From November 14 to 17, 2024, the Cellular Therapy and Immunotherapy Conference (CTI) was held in Hangzhou, China, bringing together leading experts, scholars, and industry leaders in the fields of cellular and immunotherapy from around the world. As both a platform for academic exchange and a showcase for the latest scientific breakthroughs, the event highlighted key advancements shaping the future of the field. During the conference, Oncology Frontier-Hematology Frontier had the privilege of interviewing Dr. Jean-Luc Harousseau, Chair of the French National Health Authority and Director of the René Gauducheau Cancer Center at Nantes University, France. In this interview, Professor Harousseau elaborated on the benefits, limitations, and current state of immunotherapy in multiple myeloma, as well as its future prospects. Below is a summary of his key insights.Q1: How does immunotherapy compare to traditional therapies in terms of strengths and limitations? How can these treatments be balanced in clinical practice?
Dr. Jean-Luc Harousseau: Immunotherapy stands apart from traditional treatments due to its focus on targeting specific molecules on the surface of myeloma cells, resulting in a much higher level of specificity. However, evaluating its overall efficacy is challenging because immunotherapy encompasses four different approaches.
Among these, monoclonal antibodies (mAbs) targeting CD38 are pivotal. Two highly active mAbs—daratumumab and isatuximab—are now widely used in combination with standard therapies and are suitable for both younger and older patients.
Another approach is antibody-drug conjugates (ADCs), such as belantamab mafodotin. While generally well-tolerated, belantamab mafodotin is associated with a specific toxicity: corneal damage. However, its efficacy is less impressive compared to newer therapies like CAR-T cells and bispecific antibodies.
CAR-T cells have been revolutionary in the treatment of relapsed/refractory multiple myeloma. For instance, cilta-cel (ciltacabtagene autoleucel) has demonstrated unprecedented results, with an overall response rate of 98% and a complete response rate of 82% in heavily pretreated patients. While CAR-T therapies come with unique toxicities, such as cytokine release syndrome (CRS) and neurotoxicity, these adverse effects are generally mild and reversible in multiple myeloma.
Bispecific antibodies have shown similar efficacy to CAR-T cells, achieving response rates of 60–65% in heavily pretreated patients, compared to 30% with ADCs. They also share similar toxicities with CAR-T cells, though the severity is lower. However, a specific challenge with bispecific antibodies is the higher incidence of infections, which can be severe and persist during long-term treatment.
Q2: Which immunotherapies have shown the most promise for newly diagnosed multiple myeloma patients? Are there specific populations that benefit more?
Dr. Jean-Luc Harousseau: For newly diagnosed multiple myeloma patients, the primary immunotherapy currently in use is anti-CD38 monoclonal antibodies. These therapies, including daratumumab and isatuximab, have been incorporated into standard treatment regimens, such as Revlimid plus dexamethasone (RD) or Velcade, Revlimid, and dexamethasone (VRd). These combinations have significantly improved complete response (CR) rates, minimal residual disease (MRD) negativity rates at 10^-5 sensitivity, and progression-free survival (PFS).
The role of other immunotherapies, such as CAR-T cells and bispecific antibodies, in this setting remains uncertain. Given the strong results already achieved with daratumumab and isatuximab, these newer therapies might only be used in specific cases, such as for patients with high-risk cytogenetics, poor responses to standard care plus anti-CD38 therapy, or those experiencing early relapse.
There is also potential for CAR-T cells or bispecific antibodies to be used as consolidation or maintenance therapy after autologous stem cell transplantation (ASCT), even in elderly patients. However, such treatments are prolonged, come with a risk of adverse events, and are costly. A key question is whether CAR-T cells or bispecific antibodies could serve as alternatives to traditional consolidation or maintenance therapy, optimizing outcomes for both younger and older patients.
Q3: What challenges exist in the immunotherapy of newly diagnosed multiple myeloma patients? How can we overcome them to enhance the effectiveness of these treatments?
Dr. Jean-Luc Harousseau: One of the biggest challenges is determining whether there is a need for CAR-T cells or bispecific antibodies in patients who already have excellent prognoses with standard treatments, such as those combining daratumumab or isatuximab with standard regimens.
For high-risk patients, however, CAR-T cells and bispecific antibodies undoubtedly hold promise. In particular, recent bispecific antibody combinations may offer new hope for patients with severe conditions, such as multiple myeloma with extramedullary disease.
Another critical issue is identifying which patients are most likely to benefit from these advanced therapies. While current treatments deliver outstanding results, it’s essential to strike a balance between efficacy, toxicity, and cost. Long-term use of standard therapies like daratumumab can be prohibitively expensive. Similarly, CAR-T cell therapy, though a one-time treatment, is also very costly in Western countries.
One possible solution is to limit the treatment duration of bispecific antibodies. By reducing the therapy timeframe, we could minimize side effects, improve patient outcomes, and control the costs of prolonged treatments.
Conclusion
Dr. Jean-Luc Harousseau’s insights highlight the remarkable progress and persistent challenges in the field of immunotherapy for multiple myeloma. With its high specificity, immunotherapy offers new hope for patients, particularly with innovative treatments like CAR-T cells and bispecific antibodies demonstrating extraordinary efficacy in relapsed/refractory multiple myeloma.
However, the integration of these therapies into clinical practice requires careful consideration. Balancing efficacy, toxicity, and cost remains a key challenge. For newly diagnosed patients, anti-CD38 monoclonal antibodies have become a cornerstone of treatment, while the role of other immunotherapies continues to evolve, particularly for high-risk or refractory cases.
As immunotherapy continues to advance, the focus will increasingly shift toward precise patient selection and optimizing treatment strategies. These efforts aim to deliver longer survival and improved quality of life for multiple myeloma patients, paving the way for a brighter future in the fight against this disease.
