Multiple Myeloma Treatment

research: researchWhile multiple myeloma is still incurable, the field has seen unprecedented growth with an improved understanding of the disease's biology and a plethora of new drugs, including two recent FDA approvals in recent months. In July, the FDA approved selinexor tablets in combination with the corticosteroid dexamethasone for the treatment of adult patients with relapsed/refractory multiple myeloma who have received at least four prior lines of therapies and whose disease is resistant to several forms of these treatments. Additionally, newly diagnosed patients who are ineligible for autologous stem cell transplant have another treatment option with the June approval of daratumumab in combination with lenalidomide and dexamethasone. Hematologists/oncologists who specialize in this area have had a front row seat to the significant strides that have been made in the last decade. “I have witnessed a dramatic evolution in the treatment of multiple myeloma,” noted Pamela Crilley, DO, Chair of Medical Oncology, Cancer Treatment Centers of America. “Although it remains an incurable disease, the advances in research of the biology of the disease coupled with the results of clinical trials have led to the development and approval of many new classes of drugs that have translated into improved outcomes in both disease free and overall survival for newly diagnosed and relapsed patients,” she continued. “When I began my career, we had only a single drug plus prednisone to treat these patients and now the standard of care is upfront triplet therapy for induction followed by autologous peripheral blood stem cell transplant and long-term maintenance therapy for newly diagnosed patients.” “Myeloma is the poster child for drug development because we have so many new options,” noted Jens Hillengass, MD, Chief of Myeloma at Roswell Park Comprehensive Cancer Center, Buffalo, N.Y. “Entire classes of new drugs have been developed and approved for our patients since I began my career. When I started the average survival was about 2-3 years; now it's up to years or even longer. We are seeing a huge difference in the outlook of this disease.” Utilizing CAR T-Cell Therapy One treatment with an impact that continues to grow in a variety of cancers is CAR T-cell therapy and multiple myeloma is no exception. There is a plethora of studies underway to harness the power of this approach. A recently published study outlined key safety and efficacy results of bb2121, a B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy, for relapsed and refractory multiple myeloma (N Engl J Med 2019; doi:10.1056/NEJMoa1817226). “We found that the CAR T cells were well-tolerated and that we could reliably produce [them],” noted senior author and principal investigator James N. Kochenderfer, MD, Experimental Transplantation and Immunology Branch, NCI Center for Cancer Research. “We treated patients who had very advanced, treatment-resistant multiple myeloma with a median of seven prior lines of therapy. There was an 85 percent objective response rate and an 11.8-month median progression-free survival.” Responses to bb2121 CAR T-cell infusion occurred early, with a median time to first partial response or better of 1.0 month (range, 0.5-3.0), and responses were durable, with a median duration of response of 10.9 months (95% CI, 7.2 to not estimable). Researchers found that greater CAR T-cell expansion occurred in responding patients. The most common grade ≥3 events were hematologic toxicities, including neutropenia (85%), leukopenia (58%), anemia (45%), and thrombocytopenia (45%), for the first 33 patients. Twenty-five (76%) patients experienced cytokine release syndrome (CRS); 23 (70%) were grade ≤ 2 events and two (6%) were grade 3; all events were reversible. Infection occurred in 14 (42%) patients. Peak CAR T-cell expansion was higher in patients with CRS and CAR T cells remained detectable in the blood in 57 percent of patients at 6 months following infusion, according to study findings. “CAR T-cell therapy is an important area of research for relapsed/refractory multiple myeloma patients where there remains a need for new options. We are encouraged by the expansion and persistence of the CAR T cells, as well as the deep and durable responses with a manageable safety profile we've seen for bb2121 to date,” said Kochenderfer. In November 2017, bb2121 was granted Breakthrough Therapy Designation by the FDA and PRIME eligibility by the European Medicines Agency based on preliminary clinical data from the phase I CRB-401 study. Kochenderfer, who has been working on CAR T-cell therapies for more than a decade, recognized the need for new treatments in multiple myeloma. And in 2010, he started work on a therapy for this disease. “My lab was the first to develop a CAR targeting BCMA. My group was also the first to report clinical results of anti-BCMA CAR T-cell therapy,” he noted. To date, he has participated in three clinical trials of anti-BCMA CAR T cells. “CAR T cells, especially anti-BCMA CAR T cells are a promising new therapy for multiple myeloma. This therapy has activity