The 66th American Society of Hematology (ASH) will be held in San Diego, USA from December 7 to 10, 2024. As one of the largest and most comprehensive international academic events in the field of hematology, it announces and publishes the latest hematology advances from all over the world every year.

Multiple myeloma (MM), as the second most common hematological malignancy, has attracted the attention and layout of various pharmaceutical companies. At this year's ASH conference, several Chinese bispecific antibodies/trispecific antibodies will be unveiled for MM indications.
MM: The birthplace of the billion-dollar miracle drug

Multiple myeloma is the second most common hematological malignancy after non-Hodgkin's lymphoma. It is a malignant clonal plasma cell proliferative disease that causes extensive bone destruction, accompanied by osteolytic lesions, osteopenia and pathological fractures. It is called a blood disease that "eats" bones.

According to the Chinese Multiple Myeloma Diagnosis and Treatment Guidelines (revised in 2022), there are about 1.6 multiple myeloma patients per 100,000 people in China, and the incidence rate is increasing year by year.

In the past 20 years, great progress has been made in the treatment of MM, and many "blockbuster" drugs have been born, including Bristol-Myers Squibb's lenalidomide, which will have sales of nearly $10 billion (US$9.978 billion) in 2022, and Johnson & Johnson's DARZALEX (daratumumab), which has sales of $5.6 billion in the first half of this year, and annual sales will undoubtedly exceed $10 billion.

Although there are many innovative drugs in the MM field, the existing therapies cannot change the outcome of MM relapse, and patients eventually develop relapsed or refractory multiple myeloma (RRMM), which has also attracted global pharmaceutical companies to continuously develop new generation therapies.

For example, after the pharmaceutical giant Johnson & Johnson had the billion-dollar blockbuster DARZALEX, it developed a new generation of products such as BCMA CAR-T products Carvykti, BCMA/CD3 bispecific antibody Tecvayli (teclistamab), and GPRC5D/CD3 bispecific antibody Talvey (Talquetamab) to cope with multiple rounds of relapse in MM patients.

In recent years, with the popularity of TCE bispecific antibody technology in domestic pharmaceutical companies, Johnson & Johnson's challengers from China have come one after another, and many Chinese BCMA/CD3 bispecific antibodies, GPRC5D/CD3 bispecific antibodies and CD3/GPRC5D/BCMA will be unveiled at this year's ASH conference.

TCE bispecific antibody: a "better" treatment option than CAR-T.

Carvykti (Cedaciolensai), a BCMA CAR-T product of Johnson & Johnson/Legend Biotech, changed the treatment pattern of relapsed and refractory MM with the amazing data of ORR 97% and sCR 67%.

Soon after, Johnson & Johnson launched the BCMA/CD3 bispecific antibody Teclistamab and made a bold statement: the peak sales of teclistamab will reach 5 billion US dollars. In the face of the amazing efficacy of CAR-T, what are the advantages of bispecific antibodies?

It is reported that teclistamab is a TCE (T cell engager) bispecific antibody, which is essentially an immunotherapy that activates T cells. One end (or 2 ends) of TCE connects to TAA (tumor-associated antigen) to locate tumor cells, and the other end connects to the CD3 epitope of T cells to activate T cells and exert the tumor-killing effect of T cells.

Some people call TCE bispecific antibody a "low-profile version" of CAR-T. Compared with CAR-T, TCE bispecific antibodies may not have an advantage in efficacy, but they are safer and more convenient, accessible and cost-effective than CAR-T as a ready-made drug. The

huge potential has attracted many pharmaceutical companies to deploy TCE bispecific antibodies, among which domestic biotech occupies an important position.

1. CM336

Conoya will announce the results of its Phase 1/2 study of CD3/BCMA bispecific antibody CM336 in the treatment of RRMM patients at the ASH conference.

The results showed that at a median follow-up time of 8.0 months, the ORR was 60.9% (14/23; 95%CI, 38.5%-80.3%). Among them, the ORR was 100% in the 80 mg and 160 mg dose groups (n=8). Among the 10 subjects (43.5%) who confirmed strict complete remission (sCR), 9 could be evaluated for minimal residual disease (MRD), and the MRD negative rate (threshold of 10−5 cells) was 88.9% (8/9). The median remission period and median progression-free survival were not reached. No subjects in the remission period experienced disease progression.

