulation represents an evolving treatment option in MM management ( Figure 5 ). Quadruplet therapy adds a fourth drug, such as a CD38 immunotherapy antibody like daratumumab, to a standard triple regimen (i.e., bortezomib, lenalidomide, and dexamethasone). 56 In MM, this is increasingly becoming the new standard of care especially in patients newly diagnosed with the disease. Using quadruplet therapy allows patients to achieve deeper and more durable responses to therapy than a triplet regimen alone. Multiple clinical trials have supported that quadruplet regimens are showing superior progression-free survival, including patient’s ineligible for a stem cell transplant.

The proposed synergy between quadruplet therapy and CAR T cell therapy in MM is supported by the complementary mechanistic rationale, displayed in Figure 5 . Quadruplet regimens, such as those from the PERSEUS trial, achieve rapid cytoreduction and high rates of MRD negativity. These regimens rapidly decrease tumor burden and potentially enhance the efficacy of subsequent immune-based therapies. In this context, CAR T cell therapy, as evaluated in trials such as CARTITUDE-4 have demonstrated sustained immune-mediated tumor clearance in the setting of relapsed or refractory disease states, while trials such as CARTITUDE-6 remain ongoing. Mechanistically, prior “debulking” with quadruplet therapy could reduce antigenic load and immunosuppressive signaling within the tumor microenvironment, thereby facilitating improved CAR T cell expansion and persistence. However, no completed clinical trial has yet confirmed that using quadruplet induction strategies prior to CAR-T cell therapy can benefit patients compared to current treatment approaches.

The CD38 component serves as a dual target by binding to a specific receptor on the myeloma cells and a component in the human immune system which enhances the immune activity to attack cancerous cells in the body. Combining a quadruplet therapy that requires a dual-target component has shown promising clinical benefits for targeting multiple pathways simultaneously. Researchers are testing whether it can replace autologous stem cell transplant as a frontline therapy. Current data indicates that it could be a viable treatment option due to the amplification of MRD negativity rates and prolonged progression-free survival time. These results suggest a shift in the treatment approach toward a functional cure for MM.

Minimal residual disease

Treating MM has advanced due to the introduction of drugs that have significantly improved the depth of response and survival rate. However, many of these patients eventually relapse, and a small, but clinically relevant amount of myeloma cells remains behind. This refers to minimal residual disease (MRD). Achieving MRD negativity is recognized as the most robust surrogate marker for long-term survival in MM.

Traditionally, conventional flow cytometry and molecular techniques such as quantitative PCR (qPCR) are used to assess MRD in MM patients. However, a higher level of sensitivity is needed to detect residual cells. Next generation flow (NGF) and next generation sequencing (NGS), together with digital PCR (ddPCR), mass spectrometry, and imaging techniques, provide sensitivity for assessing MRD. 57 NGF and NGS can detect one malignant cell among one million normal cells (10 -6 sensitivity). Monitoring MRD is valuable for optimizing personalized patient therapy to achieve successful CAR-T therapy or maintenance.

When combining quadruplet induction regimens with CAR-T therapy, MRD monitoring can help researchers optimize treatment sequencing based on patient responses. This assessment can drive personalized maintenance strategies, identify early relapse, and determine if treatment discontinuation thresholds are achieved by having sustained MRD negativity. Thus, MRD-guided monitoring adds a critical element to this synergistic therapy, helping achieve a safer and more effective curative outcome.

Emerging strategies and sequencing

Ongoing current trials in MM are actively exploring the sequencing of quadruplet induction and CAR-T therapy to maximize clinical benefit. The CARTITUDE-6 ( NCT05257083 ) is an active phase III open-label global trial that comparing the efficacy of CAR-T cell therapy with cilta-cabtagene autoleucel (cilta-cel) to autologous stem cell transplant (ASCT) as upfront, first-line treatment for MM. The study hypothesizes that CAR-T cell therapy can be sufficient to replace the current standard of care for treating MM. The primary goal of the study is to determine if cilta-cel improves progression-free survival and sustained MRD-negative complete response rates. In this investigation, patients will receive quadruplet induction therapy known as DVRd (daratumumab, bortezomib, lenalidomide, and dexamethasone) followed by ASCT. After DVRd consolidation and up to two years lenalidomide maintenance, researchers can evaluate whether the results have increased clinical impact. If successful, the trial could redefine combination therapy as a potential first-line treatment for MM.

Importantly, in vivo CAR-T therapy is a novel alternative that addresses the limitations of ex vivo CAR-T therapy, including complex manufacturing processes, high production costs, long production times, and immunotoxicity. Unlike the traditional ex vivo approach, the in vivo approach bypasses complex manufacturing procedures and high production costs by selectively delivering CAR genes into the patient’s T cells in the body via targeted delivery systems, thereby reprogramming them into CAR T cells in situ . Multiple delivery vectors have been engineered to enable in vivo CAR-T cell production, including viral and non-viral vectors. 58 These innovative delivery systems have been tested in early-phase clinical trials. An ongoing phase I clinical trial for relapsed or refractory MM is using ESO-T01, a nanobody-targeted, immune-shielded lentiviral vector for in vivo CAR-T therapy to assess safety, tolerability, and preliminary efficacy. 59 Expanded clinical trials are needed to assess the safety and efficacy of in vivo CAR-T therapy on a broader scale.

