Editor's Note: The conference brought together top experts in lymphoma research from home and abroad, engaging in in-depth discussions on cutting-edge topics such as novel molecular targeted therapies and cell therapies. This article, based on Professor Franck Morschhauser's report, systematically reviews the latest research progress of BMS-986458—a first-in-class, bifunctional cereblon-dependent ligand-directed degrader (LDD) of B-cell lymphoma 6 (BCL6)—in the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL), aiming to provide a reference for clinical and research colleagues. Lymphoma, as a complex hematological malignancy, has consistently garnered significant attention regarding its treatment advancements. Against the backdrop of global medical experts focusing on cutting-edge therapies, the development of novel targeted drugs offers new hope for patients with refractory disease. At the recently held conference, Professor Franck Morschhauser from CHRU-Lille, France, delivered an insightful report titled "BMS-986458, a first-in-class, bifunctional cereblon-dependent ligand-directed degrader (LDD) of B-cell lymphoma 6 (BCL6) in patients with R/R NHL: Initial Ph 1 results," providing an in-depth introduction to the preliminary results of the Phase I clinical study of the novel BCL6 degrader BMS-986458 in patients with relapsed/refractory non-Hodgkin lymphoma.Unmet Clinical Need: The Dilemma of Relapsed/Refractory Non-Hodgkin Lymphoma
Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) remain challenging problems in the field of hematological oncology, especially for patients who are resistant to chimeric antigen receptor T-cell (CAR-T) therapy or bispecific antibody treatment, where the prognosis is often poor. DLBCL is the most common subtype of NHL, and although frontline immunochemotherapy can cure most patients, up to 40% of patients experience disease relapse or become refractory to treatment. For these patients, salvage treatment options are limited, and even after autologous stem cell transplantation (ASCT), approximately half of the patients relapse. Data from the SCHOLAR-1 study show that the objective response rate (ORR) for refractory DLBCL patients was only 26%, the complete response (CR) rate was only 7%, and the median overall survival (OS) was only 6.3 months, highlighting the urgent need for more effective therapies. B-cell lymphoma 6 (BCL6), as the “master regulator” of germinal centers, plays a critical role in normal B-cell maturation and tolerance to immunoglobulin somatic hypermutation. In DLBCL, BCL6 gene dysregulation is frequently observed, with overexpression occurring in up to 40% of cases. BCL6 promotes the proliferation and survival of tumor B cells by inhibiting cell cycle arrest, DNA damage checkpoints, and preventing apoptosis. Abnormal expression or activation of BCL6 makes it an important target for lymphoma treatment; however, despite previous attempts, no BCL6-targeted compounds have entered long-term clinical use.
Novel BCL6 Degrader BMS-986458: Mechanism of Action and Unique Advantages
BMS-986458 is a first-in-class, oral, highly selective cereblon-dependent ligand-directed degrader (LDD). Professor Morschhauser elaborated on its unique mechanism of action: BMS-986458 recruits the cereblon protein, part of the E3 ubiquitin ligase complex, to specifically bind with BCL6 protein on tumor cells, forming a ternary complex. This process induces ubiquitination of BCL6 by the E3 ligase, followed by BCL6 degradation via the proteasome pathway. This degradation not only demonstrates potent anti-proliferative and pro-apoptotic effects in tumor B cells but also impacts the tumor microenvironment by phenotypically modifying follicular helper T cells (TFH) and regulatory T cells (Treg), thereby promoting their phenotypic transformation without affecting cell viability. Professor Morschhauser noted that BMS-986458’s target degradation is rapid and durable, showing broad antitumor activity against BCL6-expressing non-Hodgkin lymphoma cell lines and patient-derived xenograft models in preclinical studies. Notably, BCL6 degradation can also upregulate CD20 expression on the cell surface, restoring sensitivity to existing anti-CD20 therapies, suggesting that BMS-986458 in combination with anti-CD20 drugs may yield powerful synergistic effects. This multi-modal antitumor mechanism positions BMS-986458 as a potential novel, non-chemotherapeutic treatment option for B-cell NHL.
BMS-986458 First-in-Human Trial: Phase I Study Design and Patient Characteristics
The preliminary results of the dose-escalation part of the BMS-986458 first-in-human, multi-center, open-label Phase I clinical study were presented at the conference. This study aims to assess the safety, tolerability, and determine the recommended Phase II dose (RP2D) of BMS-986458 in patients with relapsed/refractory NHL, as well as evaluate its plasma pharmacokinetic (PK) profile and preliminary efficacy. Patients enrolled were those with relapsed/refractory DLBCL (having received at least two prior treatment regimens) and relapsed/refractory FL (including FL3B, having received at least two prior treatment regimens), who also had measurable lesions. It is important to emphasize that this study targeted patients who had exhausted all possible treatment options, including those who failed CAR-T-cell therapy and bispecific antibody therapy, with no restrictions on the interval after CAR-T-cell therapy. As of the data cutoff date of April 10, 2025, a total of 31 patients were enrolled. The median age of patients was 62 years (range 36-76 years), with two-thirds being male. DLBCL patients not otherwise specified accounted for 45%, in addition to 5 patients with triple-hit DLBCL. These patients were heavily pretreated, with a median of 4 prior treatment regimens (up to 12). Among them, 77% of patients had failed prior CAR-T-cell therapy, 58% had failed bispecific or trispecific antibody therapy, and 61% had failed immunomodulatory drugs (IMiDs) or cell modulators. Overall, 71% of patients were refractory to prior treatments, fully reflecting the treatment challenges of this patient population. The study employed two dosing regimens: twice daily (BID) ranging from 40 mg to 160 mg, and once daily (QD) ranging from 80 mg to 260 mg. Treatment duration could extend up to two years, with disease assessments conducted every two months for the first six months, and then every three months thereafter.
