In recent years, targeted cancer therapies approved by the FDA have been escalating, particularly for hematologic malignancies.In 2014, four of the 10 new molecularly targeted drugs for the treatment of blood cancers were approved by the FDA: blinatumomab (acute lymphoblastic leukemia ALL), belinostat (peripheral T-cell lymphoma), idelalisib, and ibrutinib (chronic lymphocytic leukemia CLL). ibrutinib was initially approved by the FDA in 2013 for the treatment of condylomatous cell lymphoma, while obinutuzumab and ofatumumab were also approved for the treatment of newly diagnosed CLL. As of 2015, the FDA approved four new therapies for the treatment of hematologic malignancies, including brentuximab vedotin (Hodgkin’s lymphoma), carfilzomib in combination with lenalidomide + dexamethasone (relapsed multiple myeloma), panobinostat in combination with bortezomib + dexamethasone (relapsed myeloma), and ibrutinib (Waldenstr?m macroglobulinemia). In the near future, gene technology, new combination therapies, and the optimization of chimeric antigen receptor (CAR) T-cell gene therapies are expected to benefit 162,000 patients with blood cancers annually. Therefore, in advance of the 57th Annual Meeting of the American Society of Hematology (ASH) (December 5-8, Orlando, Florida), ASCO Post organized a session attended by three congress delegates (Professors David A. Williams, Michael E. Williams, and S. Vincent Rajkumar) and focused on Recent advances in blood cancer research and the outlook for the next 10 years were discussed as follows: ASH 2015 Firstly, Prof. David Williams gave a brief overview of the clinical advances that will be presented at this year’s ASH Congress. Prof. David Williams: This congress is attended by approximately 25,000 hematologists and contains more than 6,000 abstracts, so it will be a basic research meeting with different repercussions, as well as a translational meeting and a clinical research meeting. The conference is expected to showcase ongoing advances in targeted therapies for lymphoma, leukemia and myeloma. Also, the congress will demonstrate improvements in targeted therapies in combination with conventional therapies/new immunotherapies. Of course, the conference will also introduce us to the genetic characterization of these diseases, and I personally believe that genetic mutations can contribute to therapeutic advances in blood cancers-especially in the assessment of resistance to therapy-which can help us treat patients more accurately. We have been exploring the genetic profile of these diseases, and this will allow us to better select which patients respond well/poorly to targeted therapies, and thus allow us to find more appropriate alternative therapies. At the same time, I think these advantages will improve prognosis and also reduce treatment-related adverse effects and long-term side effects. New insights How do you perceive the prevention, detection, diagnosis and treatment of hematologic tumors from your own perspective? Prof. D. Williams: We have found that certain mutations seem to predict the development of leukemia, relapse, and treatment resistance in patients. Prof. M. Williams: These advances are currently moving in two directions. One is to optimize diagnosis, that is, to gain a deeper understanding of the heterogeneity of blood tumors at the molecular and cellular level. There is also a deeper understanding of tumor markers and predicting individualized disease course. The new advances we know now can help us to tailor risk-adapted therapies for a wide range of hematologic tumors, such as lymphomas, CLL, and myeloma, leading to a better prognosis for patients. Prof. Rajkumar: For multiple myeloma, the main focus is on early diagnosis and initial treatment before organ and bone damage occurs. In the past, when treatment options were limited, we would only treat myeloma if we realized that end-organ damage had occurred. For now, on the other hand, our treatment options are so effective and also prevent complications that it makes no sense to treat initially when complications have occurred, especially extremely severe complications such as severe fractures or kidney failure. Therefore, in the next few years, the focus should be on biomarkers that can help diagnose myeloma and start early treatment. In the meantime, the conference will show us clinical trials exploring how to delay or stop disease progression in patients with negatively lit myeloma. Gene Sequencing How do you understand gene sequencing for this type of disease? For example, new mutations, subtypes and their treatment strategies. Prof. D. Williams: We are now looking at a number of new mutations in leukemia and are also exploring how genes can be used to predict treatment remission and disease prognosis, as well as risk factors for side effects and poor prognosis. In terms of new treatments for leukemia, there are multiple aspects of gene therapy that have been applied to the treatment of leukemia. First, the escalation of gene therapies targeting hematopoietic stem cells has expanded their indications. Already today, half of the diseases can benefit from stem cell gene therapy and look to be cured. Next, therapeutic options that were once not considered may also be approved for the treatment of these diseases. Second, the identification of new