High Risk Multiple Myeloma Solution and Chinese Expert Consensus

**High Risk Multiple Myeloma Solution and Chinese Expert Consensus**

Multiple Myeloma

High risk multiple myeloma (HRMM) refers to patients with multiple myeloma whose overall survival is less than 2 to 3 years under current standard treatments.

In 2024, the Chinese Society of Clinical Oncology’s Multiple Myeloma Expert Committee and the Chinese Anti-Cancer Association’s Hematologic Oncology Committee, organized by relevant experts, developed the “Chinese Expert Consensus on the Diagnosis and Treatment of High Risk Multiple Myeloma (2024 Edition),” which was officially published in the *Chinese Journal of Hematology* in May 2024. This consensus defines HRMM, outlines high-risk factors and risk stratification systems, and provides key treatment recommendations for HRMM, aiming to improve the quality of life and prognosis for HRMM patients in China.

**Definition of HRMM**

There is currently no precise definition of HRMM. Referencing the International Myeloma Working Group (IMWG)’s definition, the Chinese Expert Committee considers HRMM patients as those with an overall survival (OS) of less than 3 years after receiving autologous hematopoietic stem cell transplantation (auto-HSCT) or less than 2 years if they have not received auto-HSCT. Patients with OS of less than 2 years after receiving auto-HSCT are classified as ultra-high risk multiple myeloma (UHRMM) patients.

**Prognostic Factors of HRMM**

The biological characteristics of MM tumor cells and treatment response are key determinants in identifying HRMM.

**Static Prognostic Factors of MM**

1. **Genetic High-Risk Factors:**

   In the context of genetic high-risk factors, cytogenetic abnormalities are core indicators in the MM risk stratification system, but there is still some debate over the definition of high-risk cytogenetic abnormalities (HRCAs). The “National Comprehensive Cancer Network (NCCN) Guidelines (2024.v1)” indicate that the presence of multiple HRCAs correlates with a poorer prognosis. Fluorescence in situ hybridization (FISH) is currently the main genetic testing technique for MM, and next-generation sequencing can be performed if conditions allow (TP53 mutations have a significant impact on prognosis, while the effects of KRAS, NRAS, DIS3, BRAF, and FAM46C are less clear). All these genetic tests require enrichment and selection of plasma cells.

2. **Non-Genetic High-Risk Factors:**

   Confirmed non-genetic prognostic factors include International Staging System (ISS) stage III, extramedullary disease excluding bone lesions, circulating plasma cells, high plasma cell proliferation index, elevated lactate dehydrogenase (LDH), frailty, renal insufficiency, and thrombocytopenia.

**Dynamic Prognostic Factors of MM**

1. **Duration of Initial Treatment Response:**

   The duration of response to initial treatment is a crucial dynamic prognostic factor for MM. Patients who received auto-HSCT followed by maintenance therapy and experienced relapse/progression within less than 2 years are classified as HRMM; for those who did not receive auto-HSCT, relapse within less than 18 months after starting treatment also indicates HRMM. Functional high risk refers to MM patients without known genetic high-risk factors at diagnosis who experience early progression within 18 months after the start of treatment.

2. **Depth of Initial Treatment Response:**

   The depth of response to initial treatment is another important dynamic prognostic factor for MM. Patients who achieve negativity for minimal residual disease (MRD) in both bone marrow and imaging studies have the best survival outcomes. Achieving MRD negativity can partially overcome the adverse prognosis associated with high-risk cytogenetics. Continuous dynamic MRD monitoring has greater clinical value than a single MRD result, as sustained MRD negativity for more than 12 months can translate into long-term survival.