against advanced, treatment-resistant multiple myeloma,” he explained. “Patients appreciate CAR T cells because they often get several months of time when they do not need to take any multiple myeloma therapy. The patient with the longest response after anti-BCMA CAR T-cell therapy that I have personally treated has an ongoing response 3 years after treatment. “The bb2121 anti-BCMA CAR T-cell product is at the most advanced stage of development of any anti-BCMA CAR T-cell therapy,” he continued. “It is now in several multicenter clinical trials in the U.S., Canada, and Europe. The ultimate goal is to obtain FDA approval for bb2121.” And this is just the beginning. Kochenderfer and his team continue to develop new CAR T-cell therapies for multiple myeloma. “Improvements are anticipated,” he said. “I currently have two new phase I clinical trials open at the NIH. One is a trial of a new anti-BCMA CAR. The other trial is testing a novel CAR targeting a different protein called SLAMF7. Both of these trials are open to enrollment at this time.” Trials like this address an important area of need, according to Krina Patel, MD, MSc, hematologist/oncologist and Assistant Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. “A very vulnerable group among multiple myeloma patients are those who have relapsed on daratumumab,” she explained. “At that point they have usually had two proteasome inhibitors and two immunomodulatory drugs as well as daratumumab, so they are really out of options. That is where these trials are really helping some of these patients.” These positive results also open a window to other questions, Patel noted. “What if we used BCMA earlier? Could we utilize CAR-T therapies in the first- or second-line, instead of waiting?” Another area of study underway is CS1 CAR-T therapies. Tumor cells in 95 percent of all myeloma patients express this protein, according to Patel, making it a very promising target. Patel is currently working on an allogeneic study for CS1. “Patients who have relapsed on a BCMA therapy are often ineligible for other BCMA trials,” she noted. “Since our trial is focused on CS1, we allow patients who have received BCMA therapy to participate, which provides another option for these highly-refractory patients. “Additionally, since this is an allogeneic product, we don't have to wait 4-6 weeks to make cells and there are not as many issues with exhausted T cells,” she noted. “I think this approach has great potential for our patients.” Further Immunotherapy As outlined above, immunotherapy is a promising option for multiple myeloma patients and could result in long-term cancer remission. Two FDA-approved options for this patient population include the monoclonal antibodies daratumumab and elotuzumab that target the CD38 and SLAMF7 pathways, respectively. “Immunotherapy has changed some of our outcomes already,” noted Patel. “With the approval a few years ago of the monoclonal antibodies daratumumab and elotuzumab, we started seeing the effects of the immune system and how it reacts with the bone marrow and myeloma itself. And we continue to build on this with new immune therapies. “This area of study is exponentially growing,” she continued. “We're learning more and more about how the immune system works in myeloma. The other big thing we've learned with immunotherapy is that not only is everyone's myeloma different, but so are people's immune systems. And so, it is really important that we continue to learn all we can in order to ensure we provide patients with the therapies that are going to work best for them.” Novel Targets of Therapy Researchers are also focusing on another area of study that could lead to new avenues of care for multiple myeloma patients. One such effort is the Multiple Myeloma Research Foundation (MMRF) CoMMpass study, a research project that opened in July 2011 and involves tracking more than 1,100 patients with newly diagnosed active myeloma for at least 8 years. The aim of the study is to map the genomic profile of each patient to clinical outcomes to develop a more complete understanding of treatment responses. To date, findings from the study have shown that patients who received triplet therapy had better progression-free survival compared to those who received only two drugs, according to MMRF. Furthermore, researchers found that triplet therapy in combination with stem cell transplant had better outcomes than without. Researchers have identified 12 different molecular subtypes of the disease, each associated with its own level of risk. The subtypes include MYD88, IDH1/2, NRAS, and others. “We envision a future where each individual patient gets exactly the right treatment based on their specific disease profile, a reality that we're getting closer to achieving,” said Paul Giusti, President and CEO at the MMRF, in a press release. “With more than 80 abstracts and papers, CoMMpass continues to be an incredibly rich resource for driving new discoveries and progress for patients that brings us closer to this future, and we are thrilled to see so many researchers drawing from it as a resource.” Imaging Techniques