Targeting the immune system in multiple myeloma: CAR T cell therapy and beyond - meeting organised and funded by Celgene/BMS

Professor Xavier Leleu, Poitier University Hospital, Poitiers France:

Welcome & introduction - Multiple myeloma: understanding the unmet need 

In his welcome and introduction Professor Xavier Leleu stressed the following points:

• This symposium is a scientific presentation and discussion for the purpose of scientific exchange. Neither the symposium nor the information presented or discussed is for the promotional purpose of influencing prescribing or treatment decisions.

• This symposium may include information about investigational products and/or uses that are not approved for use in any country or in the country of your residence.

• Prescribing decisions are made by healthcare professionals. Always refer to the approved product labeling of the country where you practice before prescribing (e.g. Sm PC, US Prescribing Information).

A short summary of introductory remarks:

With an increasing number of treatment lines, more patients will be exposed to IMiD® agents, mAbs, and Pls. The triple class exposed population is faced with limited treatment options. The MAMMOTH-Study highlights the need for novel strategies to improve the overall survival of triple class exposed patients. Treatment outcomes are limited once patients become refractory to IMiD® agents, Pis and anti-CD38 mAbs. Multiple myeloma is associated with immune dysfunction, showing a clear opportunity for immunotherapies. Emerging immunotherapies may help overcome the unmet need for treatment-refractory patients. Clinical trials for emerging immunotherapies mainly focus on patients exposed to around three lines of therapy, including one or more IMiD agents or Pl.



Prof. Niels van de Donk, Amsterdam University, Amsterdam, The Netherlands :

Addressing the unmet need in multiple myeloma: Innovative Immune treatment strategies 

Lectures agenda, short summary:

Treatment options for triple class refractory patients are in development to address the poor outcomes seen in this population:


• Retreatment with drugs used in prior lines

• Antibody drug conjugates (ADCs): - Belantamab mafodotin (FDA/EMA approved)

• Nuclear export inhibitor: - Selinexor + dexamethasone (FDA/EMA approved)


• CELMoD® agents: - lberdomide and CC-92480

• Bispecific T cell engagers: - Teclistamab, CC-93269, talquetamab8 and cevostamab

• CAR T cell therapy: - lde-cel and cilta-cel

Belantamab mafodotin is an antibody-drug conjugate targeting BCMA to deliver a potent cytotoxic agent (DREAMM-2)

The role of immune dysfunction in MM provides a promising target for emerging therapies: 

Cereblon E3 ligase modulators: CELMoD® agents. lberdomide is a novel CELMoD® agent active in LEN- and PCM-resistant multiple myeloma. IBER enhances in vitro immune-stimulatory activity versus LEN and POM. IBER + DEX demonstrated efficacy and safety in heavily pre-treated patients with RRMM. Preclinical data show that IBER enhances the activity of DARA, this is supported by outcomes from MM-001. Data from MM-001 also supports the combination of I BER + BORT + DEX. - CC-92480 is a novel CELMoD® agent specifically designed for rapid protein degradation.  

T cell redirection: Bispecific antibodies. The redirection of T cells against tumor cells is a novel approach for myeloma treatment. BCMA may be a promising target for immunotherapies, including CART cell therapies and bispecific T cell engagers.

A phase 1 study of teclistamab assessed RP2D, safety, and efficacy in patients with RRMM. Early data for teclistamab show a promising safety profile with good response across the s.c. cohort. 

CC-93269 is a bispecific antibody with specific and tight BCMA binding which is being evaluated in the CC-93269-MM-001 dose-finding study in patients with RRMM. Preliminary data show an acceptable safety profile and promising efficacy. Talquetamab is a first-in-class, off-the-shelf therapy targeting GPRCSD and demonstrated tolerable safety and encouraging efficacy at the RP2D.

BFCR4350A (cevostamab) is a FcRH5/CD3 bispecific antibody, under investigation for the treatment of RRMM. the drug had a manageable safety profile and demonstrates activity, establishing FcRH5 as novel target in MM treatment.

The redirection of T cells against tumor cells is a novel approach for myeloma treatment. Novel immunotherapies have the potential to improve the poor outcomes seen in triple class refractory MM. 



Prof. Nikhil Munshi, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA :

A novel approach: targeting B-cell maturation antigen with chimeric antigen receptor T cell therapy

Lectures agenda:

In MM, several BCMA·targetlng CART cell therapies are In development, including Ide-cel, cilta-cel, P·BCMA-101, and AllO-715

The phase 2 pivotal KarMMa study assessed the efficacy and safety of idecabtagene vicleucel (ide-cel; bb2121). Patients treated at 450 x 106 cells target dose had an ORR of 82% and a CR of 39%. Of those patients with a complete response or better, 79% were negative for minimal residual disease. Ide-eel CART cells showed rapid expansion and durable persistence up to 1 year. Ide-cel treated patients had a median PFS of 8.8 months, with 78% of patients event-free at 12 months. Median PFS increased with a higher target dose and greater depth of response. Incidence of CRS increased with dose and was frequently managed with tocilizumab. Neurotoxicity was mostly low grade across all doses; cytopenias were common but not dose-related.

