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Report of the Educational Meeting on Immunology and Cellular Therapy in Plasma Cell Disorders - 24-26 November 2023 - Hamburg, Germany

Chronic Malignancies Working Party (CMWP)
Cellular Therapy & Immunobiology Working Party (CTIWP)

Plenary conference programme

Summary report written by Dr. Joanna Drozd-Sokolowska, Dr. Kavita Raj and Dr. Donal McLornan

We were delighted to participate in Scientific Working Parties Meetings and the 1st Joint Educational Meeting on Immunology and Cellular Therapy in Plasma Cell Disorders organized by the Chronic Malignancies Working Party (CMWP) and the Cellular Therapy and Immunobiology Working Party (CTIWP) of the EBMT which took place on 24th to 26th November 2023.

On the Friday, we had very successful scientific business meetings, first separately, focusing on our research project portfolio, and later a joint meeting focusing on common research themes of CAR-T in multiple myeloma (MM).

A keynote lecture was given by Dr. Carlos Fernández de Larrea (Spain), who gave a brilliant talk on placement of academic cellular therapies in the treatment algorithm of MM and immunoglobulin-related amyloidosis (AL), summarizing that these therapies are showing amazing results in patients with MM and that potentially moving CAR-T cells and bispecifics to earlier lines over the natural evolution of the disease can have a deeper impact on survival. Economic, logistic and social issues may however be the crucial issues when using and implementing these treatment strategies.

On the Saturday, we started our education meeting with a focus on  the Basics of Myeloma, with three lectures on diagnostic and treatment algorithm in MM (Patrick Hayden, Ireland), in AL (Monique Minnema, the Netherlands) and Waldenstrom Macroglobulinemia, MGCS, and MGRS (Shirley D'Sa, United Kingdom). The speakers gave a comprehensive and practical review of the current standard of care for these diseases, including IgM monoclonal gammopathies of clinical significance and monoclonal gammopathies of neurological significance.

Afterward we continued with Preclinical Models in MM, with three lectures given by distinctive speakers, i.e. Genomic Evolution (Niels Weinhold, Germany), ‘Omics (Marc Raab, Germany) and the Microbiome (Florent Malard, France). Professor Weinhold discussed the extended model of MM evolution, highlighting the issue of regional progression, while professor Raab, concentrated on the tumor microenvironment including tumor- microenvironment interactions. Professor Florent Malard discussed the issue of interplay between diet, microbiota and PCM, presenting data for the deleterious impact of dysbiosis on progression-free (PFS) and overall survival (OS), as well as the increased risk of relapse.

After a short break, the next session focused on Immune Microenvironment in Disease, and specifically on T-cells (Kim de Veirman, Belgium), NK cells (Michael O’Dwyer, Ireland), and Mechanisms of EMD, discussed by Tomáš Jelinek, Czech Republic. The presentations evoked vivid discussion including evasion from the NK-cell surveillance of the MM cells, and the issues surrounding the criteria for diagnosis of plasma cell leukaemia. The session also included a presentation of an excellent case report of a patient with extramedullary disease, given by resident Dr. Esra Gülderen, Turkey.

Afterwards we continued with the session Novel Cellular Therapies, chaired by Dr. Lydia Lee (United Kingdon). The first talk was by Luis G. Rodríguez-Lobato (Spain) on Novel Targets, who discussed the requirements for the ideal tumor antigen, as well provided an in-depth presentation of the BCMA antigen, being the common target for both CAR-T cells and TCE, as well as GPRC5D. Dr Rodríguez-Lobato also focused on the issue of acquired resistance to anti-BCMA TCE, stressing that it does not equate to pan-resistance to other anti-BCMA TCE or anti-BCMA CAR-T. The subsequent talks were on NK cells, Macrophages, Fibroblasts given by Professor Niels Weinhold (Germany), Harvesting the Therapeutic Potential of gdT given by Professor Jürgen Kuball (Germany) and Immune Signalling at the Tumour: Bone Marrow Niche in Multiple Myeloma: a View to a Kill given by Dr Graeme Sullivan (Ireland).

After lunch, Professor Christian Chabannon (France) tackled the subject of Cell Collection and Manufacturing, while Dr Alexander Oeser (Germany) introduced us to a modern topic of artificial intelligence and this can be applied in haematological research algorithms.

The session New and "Old" Kids on the Block was chaired by Professor Gösta Gahrton (Sweden). Professor Fredrik Schjesvold tackled the difficult problem of Finding the Optimal Drug Combination for rrMM, first presenting the considerations at relapse (therapy-, patient- and disease-dependant). After presenting the “standard” combinations Professor Fredrik Schjesvold showed the results of the Ide-cel clinical trials, as well as presented the rationale of MM-5 study, analyzing the impact of elranatamab, a TCE, on the outcome of rrMM. Professor Mauricette Michallet (France), went initially through the indications for auto-HCT, including cytogenetics asking the question whether all transplant eligible patients should be offered an auto-HCT in the first line setting and presenting the trials of TCE in maintenance setting. Finally, Professor Michallet concluded, that until new data become available all transplant eligible patients should still be offered an auto-HCT.

