The rapid emergence of CAR-T cell therapies and bispecific antibodies has transformed the treatment landscape for relapsed/refractory multiple myeloma (RRMM), leading to substantial improvements in patient outcomes. However, limitations related to accessibility, treatment costs, manufacturing complexity, and toxicity management continue to restrict their widespread use. As a result, there remains a pressing need for innovative therapies that combine efficacy, safety, and broad clinical applicability.At the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, the team led by Professor Lijuan Chen from West China Hospital, Sichuan University, presented results from a Phase Ib/II study evaluating Purinostat Mesylate (PM)—the world’s first highly selective HDAC I/IIb inhibitor—in combination with pomalidomide and low-dose dexamethasone (Pd). The findings suggest a promising new treatment option for patients with RRMM.
During ASCO, Professor Chen spoke with international media to discuss the study results, the biological rationale behind the regimen, and its potential future role in multiple myeloma treatment.
Encouraging Early Clinical Activity in a High-Risk RRMM Population
Professor Chen explained that the study was an open-label, multicenter Phase Ib/IIa trial jointly conducted by West China Hospital of Sichuan University and Peking University People’s Hospital. The principal investigators were Professor Ting Niu and Professor Jin Lu.
Eligible patients had received at least one prior line of therapy and had previously been exposed to both a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD).
In the study design, pomalidomide was administered at a fixed dose of 4 mg on Days 1–14, while dexamethasone was given at a fixed dose of 20 mg. Purinostat Mesylate was evaluated across four escalating dose levels—4.0, 6.0, 8.4, and 11.2 mg/m²—based on findings from earlier Phase I studies.
Because Purinostat Mesylate was anticipated to cause thrombocytopenia and neutropenia, investigators explored two dosing schedules. Cohort A received treatment in 21-day cycles, with PM administered for two consecutive weeks followed by one week off therapy. Cohort B received treatment in 28-day cycles, with PM administered on Days 1, 4, 8, and 15.
The initial results revealed important differences between the two schedules. Cohort A achieved a higher overall response rate (ORR) of 50%, including one stringent complete response (sCR) and two partial responses (PRs). However, all patients in this cohort experienced Grade 3 thrombocytopenia, raising concerns regarding long-term tolerability.
By contrast, Cohort B maintained meaningful antitumor activity while significantly reducing hematologic toxicity. The incidence of Grade 3 thrombocytopenia fell to approximately 54%, leading investigators to select PM 8.4 mg/m² using the Cohort B schedule as the recommended Phase II dose (RP2D).
Further evaluation in an expansion cohort of 16 patients demonstrated continued clinical activity despite the inclusion of many ultra-high-risk patients, including those with extramedullary disease, high-risk cytogenetic abnormalities, and multiple prior treatment failures.
Among these patients, the ORR reached 43.75%, including one complete response (CR), three very good partial responses (VGPRs), and three partial responses. An additional four patients achieved minimal response (MR), reflecting a substantial overall clinical benefit rate.
At the time of analysis, neither median progression-free survival (PFS) nor median duration of response (DOR) had been reached, suggesting that a proportion of patients continued to derive durable benefit. Importantly, the optimized dosing schedule significantly improved management of platelet toxicity, further supporting the regimen’s clinical feasibility.
Activity Beyond Multiple Myeloma
Professor Chen noted that the therapeutic potential of Purinostat Mesylate extends beyond multiple myeloma.
In relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), PM monotherapy has already demonstrated notable clinical activity. In a Phase I study involving 11 patients with R/R DLBCL, the ORR reached 64%, with six patients achieving complete remission, corresponding to a CR rate exceeding 54%.
Subsequent Phase IIa results were even more encouraging. In the 11.2 mg/m² cohort, the ORR increased to 71.4%, leading to selection of the study as a Late-Breaking Abstract (LBA) at the 2024 ASCO Annual Meeting.
In a subsequent Phase IIb study, 56 patients with third-line or later R/R DLBCL received treatment at the recommended dose. The study achieved an ORR of 64.3% and a CR rate of 25%, with a median progression-free survival of 6.2 months and a median overall survival of 14.8 months.
According to Professor Chen, these outcomes compare favorably with those reported for certain antibody-drug conjugates (ADCs) and bispecific antibodies, making PM one of the most competitive small-molecule monotherapies currently under investigation in heavily pretreated DLBCL.
A registrational Phase III study comparing PM with selinexor is currently ongoing, and the company plans to seek conditional approval for third-line R/R DLBCL in 2027.
The Scientific Rationale: Overcoming the “CRBN Trap”
Professor Chen explained that the concept of combining HDAC inhibitors with immunomodulatory agents and dexamethasone is already familiar to hematologists. The rationale is based on the potential synergy between these therapeutic classes.
IMiDs such as pomalidomide exert their effects through binding to cereblon (CRBN), a critical component of the E3 ubiquitin ligase complex. CRBN-mediated degradation of IKZF1 and IKZF3 subsequently suppresses downstream oncogenic drivers including c-Myc and IRF4, ultimately inducing myeloma cell death.
In theory, HDAC inhibitors can enhance CRBN expression and increase sensitivity to IMiDs while simultaneously suppressing anti-apoptotic pathways. However, broad-spectrum HDAC inhibitors such as panobinostat present a major challenge: although they possess antitumor activity, they may also reduce CRBN expression, thereby diminishing IMiD efficacy. This phenomenon has been described as the “CRBN trap.”
