Doctors Wujiang, Professor Shen Zhixiang and Professor Ma Jun, wish the world's first oral XPO1 inhibitor Celiniso to be approved for marketing!

Multiple myeloma (MM) is a type of clonal plasma cell tumor with a high degree of heterogeneity
.

Plasma cells in the bone marrow produce large amounts of abnormal monoclonal immunoglobulins, which can cause damage to multiple organs throughout the body
.

In recent years, MM has become the second most common tumor in the blood system.
With the improvement of medical standards, the emergence of new therapeutic drugs, and the continuous advancement of multidisciplinary diagnosis and treatment models, the treatment level of MM in China has continued to develop, but the primary drug resistance and disease recurrence As a result, MM is still incurable, and MM patients lack effective treatment after relapse, and treatment options are limited
.

As the world's first oral selective nuclear export inhibitor (SINE) for a new mechanism of tumor treatment, Sivio® (Celinisol) can promote a variety of MM-related tumor suppressors by inhibiting nuclear export protein 1 (XPO1) Proteins (TSPs) remain in the nucleus and are reactivated to exert anti-tumor effects; in addition, they can also reduce the level of oncoproteins in the cytoplasm (including c-Myc, BCL-xL, etc.
), and activate glucocorticoid receptors (GR) Pathway, restore hormone sensitivity, so as to achieve anti-tumor effect
.

In December 2021, the National Medical Products Administration (NMPA) of China approved the new drug listing application of Deqi Pharmaceutical's Civio® (Celinisol, ATG-010).
Through the combination with dexamethasone, the treatment of previously accepted drugs Relapsed or refractory multiple myeloma (RRMM) refractory to treatment with at least one proteasome inhibitor, an immunomodulator, and an anti-CD38 monoclonal antibody
.

Celiniso's approval not only means that Deqi Pharmaceutical has entered a new stage of commercialization, but also brings long-awaited hope of treatment for patients with hematological tumors
.

Safe and effective: MARCH research advances the approval process of Celiniso.
This approval of Celiniso is based on the MARCH research carried out in China
.

MARCH is an open, single-arm, phase II clinical study, which aims to evaluate the effectiveness and safety of the Celinisol + Dexamethasone (Xd) treatment regimen in the treatment of Chinese RRMM patients
.

The study population was MM patients who had previously received PI and IMiD treatment and were refractory to the two drugs and refractory to the end-line regimen
.

The Xd program takes every four weeks as a course of treatment
.

The primary study endpoint is the overall response rate (ORR) assessed by the Independent Review Committee (IRC)
.

The study enrolled 82 patients with RRMM.
The Xd regimen achieved good results, the ORR was 29.
3%, and the median overall survival (OS) was 13.
2 months; they had received treatment in the past and were treated with at least one IMiD, one PI, and anti-CD38 The ORR of patients refractory to monoclonal antibody still reached 25%, and the median OS was 11.
9 months
.

The results of the MARCH study confirmed that the Xd program has good effectiveness and controllable safety in Chinese RRMM patients who are refractory to IMiD and PI two drugs and three drugs (+CD38 monoclonal antibody)
.

A number of studies have confirmed that the treatment regimen containing Celiniso has significant benefits.
In addition to the MARCH study, multiple studies have confirmed that the regimen containing Celiniso has a good effect in RRMM patients
.

1STORM study STORM is a phase 2b open, single-arm clinical trial, divided into two parts: The first part evaluates the Xd regimen for the treatment of bortezomib, carfilzomib, lenalidomide, pomalidomide, Patients treated with raltuomab (Dara) who are refractory to 4 drugs or refractory to 5 drugs
.

Among the 79 patients included, 48 were refractory to four drugs and 31 were refractory to five drugs.
In the overall population, the ORR was 21%, and the ratio between the two groups was similar (21%; 20%)
.

In the high-risk cytogenetics population, the ORR is 35% [1]
.

The second part of the study evaluated the Xd regimen in the treatment of MM patients who have received bortezomib, carfilzomib, lenalidomide, pomalidomide, Dara and at least one IMiD, one PI and Dara triple refractory MM patients.
A total of 122 patients were enrolled in the study, with a median age of 65 years, 53% of patients were at high risk of cytogenetics, and 68% of MM patients were refractory to five drugs
.

