Prof. Jianqing Mi: JCO published the results of the Phase II CARTIFAN-1 clinical study of Sida Oquirenxel

Multiple myeloma (MM) is a malignant disease with abnormal proliferation of clonal plasma cells, which has a high
incidence in China.
In recent years, with the application of new drugs such as proteasome inhibitors (PI) and immunomodulators (IMiDs), the overall survival of MM patients has improved significantly, but most patients will eventually relapse and progress.

In order to improve the treatment efficiency or survival of patients with relapsed and refractory (RR) MM, a large number of new drugs such as CAR-T therapy are in full swing
.
Recently, Professor Mi Jianqing of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, as the first author, published the research data of cilta-cel in RRMM patients.

The contents are organized below
.

MM is one of the common blood diseases in China, almost every MM patient will experience 1 to multiple recurrences, can you please talk about the current status and challenges of RRMM diagnosis and treatment based on your previous diagnosis and treatment experience?

In recent years, although the median survival of MM has been significantly improved with the emergence of some new drugs, including PI, IMiDs, CD38 monoclonal antibodies, and nuclear protein output inhibitors, it is still not curable
.
Therefore, clinicians should consider whether there are other new drugs that can prolong patient survival, improve patients' quality of life in treatment, and even cure diseases
.

At present, the objective response rate (ORR) of RRMM is only 29% to 36%, and the response time gradually decreases
with the increase of the number of treatment lines.
Although many new drugs appear, the time to remission increases by only 6-9 months, up to 1 year, and even when combined with more drugs, the remission time is limited
.
Therefore, whether the use of new treatment strategies or changes in treatment models can cure the disease is a very important challenge
at present.

Recently, Ruijin Hospital participated in the BCMA CAR-T Cidaquiolensis China registered clinical study CARTIFAN-1 ^[1] of BCMA CAR-T and Janssen Pharmaceutical's BCMA CARTIFAN-1 as the team leader, and its data were first published in the Journal of Clinical Oncology
.
As the leading PI of this research, what are your experiences and experiences in the process of this cooperation?

The key to this article being published in the Journal of Clinical Oncology is the joint efforts
of experts from eight centers: Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, The Second Affiliated Hospital of Xi'an Jiaotong University, Peking University Third Hospital, Shanghai Changzheng Hospital, Fujian Medical University Union Hospital, Jiangsu Provincial People's Hospital, The First Affiliated Hospital of Zhejiang University School of Medicine, and West China Hospital of Sichuan University.
Through this collaboration, we will also lay the foundation for
future clinical trials.
Only through multi-center joint research can the research results be closer to the real world and more recognized
abroad.

At the same time, through multi-center cooperation, articles are published in international journals, so that Chinese scholars can be more influential
in the world.
I hope that in the future, China's academic level can lead in a certain field, so that China's medical level can be better improved
.

Can you interpret the data of the CARTIFAN-1 study published in the Journal of Clinical Oncology, and what are the highlights of this study?

CARTIFAN-1 is a Phase II study to explore the efficacy and safety of BCMA CAR-T CEDARQUIOLENSEL IN patients with RRMM who have received at least three prior therapies with more than three lines, including a total of 48 patients
.
The number of target cells instilled by the study was about 0.
75×1 0 6 ^CAR-positiveT cells/kg (range: 0.
5-1×10⁶CAR-positive T cells/kg), which is 1/10 of some similar products in the United States, indicating that the treatment intensity of cedarquiolensel is relatively high
.

In this study, at 18 months of median follow-up, the ORR reached 89.
6%, 77% of patients achieved CR or above, and 35 patients achieved minimal residual disease (MRD) was negative, and the median duration of response was not achieved
.
The ORR of the study was similar to that of the Phase I Legend-2 study with 88% of the ORR, indicating that the study was highly
reproducible.
In terms of survival, median progression-free survival (PFS) and overall survival (OS) were not achieved, with median PFS and OS rates of 66.
8% and 78.
7%
at 18 months, respectively.
This data is very proud of Chinese scholars, indicating that first, this product is very good, and second, we are also very lucky to make a very good product that can benefit
our Chinese people.

Cedarquiolensic contains a 4-1BB co-stimulatory domain and two targeted BCMA nanobodies
designed to improve affinity.
Different from conventional murine heavy chain antibodies, Cedakiolensel innovatively uses camel-derived nanobodies, using the smallest known antigen recognition structure, while targeting two different BCMAs, which makes the relative "grip" of the product stronger and more
effective.

Yimaitong: The median follow-up time published in the CARTIFAN-1 study has reached 18 months, are there any very typical cases of MM in the patients you have followed for a long time, can you please share it?