In terms of safety, CM336 treatment was well tolerated, all cytokine release syndrome events were completely resolved, and no immune effector cell-associated neurotoxicity syndrome (ICANS) events were reported.

It is worth mentioning that on November 17, Conoya entered into an exclusive license agreement with Platina Medicines Ltd (PML), granting PML the exclusive right to develop, produce and commercialize CM336 globally outside of China. Conoya received an initial payment and recent payments of $16 million, as well as additional payments and sales shares of up to $610 million. At the same time, Conoya also acquired a minority stake in Ouro Medicines, the parent company of PML.

2.Emb-06

Bankma Bio will report preliminary results of its multicenter, first-in-human Phase 1 study of CD3/BCMA dual antibody EMB-06 in the treatment of RRMM patients.

Among the 38 evaluable patients, the overall response rate (ORR) was 39% (15/38). Among the 12 patients treated with a dose of ≥120 mg, the ORR was 92%, including 1 strict complete remission (sCR), 3 complete remissions (CR), 5 VGPRs, and 2 PRs.

It is worth mentioning that on September 4, Epimed Bio granted Vignette Bio the exclusive right to develop and commercialize EMB-06 outside of Greater China. Epimed Bio will receive a total of $60 million in cash and Vignette equity as an initial payment, and will be entitled to receive up to $575 million in development, marketing, and commercialization milestone payments, as well as sales.

3. TQB2934

Zhengda Tianqing will announce the preliminary results of its CD3/BCMA bispecific antibody TQB2934 in RRMM patients.

Among the 19 evaluable patients, the median treatment duration was 1.3 months, 6 patients achieved partial remission or better (total remission rate was 31.6%), of which 2 (10.5%) achieved complete remission (CR).

In terms of safety, 90% of patients reported treatment-related adverse events (TEAEs), of which 74% of patients had TEAEs of grade 3-4.

4.QLS32015

Qilu Pharmaceutical will announce the results of its first human trial of CD3/GPRC5D dual antibody QLS32015 in RRMM patients.

Among the 8 patients who could be evaluated for efficacy, the ORR was 75.0% (6/8), and 5 (62.5%) patients were evaluated as partial remission (PR); the median duration of remission, median progression-free survival, and median overall survival were not reached.

In terms of safety, 11 patients (100%) reported treatment-related adverse events (TRAEs), all of which were ≥ grade 3, but no TRAEs led to discontinuation or death. The drug is currently undergoing a dose escalation trial.

5.LBL-034

Weilizhibo's LBL-034 is also a CD3/GPRC5D dual antibody. This ASH conference will announce its preliminary Phase 1/2 clinical data in RRMM patients.

The results showed that after one cycle of treatment in 13 patients, 8 patients (61.5%) had decreased M protein, and 3 patients had negative serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP). The clinical benefit rate (CBR) was 50%. Five of the eight evaluable fifth-line refractory patients responded to LBL-034, with a CBR of 62.5%.

It is worth mentioning that in November this year, LBL-034 was granted orphan drug status by the US FDA for the treatment of MM.

In addition to dual-antibody drugs, at this ASH conference, two Chinese GPRC5D/BCMA/CD3 trispecific antibodies will announce their clinical data for the treatment of multiple myeloma patients, including SIM0500 from Xiansheng Zaiming and MBS314 from Tianguangshi Biotechnology. However, there is currently little patient data available for evaluation, and its advantages cannot be seen.

In recent years, more and more Chinese innovative pharmaceutical companies have chosen to announce their pipeline progress at international academic conferences. According to statistics, at this year's ASH Annual Meeting, more than 70 studies led by Chinese scholars were selected for oral presentations, setting a record high. Behind these reports are China 's active exploration and breakthroughs in innovative drugs. Especially in the newly emerging TCE bispecific antibody/trispecific antibody and other cutting-edge technology fields, more and more Chinese innovative drugs are emerging, and we look forward to their eventual entry into the market and benefiting patients.

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