In the overall population, ORR reached 26%, including 2 cases of strict complete remission (sCR), 6 cases of very good partial remission (VGPR), and 24 cases of partial remission (PR).
The minimum remission was PR and the minimum remission was In the minimal response (MR) subgroup, the median OS was 15.
6 months
.

2BOSTON Study BOSTON is an international, open, randomized, phase III clinical study
.

According to the International Myeloma Working Group (IMWG) criteria, patients aged ≥18 years old, histologically confirmed as MM, and previously received 1-3 systemic anti-MM regimens were included
.

A total of 402 patients were enrolled in the study and randomized.
Among them, 195 patients were in the XVd (celinisol + bortezomib + dexamethasone) group and 207 were in the Vd group.
47.
8% of the patients had high-risk cytogenetic abnormalities
.

The median progression-free survival (PFS) of the XVd group was 13.
93 months, and that of the Vd group was 9.
46 months
.

Among patients with high-risk cell abnormalities, the median PFS and ORR of the XVd group were better than those of the Vd group ([median PFS: 12.
9 months vs 8.
6 months]; [ORR: 78.
6% vs 57.
7%]); in standard risk Among cytogenetics patients, the median PFS and ORR of the XVd group were better than those of the Vd group ([Median PFS: 16.
62 months vs 9.
46 months]; [ORR: 75.
2% vs 64.
7%])
.

3STOMP Study The STOMP trial is a multi-center, open-ended, randomized dose escalation (phase 1) and dose extension (phase 2) clinical study, which aims to evaluate the maximum tolerated dose (MTD) of Celinisol, and a phase 2 recommendation Dosage (RP2D) and effectiveness and safety
.

Phase 1 dose escalation determines the weekly dose (QW) or twice-weekly dose (BIW) MTD of celinisol combined with standard therapy (SOC) in the treatment of MM patients, and the second phase dose expansion determines the combined use of celinisol ORR of SOC treatment of MM patients
.

In the XRd (celinisol + lenalidomide + dexamethasone) regimen treatment group, the overall ORR was 60%, and the RP2D of Celinisole was 60 mg (QW)
.

In the XPd (celinisol + pomalidomide + dexamethasone) regimen treatment group, the overall ORR was 65%, and the RP2D of Celinisole was 60 mg (QW)
.

In the XKd (Celinisole + Carfilzomib + Dexamethasone) regimen treatment group, RRMM patients who have previously received median 4-line therapy still have a high remission rate, with an overall ORR of 78% and a median PFS It was 23.
7 months; the ORR of 18 patients who had received Dara in the past was still 67%, the median PFS was 23.
7 months, and the RP2D of Celiniso was 80 mg (QW)
.

In the XDd (celinisol+daratumumab+dexamethasone) regimen treatment group, deep and long-lasting curative effects were obtained in RRMM patients who had previously received multi-line therapy.
The median PFS of all patients was 12.
5 In August, the overall ORR of all patients in the XDd program reached 69%, and Celiniso's RP2D was 100 mg (QW)
.

In the XVd regimen treatment group, the overall ORR was 80%, and Celiniso's RP2D was 100 mg (QW)
.

Authoritative recognition: domestic and foreign guidelines unanimously recommend based on Celiniso's unique and effective mechanism of action and excellent results in clinical trials.
The treatment plan based on it has been included in the 2021 NCCN guidelines, ESMO guidelines, and China CSCO guidelines in many countries.
The definitive guide
.

NCCN MM Diagnosis and Treatment Guidelines (Version 2021 V4) [2] recommends Celinisol + Bortezomib + Dexamethasone (XVd) treatment plan for the treatment of R/R MM patients (Class I recommendation)
.

EHA-ESMO MM clinical practice guidelines (2021 edition) [3] recommend the XVd combination regimen for the first-line treatment of relapsed patients with bortezomib, lenalidomide and dexamethasone (VRd) regimen (I, A); also used In the first-line treatment of patients who relapsed with daratumomab + lenalidomide + dexamethasone (Dara-Rd) regimen (I, A)
.

The 2021 CSCO guidelines [4] I level expert recommendation (Class 1 evidence) Celiniso+ Dexamethasone (Xd) treatment regimen for the treatment of relapsed MM patients
.

Summary XPO-1, as a new therapeutic target for MM, has broad application prospects
.