Just as new therapeutic approaches have improved outcomes for multiple myeloma patients, newer imaging techniques are enhancing detection of the disease and leading to earlier treatment. However, there has been a lag in guidelines to help clinicians optimize the use of advanced imaging. That changed with the recent release of new recommendations—the first in 10 years (Lancet Oncol 2019; doi:10.1016/S1470-2045(19)30309-2). This International Myeloma Working Group (IMWG) effort, which sought to compile new recommendations for imaging techniques offering more sensitive and accurate diagnosis and monitoring for multiple myeloma and other plasma cell disorders, was led by Jens Hillengass. “Use of newer imaging techniques is changing the whole landscape, from diagnosis to treatment to supportive care to survivorship, and all those things are coming into this direction of research in multiple myeloma right now,” he noted in a statement. Along with Suzanne Lentzsch and Saad Usmani, Hillengass developed the guidelines, which were then reviewed by the entire working group. The team compared CT and X-ray imaging from several countries and found that utilizing only conventional X-ray misses 25 percent of patients who have bone destruction already and need treatment. “Myeloma has a very high incidence of osteolytic lesions, or bone disease,” Hillengass told HemOnc Times. “Given that there has to be destruction of 30-50 percent of the bone, sometimes up to 70 percent, before you see anything on X-ray, more advanced imaging is crucial for disease assessment as well as follow-up care.” The new imaging guidelines include a major change: replacing conventional skeletal survey with whole-body low-dose CT as the standard imaging technique for assessing bone destruction. The team recommends that this technique and others, including PET-CT and MRI, be introduced into clinical practice. According to Hillengass, the broader application of these newer imaging techniques could lead to more refined imaging as well as more accurate diagnoses and earlier treatment. “This could have a significant impact on how we approach treatment for patients with multiple myeloma,” he noted. “There's a lot of research underway now exploring whether incorporating more specific tracers or dyes into various imaging techniques will be beneficial, and also to figure out how we can assess minimal residual disease, or very low tumor burden after treatment,” Hillengass emphasized. “Therefore, we need much higher sensitivity and also functional information that cutting-edge imagery can provide. There are important questions still to be asked as these technologies evolve.” Commitment to a Cure Multiple myeloma has seen a positive shift in its outlook for patients, but where do these advancements lead? Researchers are now trying to determine how to combine these various treatment approaches to provide the best care. However, this can be a difficult endeavor, according to Crilley. “The most pressing challenge for oncologists at present is that, although we have a number of effective therapies, we do not yet understand the best combination and sequence to afford the most effective and most durable outcomes in our patients.” With the ongoing progress in multiple myeloma treatments, hematologist/oncologists are dedicated to their pursuit of a cure. “I believe the evolution began with the development of immunomodulatory drugs (thalidomide/lenalidomide) followed by the proteasome inhibitors (bortezomib), which led to an expansion in the role of high-dose therapy and stem cell transplant resulting in the attainment of complete responses in the majority of patients,” noted Crilley. “Despite this, the goal of curability has not been achieved. Further development in identifying minimal residue disease coupled with the addition of targeted treatments such as the monoclonal antibodies daratumumab and elotuzumab as well initiation of immune therapy such as CAR-T offer the true hope of curability. “The ultimate goal of multiple myeloma treatment is to cure the disease with the least short- and long-term toxicity as possible. That goal will only be achieved through ongoing research to identify and eliminate minimal residue disease,” she continued. “This will be accomplished by ongoing bench, translational, and clinical research using the current crop of effective drugs as well as the development of new ones.” While Hillengass is not convinced that a broadly curative therapy for multiple myeloma has been developed yet, he believes there's reason to expect expanded survival benefits from new treatments and combinations. “New treatment options, including cellular therapies, and new combination approaches have significantly improved the survival of myeloma patients, but we're still waiting on proof that a significant number of patients have been cured by them,” he said. “I do hope, though, that approaches to initiate treatment earlier and continue it for a longer duration will soon lead to life expectancies for patients with the disease that are not very different from those of people without myeloma.” Catlin Nalley is a contributing