After a short coffee break, we had a chance to listen to a session entitled Current State of CAR-T in PCD, chaired by Dr Nico Gagelmann. Professor Yael Cohen (Israel) during a lecture entitled Ide-cel and Cilta-cel: Trial Insights gave a brilliant talk on the available CAR-T cell products for MM, discussing in detail the trials that led to approval of these products as well as differences in the treated populations. Professor Cohen discussed also in details the efficacy and safety profile of the two products and also presented the results of matching comparison. She presented the data on efficacy of cilta-cel in rrMM patients, who were previously exposed to anti-BCMA TCE. Dr Nico Gagelmann focused on Real-world and GOCART stressing the role of international cooperation. Dr Lydia Lee (United Kingdom) presented the data for Academic CAR-T, discussing among others the APRIL CAR, targeting both BCMA and TACI, and future academic CAR products from her laboratory. 

This was followed by the keynote lecture given by Professor Nicolaus Kröger, entitled Lessons and New Insights in Allogeneic CAR-T and Transplant, who recollected that the 1st joint CMWP / CTIWP meeting occurred in Hamburg in 2016.

On the Sunday, 26th of November, the first session chaired by Dr. Annalisa Ruggeri (CTIWP chair) focused on Biology of Response and Relapse. Professor Christoph Schaefers debated High-risk Myeloma transplant vs CART, trying to stress that definition of high risk undergoes a dynamic evaluation and presenting the EMN28/CARTITUDE-8 study design, being a comparison between auto-HCT and Cilta-cel. Dr. Sarah Gooding (United Kingdom) focused on Antigen Loss and Microenvironment, presenting first the graph indicating the plentiful reason for failure of (immune)therapies in MM. Dr. Gooding reported that high risk, genetically unstable mm  predominate in antigen loss, with most BCMA inactivation occurring after TCE and not CAR-T. Similarly, biallelic loss of GPRC5D is also frequent at relapse in patients previously exposed to anti-GPRC5D TCE. However, as stressed by Dr. Gooding data on incidence of antigen loss in immunotherapy are unknown for larger population of patients. During the session we could also participate in an intellectual challenge of asking the question of immune biomarkers of relapse and immune drivers of relapse and their equality. Professor Christof Scheid (Germany) talked about practical issues of Immune Monitoring, providing detailed list of useful tests in everyday clinical practice, as well as pointing to assessing risk of infections and monitoring exhaustion markers.

The Industry Symposium on “Novel therapies in multiple myeloma” sponsored by Janssen was chaired by Professor Hermann Einsele (Germany), who also gave the first talk on Novel Immune and Cellular Therapies.  Professor Einsele went once more through the approved novel immunotherapies, incl. ide-cel, cilta-cel, teclistamab, elranatamab, talquetamab, their efficacy, safety but also mechanisms of resistance to anti-BCMA directed T-cell therapies in MM. Attention was given also to potential benefits of earlier application of CAR-T/ TCE with fitter T-cells and increased immunogenicity of tumor cells being in favour. Professor Einsele also presented the design of studies (e.g. Kar-MMa-9, CARTITUDE-6, CARTITUDE-5) incorporating CAR-T already early in the treatment plan. Professor Christof Scheid continued with CAR-T Cells - Patient Selection and Treatment of Toxicities, indicating that there is no age limit, and that patients with comorbidities can also be offered CAR-T therapy. Importantly CAR-T-eligible does not equal transplant-eligible. Dr. Cyrus Khandanpour (Germany) spoke about Management of Infections & Mitigations Strategies. In his talk he presented the data for neurotoxicity as well as the increased rate of infection in patients exposed to anti-BCMA therapies. Dr Khandanpour cited the recently published consensus report on the prevention and management of adverse events during treatment with TCE or CAR-T.

After a short coffee break, we continued with Monitoring and Treating Resistance, chaired by Professor Yael Cohen (Israel). Professor Mohamad Mohty (France) presented the possibilities of Multi-targeting in MM. Dr. Noemi Puig (Spain) tackled the Role of MRD.  She provided an insightful and expert summary of the available heterogeneous data focussed on MRD measuring and use in clinical practice. Professor Hermann Einsele (Germany) gave a very in-depth overview of Bispecifics.

This was followed by the last session of the day focused on Patient Fitness and Toxicities, chaired by Dr. Donal McLornan (CMWP Chair, United Kingdom), with three distinctive speakers: Professor Ibrahim Yakoub-Agha (France), Dr. Laurent Garderet (France), and Professor Meral Beksac (Turkey).

Dr. Donal McLornan and Dr. Annalisa Ruggeri thanked all the participants, the speakers and chairs and the Events and Education team and ended three stimulating days of focused discussion on CAR-T and TCE in PCM.

We at the CMWP plan our next business meeting virtually in February 2023, and we look forward to meeting again in person at the next Annual Meeting of the EBMT in Glasgow in April, and afterwards in Warsaw in November 2024, during a 2-day meeting dedicated to myelodysplastic neoplasms and myelodysplastic/ myeloproliferative neoplasms.

