Professor Ma Jun: Seliniso has emerged, and the treatment of multiple myeloma is effective!

Although survival rates in patients with multiple myeloma (MM) have improved unprecedentedly in recent years thanks to the advent of drugs such as proteasome inhibitors (PIs), immunomodulators (IMiDs), and monoclonal antibodies, MM remains incurable and with each recurrence, patients develop stronger resistance, so multiline relapse-refractory MM therapy remains challenging and requires alternative therapies to overcome drug

Currently, novel targeted therapies have shown encouraging efficacy

Ma Jun, Professor

• Chief Physician, Professor, Doctoral Supervisor

• Director of Harbin Institute of Hematology and Oncology

• Chairman of the Supervisory Board of the Chinese Society of Clinical Oncology (CSCO).

  
  

• Vice Chairman of the Asian Society of Clinical Oncology

• Chairman of the Leukemia Expert Committee of the Chinese Society of Clinical Oncology

• National Health Commission Capacity Building and Continuing Education Center Lymphoma

• Leader of the expert group for specialized construction projects

• Honorary Consultant of the Nursing Group of the Lymphoma Expert Committee of the Chinese Society of Clinical Oncology

• In 1979, he went to the Faculty of Medicine of the University of Tokyo in Japan to study, and has been committed to the diagnosis and treatment of benign and malignant diseases of the blood system, especially for the treatment of leukemia and lymphoma

  
  

In terms of immunotherapy, monoclonal antibodies are the first immunotherapy approved for MM, including monoclonal antibodies that target CD38 (dara, isatuximab) and SLAMF7 (elotuzumab

In terms of new small molecule drugs, the nuclear output of tumor suppressor protein is an important mechanism for tumor cells to evade apoptosis, and nuclear output protein 1 (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 cancer suppressor protein is a promising anti-tumor therapy

Figure 1.

MMA: MM has a variety of therapies, but unfortunately, MM is still an incurable disease
.

Can you please combine the current situation in China and talk about what remaining problems in the treatment of MM?

China is gradually entering an aging society, by 2030 China's > 60-year-old population will account for 25%, similar to Japan, Europe and the United States and other countries, therefore, multi-line recurrence is difficult to treat is the primary problem
for elderly MM patients.

The treatment of refractory patients with commonly used drugs such as IMiDs, PIs, and monoclonal antibodies remains the Achilles heel
of MM therapy.

Patients with MM who are triple refractory or even multi-drug refractory remain clinically challenging
.

Studies have shown that the median total survival (OS) period is only 5.
6 months in patients who are resistant to ANTI-CD38 monoclonal antibodies, 2 types of IMiDs, and 2 types of PIs resistance (i.
e.
, "five-drug refractory") ¹
.

Survival rates in MM patients have improved significantly due to the introduction of various new drugs such as IMiDs, PIs, and monoclonal antibodies, but most patients tend to eventually relapse with more aggressive diseases due to further genetic ^changes2
.

Therefore, how to solve the problem of aggressive recurrence of MM is also one
of the difficulties of current MM treatment.

For patients with high-risk MM in stage III R-ISS, the clinical outcomes are currently relatively modest, with a 5-year progression-free survival (PFS) rate of only 24% and a 5-year OS rate of only 40%³
.

In patients with MM with extramedullary disease (EMD), one study showed that the OS was significantly worse in patients with EMD than those without EMD (38 months vs.
109 months; P<0.
001) ⁴
.

In addition, the current mechanism of EMD occurrence is not fully clear, and there is no consensus or guideline
for the treatment of EMD in the world.

In summary, multiple drug resistance, aggressive recurrence, R-ISS stage III, with EMD and other prognostic factors, so that the already incurable MM patients are in danger of egg accumulation, and the emergence of new treatments is urgently needed to bring longer relief and survival
to patients.

As the primary problem of MM treatment, what are the recent cutting-edge developments in R/R MM that deserve attention?

Recently, the results of a single-arm, multicenter, Phase II registered clinical study (MARCH study ⁵) in China were published
in the journal BMC Med.

Based on the global Phase II STORM study, Celinenisol combined with low-dose dexamethasone (Xd) showed significant clinical benefits
in patients with R/R MM who were refractory to PIs, IMiDs, and anti-CD38 monoclonal antibodies.

The MARCH study further validated the results
of the Xd protocol in patients with R/R MM in China.

A total of 82 patients with R/R MM were included in the MARCH study, of which 55 (67.
1%) had high-risk cytogenetic abnormalities and 18 (22.
0%) patients had renal dysfunction
.

The median number of patients with previous treatment lines was 5, all patients were refractory to PIs (bortezomib) and IMiDs (lenalidomide), of which 20 cases (24.
4%) belonged to the triple refractory population of PIs (bortezomib), IMiDs (lenalidomide) and anti-CD38 monoclonal antibodies (darrituliumab), and 12.
2% of patients had received CAR-T treatment
.