Safety and Pharmacokinetics: Good Tolerability and Rapid, Durable Target Degradation
Professor Morschhauser noted that BMS-986458 was generally well-tolerated. The most common treatment-related adverse events (TRAEs) included arthralgia (19%) and fatigue (16%). Grade 3-4 TRAEs occurred in 5 patients (16%), including pneumonia, arthritis, bone pain, peripheral neuropathy, QT interval prolongation, and myalgia, with one case each. Notably, no Grade 3 or higher hematological treatment-related adverse events were observed in this study, which provides a good basis for future combination therapies with other drugs. Dose interruptions due to TRAEs occurred in 48% of patients, dose reductions in 6.5% of patients, and treatment discontinuation in 16% of patients. Two patients experienced dose-limiting toxicities (DLT): one with arthritis and bone pain (40 mg BID), and another with QT interval prolongation (260 mg QD). However, both patients were able to continue treatment after dose reduction, with symptom improvement.
In terms of pharmacokinetic evaluation, both BID and QD dosing regimens of BMS-986458 produced effective exposure on Day 1 and at steady state. Pharmacodynamic assessment showed that the drug induced rapid and durable BCL6 degradation in peripheral blood mononuclear cells and tumor tissue. A complete decrease in BCL6 was observed as early as 5 hours post-dosing, and this degradation persisted at all evaluated doses. In a fine-needle aspiration biopsy from one follicular lymphoma patient who achieved complete remission, immunohistochemistry evaluation showed complete disappearance of BCL6 expression, demonstrating the correlation between effective target degradation and clinical efficacy.
Breakthrough Efficacy: Deep and Durable Antitumor Activity
The study results showed that BMS-986458 demonstrated encouraging deep and rapid antitumor activity. In the overall study population, the objective response rate (ORR) was as high as 81%, with a complete response (CR) rate of 23.8%. By histological subtype: Diffuse large B-cell lymphoma (DLBCL): ORR was 80%, CR rate was 7%. Follicular lymphoma (FL): ORR was as high as 80% (5 out of 6 patients), with a CR rate of 67%. Notably, one patient with triple-hit DLBCL also achieved complete remission. Professor Morschhauser emphasized that despite limited follow-up time, preliminary data showed that responses were often observed at the first assessment. Currently, the durability of response in follicular lymphoma patients appears to be superior to that in DLBCL patients. During the Q&A session, Professor Morschhauser further explained the differences in response depth between DLBCL and FL, suggesting that FL typically achieves responses and complete responses more readily, but noted that it is still an early stage with no clear explanation yet. However, the durability of response in FL patients appears to be better. Regarding efficacy differences between ABC-type (activated B-cell-like) and GCB-type (germinal center B-cell-like) DLBCL, preliminary data (as assessed by investigators) showed that 4 out of 5 ABC-type patients achieved response, while 3 out of 6 GCB-type patients achieved response. A clear correlation was also observed between BCL6 expression intensity and efficacy, with biopsy results showing rapid and complete downregulation of BCL6 expression associated with response. Furthermore, a history of prior IMiDs treatment did not affect efficacy, as the study incorporated a washout period of at least one month.
Expert Opinion and Clinical Application Outlook
Professor Franck Morschhauser concluded that BMS-986458 demonstrated good tolerability in patients with relapsed/refractory non-Hodgkin lymphoma, with no hematological toxicity, making it an ideal candidate for combination therapy. The drug rapidly and durably degrades BCL6 in peripheral blood mononuclear cells and tumor tissue. In heavily pretreated DLBCL and FL patients, BMS-986458 showed potent antitumor activity, with impressive ORR and CR rates, especially in FL.Given its favorable safety profile and observed efficacy, Professor Morschhauser believes that all evidence supports the continued development of BMS-986458, both as a monotherapy and in combination with other agents, in the non-Hodgkin lymphoma landscape. Future research will require longer follow-up data to fully assess its long-term efficacy and safety.The preliminary results of this study open new avenues for the treatment of relapsed/refractory non-Hodgkin lymphoma. The successful development of the BCL6-targeted degrader BMS-986458 not only enriches the armamentarium for lymphoma treatment but also offers new hope for patients facing treatment challenges. It marks another significant advancement in precision targeted therapy for lymphoma.Provided/Interview Source: Oncology Outlook – Oncology News