CARTITUDE-1: a phase1b/2 trial of cilta-cel (JNJ-4528) BCMA CAR T cell therapy. CRS after cilta-cel treatment was low-grade and manageable in most patients with RRMM. Treatment with cilta-cel resulted in deep responses & in a 12-month PFS of 76%, with median PFS yet to be reached.

KarMMa subgroup analysis: Ide-eel yielded high response rates in most subgroups, including high-risk patients & Ide-eel yielded durable PFS and DOR in most subgroups. 

Plans to improve the outcome of CART cell therapy

- Improve the CART cell product:

Improve response and overcome resistance:- Dual antigen bindlng - RNACARs - Peptide stimulated T cells with vaccine - Find novel targets ( e.g. GPRC5D)

• Improve expansion and reduce risk of toxicities: - Suicide genes/safety switches as a means to deactivate CAR T cells - Gene editing (e.g. P0-1 knockdown) - Select CD4: CDS ratios - P13K inhibitors

• Reduce turnaround time: - Gene editing of allogeneic CAR T cells

- Increase target expression 

Gamma-secretase inhibitors for BCMA

- Improve the CAR T cell treatment protocol

• Optimize Infusion schedule: - Retreatment at progression•

• Improve patient selection: - Treat at an earlier line of therapy' - Treat patients with a low disease burden' - Treat

   patients regardless of high-risk disease'

Use rational combinations OR maintenance therapy: - Checkpoint inhibitors, IMiD agents

Presenters conclusion:

• BCMA is an exciting target for tumor immunotherapy • BCMA CART cell therapy has shown durable responses in patients with relapsed disease • Evaluation of CART cell therapy in high-risk patients is in the early stages • There are other emerging CART cell therapies in early-stage development • The task for physicians is to sustain/maintain the response to CART cell therapy, using combination therapies if required, and to find approaches to mitigate toxicities




Professor Xavier Leleu, Poitier University Hospital, Poitiers, France:

The patient and the process: putting CAR T cell therapy into practice

Overview of the CART cell administration process:

- Identify patients eligible for CAR T cell therapy:

Patient eligibility should be determined prior to leukapheresis. Patients who have received at least three prior MM treatment regimens. Including a Pl, an IMiD agent, and an anti-CD38 mAb.

Patients who have progressive disease: • Do not need to be refractory to the last treatment regimen; stable disease or minimal response is acceptable • Do not need traditional measurable disease; imaging is adequate.

No age limit for eligibility to receive CART cell therapy. If patients are over 75 then they will be judged on an individual basis.  Patients must be willing and able to adhere to the clinic visit schedule and other requirements. Patients must agree to continued follow-up for gene therapy trials (as mandated by the regulatory guidelines).

In a KarMMa subanalysis outcomes for elderly patients were comparable with those observed in the overall population 

- Evaluation and selection of the patient In the CART cell therapy center.

Comorbidities and relevant considerations are discussed as well as Important patient history considerations for eligibility and Factors impacting CART cell therapy outcomes and the risk of toxicities (see slides). CART cell therapy differs from ASCT. It is important to consider patient eligibility and treatment characteristics when deciding between CAR T cell therapy and ASCT. CART cell therapy can result in rapid and clinically meaningful Qol outcomes. 

- Apheresis and transport of cells to CART cell manufacturing site

Important considerations for apheresis: • It is preferable to avoid agents with an effect on lymphocyte counts, such as bendamustine, melphalan, or cyclophosphamide, within 6 months prior to treatment • A 4-week interval from any other treatment is adequate but not mandated.

Steroids (e.g. dexamethasone) prior to apheresis are prohibited (due to lymphodepleting activity) 2 weeks wash-out time is recommended. Minimum wash-out time for antimyeloma treatment. 2 weeks for standard agents (proteasome inhibitors, IMiD agents, chemotherapy) 3 weeks for monoclonal antibodies. 

- Bridging therapy (post apheresis, and typically stopped 2 weeks prior to infusion)

Bridging therapy is an important tool to help limit the impact of disease burden: • Patients with any disease burden may be eligible for CART cell therapy • Patients with a higher disease burden may have a higher likelihood of CRS. Further reduction of underlying myeloma can maintain the patient in a good condition and preserve organ function (e.g. kidney function) Reduce the risk for severe adverse events associated with CART cell infusion. If new options are not available, retreatment with a previous regimen can be considered. Bridging therapies associated with a significant risk of toxicity (e.g. combination chemotherapy) are to be avoided. During the bridging period patients should be closely monitored. Bridging therapy needs to be discontinued at least 2 weeks before CART cell infusion.

- Lymphodepletion therapy (3 consecutive injections 3 5 days before CART cell infusion)

• Creates a favorable environment in the body (e.g. by the elimination of regulatory T cells) • Upregulates tumor immunogenicity • Promotes homeostatic proliferation of transferred CART cells • Most commonly used regimen: cyclophosphamide and fludarabine (Cy/Flu) daily for 3-5 days. Using cyclophosphamide and fludarabine together results in improved CART cell expansion and persistence vs. cyclophosphamide alone.

- Infusion and monitoring (infusion to Day 28) 

Patients should be closely monitored for common toxicities (see slide)

- Monitoring (Day 28·100) and long-term (> Day 100) complication 

There is a need for timely discussions around CART cell therapy (Clinical considerations & Patient considerations)