The successful development and marketing of XPO-1 selective inhibitor Celiniso provide a new option for the treatment of MM
.

Relevant studies have shown that Celiniso not only has a good therapeutic effect on MM, but also has a good therapeutic effect on other tumors such as non-Hodgkin's lymphoma
.

Based on the excellent results in clinical trials, Celiniso's multiple treatments for hematological tumors have received heavy recommendations and support from guidelines/evidence-based studies
.

Professor Shen Zhixiang commented that the human nuclear export protein XPO-1 is a key nuclear and cytoplasmic transporter in cells, responsible for transporting proteins (including tumor suppressor proteins) out of the nucleus
.

The nuclear export of tumor suppressor protein is an important mechanism for tumor cells to escape apoptosis
.

Therefore, XPO-1 can be used as a therapeutic target for MM.
Celinisol is the world's first selective nuclear export (SINE) inhibitor for the treatment of MM, which can specifically antagonize XPO-1
.

A number of studies have shown that in RRMM patients, various programs including Celinisol, such as Xd, XVd, XRd, XPd, XKd, and XDd, have achieved good curative effects
.

Celiniso's new mechanism of action brings new hope for the treatment of MM patients in China
.

Here, I wish the innovative treatment plan can benefit patients with hematological tumors around the world
.

Professor Ma Jun commented that MM is the second most common malignant tumor of the hematological system after lymphoma.
The recurrence rate is extremely high and the prognosis is poor.
For patients with relapsed and refractory MM after multi-line treatment, the treatment effect and survival prognosis are facing challenges.
MM is transforming into a long-term, chronic disease management model, which requires brand-new treatment plans and drugs
.

As more and more new drugs are used in the clinic, more treatment options are brought to R/R MM patients after multi-line treatment
.

The drug Celiniso with a new mechanism of action can inject new vitality into the entire disease treatment model, and bring new hope to patients who have been refractory to multiple drug treatments.
Through more individualized medication guidance, they will surely be able to let them Live longer, live better! I believe that through the continuous in-depth research of Celiniso, there will be more and better clinical evidence to support its entry into the global market
.

Professor Zhixiang Shen graduated from Shanghai Second Military Medical University.
He is currently the tenured professor of internal medicine, chief physician, and doctoral supervisor of Ruijin Hospital affiliated to Shanghai Jiaotong University.
The deputy editor-in-chief of "Chinese Medical Journal (English Edition)" and other journals have successively won the second prize of the National Natural Science Award, the third prize of the Science and Technology Progress Award, the second prize of the Chinese Medical Science and Technology Award, and the Shanghai Medical Achievement Award Second Prize, Medical Achievement Third Prize, In 1999, he won the third national individual citation frequency of a single international paper, the first prize of China Medical Science and Technology Award in 2004, the first prize of Shanghai Medical Science Award in 2004, and the National Natural Science Award in 2004 Second Prize of Science, First Prize of 2006 Shanghai Science and Technology Award Professor Ma Jun, Chief Physician, Professor, and Doctoral Supervisor, Director of Harbin Institute of Hematology and Oncology, Chairman of the Supervisory Board of the Chinese Society of Clinical Oncology (CSCO) Deputy Director of the Asian Society of Clinical Oncology Committee Member CSCO Anti-Leukemia Alliance Chairman, Chinese Medical Association Hematology Branch Vice Chairman, Chinese Medical Doctor Association Hematologist Branch Vice Chairman, Chinese Medical Doctor Association Oncology Branch Vice Chairman CSCO Anti-Lymphoma Alliance Former Chairman Reference: [1] Vogl DT, Dingli D, Cornell RF, et al.
Selective inhibition of nuclear export with oral selinexor for treatment of relapsed or refractory multiple myeloma.
J Clin Oncol.
2018;36(9):859–866.
[2] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Multiple Myeloma.
Version 4.
2021.
[3] Dimopoulos MA, Moreau P, Terpos E, et al.
Multiple Myeloma: EHA-ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up[J].
HemaSphere, 2021 ,5(2):e528.
[4] Zhu J, Ma J, Union for China Lymphoma Investigators of Chinese Society of Clinical Oncology.
Chinese Society of Clinical Oncology(CSCO) diagnosis and treatment guidelines for malignant lymphoma 2021(English version)[J ].
Cancer Research in China: English Edition, 2021, 33(3): 289-301.
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