Editorial Note: Multiple myeloma is a clonal plasma cell proliferative disorder that has seen significant therapeutic advancements over the past few decades due to deepening biological research. With the development of proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, Chimeric Antigen Receptor T-cell (CAR-T) therapy, and other new drugs, the survival and prognosis for patients with multiple myeloma have undergone milestone changes. From April 14 to 17, 2024, the 50th European Society for Blood and Marrow Transplantation (EBMT) annual meeting was held in Glasgow, UK. At the conference, Professor Reuben Benjamin from King’s College Hospital in London gave a special report on the clinical application and future prospects of hematopoietic stem cell transplantation and CAR-T cell therapy in multiple myeloma patients. Hematology News invited Professor Benjamin to share his insights with a broad audience.
“Oncology Frontier – Hematology Frontier“: Hematopoietic stem cell transplantation has been the most effective and mature human stem cell therapy technique to date. Could you summarize the main advances made in this field in recent years?
Professor Benjamin: Humans have been using stem cell transplantation to treat malignant hematological diseases for quite some time now. Over the past few decades, we have made significant strides in transplantation methods and outcomes. At this EBMT conference, we reviewed major advancements in the field of stem cell transplantation. First and foremost, finding suitable stem cell transplant donors has been one of our major advancements. Now, we have a better understanding of who the best donors are, which ultimately determines the outcome of the transplantation. We have better donor registries globally, making it easier to find a suitable donor. Secondly, we have made significant progress in the types of transplants, especially in haploidentical transplantation (half-matched transplant), which has completely changed the landscape of transplantation. No longer needing a perfectly matched donor, we can safely perform stem cell transplants using a patient’s mother, father, or child (meaning everyone has a potential donor), even though it’s in a haploidentical manner. These are the major advancements we have made in the field of stem cell transplantation.
Stem cell transplantation has been around for quite some time, but we have seen significant improvements both in the way we deliver the transplant as well as in the outcomes following the transplant over the last couple of decades. Today I was at a session where Dr Mary Horowitz was talking to us about where we have come in the field of stem cell transplantation. One of the major advances we have had is on identifying appropriate donors for stem cell transplants. We are now able to have a much better idea of who our best donor would be for transplant, and that ultimately then determines outcomes. We have much better donor registries internationally now, so finding a donor is becoming a lot easier. Then we have had advances in the type of transplant, namely haploidentical transplants. This has revolutionized the field, because no longer is it the case that you have to find an unrelated donor, but you can now approach your mother/father/children, who may only be matched in a haploidentical manner to you and nevertheless, we can safely do a stem cell transplant. I would say that identifying appropriate donors, moving into haploidentical stem cell transplants, delivering transplants more safely these have led to the success of stem cell transplantation in recent years.
“Oncology Frontier – Hematology Frontier“: With the rise of targeted molecular therapies and immunocellular therapies, will HSCT be replaced? Could you share your views?
Professor Benjamin: This is an incredibly exciting time in the field of cellular therapies. We have CAR-T cell therapy, as well as other forms of targeted cell therapies like CAR-NK cell therapy, CAR-macrophages, and CAR-invariant natural killer T (iNKT) cells, and T-cell receptor-modified T cells (TCR-T) therapies. Currently, we have several CAR-T cell products approved for treating lymphomas, leukemias, and multiple myeloma, and this number is sure to continually increase. Last year, we also saw very exciting data in the use of CAR-T cells for treating autoimmune diseases, and within the next two to three years, it’s likely that we will have CAR-T cell products approved for treating conditions like lupus arthritis.
However, I believe that in the foreseeable future, the role of stem cell transplantation will not be replaced. Hematopoietic stem cell transplantation (HSCT) will remain a cornerstone for treating many malignant hematological diseases such as leukemia, despite the fact we do not have long-term data for these CAR-T cell therapies. This is because, four or five years down the line, we might still see patients with late relapses who will require stem cell transplantation. Additionally, there are still some potential safety concerns with CAR-T cell therapy. Recently, there have been concerns about the safety of CAR-T cell therapy in patients with T-cell lymphomas and other types of hematologic malignancies. Will this occur more frequently? We don’t know yet, but this may mean that stem cell transplantation will continue to be the mainstay treatment for the majority of hematologic cancers.