The Expert Committee considers newly diagnosed MM to be classified as HRMM if any of the following criteria are met:

1. R-ISS stage III, extramedullary disease excluding bone lesions, presence of circulating plasma cells (plasma cell leukemia is defined as ≥5% plasma cells in peripheral blood), presence of one or more HRCAs [t(4;14), t(14;16), t(14;20), del(17/17p), 1q21 gain/amplification, del(1p32), TP53 mutation], although 1q21 gain alone does not define HRMM;

2. MM patients who have received auto-HSCT followed by maintenance therapy and experience relapse within less than 2 years from the start of treatment;

3. Patients who have not received auto-HSCT and experience relapse within less than 18 months from the start of treatment;

4. Functional high risk;

5. Extramedullary relapse/secondary plasma cell leukemia;

6. New occurrence of 1q21 gain/amplification and/or del(17/17p)/TP53 mutation at relapse.

**Treatment of HRMM**

**Principles of Treatment for Newly Diagnosed HRMM**

The standard treatment for HRMM has not yet been established. The overall treatment strategy includes:

1. Utilizing combination therapies with drugs that have different mechanisms of action;

2. Aiming to eradicate all tumor clones, with the goal of achieving and maintaining MRD negativity both inside and outside the bone marrow;

3. Implementing a treatment strategy that adjusts based on the effectiveness of the therapy;

4. Acknowledging that current treatment outcomes for HRMM are still unsatisfactory, and encouraging the exploration of experimental therapies.

**Treatment for Newly Diagnosed HRMM Suitable for Transplantation**

1. **Induction Therapy Before Transplantation:**

   For HRMM, induction therapy with the RVd regimen as a bridge to auto-HSCT has not met expectations in terms of depth of response and long-term prognosis, and achieving MRD negativity is more challenging compared to standard-risk patients. Some studies with novel drug-modified regimens have shown that patients with one HRCA receiving the KRd regimen (carfilzomib, lenalidomide, and dexamethasone) sequentially followed by auto-HSCT achieved similar MRD negativity rates and progression-free survival (PFS) as standard-risk patients, with no statistically significant difference. Meta-analyses indicate that incorporating a CD38 monoclonal antibody as part of the treatment backbone in early-line therapy provides clinical benefits for patients with HRCAs. For UHRMM patients, more intensive treatment regimens, such as the Dara-VRdC regimen (OPTIMUM/MUKnine study) and the Dara+KTD-PACE regimen (TT7 study), can be considered.

2. **Auto-HSCT:**

   Tandem transplantation involves performing a planned second auto-HSCT within 3–6 months after the first. It is recommended that HRMM patients collect sufficient hematopoietic stem cells for two auto-HSCTs during the first mobilization. Regardless of the response achieved after the first transplant, it is advised to perform the tandem transplant within six months. The conditioning regimen for both transplants typically includes high-dose melphalan.

3. **Consolidation Therapy:**

   If tandem transplantation is not performed, the original induction regimen can be continued for consolidation therapy for an additional 2–4 cycles.

4. **Maintenance Therapy:**

   For HRMM patients, maintenance therapy should consider a combination of proteasome inhibitors, immunomodulators, and CD38 monoclonal antibodies, in either dual or triple drug regimens. It is recommended to continue maintenance therapy until disease progression or intolerance.

5. **Allo-HSCT:**

   The long-term efficacy of allo-HSCT remains debatable and should only be considered within the context of clinical trials and for select high-risk patients.

#HRMM #AutoHSCT #CancerTreatment #MultipleMyeloma #InductionTherapy #TandemTransplantation #ConsolidationTherapy #MaintenanceTherapy #ProteasomeInhibitors #Immunomodulators #CD38MonoclonalAntibodies #AlloHSCT #UHRMM #NovelTherapies

Expert Consensus on the Treatment of HRMM

①Induction Therapy: For pre-transplantation induction therapy in HRMM, it is recommended to use a regimen based on CD38 monoclonal antibodies combined with proteasome inhibitors and immunomodulators. Recommended regimens include: Dara+KRd, Isa+KRd, Dara+VRd, and Isa+VRd. For patients who cannot tolerate a four-drug regimen, the KRd regimen is an alternative. For patients with significant extramedullary involvement (soft tissue or peripheral blood), additional cytotoxic drugs and, if necessary, radiotherapy can be added.