writer. One Patient's Journey With Multiple Myeloma Rita Lakes, MD, a retired pediatrician, was diagnosed with multiple myeloma in June 2009. Her treatment journey is an example of the advancements that continue to be made in the field, but also how far there still is to go to enhance patient care and find a cure. Lakes received her first autologous stem cell transplant in November 2009 that led to a remission of 1.5 years. In January of 2012, a case of Tic Convulsive disseminated shingles, with an extensive hospital stay, complicated her treatment, she told HemOnc Times. After being referred to MD Anderson in April 2012, she underwent several courses of chemotherapy and received a second autologous stem cell transplant in January of 2013, which resulted in a 14-month complete remission. “Treatment for multiple myeloma was brutal. The side effects from the medicine including neutropenia, thrombocytopenia, and electrolyte and neurologic disturbances with decreased immune function became almost unbearable even though expected,” she explained. “The brain fog from chemotherapy with word recall difficulty, problems with short-term memory, and forgetfulness were often worse.” Lakes participated in an initial CAR T-cell BCMA study at NIH from September to November 2014 with subsequent progression of her disease. Following numerous courses of chemotherapy at MD Anderson, she underwent another CAR T-cell trial at NIH in February 2017. Her apheresed cells from the initial study were utilized and resulted in a complete, stringent remission until June 2018. “Having had two stem cell transplants and numerous failures on various chemotherapy regimen, I was elated when there was an experimental NIH CAR T-cell study that potentially could be as effective as a transplant and also a potential treatment modality for future myeloma patients where a curative therapy had not been found,” Lakes explained. “The biggest thrill came in 2017 when I became eligible for the second treatment with the therapeutic dose of CAR T-cells. “This was the most dramatic treatment in my history. Within a few minutes after treatment, I could feel numerous plasmacytomas in my body resolve,” she recalled. “The results were miraculous. Even though I had the hoped-for cytokine response and was transferred to ICU, I emerged feeling better than I had in years. I had a 14-month drug-free remission. This was as good as a stem cell transplant with much fewer side effects.” Today, Lakes' disease is managed by Krina Patel, MD, MSc, hematologist/oncologist and Assistant Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center. Lakes' multiple myeloma is controlled by carfilzomib, daratumumab, dexamethasone, and pomalidomide. “Dr. Lakes case is a very unique one,” Patel said. “She was receiving drugs as they were getting approved. Additionally, she was the first patient to receive CAR T-cell therapy for multiple myeloma, placing her at the forefront of treatment. Her experience not only helped her, but it will also help other patients as we learn more about what CAR T-cell therapy can offer.” When discussing the outlook for newly diagnosed patients, Lakes shared a positive perspective. “It has been my experience that with research another drug or treatment modality will soon be released,” she said. “The FDA has approved many chemotherapeutic agents since my diagnosis. Many of the clinical trials had not been discovered, or released, at the time of my diagnosis. Hope abounds and the future is bright for those starting therapy.” A Patient's Perspective From Rita Lakes, MD On the challenges of treatment “The most challenging part of my treatment has been negotiating the various medical disciplines, coordinating with each other, and being referred back and forth. Any lack of communication is in addition to the harrowing side effects brought about by the chemotherapy itself. The immune compromise subjects one to isolation in order to prevent contracting communicable illnesses and preventing emergency room and additional clinical/hospital visits.” On the importance of clinical trials “I feel that clinical trials are important for the advancement of medicine. For those of us with chronic diseases, or incurable diseases with poor prognosis, clinical trials expand the knowledge of researchers in cutting-edge treatments for the future and give present day hope for us now undergoing treatment. I have the satisfaction that the CAR T-cell trials will be refined and modified so as to eliminate the need for more toxic chemotherapies or stem cell transplants, with the down time associated with them, and that CAR T will potentially provide a cure for an otherwise incurable cancer.” On what oncologists need to know “Dr. Patel's group has communicated well with other disciplines over the last 1.5 years. Oncologists are encouraged to have ongoing communication with all medical departments and physicians administering care to their cancer patient and make sure the patient knows how well the overall medical team is focused on providing complete care to them as they fight for their lives.”

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.