These are really exciting times for the field of cell therapy, predominantly with CAR T-cell therapy, but also with other forms of targeted cellular therapy like CAR NK-cell therapies, CAR macrophages and CAR iNKT-cells, as well as TCR (T-cell receptor) therapies. We now have established approved CAR T-cell products for lymphoma, leukemia and myeloma, and I think that is only going to increase. In the last year, we have had very exciting data with CAR T-cells in autoimmune disease, and it is not impossible to think that in the next two or three years, we may have a licensed product for lupus arthritis, for instance. I don’t think we are going to see replacement of stem cell transplant for the foreseeable future. Stem cell transplants are still going to be the backbone of treatment for many blood cancers like leukemias. We don’t have long-term data on these cell therapies. I could be that four or five years down the line, we may see late relapses occurring, and then stem cell transplants may still be required. There are also potential safety issues with cell therapies that we are currently unaware of. There have been recent safety concerns about T-cell lymphomas in patients who have had CAR T-cells, and other types of blood cancers. Will this happen more frequently? We don’t know yet, but that could also mean that transplants will remain a mainstay of treatment for most blood cancers.
Oncology Frontier – Hematology Frontier“: With targeted therapy, immunocellular therapy, and HSCT each having its unique advantages and limitations, which combination of treatments do you believe holds promise for benefiting more patients with multiple myeloma?
Professor Benjamin: We are fortunate in the field of multiple myeloma to have a variety of treatment options available. Over the past decade, the survival rate for multiple myeloma patients has doubled, yet we are still unable to completely cure the disease. This is where CAR-T cell therapy could potentially change the game, as it has shown excellent results even in patients with high genetic risk. The question remains whether CAR-T cell therapy can be applied early in the disease course, or even replace some traditional therapies, which is still an open issue. Currently, there are clinical studies comparing stem cell transplantation with CAR-T cell therapy, and some are investigating whether CAR-T cells can be used as a first-line treatment. There are also trials exploring CAR-T cell therapy in patients with smoldering multiple myeloma. We need to wait for the results of these studies to clearly say whether CAR-T cell therapy can replace other forms of drug therapy. But for now, CAR-T cell therapy offers an additional option for multiple myeloma patients.
Furthermore, we can combine CAR-T with other drug therapies. For example, using lenalidomide or other immunomodulatory drugs after CAR-T cell therapy might improve survival rates and possibly enhance the efficacy of the CAR-T treatment. However, we must await the results of these studies to draw definitive conclusions. Overall, I believe the rise of cellular therapy indeed brings an exciting time for us in treating multiple myeloma patients.
I think we have been very lucky in multiple myeloma that we have lots of different types of therapies. The survival in myeloma has doubled in the last ten years. But we still cannot cure multiple myeloma. This is where the introduction of cellular therapies like CAR T-cells for myeloma are potentially game-changers, because they are blind to the genetics of the condition. Even poor risk genetics patients are responding really well to CAR T-cells for multiple myeloma. The question is, can CAR T-cells for myeloma be given earlier in the disease, and can it even replace some of the conventional treatments? That is still an open question. There is an ongoing trial comparing transplant versus CAR-T in myeloma. There are trials looking at CAR T-cells as first-line treatment. And there are also CAR T-cell trials looking at smoldering myeloma. We will have to wait for the results of these trials before we can say definitively that CAR T-cells will replace other forms of drug treatment, but currently, it is offering another option on top of the other treatments. We are also combining CAR T-cells with other drugs. The use of lenalidomide or other immunomodulatory drugs following CAR T-cells may improve survival and may improve the effectiveness of these CAR T-cell treatments. But again, we have to wait for the results of these studies before we can conclusively say that. I think these are really exciting times for myeloma with regards to cellular therapy.