Therapy Regimens

②Auto-HSCT: Early auto-HSCT is the standard treatment for HRMM. For patients who receive auto-HSCT without significant adverse effects, tandem transplantation within six months post-transplant is recommended.

③Consolidation Therapy: For patients who do not undergo tandem transplantation, it is advised to continue consolidation therapy with the original induction regimen for 2–4 cycles.

④Maintenance Therapy: Maintenance therapy should involve a combination of proteasome inhibitors, immunomodulators, and CD38 monoclonal antibodies, either as dual or triple drug regimens. Therapy should continue until disease progression or intolerance.

⑤Clinical Research: Clinical studies targeting HRMM are encouraged, and it is recommended that HRMM patients prioritize enrollment in clinical trials.

**Treatment for Newly Diagnosed HRMM Not Suitable for Transplantation**

For MM patients not suitable for transplantation, an individualized treatment plan should be selected based on the patient’s fitness status score (IMWG GA score is recommended). For patients with good or moderate health, it is recommended to continue using the same regimen as for transplant-eligible patients. For frail patients, the VRd-lite (modified bortezomib + lenalidomide + dexamethasone) regimen and the DRd (daratumumab + lenalidomide + dexamethasone) regimen are currently the most commonly used first-line treatments.

**Treatment of Relapsed HRMM**

For patients with functional high risk and those defined as HRMM based on dynamic risk factors, re-induction regimens should include combinations of next-generation drugs or drugs with different mechanisms of action. Several clinical studies have shown that CAR-T cell (BCMA CAR-T) therapy can sustain efficacy in relapsed HRMM.

**Expert Consensus**

1. For relapsed HRMM patients, it is recommended to select combination regimens involving next-generation drugs or drugs with different mechanisms of action.

2. Patients with relapsed HRMM are encouraged to participate in clinical studies of CAR-T cell therapy or bispecific antibody immunotherapy.

**Summary**

For the treatment of HRMM, it is recommended to use multi-drug combination therapies with different mechanisms of action and bridge to auto-HSCT, aiming for deep and sustained MRD negativity and prolonging overall survival (OS) in patients. Currently, clinical trials of CAR-T cell therapy for newly diagnosed HRMM are being conducted, and combining auto-HSCT with CAR-T cell therapy can leverage the therapeutic benefits of both. Besides the BCMA target, CAR-T cell therapies targeting GPRC5D and FcRH5, as well as bispecific antibodies, have shown good efficacy in relapsed and refractory MM. New drugs and innovative diagnostic and therapeutic strategies, including immunotherapy, hold promise for overcoming the challenges in HRMM treatment.

🎉🎉To assess whether the condition is suitable for CAR-T or clinic therapy, you can submit Advanced Medicine in China for preliminary evaluation!
WhatsApp: +8613717959070
Email: doctor.huang@globecancer.com

#HighRiskMultipleMyeloma #HRMM #MultipleMyeloma #CancerTreatment #Hematology #Oncology #MedicalResearch #CancerCare #CancerAwareness #ChinaMedicalAdvances #AutoHSCT #MedicalConsensus #UHRMM #BloodCancer

#CancerPrognosis #GeneticRiskFactors #CancerResearch #MMTreatment #MRD #Hematology #CancerSurvival #PrognosticFactors

#CancerCriteria #Hematology #HighRiskMyeloma #PlasmaCellLeukemia #CancerRelapse #CytogeneticAbnormalities

#InductionTherapy #TandemTransplantation #ConsolidationTherapy #MaintenanceTherapy #ProteasomeInhibitors #Immunomodulators #CD38MonoclonalAntibodies #AlloHSCT #NovelTherapies