There are many typical cases, and I will briefly share the first patient
in the CARTIFAN-1 study.
She is an elderly patient with RRMM with extramedullary infiltration, with a significant mass
at the top of the head.
Most lesions in MM patients are intramedullary, and if the lesions are extramedullary, it indicates a poor prognosis, and the response to conventional treatment methods or chemotherapy is poor
.
If targeted therapy is used, only some patients will be effective
.
This patient had extramedullary invasion and complicated disease, but was treated with cedarquiolensel with significant results, and the mass at the top of the head resolved
after one month.
At present, the patient has survived for more than three years, the quality of life is very good, she usually likes to square dance, has returned and enjoyed her normal life
.

Cedarquiolensis was approved for marketing in the United States in February this year, and you previously participated in the Legend-2 study ^[2], which has a median follow-up time of 48 months
.
Can you talk about the benefits of cedarquiolensel in patients with RRMM based on your two studies?

The Legend-2 study is a Phase I clinical study and the CARTIFAN-1 study is a Phase II clinical study
.
The Legend-2 study was conducted from 2016 to 2018, with the participation of the Second Affiliated Hospital of Xi'an Jiaotong University in Northwest China, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Changzheng Hospital and Jiangsu Provincial People's Hospital, and the study found that cedarquiolensel had significant efficacy and was later approved for phase II studies to further observe the efficacy and toxic side effects of the product under the premise of recognizing the safety of the product
.

In terms of efficacy, Legend-2 has longer follow-up data, with a median follow-up of 47.
8 months, 74 patients with an ORR of 87.
8%, 73% of patients reaching CR and above, so far, there are still more than a dozen patients in the phase I study who have long-term survival, and the patients enrolled in Ruijin Hospital have also survived for more than 5 years, completely returning to normal life
.
The Phase II clinical study is based on the Phase I clinical study, and it is hoped that the long-term follow-up results of Phase II will be as significant
as Phase I.

Cedarquiolensis reaccompanies us to CAR-T, which may be the most effective therapy for RRMM treatment this century, as a new BCMA CAR-T product, it is alive, and CAR-T cells can be long-term beneficial
to patients by being infused back into the patient, expanding in the body and further targeting the killing of tumor cells.
At present, cedarquiolensis has been listed in the United States and will be listed in China in the future, which will benefit more RRMM patients
after marketing.

As a new type of BCMA CAR-T therapy, can you please talk about its advantages and challenges in RRMM treatment compared with other drugs?

The greatness of BCMA CAR-T lies in: First, it shows that CAR-T cells are feasible in the treatment of acute lymphoblastic leukemia and lymphoma, but also feasible in MM treatment and have better efficacy, which is also the result of the joint efforts of international scholars and Chinese scholars; Second, to illustrate the feasibility of BCMA as a target, BCMA targets can not only be used in CAR-T, but also for other immunotherapies
with this target.
In the future, cedarquiolensis will bring great opportunities, and after CAR-T cell immunotherapy, MM cure will become possible, and even become a disease
that can be cured for most patients.
At present, more than a dozen patients have survived more than five years, and if these patients do not relapse in the next five years of follow-up, it means that some patients with MM can be cured
.
Of course, opportunities always come with challenges, and whether BCMA CAR-T therapy can be combined with other drugs to further cure MM is a question
worth considering.

Professor Mi Jianqing

• Professor and doctoral supervisor of Shanghai Jiao Tong University School of Medicine
• Deputy Director of Hematology and Chief Physician of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
• National Committee Member of Hematology Branch of Chinese Medical Association
• Member of the Standing Committee of Hematotranslational Medicine Professional Committee of Chinese Anti-Cancer Association
• Standing Committee Member of Hematology Branch of Chinese Geriatrics Association
• Chairman of the Hematology Medicine Transformation Professional Committee of Shanghai Pharmaceutical Industry Association
• Director of Shanghai Anti-Cancer Association, Vice Chairman of Hematology and Oncology Branch
• Member of Hematology Branch of Shanghai Medical Association

References:

1.
Mi JQ, Zhao W, Jing H, et al.
Phase II, Open-Label Study of Ciltacabtagene Autoleucel, an Anti-B-Cell Maturation Antigen Chimeric Antigen Receptor-T-Cell Therapy, in Chinese Patients With Relapsed/Refractory Multiple Myeloma (CARTIFAN-1) .
J Clin Oncol.
2022; JCO2200690.

2.
Zhao WH, Wang BY, Chen LJ, et al.
Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: a phase 1, single-arm, open-label, multicenter study in China (LEGEND-2).
J Hematol Oncol.
2022; 15(1):86.