Professor Chen emphasized that Purinostat Mesylate appears to avoid this limitation.
As a highly selective HDAC1/IIb inhibitor, PM preserves CRBN function and therefore allows genuine pharmacologic synergy with pomalidomide. This advantage appears to operate through three complementary mechanisms.
First, the combination achieves dual suppression of c-Myc. Pomalidomide inhibits c-Myc indirectly through CRBN-mediated degradation of IKZF proteins, while PM suppresses c-Myc transcription through epigenetic regulation of histone acetylation. Together, the two agents attack one of the central oncogenic drivers of myeloma from distinct biological angles.
Second, PM preserves CRBN expression, avoiding the resistance mechanisms associated with broad-spectrum HDAC inhibitors and enabling sustained synergy with IMiDs.
Third, the regimen appears capable of remodeling the tumor immune microenvironment. Preclinical studies have shown that PM activates IFN-α and IFN-γ signaling pathways, upregulates MHC-I and MHC-II expression, and promotes CD8-positive T-cell infiltration. Since pomalidomide itself enhances T-cell and natural killer (NK) cell activity, the combination may produce a dual effect of epigenetic regulation and immune activation.
Professor Chen also noted that increased MHC expression may enhance antibody-dependent cellular cytotoxicity (ADCC) mediated by anti-CD38 antibodies such as daratumumab, providing a potential rationale for future combination strategies.
Defining a Place in an Evolving Treatment Landscape
As CAR-T therapies and bispecific antibodies become increasingly important in RRMM, Professor Chen believes that important unmet needs remain.
CAR-T therapy requires complex manufacturing processes and remains inaccessible for many patients. Although bispecific antibodies have improved treatment convenience, cytokine release syndrome (CRS), infections, and other immune-related toxicities continue to require careful management.
Against this backdrop, PM plus Pd may fill an important gap between conventional therapies and T-cell–directed treatments.
For patients who are unable to receive CAR-T therapy, the regimen offers a fully oral, outpatient-based treatment option without the logistical complexities associated with cellular therapy.
For patients who relapse after bispecific antibody treatment, PM plus Pd may provide a valuable alternative because its mechanism of action is independent of BCMA and GPRC5D, minimizing concerns regarding cross-resistance.
The regimen may also be particularly attractive for elderly or frail patients because it is not associated with CRS or neurotoxicity. Furthermore, the use of low-dose dexamethasone may help reduce infection risk and steroid-related adverse effects.
Professor Chen also suggested that the regimen could potentially serve as an effective bridging strategy for patients awaiting CAR-T therapy, helping control disease without compromising subsequent cellular treatment.
Conclusion
Overall, Purinostat Mesylate combined with pomalidomide and dexamethasone represents a novel therapeutic strategy built upon three key principles: selective HDAC inhibition, preservation of CRBN function, and immune microenvironment remodeling.
The regimen has demonstrated encouraging efficacy and manageable safety in heavily pretreated and high-risk patients with RRMM. As clinical development progresses and more mature data become available, this fully oral, non–T-cell-based, non-BCMA-targeted approach may become an important addition to the RRMM treatment landscape and offer a valuable option for patients who are unable to benefit from CAR-T cell therapies or bispecific antibodies.
Expert Profile
Professor Lijuan Chen
West China Hospital, Sichuan University
Second-Level Professor, Sichuan University
First-Level Professor, West China Hospital
Professor Chen has devoted her career to the discovery and development of innovative therapies for malignant tumors, autoimmune diseases, and metabolic disorders. Her research led to the identification of the internationally recognized Pironetin binding site and Cevipabulin binding site.
She has spearheaded the development of seven innovative therapeutic agents spanning oncology and autoimmune diseases, all of which have successfully advanced into clinical development. Among these programs, six have received approval for clinical investigation in China and one has entered clinical development in the United States. Four candidates are currently in Phase II trials, while two remain in Phase I development.
Purinostat Mesylate for Injection has completed Phase I and Phase IIa studies. Owing to its outstanding Phase IIa results, it was selected as a Late-Breaking Abstract at the ASCO Annual Meeting—one of only four Chinese-origin innovative drugs to receive this distinction. The agent is currently being evaluated in a Phase IIb study and is expected to seek conditional approval in 2027 for the treatment of relapsed/refractory diffuse large B-cell lymphoma.
Another investigational agent, Flunotinib Malate Tablets, is currently being studied in a multicenter Phase IIb trial for intermediate-2 and high-risk myelofibrosis. Several additional programs targeting autoimmune diseases are also in early-stage clinical development.
In 2019, Professor Chen founded Chengdu Zeling Biopharmaceutical Technology Co., Ltd. and currently serves as Chairwoman of the company. As corresponding author or co-corresponding author, she has published more than 410 SCI-indexed papers in journals including Science Advances and Nature Communications. Her work has been cited more than 10,000 times, and she has an H-index of 57.
From 2020 to 2023, Professor Chen was recognized for four consecutive years as a Highly Cited Chinese Researcher and was included among the world’s top 100,000 most influential scholars. She has led 25 major research projects, including grants from the National Natural Science Foundation of China and national key drug development programs.
Her team has secured 20 international patents and 40 Chinese patents. Ten technology-transfer projects have generated cumulative institutional funding exceeding RMB 100 million. Professor Chen has delivered invited presentations at 15 international scientific conferences and serves as principal investigator of a national 863 Program key project. She has also been recognized as a leading talent under the Tianfu Talent Program and the Chengdu Rongpiao Talent Program.