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5 months ago CAR-T

2024EHA | Professor Huang He: Targeting CD7 Universal CAR-T Therapy Shows Significant Efficacy and Good Safety in Treating R/R CD7+ T-ALL/LBL Patients

**2024EHA | Professor Huang He: Targeting CD7 Universal CAR-T Therapy Shows Significant Efficacy and Good Safety in Treating R/R CD7+ T-ALL/LBL Patients**

The 29th Annual Meeting of the European Hematology Association (EHA) 2024 concluded successfully on June 16, 2024, in Madrid, Spain. As a premier event in the international hematology field, it showcased the latest advancements in foundational and clinical practices.

At this year’s EHA meeting, several studies from Professor Huang He’s team at the First Affiliated Hospital, Zhejiang University School of Medicine were selected. One of these studies, titled “Phase I Study of Targeting CD7 Universal CAR-T Therapy for Relapsed/Refractory CD7+ T-ALL/LBL Patients,” was featured in a poster presentation.

T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are aggressive malignancies originating from precursor T cells, often affecting the bone marrow (BM), central nervous system (CNS), and mediastinum. Despite multiple lines of chemotherapy or allogeneic hematopoietic stem cell transplantation, some patients progress to a relapsed/refractory stage with poor prognosis, posing a significant clinical challenge. Current CAR-T cell therapies primarily target B-cell hematologic malignancies and multiple myeloma, such as CD19 CAR-T and BCMA CAR-T, while mature targets for T-cell hematologic malignancies are lacking. Preliminary research data indicate that CD7 could be a potential therapeutic target for T-cell hematologic malignancies. Based on this, the team developed a universal CAR-T product targeting CD7, named RD13-02, characterized by CRISPR/Cas9 technology to modify T-cell receptors (TCR) and CD7, creating an innovative “off-the-shelf” CAR-T cell therapy product aimed at truly achieving shelf-ready cell therapy.

The objective of this study was to evaluate the safety and efficacy of RD13-02 in treating R/R T-ALL/LBL. A total of 12 eligible R/R T-ALL/LBL patients (7 ALL, 5 LBL) were enrolled in the study, all exhibiting CD7 antigen expression. Six patients had extramedullary disease; all had blast cells in the bone marrow, with a median proportion of 64% (range: 6% to 89%), indicating high-risk end-stage patients. The patients, aged 3 to 70 years, were enrolled in a “3+3” dose-escalation study. Based on the total dose of RD13-02, they were randomly divided into four dosage groups (DL-1: 0.5×10^8 CAR+T cells; DL1: 2×10^8 CAR+T cells; DL2: 4×10^8 CAR+T cells; DL3: 6×10^8 CAR+T cells). All patients received a standardized lymphodepletion regimen of fludarabine (30mg/m2/day) and cyclophosphamide (500mg/m2/day) for three consecutive days (Day -5 to Day -3) before CAR-T infusion. Preliminary disease assessment was conducted on Day 28. After determining the MTD and RP2D, dose expansion will be carried out.

The study results indicated that no dose-limiting toxicity (DLT), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GVHD) was observed at any dose level. Cytokine release syndrome (CRS) was manageable, mostly mild (G1, n=8; G2, n=2; G3, n=2). Due to the occurrence of Grade 3 CRS in one patient each in the DL2 and DL3 groups, the DL1 dose was set as RP2D, focusing on safety and efficacy. In the initial 28-day evaluation post-infusion, 9 out of 12 patients achieved CR/CRi. By the second month post-infusion, an additional 2 patients achieved CR/CRi, with an ORR of 92%. All patients showed expansion observed through qPCR, with the expansion occurring between Days 6 to 15 and peaking between Days 8 to 27, with a median duration of 33 days (15-79). The study preliminarily confirmed that the anti-CD7 universal CAR-T product RD13-02 is safe and effective for CD7+ R/R T-ALL/LBL. Long-term efficacy needs more patients and extended follow-up for validation. To date, this study has shown the best clinical results for universal CAR-T therapy for R/R T-ALL/LBL, attracting widespread attention from peers both domestically and internationally at this EHA meeting. Additionally, the Bone Marrow Transplantation Center at the First Affiliated Hospital, Zhejiang University School of Medicine is developing multiple targeted CAR-T cell therapy products for various hematologic malignancies, including B-cell, T-cell, and myeloid malignancies.

