Continuous Lenalidomide Plus CAR-T Tests Persistence Hypothesis Without Combination Precedent

Starton Therapeutics Partners with Stanford for CAR-T Combination Trial

Starton Therapeutics has signed a clinical trial agreement with the Stanford School of Medicine to evaluate its lead candidate, STAR-LLD, in combination with a novel CAR-T cell therapy for patients with relapsed or refractory multiple myeloma. This investigator-initiated trial aims to assess the safety and preliminary efficacy of the combination, while exploring STAR-LLD's potential to enhance the performance of next-generation CAR-T therapies. The collaboration seeks to improve therapeutic responses and clinical outcomes by leveraging STAR-LLD's continuous delivery of lenalidomide, which is hypothesized to boost CAR-T cell expansion and persistence while minimizing the known toxicities associated with traditional immunomodulatory imide drugs (IMiDs).

• Starton Therapeutics has entered into a clinical trial agreement with the Stanford School of Medicine to investigate STAR-LLD in combination with a novel CAR-T therapy for relapsed or refractory multiple myeloma. This strategic collaboration aims to assess the safety and preliminary efficacy of the combination, with a key objective of exploring how STAR-LLD can enhance CAR-T cell expansion and persistence while mitigating the significant toxicities often associated with immunomodulatory imide drugs (IMiDs) when used alongside CAR-T therapies.
• STAR-LLD is a proprietary continuous delivery formulation of lenalidomide, designed to provide a low-dose, sustained exposure of this immunomodulatory imide drug. This innovative delivery method is intended to maintain lenalidomide's beneficial immunologic activities—such as improving immune cell fitness, fostering a favorable tumor microenvironment, and reducing T cell exhaustion—while significantly decreasing the severe or life-threatening toxicities commonly observed with higher-dose oral lenalidomide formulations, thereby improving tolerability.
• Preclinical and early clinical data support the potential of STAR-LLD. A preclinical study demonstrated that multiple myeloma tumors shrank by 80% with STAR-LLD over a 28-day cycle, achieving a 100% overall response rate and 20% of animals tumor-free after 100 days, outperforming daily lenalidomide. Furthermore, a Phase 1b clinical study in six relapsed/refractory MM patients showed objective responses in all participants (1 complete response, 5 partial responses) with no drug-related hematologic toxicity greater than grade 2, indicating meaningful efficacy and improved tolerability.

Addressing Unmet Needs in Relapsed/Refractory Multiple Myeloma

Recent literature converges on relapsed or refractory multiple myeloma with limited effective options and poor survival, driving development of BCMA-directed CAR T-cell therapies, bispecific antibodies, and novel constructs. Focus has shifted to risk-adapted sequencing, salvage after T-cell redirection, and balancing deep remission with infection, cytopenia, and immune recovery.

• Triple-class exposed, triple-class refractory and penta-refractory disease: Studies characterize triple-class exposed relapsed/refractory MM with median OS of 14.2 months, PFS 6.2 months, and TTNT 7.2 months, with significantly worse prognosis with triple- and penta-class refractoriness, high attrition, and high healthcare utilization, defining a population targeted with teclistamab, elranatamab, talquetamab, ciltacabtagene autoleucel, idecabtagene vicleucel, and belantamab mafodotin plus pomalidomide and dexamethasone.

• High-risk cytogenetics and functional high-risk early relapse: Del17p, t(4;14), t(14;16) or gain 1q, concurrent del(17p) and t(4;14), and early relapse within 12 months of therapy initiation are highlighted with inferior PFS and OS, prompting evaluation of selinexor-based regimens, isatuximab plus carfilzomib and dexamethasone, carfilzomib-based regimens, tandem autologous stem cell transplantation, and early integration of immunotherapies.

• Extramedullary disease and plasma cell leukemia: Extraosseous extramedullary disease, extramedullary disease, and plasma cell leukemia including primary and secondary disease are described as unmet need with inferior outcomes, targeted in trials of anti-BCMA/GPRC5D bispecific CAR T cells with overall response rate of 86% and 97% in extraosseous EMD cohorts.

• Relapse after BCMA-directed CAR T-cell therapy and multi-antigen refractory disease: Relapse after B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy remains frequent with no established standard for maintenance or salvage, driving strategies based on clinical tempo, disease compartment, contemporary expression of BCMA, G protein-coupled receptor class C group 5 member D (GPRC5D), and Fc receptor-homolog 5 (FcRH5), including BCMA retargeting, switch to GPRC5D or FcRH5, bispecific antibodies, antibody-drug conjugates, and second cellular platforms.

• Elderly, frail and transplant-ineligible patients with tolerability constraints: Patients aged ≥75 years, frail patients, and transplant-ineligible patients with newly diagnosed or relapsed disease are underrepresented in trials and face toxicity with triplet regimens, supporting dose-adjusted DRd and VRd-lite, Rd, VMP, home infusion therapy, and assessment of progression-free survival together with infection-free survival, treatment-free interval, immune recovery, quality of life, and responsiveness to subsequent salvage.