Future directions/challenges

Manufacturing and accessibility

Although CAR-T therapy is revolutionary in cancer treatment, many limitations exist, including cost, access, and production time. 52 During this process, a patient’s own cells are collected and engineered ex vivo , prior to reinfusion into the patient. By reprogramming CAR-T cells, clinical studies have shown promising results leading to many US FDA approvals for various hematologic malignancies. However, many common barriers to therapy need further evaluation to overcome these challenges.

Surveys have been conducted worldwide to assess manufacturing issues for CAR-T therapy, aiming to gain a better overall understanding of the variability and challenges faced. Key themes in the RedCap Survey included recurring manufacturing challenges such as equipment costs (70%), facility requirements (60%), and personnel training (50%). 60 US institutions are more likely to emphasize challenges related to FDA regulatory requirements for meeting quality control standards compared to international institutions.

Universal CAR-T products can be produced in bulk and cryopreserved for later use. However, this introduces additional challenges including graft-versus-host disease, where the donor’s immune cells (graft) reject and attack the recipient’s (host) tissues. 61 In response, optimized gene-editing protocols and immunosuppressive procedures are required as preventative measures. Expanding manufacturing and accessibility infrastructures can help provide sustainable, optimal CAR-T therapy for all patients with MM.

Combination strategies

Despite advancements in CAR-T therapy, some MM patients do not respond to it. Hence, optimizing the design is necessary to enhance responsiveness in high-risk patients. Combination strategies aim to target immune checkpoints to maximize tumor eradication while reducing the risk of relapse.

Coalescing CAR-T therapy with common immune checkpoint inhibitors (ICIs), such as PD-1 or PD-L1 blockers, shows promising results in anti-tumor activity. 62 CD8 + T cells in malignant tumors are associated with TCR signaling and lead to high PD-1/PD-L1- expression, contributing to CAR-T cell exhaustion. Researchers have found that high levels of PD-1 on a patient’s T cells affect the killing function of the prepared CAR-T cells and exhaust CAR-T cell epitopes. Therefore, the PD-1/PD-L1 pathway plays a crucial role in CAR-T therapy. Combining CAR-T therapy with immune-checkpoint inhibitors can be an effective approach to treating solid tumors. The advantage of combination therapy is that it improves the objective remission rate in advanced patients. Limitations still persist, including the blocking effect of PD-1 inhibitors, which is transient and requires repeated administration. Additionally, PD-1 inhibitors do cause common adverse events such as diarrhea, rash, thyroid dysfunction, and less commonly neuromuscular disease. 63 Although a desirable option, future studies need to be conducted to seek alternative ways to mitigate adverse events.

Depleting regulatory T cell (Treg) is another promising strategy that, when combined with CAR-T therapy, can enhance responses in patients without needing higher CAR-T doses. Combining both offers more targeted and durable disease remission, suggesting a potential innovative cell therapy option to address the unmet need for remission in individuals with autoimmune diseases. 64 Regulatory T cells are a diverse subset of lymphocytes that maintain immunological homeostasis in response to both self and foreign peptides. 65 In patients with autoimmune diseases, T-regulated cells are often dysregulated, leading to further complications. CAR-T therapy has been successful in demonstrating promising results that are both safe and effective across various conditions. However, larger-scale clinical trials with longer follow-up periods are necessary to confirm the long-term safety and efficacy. Anti-CD25 medications such as CAR Treg cell therapies provide an extended and appropriate approach for treating diseases characterized by dysregulated T cell activation and inflammation. 66 By suppressing pathogenic T cells and inflammation, it can address future challenges and allow CAR-T to promote a sustained anti-tumor response.

Biomarker development

Emerging biomarkers such as immunological proteins and cytokines like soluble BCMA, IL-6, and IFN-gamma, are a strong predictor of toxicity and help guide re-infusion timings. 67 Monitoring these cytokines provides valuable insight into disease burden and the risk of CRS. Although fever is the most common symptom of CRS, other symptoms such as tachycardia, hypotension, hypoxia, and additional symptoms can persist. There are also neurological toxicities that can persist, such as aphasia, delirium, headache, and less commonly; seizures can also persist. 68 Side effects after CAR-T cell infusion can manifest with a wide range of clinical presentations. Therefore, elevations of these inflammatory mediators into the bloodstream can help guide researchers in managing interventions promptly.