**Current Clinical Treatment of T-ALL/LBL**

The treatment of T-ALL/LBL remains a significant clinical challenge. Current strategies involve achieving remission with existing frontline therapies followed by sequential allogeneic or autologous hematopoietic stem cell transplantation, with most patients achieving long-term survival. However, some patients face refractory or relapsed disease with poor prognosis. For these patients, clinical studies of new drugs or treatment strategies, such as innovative drugs based on disease targets and pathways, are actively being conducted but have not achieved significant progress. CAR-T cell therapy, with its excellent efficacy and safety, is currently the most promising innovative therapy. It is hoped that with further research, CAR-T cell therapy can bring more survival benefits to T-ALL/LBL patients.

**Challenges and Strategies in CAR-T Cell Therapy**

Cellular immunotherapy has been a milestone in the medical field over the past decade, showing breakthrough efficacy in hematologic malignancies, but it still faces several challenges that need to be addressed.

First, the discovery of new targets. Current mature CAR-T cell therapy products mainly focus on B-cell hematologic malignancies, and new targets are urgently needed for T-cell, myeloid, and solid tumors.

Second, improving efficacy. Existing CAR-T cell therapy for B-cell hematologic malignancies has an efficacy rate of about 50%, and continuous technological improvements are expected to develop more effective cell therapy products for clinical application.

Third, existing CAR-T products are autologous CAR-T, which are costly and have long treatment cycles, necessitating the development of universal CAR-T to improve patient compliance.

The team’s novel cell therapy research, including the study selected for this EHA meeting, addresses these clinical challenges. Additionally, last year, the team published results on “function-enhanced” CAR-T in the journal *Nature*, using PD-1 site-specific integration and non-viral delivery methods to successfully prepare CAR-T cells, significantly enhancing their therapeutic effects.

Furthermore, managing CAR-T cell therapy complications, such as ICANS and CRS, requires in-depth exploration. Progress has been made in understanding the mechanisms of complications, leading to gene functionalization of CAR-T cells and developing “smart” CAR-T products to achieve “efficacy enhancement and toxicity reduction.” Additionally, exploring CAR-T combinations with small molecule targeted drugs and immunotherapeutic drugs could achieve better efficacy. The team recently published in the *New England Journal of Medicine* on the sequential “integrated” regimen of CD7 CAR-T cell therapy and allogeneic hematopoietic stem cell transplantation (HSCT), showing excellent efficacy in relapsed/refractory hematologic malignancies.

**Future Prospects of Cellular Therapy**

It is well known that hematology has always been at the forefront of medical development, including the application of the first small molecule targeted drugs and the first antibodies. The remarkable efficacy of cellular therapy in hematologic diseases has demonstrated its great potential in clinical practice. In the future, it is believed that with the development and commercialization of more novel cellular immunotherapy products, their efficacy will continue to improve, side effects will gradually decrease, and indications will expand.

In the field of hematologic diseases, in addition to traditional chemotherapy, small molecule targeted drugs, antibody drugs, and hematopoietic stem cell transplantation, cellular therapy has improved the clinical treatment landscape of hematologic diseases and holds a significant position. It is anticipated that in the future, the treatment of hematologic diseases may enter a chemotherapy-free era, bringing higher cure rates and better quality of life for patients.