Nurses' track

Summary report written by Maaike de Ruijter, CMWP Nurse, Department of Haematology, Amsterdam UMC

We had a great meeting with nurses, research nurse and data managers. Small group but therefore room for discussion, time for questions and time to learn from each other’s experiences.

Here is a short overview of the day:

Session I: Multiple myeloma, the basics and new treatment options

We started the day with a great talk about multiple myeloma. Presented by Laurens Garderet, hematologist in Paris France

With multiple myeloma it is all about the plasma cells, that will normally protect against infections.

With multiple myeloma the plasma cells grow out of control. Growing from MGUS tot smoldering myeloma to multiple myeloma and sometimes plasma cell leukemia.

Some interesting facts:

  • From the general population 1% has MGUS at 50years, and 10% at 70years.
  • With all the different cytogenetics it makes that some patients will have a OS of 1 year and some 20 years.
  • We have more and more therapy options but we cannot cure it yet
  • New on measuring response is ‘minimal residual disease’, MRD. It refers to the small number of malignant cells below the limit of detection available with conventional morphologic assessment, by using Next Generation Flowcytometry of Sequencing (in bone marrow, and in some studies in peripheral blood)
  • Standard first line therapy in transplant eligible patients is daratumumab with Velcade Revlimid (or thalidomide) and dexamethason followed by high dose melfalan and autologous transplantation.
  • On the elderly patients DRD (Daratumumab, Revlimid, Dexamethason) is advised, with a PFS of 5 years.

Next in treatment options is cellular therapy.

Teclistamab has almost magical responses after just 1 ore 2 cycles. But it gives a higher infection risk. In studies it is been recommended to prescribe IVIG (immunoglobulines).

The differences between CART/Bispecific is that bispecific is (almost) immediately available and with CART we need to wait around 6 weeks until we have the product.

What about CART eligibility? The main factors are:

  • Disease related (high tumor load, ferritin, TCL, cytogenetic)
  • Patient related (age, comorbidities, renal and cardiac insufficiency)
  • Treatment related (manu previous lines of therapy, prior BCMA therapy)

But what about age and cellular therapy? Does it matter? In lot of countries there are no age limitation.

Session II: Toxicity Bispecific and CART

Maaike de Ruijter (nurse practioner Amsterdam UMC) started with a short overview about the CART options and results in myeloma treatment. There are two FDA approved CART cell options for multiple myeloma patients: Cilta-cell and Ide-cell, both BCMA targeted CART cells. They are also used in several clinical trials. New option available in clinical trial is GPRC5D targeting CART cell therapy. Maaike presented the CART therapy pathway, patient selection and a short overview of CART toxicity. Short because we continued with a presentation about Bispecific, presented by Marianne Elswout. She works as a nurse in Utrecht NL, on the hematology department. Previously nurses saw only a few multiple myeloma patients on the inpatient ward/clinic. Bispecifics and cart cell therapy changed that.

Marianne presented a case with us and gives a great overview about the specific toxicities with Bispecifics, and different monoclonal antibodies (mAbs).

Some facts about mAbs:

  • Nude mAbs (daratumumab), also called Naked monoclonal antibodies and work alone
  • Conjugated mAbs: (BelantmamaB) are paired with chemotherapy or a radioactive compound
  • Bispecific mAbs: (Teclistamab/Talquetamab) combine two different mAbs to target two different proteins at the same time

Facts about Bispecifics:

  • It binds BCMA to CD3, CD3 binds to t-cell, and then will be connected to BCMA on the plasma cell
  • Premedication tavegyl, paracetamol and dexamethason (first dosis, and after that if necessary)
  • Also, profylaxe with cotrimoxazol and valaciclovor

The toxicity we see: CRS, cytopenia, infections, dysgeusia, skin/nails disorders, ICANS. (but is is rare, about 5%).
With Teclistamab there are no skin and nail toxicity and no dysguesia. But we do see more infections and some local skin reactions.

Next is the RedirectTT 1 study; combining Talquetamab and Teclistamab. And new combinations of Bispecific and other therapies (for example with daratumumab).
More important is moving bispecifics therapy in the earlier line of therapy.

Session III: the role of the research nurse and nurse specialist

Maaike and Sandy Kruijswijk (AmsterdamUMC, NL) are both working in the myeloma field, with a special interest in clinical trials. In this presentation they explaned the role of nurse practitioner and research nurse in this work field.

Starting with an overview from Maaike of all the different types of advanced practice nurses (APN), and the role of physician assistant (PA) and nurse practitioner. Different nurses’ roles, with different tasks and responsibilities.

Fact: The first training programme for NP started in 1965 in Colorado, USA

Added value of NP: more focused on side effects like pain and neuropathy and starting early treatment, more focused on live around the patient, faster referral to physiotherapy, dietitian, social worker and local projects for patients with cancer and their relatives

Sandy showed us why a research nurse is a great value in the clinical trials, with an interesting article that is been published in 1996 and already showed us back than that when a nurse was added to the trial team more patients where included.

In the next slides Maaike and Sandy informed us about their role during CART or bispecific treatment, working a lot together or/and with the physician. The research nurse always keeps the overview during treatment and is the first point of contact for the patients. A very important role for these patients.