targets can lead to the construction of CAR-T cells that can recognize specific proteogens on tumor cells. To date, the greatest success has been the application of CAR-T cells targeting CD19 in the field of B-cell leukemia. It also recognizes a number of other antigens that can be applied in immunotherapy, which is the subject of some current basic research. Therefore, continued exploration of immunotherapy, CAR-T cell construction and tumor molecularity will all contribute to the development of precision medicine. Prof. M. Williams: For lymphomas, we now recognize molecular subtypes that are closely related to the clinic. Diffuse large B-cell lymphoma is a good example. There are now 2 main subtypes of the disease, one is germinal-centered and the other is nongerminal-centered. The prognosis of patients varies based on different treatment options, such as R-CHOP or adjusted EPOCH-R. In addition, although the prognosis of non-growth-centered diffuse large B-cells is poorer, this subtype is more sensitive to some of the newer drugs (e.g., lenalidomide, ibrutinib, and proteasome inhibitors). This has therefore prompted the integration of these drugs into initial therapy. Some early findings have shown that integrating lenalidomide into R-CHOP eliminates the adverse effects of the non-growth center B-cell subtype, and the combination is expected to become a routine therapy for diffuse large B-cell lymphoma. Prof. Rajkumar: Cytogenetically, there are at least six subtypes of myeloma. And, each of these subtypes has a unique clinical presentation, clinical course, response to therapy, and prognosis. Myeloma is a rare disease and clinical trials for each subtype have been difficult to conduct. However, we have clarified that certain specific myeloma subtypes respond better to certain specific therapies. For example, patients at high risk for t(4;14) myeloma respond well to bortezomib and require bortezomib maintenance therapy after bone marrow transplantation; bortezomib maintenance therapy improves overall survival in patients with del17p myeloma; and myeloma patients with trisomic chromosomes are very sensitive to lenalidomide. As a result, we can now tailor the treatment regimen of myeloma to its cytogenetic type. Typically, fluorescence in situ hybridization (FISH) is used primarily for disease diagnosis, but now the technique and some novel genetic approaches are increasingly being used to predict prognosis and screen myeloma treatments. Through a series of studies, we are increasingly understanding myeloma genetic abnormalities. While there are now many frequent mutations, each occurs in only a very small number of patients, but there are some-such as the BRAFV600E mutation that has been found in 5% of myeloma patients.Patients with BRAF mutations have been treated with verofenib, which produces a sustained remission. We are currently seeking to obtain myeloma patients from the MATCH trial analysis, which will allow us to define new targeted treatment options. In terms of new therapies, there has also been considerable progress and many have been approved by the FDA. Relevant studies have clarified the activity of at least three proteasome inhibitors in the treatment of myeloma: ixazomib, oprozomib, and marizomib. at the same time, immunomodulatory drugs have been improved. While we welcome the arrival of these new drugs, improvements limited to the same class of drugs are not major advances. That’s why it’s more important to develop drugs with different mechanisms of action than those known at this time. Next, at least 2 anti-CD38 monoclonal antibodies were cleared by the FDA. One is elotuzumab – used in combination with lenalidomide + dexamethasone to significantly improve remission and progression-free survival in patients with refractory/recurrent myeloma. Another is daratumumab – an anti-human CD38 monoclonal antibody that is highly effective as a single agent in the treatment of refractory/recurrent myeloma. There are also several novel cell cycle protein-based kinase inhibitors that have demonstrated activity in the single-agent treatment of recurrent myeloma; venetoclax – a Bcl-2 selective inhibitor, LGH447 – a Pan-Pim kinase inhibitor and filanensib – spindle kinesin inhibitor. Many of these drugs have demonstrated significant synergistic effects in combination with known active agents in the treatment of myeloma. However, due to the significant activity of single agents in refractory/recurrent disease, these drugs mentioned above are preferred, especially elotuzumab. therefore, these drugs will be powerful therapeutic tools in the future! In addition, CAR-T cell inhibitors, immune checkpoint inhibitors and other such immunomodulatory drugs have also attracted the attention of many researchers. Many studies have shown that CAR-T cells can directly counteract B-cell maturation antigens. In addition, studies related to checkpoint inhibitors are underway. Time will tell how effective immunotherapy is in treating myeloma. As of 2015, the FDA approved four new therapies for hematologic malignancies, including brentuximab vedotin (Hodgkin’s lymphoma), carfilzomib in combination with lenalidomide+ dexamethasone (relapsed multiple myeloma), panobinostat in combination with bortezomib+ dexamethasone (relapsed myeloma), and ibrutinib (Waldenstr?m macroglobulinemia).