 

🎉🎉To assess whether the condition is suitable for CAR-T or clinic therapy, you can submit Advanced Medicine in China for preliminary evaluation!
WhatsApp: +8613717959070
Email: doctor.huang@globecancer.com

#CAR_T #TALL #LBL #EHA2024 #Immunotherapy #Hematology #CancerResearch #CD7 #CellTherapy #MedicalAdvancements

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5 months ago CAR-T

2024 EHA | New Generation BCL-2 Inhibitor Sonrotoclax Expected to Be a New Treatment Option for RRMM

**2024 EHA | New Generation BCL-2 Inhibitor Sonrotoclax Expected to Be a New Treatment Option for RRMM**

RRMM

The 29th Annual Meeting of the European Hematology Association (EHA) was held from June 13-16, 2024, in Madrid, Spain. During this event, the results of the study on the new-generation BCL-2 inhibitor Sonrotoclax (BGB-11417) combined with dexamethasone for the treatment of relapsed/refractory multiple myeloma (RRMM) patients with t(11;14) were presented.

**Ib/II Phase Study of Sonrotoclax (BGB-11417) Combined with Dexamethasone for the Treatment of RRMM with t(11;14)**

**Study Background**

The B-cell lymphoma-2 (BCL-2) protein helps multiple myeloma (MM) tumor cells evade apoptosis and promote cell survival. Studies have found that MM cells with t(11;14) have significantly higher BCL-2 protein expression compared to other cells. BCL-2 inhibitors can block anti-apoptotic mechanisms and induce cell apoptosis. Currently, data have shown that BCL-2 inhibitors have significant anti-MM potential in RRMM patients with t(11;14) who have failed multiple lines of treatment. However, to date, no BCL-2 targeted therapy has been approved for MM treatment.

Sonrotoclax (BGB-11417) is a new-generation BCL-2 inhibitor. Preclinical studies have found that it has over ten times the BCL-2 inhibitory ability of the first-generation BCL-2 inhibitors, a shorter half-life, and no dose accumulation. BGB-11417-105 (NCT04973605) is an ongoing Ib/II phase trial aimed at evaluating the efficacy and safety of Sonrotoclax combined with dexamethasone ± carfilzomib/daratumumab/pomalidomide in treating RRMM patients with t(11;14). The latest data from this study were reported at this EHA meeting.

**Study Design**

The enrolled patients were all RRMM with t(11;14), who had failed at least three treatments, including proteasome inhibitors (PI), immunomodulatory drugs (IMIDs), and anti-CD38 monoclonal antibodies, and were refractory/relapsed to the most recent treatment. In the first part, dose escalation cohorts, patients took 80, 160, 320, or 640 mg of Sonrotoclax daily, combined with 40 mg of dexamethasone weekly until intolerance, disease progression, or death. The primary endpoints were safety/tolerability, determining the maximum tolerated dose (MTD)/maximum assessed dose (MAD), and recommending the dose for the expansion phase (RDFE). The second part, dose expansion, primarily evaluated the tolerability and antitumor activity of Sonrotoclax combined with dexamethasone ± carfilzomib/daratumumab/pomalidomide.

**Study Results**

The initial report at 2023 ASH showed that Sonrotoclax (640 mg) was well tolerated, with no dose-limiting toxicities (DLTs) observed in any patients, establishing 640 mg as the RDFE. The overall response rate (ORR) for this cohort was 70%, and the rate of very good partial response (≥VGPR) was 40%.

Updated in this report: as of March 25, 2024, 32 patients received the RDFE dose of 640 mg Sonrotoclax combined with dexamethasone (10 in the first part and 22 in the second part). The median follow-up time was 4.6 months (0.1-19 months).

The median age of patients was 69 years (48-80 years), with a median of 3 prior lines of treatment (1-12 lines), and 28.1% had high-risk cytogenetic abnormalities. All patients had been exposed to PI and IMiD treatments, and 72% had been exposed to anti-CD38 monoclonal antibody treatments. 56% were PI-refractory, 72% were IMiD-refractory, 56% were anti-CD38 monoclonal antibody-refractory, and 47% were triple-refractory.

