Professor Li Fei: Seliniso rises to the challenge and breaks the dilemma of multiple myeloma recurrence and incurability!

Multiple myeloma (MM) is the second most common hematological tumor, accounting for about 10% of hematologic malignancies, second only to non-Hodgkin lymphoma, and more common in middle-aged and elderly people
.
At present, MM is still incurable, and with the increase in the number of MM recurrences or the number of treatment lines, the patient's remission time will become shorter and shorter, the disease progresses faster and faster, and treatment becomes more and more difficult
.
Therefore, the choice of treatment for the first recurrence of MM is very important
.

With the continuous advent of new drugs and the innovation of treatment methods, MM treatment has been gradually optimized and improved
.
Celiniso (trade name: Silvio ^®) is the world's first orally selective nuclear output protein inhibitor with a novel mechanism, approved by the National Medical Products Administration (NMPA) of China in 2021 in combination with dexamethasone for previously treated relapsed/refractory MM (R/R MM) refractory to at least one proteasome inhibitor,
an immunomodulator, and an anti-CD38 monoclonal antibody.
On this occasion, Yimaitong specially invited Professor Li Fei of the First Affiliated Hospital of Nanchang University to share the treatment experience of R/R MM based on the unmet needs of myeloma treatment, combined with clinical and scientific research experience, so as to feed readers!

Professor Li Fei

• Chief physician, professor and doctoral supervisor of the Hematology Center of the First Affiliated Hospital of Nanchang University

• Director of Jiangxi Clinical Research Center for Hematology; Director of the Biological Cell Therapy Research Center of the First Affiliated Hospital of Nanchang University

• Director of the Institute of Lymphoma Diseases, Nanchang University

• Jiangxi Province "Voyage Project" talents

• Academic and technical leader of major disciplines in Jiangxi Province - leading talents

• Training object of young scientists in Jiangxi Province

• Review expert of the National Natural Science Foundation of China

• Chairman-elect of Hematology Branch of Jiangxi Medical Association

• Corresponding Editorial Board Member, Chinese Journal of Hematology

• Member of the Lymphatic Disease Group of the Hematology Branch of the Chinese Medical Association

• Member of China CSCO Anti-Lymphoma Alliance

• Member of the Hematological Oncology Committee of the Chinese Anti-Cancer Association

• Member of the China Slow Leaching Expert Group

• Member of the expert group of the Chinese Hemophagocytic Syndrome Alliance

The incurability of MM and the refractory nature of relapsed patients make MM patients have huge unmet clinical needs
.
First of all, could you please talk about the intrinsic causes of MM's incurability and refractory?

Minimal residual lesions (MRDs) in patients are the underlying cause of MM ^recurrence1, and even if MM patients achieve strictly defined complete remission (sCR), a certain number of tumor cells
may still be present.

With the continuous advent of new drugs and the innovation of treatment methods, MM treatment has been gradually optimized and improved
.
What therapies are worth paying attention to in the therapeutic area of R/R MM?

Once MM patients have progressed to the relapse-refractory stage, there are fewer treatment options, the prognosis is poor, and the progression-free survival (PFS) and overall survival (OS) of patients with R/R MM who do not respond to lenalidomide and bortezomib are shortened, with a median time of only 5 and 9 months, ^{respectively1.}

a new generation of proteasome inhibitors such as carfilzomib and isazomib; Immunomodulators such as pomalidomide and monoclonal antibodies such as daratumumab and Elotuzumab provide new options for the treatment of R/R MM, which prolongs
the survival of patients.
However, these methods ultimately do not avoid recurrence caused by myeloma stem cells or MRD, and there are still many challenges
in the treatment of R/R MM in the future.

MM is closely related to genomic abnormalities, immune evasion and other factors, and research in these directions will further guide the development of precision ^therapy1
.
Notable therapies are as follows:

The first is therapy
that targets abnormal genes and signaling pathways in MM.
(1) BCL-2 pathway: one of the important targets of MM, BCL-2 inhibitor veneclax can induce myeloma cell death, accompanied by t(11; 14) of MM patients are more likely to benefit
from it.
(2) RAS/RAF/MEK/ERK pathway: Early studies of the MEK1 inhibitor Cobimetinib monotherapy or combination
venecneclaxle are being carried out.
(3) Nuclear output protein 1 (XPO1): The nuclear output of tumor suppressor protein is an important mechanism for tumor cells to evade apoptosis, XPO1 is a nuclear output protein responsible for transporting more than 200 proteins such as tumor suppressor protein (TSP), so targeting XPO1 to inhibit the nuclear output of tumor suppressor protein is a promising anti-tumor therapy
。 Celiniso, an orally selective XPO1 inhibitor with both synergistic anti-myeloma activity in combination with bortezomib or dexamethasone, was approved by the NMPA in 2021 as the world's first oral nuclear output protein inhibitor for the treatment of previously treated relapsed refractory myeloma with at least one proteasome inhibitor, one immunomodulator, and one anti-CD38 monoclonal antibody
.