Exploring Novel CAR-T Combinations for Multiple Myeloma

Daratumumab-based quadruplet regimens are under intensive evaluation in newly diagnosed multiple myeloma (MM). The prospective, Phase II EMN19 study assessed daratumumab plus bortezomib, cyclophosphamide, and dexamethasone (DaraVCD) in 40 patients with newly diagnosed MM (NDMM; n = 29) or at first relapse (RMM; n = 11) and positron emission tomography or computed tomography (PET/CT)-confirmed extramedullary plasmacytomas. The overall hematologic ≥CR rate was 47.5% (19/40; NDMM patients: 58.6% [17/29]; RMM patients: 18.2% [2/11]), and the overall median progression-free survival was 25.8 months. Meta-analyses of randomized controlled trials in NDMM report that quadruplets demonstrated a 46% reduced risk for disease progression or death (HR = 0.54, 95% CI: 0.46-0.64) with pooled 2-, 3- and 4-year progression-free survival (PFS) rates of 89%, 77% and 86%, respectively, a pooled proportion of patients achieving at least complete response of 64%, and a pooled MRD negativity rate of 62%. A GRADE assessed meta-analysis of 7 RCTs containing 3,443 patients (1,759 in the daratumumab group and 1684 in the non-daratumumab group) showed significantly higher PFS (HR 0.50, 95%CI: 0.43- 0.58, p < 0.00001) and high MRD negativity (RR 1.99, 95%CI 1.59-2.50, P<0.00001), with increased neutropenia (56.2% vs 40.3%), thrombocytopenia (40.7% vs 32.5%), and infections (33.1% vs 23.3%).

Bispecific antibody (BsAb)-based combinations are reshaping treatment across NDMM and relapsed/refractory MM (RRMM). In early RRMM, the phase III MajesTEC-3 trial demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits with BsAb teclistamab plus daratumumab compared to other standard triplets, with response rates approaching those historically observed with chimeric antigen receptor (CAR) T cell therapy. A rational BsAb combination of BsAb elranatamab and a cereblon E3 ligase modulatory drug (CELMoD) iberdomide in MagnetisMM-30 showed promising synergy despite cytopenias and updates to combination BsAb targeting in RedirecTT-1 demonstrated major activity in difficult to treat extramedullary myeloma (EMM). In NDMM, minimal residual disease (MRD)-adaptive consolidation with linvoseltamab in IMMUNOPLANT converted persistent MRD positivity to MRD negativity in all evaluable patients, while TecLille showed that antibody-only therapy achieved deep responses with manageable infection risks in transplant-ineligible (TIE) NDMM patients.

CELMoD plus anti-CD38 combinations and engineered immune platforms represent additional investigational approaches. EXCALIBER-RRMM is a phase III trial of iberdomide, daratumumab, and dexamethasone in relapsed/refractory multiple myeloma designed to compare the selected IberDd dose with DARA, bortezomib, and DEX in patients with early-line (1 or 2 prior lines of therapy) RRMM, building on phase I/II data where IBER in combination with DARA and DEX (IberDd) was well tolerated and demonstrated promising preliminary efficacy in patients with heavily pretreated RRMM. In the CAR-T space, ciltacabtagene autoleucel (cilta-cel) CAR T-cell therapy led to minimal residual disease (MRD)-negative disease status in a 71-year-old man with stage III MM and high-risk cytogenetics [del(17p)] who subsequently underwent living donor kidney transplantation, maintaining MRD-negative, complete hematologic remission at 17 months post-transplant. First-in-human inMMyCAR data introduced an in vivo CAR-T product as a proof-of-concept platform, with tremendous potential to streamline the access to therapy.

STAR-LLD's Differentiated Safety Profile in Multiple Myeloma

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Continuous Lenalidomide: A Strategic Boost for CAR-T in Myeloma

The therapeutic landscape for multiple myeloma has undergone a profound transformation, yet despite significant advances with novel agents, immunomodulatory drugs, and particularly, B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T-cell (CAR-T) therapies, the disease remains largely incurable. CAR-T products like cilta-cel have set a new benchmark for efficacy in relapsed or refractory multiple myeloma (RRMM), demonstrating impressive response rates and prolonged progression-free and overall survival, even in patients who are refractory to lenalidomide and other standard treatments. However, challenges remain, including the durability of responses and the management of associated toxicities such as cytokine release syndrome, neurotoxicity, and cytopenias.

Against this backdrop, the exploration of STAR-LLD, a continuous delivery formulation of lenalidomide, in combination with CAR-T therapy represents a strategic effort to push the boundaries of treatment. Lenalidomide is a well-established immunomodulatory drug with known anti-tumor and immune-enhancing properties. The hypothesis underpinning this trial is that continuous lenalidomide delivery could optimize the CAR-T cell environment, fostering better expansion and persistence of these engineered T-cells, while potentially mitigating some of the dose-limiting toxicities associated with intermittent, higher-dose immunomodulatory drug regimens. If this hypothesis holds true, it could lead to more profound and lasting responses for patients.

However, this innovative approach is not without its considerations. Combining two potent therapies, each with its own toxicity profile, necessitates careful monitoring for additive or synergistic adverse events. Lenalidomide is known for hematologic toxicities and venous thromboembolism, while CAR-T therapies are associated with significant hematologic events, cytokine release syndrome, and neurotoxicity. The continuous pharmacokinetic profile of STAR-LLD will need to be meticulously managed to ensure therapeutic benefit without undue toxicity. Furthermore, with CAR-T therapies already demonstrating remarkable efficacy, the bar for showing a clinically meaningful incremental benefit with the addition of STAR-LLD is high. This trial is a crucial step in understanding how to best sequence and combine advanced immunotherapies to achieve the ultimate goal: more durable remissions and improved quality of life for patients battling this complex malignancy.