Efficacy and Safety of Chidamide Combined with Thalidomide, Cyclophosphamide, and Dexamethasone (TC2D) As a Novel Oral Quadruplet Regimen for the Treatment of Relapsed/Refractory Multiple Myeloma: Initial Results of a Phase IIa, Multicenter Clinical Trial
Authors: Li Yi , He Jingsong , Han Xiaoyan , Zheng Gaofeng , Zhang Enfan , Chen Qingxiao , He Donghua , Zhao Yi , Fu Jiaping , Shou Lihong , Jiang Wenhua , Jiang Wei , Qian Shenxian , Hu Huixian , Huang He , Cai Zhen 
Published: November 2021

Abstract
Background
Research has demonstrated that histone deacetylase (HDAC) is overexpressed in plasma cells. Panobinostat was the first HDAC inhibitor (HDACi) approved by FDA for the treatment of patients with relapse and refractory multiple myeloma (RRMM) in 2015. Chidamide is an oral subtype-selective HDACi, which was independently developed in China and approved as peripheral T-cell lymphoma. Preclinical findings have demonstrated the anti-myeloma activities of chidamide in vitro and in vivo. Currently, patients are recommended to take bortezomib and/or lenalidomide in first line treatment and might become less sensitive or resistant when disease progressed. Choices are limited for these patients as not all the new agents (i.e., second generation of PIs/ IMiDs, monoclonal antibody, et al.) were covered by insurance in China, which calls for more efficient and economical options. Here we report the initial efficacy and safety of this prospective, phase IIa, multicenter clinical trial with the chidamide based oral quadruplet regimen in patients with RRMM (ChiCTR2000035100).
Methods
The TC2D regimen (thalidomide 100mg on days 1-28, chidamide 5mg on days 1-24, cyclophosphamide 50mg on days 1-24 and dexamethasone 20mg on days 1,8,15 and 22) was administered to patients with RRMM of a 28-day cycle. In this trial, evaluation of overall response rate (ORR) was based on patients whose response ≥MR and clinical beneficial rate (CBR) was calculated in patients completed at least 3 cycles of TC2D regimen and reached ≥SD in this trial.
Results
A total of 32 patients were enrolled as of June 30, 2021, with a median age of 63.5 years (range 49-74). iFISH detected high-risk cytogenetics (defined by the presence of del (17p) or p53 mutation, t (4:14), t (14:16), t (14:20), amp (1q)) in 23 patients, and 82% (19/23) of which had unfavorable cytogenetics. All patients were exposed to at least one kind of PIs and/or IMiDs and 75% were double refractory to bortezomib and lenalidomide. 18 patients received 1-3 prior lines and 43% (14/32) were heavily pre-treated (&gt;3 lines). The median number of cycles completed was 3 (range 1-15) and 59% (19/32) patients completed ≥ 3cycles at the cut-off date (Table 1).
With the median follow-up of 6 months (range 0.7-19.5), the median progression free survival (PFS) was 3.3 months and the 6-mon PFS rate was 27.5% (Fig1a). Median overall survival (OS) has not reached yet, 6-mon survival rate was 82%, and the estimated 12-month survival rate was 65% (Fig 1b). Study end points were death (8 cases, 25%) and disease progression (24 cases, 75%). Patients who received ≥3 cycles of treatment had a superior median PFS (3.8 vs 1.4 months, P=0.01) than &lt; 3 cycles. Of the 28 patients whose follow-up time more than 3 months, ORR was 25% and CBR was 46.4%, respectively. Better CBR (56.3% vs. 33.3%) and ORR (31.3% vs. 16.7%) were observed in patients who received less than 3 prior lines of therapy, although with no significant statistical difference. Stratified analysis of PFS showed no significant differences in sex, age, clinical classification, cytogenetic risk, prognosis score (DS and ISS staging system), and the status of ASCT. Stratified analysis of OS showed similar results to those associated with PFS.
Grade 3/4 adverse events were mainly hematological toxicity (neutropenia 28%, anemia 34%, thrombocytopenia 15.6%), which could be tolerated. Fatigue was reported in 68.8% (22/32) of the patients. The incidence of all-cause infection was 37.5% (12/32). There were no treatment related deaths observed.
Conclusions
To our knowledge, this is the first report of chidamide-based oral quadruplet regimen for patients with RRMM. The preliminary results suggested excellent efficacy and relatively high safety, and different groups of patients could benefit from treatment with this regimen. A longer treatment period may strengthen this effect. The most common adverse events were hematological toxicity which could be controlled. As we known, choices of treatment are also influenced by physical and emotional impact of hospitalization or frequent hospital visits, which reflects the patient's ability to continue their treatment and quality of life. Hospitalization and intravenous fluids are not involved in this oral quadruplet treatment, which bring far more convenience and could be a cost-effective alternative for patients with RRMM. Updated results will be presented at the following trial.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.