The second alternative therapy is immunotherapy
for MM.
Enhancing the anti-tumor immune response mediated by T cells is the mainstream method of MM immunotherapy, such as antibody targeted therapy, chimeric antigen receptor T (CAR-T) cells, etc.
to stimulate immune activity through regulation or activation mechanisms, thereby improving the anti-myeloma effect
to a certain extent.
At present, the commonly used target antigens of CAR-T are CD19, CD38, CD138, and BCMA, among which BCMA CAR-T therapy is the most widely used and has the most outstanding ^efficacy2
.

Yimaitong: Could you please talk about the importance of treatment options for the first recurrence based on your clinical experience?

Almost all patients with MM eventually relapse or develop drug resistance, and treatment of patients with late-line recurrence often faces greater challenges (Figure 1).

Because with the increase of the number of MM recurrences or the number of treatment lines, the drug treatment effect of MM will gradually weaken with multiple recurrences of the disease, the remission rate will gradually decrease, the disease progresses faster, the duration of remission is continuously shortened, the remission time after treatment will be shorter and shorter, the survival period will continue to decrease, and the treatment will become more and more ^difficult3
.
A real-world study in the United States showed that median PFS gradually decreased as the number of relapses increased, with median PFS of only 5.
4 months in patients receiving fifth-line ^therapy4
.
Therefore, the choice of treatment when MM first recurs is very important
.

Fig.
1 MM course characterized by malignant transformation

Yimaitong: At present, R/R MM treatment options are abundant, and the increase in access to new drugs has gradually improved the prognosis of patients with first-relapse MM, can you please talk about how to develop the best treatment strategy for patients with first-relapsed MM?

For the first recurrence of MM patients, individualized treatment should be carried out based on the patient's general condition, recurrence type, previous medication, etc.
; In addition, the treatment goals of patients with first-time recurrent MM should also be considered, and domestic and foreign guidelines emphasize that the treatment goals are to obtain deep remission and prolong progression-free survival
.

Patients with first-time relapse treated with traditional proteasome inhibitor or immunomodulator regimens have limited depth of remission despite improved response rates
.
The addition of monoclonal antibodies (e.
g.
, daratumumab, Elotuzumab) and nuclear output protein inhibitors makes up for the lack
of therapeutic mechanisms.
The Guidelines for the Diagnosis and Treatment of Multiple Myeloma in China (2022 Revision⁾⁵ points out that 3-4 drugs containing proteasome inhibitors, immunomodulators, daratumumab and nuclear output protein inhibitor celinisol can be selected as much as possible, and salvage autologous hematopoietic stem cell transplantation (ASCT) can be performed if possible
。

BOSTON ^STUDY7 SHOWED THAT THE MEDIAN PFS IN THE CELINISO PLUS BORTEZOMIB AND DEXAMETHASONE (VD) GROUPS WAS SIGNIFICANTLY LONGER THAN IN THE BORTEZOMIB PLUS DEXAMETHASONE (VD) GROUP (PFS: 13.
93 MONTHS vs.
9.
46 MONTHS; P = 0.
0075), with a lower risk of disease progression or death in group XVd in patients older than 65 years (PFS: 21 versus 9.
5 months; P=0.
002), and ORR was higher in the XVd group as a whole and subgroups (overall population ORR: 76.
4% vs.
62.
3%; P=0.
0012), deep response rate was higher in the XVd group (≥ VGPR: 44.
6% vs.
32.
4%; P=0.
0082）
。 Currently, other joint protocols for Seliniso (STORM ^{Study 8}: Xd; STOMP ^{Study 9}: XPd, XKd, XDd) has carried out a number of clinical trials at home and abroad, and has shown good anti-tumor activity
in MM patients.

*P: Pomalidomide; K: Kafizomib; D: daratumab

Yimaitong: Based on your rich clinical and scientific experience, what difficulties and challenges do you think the current new immunotargeted therapy faces in the clinical practice process of R/R MM that need to be overcome in the future?

In recent years, thanks to the breakthrough of new technologies and new therapies, patients with first-time relapse MM have more treatment options, and there are still some problems that need to be solved in the clinical practice process of new drugs applied to R/R MM, such as: the accessibility of innovative drugs; New drugs are constantly emerging, how to rationally arrange troops to maximize the benefits of patients; Future R/R MM treatment depends on the continuous deepening of molecular biology, genomics, cancer stem cells and clonal evolution by researchers to develop R/R MM patients from incurable diseases to chronic diseases or cured diseases
.

Note: Silvio ^® is the trade name
of Celiniso.
In December 2021, China's National Medical Products Administration (NMPA) approved Antengene's new drug application for celinisol for the treatment of previously treated relapsed or refractory multiple myeloma (R/R MM)
in combination with dexamethasone for the treatment of at least one proteasome inhibitor, one immunomodulator, and one anti-CD38 monoclonal antibody.

In June 2020, the US Food and Drug Administration (FDA) approved celinisol for the treatment of patients with third-line or above diffuse large B-cell lymphoma (DLBCL); In addition, Seliniso has also received multinational approval for the treatment of patients
with relapsed and refractory DLBCL.

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Research progress in immunotargeted therapy for relapsed/refractory multiple myeloma[J].
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Relapsed or Relapsed/Refractory  Multiple Myeloma.
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