**Safety**

No patients experienced DLTs. The most common treatment-emergent adverse events (TEAEs) were fatigue and insomnia (28% each), diarrhea (22%), constipation, and nausea (16% each). Only 4 patients (13%) experienced hematologic TEAEs (grade 3 thrombocytopenia, grade 1 and 3 platelet count decrease, and grade 3 neutropenia). Two patients died, both unrelated to treatment (one due to pancreatic cancer complications and one due to liver cancer and liver failure).

**Efficacy**

Among the 24 evaluable patients, the ORR was 75%, with a ≥VGPR rate of 50%. The complete response (≥CR) rate was 21% (CR, n=4; sCR, n=1), with two patients achieving minimal residual disease (MRD) negativity (10^-5). The median time to response was 0.7 months, and the median duration of response (DOR) was 8 months. As of the follow-up, the longest DOR was 18 months.

**Conclusion**

Sonrotoclax (640 mg) combined with dexamethasone was well tolerated in heavily pretreated RRMM patients with t(11;14), with low rates of hematologic toxicity and infection. It provided deep and durable responses: ORR was 75%, ≥VGPR rate was 50%, and ≥CR rate was 21%. This study will continue to explore Sonrotoclax in combination with other novel agents.

**Interpretation by Professor Lu Jin**

The t(11;14) translocation is a common genetic abnormality in MM patients, present in approximately 15%-20% of newly diagnosed MM cases. Before the era of novel drugs, many researchers believed that patients with t(11;14) had favorable treatment outcomes and were classified as a standard-risk group. However, recent studies have found that patients with t(11;14) are less sensitive to bortezomib regimens, and even with the VRd regimen, patients with t(11;14) have significantly lower deep response rates (≥VGPR) and PFS benefits compared to other standard-risk patients. This suggests that t(11;14) may be an influencing factor for poor efficacy of novel drugs, necessitating other therapies to improve prognosis.

Studies have found that tumor cells with t(11;14) often have high BCL-2 expression and high sensitivity to BCL-2 inhibitors. The phase III CANOVA study demonstrated that venetoclax combined with dexamethasone resulted in deeper response rates (ORR 62% vs. 35%, p<0.001; ≥VGPR rate 39% vs. 14%, p<0.001) and longer median PFS (9.1 months vs. 4.9 months, p=0.237) compared to pomalidomide combined with dexamethasone in treating RRMM patients with t(11;14), though without significant statistical difference. The failure to meet the primary endpoint might be due to more patients in the control group not reaching IMWG-defined disease progression and thus being treated with new regimens, resulting in censored data in the initial PFS analysis. In the latest post-hoc analysis, including new treatment as an event in PFS, the analysis showed a significant statistical difference in median PFS (9.4 months vs. 4.0 months, p=0.003).

Therefore, the benefits of BCL-2 inhibitors still warrant further exploration. Sonrotoclax is a second-generation highly selective and potent BCL-2 inhibitor. In preclinical trials, Sonrotoclax had an IC50 for BCL-2 protein over ten times lower than that of the first-generation BCL-2 inhibitors (0.014 nM vs. 0.2 nM). It also showed ≥2000 times selectivity over BCL-XL, BCL-W, MCL-1, and BCL2A1 and stronger cytotoxicity against MM cell lines. Additionally, Sonrotoclax has a shorter half-life (approximately 4.5 hours), allowing more flexible exploration of rapid dose escalation plans without the risk of off-target toxicity due to drug accumulation.

The Ib/II phase study reported at this EHA meeting demonstrated that Sonrotoclax combined with dexamethasone was well tolerated in RRMM patients previously treated with multiple lines of therapy. The 640 mg RDFE dose achieved a 75% ORR, ≥VGPR rate of 50%, and ≥CR rate of 21%. We look forward to the release of more results from Sonrotoclax combination therapies. Additionally, as the proportion of t(11;14) in systemic light chain amyloidosis and plasma cell leukemia is higher than in MM, the exploration of BCL-2 inhibitors in these plasma cell diseases is also ongoing.