The primary endpoint of the study was objective response rate (ORR
).

The results of the study (as shown in Table 1) show that the lower limit of 95% CI of orR (19.
7%) is greater than the pre-defined critical point of 15%, and the study endpoint has been reached
.

In addition, patients had a median time of 1 month to achieve partial response (PR) or deeper response, and a median duration of response (DOR) of 4.
7 months (95% CI 2.
02, NE
).

As the duration of treatment increases, patients may experience deeper remission
.

This result confirms that the Xd regimen has considerable efficacy
in multi-line therapy in China for high-risk MM patients.

Table 1.
Summary of optimal overall ^mitigation5

In triple refractory patients, the ORR was 25.
0%.


The mITT population had median PFS and OS at 3.
7 months and 13.
2 months
, respectively.

Efficacy was consistent across subgroups (see Figure 2
).

The most common grade 3/4 adverse events (AEs) included anemia (57.
3%), thrombocytopenia (51.
2%), lymphopenia (42.
7%), etc
.

No significant accumulation of the drug was shown after multiple administrations
.

No racial differences in pharmacokinetics (PK) were found between Chinese and Western populations
.

Figure 2.
Subgroup analysis
of ORR.

The dotted line indicates that the study studies orr ≤ 15% null ^hypothesis5

In short, the ORR results of the MARCH study are encouraging, confirming that the Xd regimen can provide significant clinical benefits
for patients with R/R MM in China, including those with triple refractory disorders.

Moreover, through supportive therapy and drug dose adjustment, safety is controllable and no unexpected AEs
occur.

In addition to the clinical benefits of the Seliniso combination regimen in patients with R/R MM, the combined celinesso regimen has also demonstrated encouraging efficacy
in patients with MM with EMD.

The benefits of MM patients with EMD from the era of new drugs are limited
.

In the STORM study, 27 patients
with EMD who received the Xd regimen were analyzed.

Of the 16 assessable patients, 1 achieved a very good partial response (VGPR), 4 achieved a partial response (PR), 2 patients achieved a minor response (MR), and 4 patients achieved ^{disease stabilization4} (SD
).

As seen in the two studies above, the combined Celineso regimen may offer new therapeutic hopes
for patients with RElapse refractory treatment, multidrug resistance, advanced stages, and/or MM with risk factors.

Imaitong: What are your prospects for the current application of new immune-targeted therapies in MM, and what benefits do you think Celineiso will bring to Chinese myeloma patients?

At present, the National Comprehensive Cancer Network (NCCN), the European Haematology Association and the European Society of Oncology (EHA-ESMO), the Chinese Society of Clinical Oncology (CSCO), and the Chinese Guidelines for the Diagnosis and Treatment of Multiple Myeloma and other authoritative guidelines at home and abroad have included the Celineiso protocol in the guidelines of
R/R MM.

Moreover, the Xd regimen has been approved by the FDA and NMPA for the treatment
of patients with R/R MM.

With the listing of Selinisso in China, the accessibility of medications has greatly improved, which is expected to benefit more MM patients
.

A variety of new joint schemes of Selinisso, such as combined with other small molecule targeted drugs, monoclonal antibodies, ADCs, etc.
, have great application prospects, and it is expected that more Seliniso combination schemes can be applied to Chinese patient data in the future, forming a "Chinese experience" and bringing more treatment options to the majority of Chinese MM patients and clinicians
.

In the era of new drugs, various new treatment methods such as monoclonal antibodies, small molecule targeted drugs and immunotherapy have come one after another, which has greatly enriched the treatment options of MM patients and significantly improved
the survival of MM patients.

However, there is still no standard treatment method, which can reverse the dilemma caused by a variety of adverse prognostic factors of MM, and the problems such as multi-line recurrence, multiple refractory treatment, and accompanying EMD need to be solved
urgently.

As the world's first oral selective nuclear-output protein inhibitor with a new mechanism, Selinisso has shown excellent application prospects in Chinese R/R MM and MM patients with EMD, and it is expected that more research results will be published in the future, contributing to the clinical benefits of the majority of Chinese MM patients!

Note: Civio ^® is a Selinisso trade name
.

In December 2021, the State Drug Administration of China (NMPA) approved a new drug listing application for Celineso of Deqi Pharma, which, in combination with dexamethasone, treated with at least one previously treated proteasome inhibitor, one immunomodulator, and one anti-CD38 monoclonal refractory relapsed or refractory multiple myeloma (R/R MM).

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References:

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Sgherza N, Curci P, Rizzi R, Musto P.
Novel Approaches Outside the Setting of Immunotherapy for the Treatment of Multiple Myeloma: The Case of Melflufen, Venetoclax, and Selinexor.
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5.
Qiu L, Xia Z, Fu C, et al.
Selinexor plus low-dose dexamethasone in Chinese patients with relapsed/refractory multiple myeloma previously treated with an immunomodulatory agent and a proteasome inhibitor （MARCH）: a phase II, single-arm study.
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