Global factors and ethical concerns

Ensuring fair and equitable access to CAR-T therapy is a global challenge for diverse patient populations. 69 Global factors and ethical concerns surrounding CAR-T cell therapy can lead to disparities in accessibility and resource allocation. The high cost of CAR-T cell therapy is a major barrier and can place financial strain on many patients in need. 70 Limited treatment centers that specialize in CAR-T procedures are less common geographically and require patients to travel and stay near the site for an extended period, which increases expenses. Supply chain challenges like reagents and staff shortages can be worsened by global events, which further make timely delivery difficult. Recent advancements have been exploring artificial intelligence (AI) use in CAR-T cell therapy, which can provide beneficial opportunities to improve manufacturing efficiency and accuracy while optimizing logistics. Integrating AI into the field of CAR-T therapy systems of existing workflows plays a pivotal role in predicting treatment response and potential toxicities. This, AI-based bioinformatics is a tool that can accelerate target discoveries and make CAR-T both more effective and ethically equitable for all patients across the globe.

Early-line strategies

Current ongoing trials such as KarMMa-3, CARTITIUDE-6 and IMROZ have demonstrated improved outcomes for evidence-based CAR-T therapies, potentially replacing the novel standard of care. Administration of combined dual targeted therapy with quadruplet regimens may enhance T cell quality, leading to increased functional outcomes in MM patients. 64 Studies have shown that doing so results in more durable MRD-negative remission states and improves disease eradication. Further phase III studies focusing on dosing and maintenance strategies can help researchers determine the safety and efficacy of CAR-T therapy combinations as a frontline standard of care.

Future directions

Despite improved clinical outcomes for patients with relapsed/refractory MM, the use of CAR-T therapy still remains limited in real-world settings due to several barriers. These include rapid disease progression, manufacturing delays, geographic limitations, insurance coverage issues, severe toxicities, and racial disparities that can affect patients’ treatment plans. 71 Delays in care, especially due to insurance timelines and manufacturing delays, can exacerbate the risk for toxicities such as ICANS and CRS, contributing to poorer clinical outcomes and disease progression. Geographic limitations also play a major role, as CAR-T therapy is primarily available at specialized centers, especially in larger cities, meaning those in rural areas must travel longer distances, which may be expensive and difficult to accommodate. Furthermore, racial and socioeconomic disparities are prevalent where minority patients receive less access to CAR-T therapy, often being underrepresented, especially in underserved populations. These findings highlight the importance of ethical concerns and real-world barriers in the treatment and equitable access to CAR-T therapy. Expanding policy-level interventions and improving insurance coverage by increasing the number of specialized centers can help address disparities in clinical trial enrollment and ensure CAR-T is more widely available and more diverse. Addressing these issues will be important moving forward to make sure CAR-T therapy is not only effective, but also accessible to all treatment-eligible patients with MM.

Conclusion

MM remains a disease with unmet medical needs. The most significant unmet need is for patients with high-risk disease, due to the severity of adverse events that follow. Converging quadruplet induction therapy with dual-antigen CAR-T therapy represents a transformative progression for both transplant-eligible and ineligible MM patients. Individually, both treatment options provide optimal advancement in progression-free survival and MRD negativity. Together, they can redefine immunotherapy for managing higher-risk patients, improving their disease status and offering longer-lasting remission. The CEPHEUS phase III clinical trial demonstrated that adding the subcutaneous monoclonal antibody daratumumab to a standard three-drug regimen improves outcomes in transplant-ineligible or transplant-deferred MM, leading to deeper, more sustained responses. Beyond clinical efficacy, integration of daratumumab-containing quadruplet regimens with CAR-T therapy has an enhanced mechanistic rationale. Daratumumab can deplete CD38 + immune regulatory cells, promoting T cell expansion within the bone marrow microenvironment. Furthermore, the data suggest a multidimensional, immunomodulatory role for daratumumab that improves long-term clinical outcomes and enhances survival in MM patients. 72

Future research in this area involves ongoing trials that will broaden our understanding of innovations to refine the current standard of care. Collaborative research is focused on optimizing sequencing, identifying biomarkers related to toxicity, and developing systems that are more accessible to patients and easily manufactured worldwide. Overall, the treatment paradigm is rapidly shifting by combining immune modulation with quadruplet therapy. This precision-based approach can be tailored to individual patients, enabling clinicians to achieve longer-lasting, durable responses that are both safe and effective for MM patients.

Acknowledgments

All the figures are prepared using the BioRender tool purchased online. This work is supported by the University of Saint Joseph’s Teaching and Learning Center grant awarded to A.G.

Author contributions

Conceptualization, M.K. and A.G.; methodology, M.K. and A.G.; formal analysis, M.K. and A.G.; investigation, M.K., D.A., and A.G.; visualization, M.K. and A.G.; writing – original draft, M.K. and A.G.; writing – review and editing, M.K., D.A., and A.G.; supervision and project administration, A.G.; funding acquisition, A.G.

Declaration of interests

The authors declare no competing interests.

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