**Professor Lu Jin**

Chief Physician, Professor, Ph.D. Supervisor

Peking University People’s Hospital, Peking University Institute of Hematology

Specializes in clinical and laboratory research on multiple myeloma, primary systemic amyloidosis, lymphoma, and cellular immunotherapy.

General Secretary and Standing Committee Member of the Hematology Physician Branch of the Chinese Medical Doctor Association

President of the Hematology Physician Branch of the Beijing Medical Doctor Association

Vice Chairman of the Multiple Myeloma Professional Committee and the Histiocyte Disease Professional Committee of the Chinese Medical Doctor Association

Vice President of the Hematology Branch of the Chinese Society of Geriatrics and Chairman of the Multiple Myeloma Academic Committee

Deputy Leader of the Plasma Cell Group of the Hematology Branch of the Chinese Medical Association

Deputy Leader of the Multiple Myeloma and Related Diseases Professional Group of the Hematology Professional Committee of the Chinese Women Physicians Association

Member of the Chinese and International Primary Systemic Amyloidosis Collaboration Group

Member of the International Myeloma Working Group and the Asia-Pacific Myeloma Working Group

To assess whether the condition is suitable for CAR-T or clinic therapy, you can submit Advanced Medicine in China for preliminary evaluation!

WhatsApp: +8613717959070

Email: doctor.huang@globecancer.com

#Sonrotoclax #RRMM #BCL2Inhibitor #MultipleMyeloma #EHA29 #Hematology #NewTreatment #CancerResearch #2024EHA

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6 months ago CAR-T

#EBMT / #EHA Leading the Frontiers of Medicine: China’s Top Medical Expert Explains the Groundbreaking CAR-T Cell Therapy

#EBMT / #EHA Leading the Frontiers of Medicine: China’s Top Medical Expert Explains the Groundbreaking CAR-T Cell Therapy

Expert:**Huang He**

Chief Physician and Doctoral Supervisor.

Currently serves as the Director of the Hematology Institute at Zhejiang University, Director of the Zhejiang Provincial Engineering Research Center for Stem Cell and Cellular Immunotherapy, Chief Scientist for the “Hematology and Immunology Diseases” division at the Liangzhu Laboratory, and Director of the Bone Marrow Transplantation Center at the First Affiliated Hospital of Zhejiang University School of Medicine.

He is the Vice Chairman of the Asia Cell Therapy Organization and Deputy Leader of the Hematopoietic Stem Cell Application Group of the Hematology Branch of the Chinese Medical Association.

He has published over 300 papers (including over 200 as corresponding author) in journals such as The New England Journal of Medicine, Nature, Cell Metabolism, Lancet Haematology, Blood, and Leukemia.

He has received 17 provincial and ministerial-level awards and holds 23 authorized invention patents.

In the past five years, he has served as chairperson, invited speaker, and oral presenter at over 60 international conferences. As the conference chair, he organized the Asia-Pacific International Bone Marrow and Hematopoietic Stem Cell Transplantation Conference in Hangzhou in 2005 and 2014.

He is the chief editor of “CAR-T Cell Immunotherapy” and “Hematology” published by People’s Medical Publishing House.

He serves on the editorial boards and committees of multiple international journals and organizations.

To assess whether the condition is suitable for CAR-T or clinic therapy, you can submit Advanced Medicine in Chinafor preliminary evaluation!

WhatsApp:+8613717959070
Email: doctor.huang@globecancer.com

#MedicalInnovation #CAR_Therapy #Hematology #MedicalBreakthrough #ExpertTalks #CuttingEdgeMedicine #cart #EHA2024

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