It’s the middle of the year—the best time to provide a mid-year science update on the status of myeloma care, especially with the recent conclusion of several very important events this month: the American Society of Clinical Oncology (ASCO) annual meeting in Chicago, IL and the European Hematology Association (EHA) annual meeting in Frankfurt, Germany, where top abstracts in myeloma research were presented and discussed in detail by pre-eminent myeloma experts across the globe.
Additionally, June has been a very exciting month for members of the International Myeloma Working Group (IMWG), as it held its annual summit in Frankfurt as well. It was here that the International Myeloma Foundation (IMF) proudly honored this year’s research achievement awardees during an in-person awards ceremony, with Maria-Victoria Mateos, MD, PhD (Head of Myeloma and Clinical Trials Unit at the Haematology Department and Professor of Medicine at the University of Salamanca, Spain) receiving the highly acclaimed Robert A. Kyle Lifetime Achievement Award; and Thomas G. Martin, III, MD (Professor of Clinical Medicine; Associate Chief of Adult Hematology, Blood Marrow Transplantation and Cell Therapy; Co-Director of the Myeloma Program; and Clinical Research Director of Hematologic Malignancies at UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco Medical Center) receiving the prestigious Brian G.M. Durie Outstanding Achievement Award.
Again, my warmest congratulations to both for this well-deserved recognition. Now, on to my mid-year science update, as we enter a new era of myeloma care.
Evolution to the Era of Immune Therapy
Over 20 years ago, we transitioned from chemotherapy to what was called “novel therapies” at the time.
Instead of using VAD [vincristine, Adriamycin (doxorubicin), plus 4 days of high-dose dexamethasone], an intravenous chemotherapy combination which causes hair loss, we switched to using VRd [bortezomib (Velcade), lenalidomide (Revlimid) plus low-dose dexamethasone ]—a novel therapy which was much more effective and better tolerated.
Now, with the introduction of immune therapies, we are transitioning to immune plus novel therapy combinations. In the frontline setting, daratumumab is added to the VRd to give Dara-VRd (quad or 4-agent regimen) for transplant eligible patients and Dara-Rd for transplant ineligible and/or frail patients with the emerging strategy to introduce engineered CAR T cells and/or bispecific antibodies early in the disease course to achieve even better outcomes.
How exactly the landscape will change remains to be seen, but the fact that novel therapies had overall response rates (ORR) of 20 -30% in the relapsed/refractory multiple myeloma (RRMM) setting whilst CAR T cells and bispecifics have ORRs of over 60% to close to 100% in RRMM raises great hope that a revolution is underway with the prospect and expectation of dramatically longer remissions and quality of life for myeloma patients.
Results from 2023 ASCO, EHA, and the IMWG Summit: What the Data Show
Top Abstract at ASCO and EHA 2023: The CARTITUDE-4 Trial
The results of the CARTITUDE-4 trial were presented as part of a special CAR T session at ASCO and as an oral presentation at the EHA Plenary Abstracts Session.
This trial evaluates CAR T treatment with cilta-cel (ciltacabtagene autoleucel) CAR T cells versus standard of care (SOC) novel therapies in the early relapse setting. Results indicated a 74% reduction in the risk of progression, with CAR T cells versus SOC treatment. The rate of complete response (CR) plus stringent complete response (sCR) was 73.1% with CAR T versus 21.8% with SOC. At current follow up, the SOC median progression-free survival (PFS) is 11.8 months and has not yet been reached for CAR T.
This is similar to the results of the KarMMa-3 Trial, which compared idecabtagene vicleucel (Ide-cel) CAR T with SOC also with substantial PFS benefit for the CAR T approach . Results were also superior to results of using CAR T in the RRMM setting in both cases.
The use of CAR T cell treatment in this earlier disease setting is very promising.
Access to CAR T Cell Therapies
A key aspect of CAR T cell therapy is that it can only be given in specialized centers—limiting broad access at this time. Access was also limited by supply issues brought about by the COVID-19 pandemic.
In addition, the process of collecting the patient’s own T cells, engineering them to attack the myeloma, and growing enough T cells to do the job takes several weeks, during which time the so-called bridging therapy (treatments between apheresis and lymphodepleting chemotherapy) is required to keep the myeloma under control.
At the ASCO and EHA annual meetings, data on several new CAR T therapies were presented: ALLO-715; PHE 885; GPRC5D; LUMMICAR-2; CAR T ddBCMA; as well as Fast CAR-T GC012F; CAR-NK; and dual CAR T, to mention a few.
Thus, new and better CAR T therapies may become available, to speed up and simplify access. In the meantime, while this is a wonderful treatment, the lack of broad access is definitely an issue and concern. The fact that CAR T therapy is usually a single treatment with the patient then being followed off treatment is a very attractive feature which will definitely spur efforts toward broader access.
Emerging Data with Bispecific Antibodies
In addition to CAR T cell therapies, many new bispecific monoclonal antibodies are moving through clinical trials with even more on the way.
At ASCO & EHA a whole range of publications and posters dealing with the bispecifics were presented, including Abstract e20034; Abstract e20049; Abstract 8022; Abstract 8041; Abstract TPS8064; and Abstract 8033.
The greatest interest was focused on the first results from the RedirecTT-1 Trial, a study evaluating the impact of two bispecifics given together simultaneously. These antibodies targeted BCMA (using teclistamab that has already been approved by the FDA in RRMM ] and GPRC5D (using talquetamab; under study as a non-BCMA targeting bispecific). This double combo was evaluated in a dose finding phase 1b trial in which 33% of patients had high risk genetics and 32% had extramedullary disease (EMD).
The side effects were significant as expected and included infections such as pneumonia, fatigue, and reduced blood counts . At the expansion (MTD) dose level, the results were impressive—with an ORR of 96.3% and with 40.7% of patients achieving CR or sCR.
An unexpected finding was the very high response rate of 85.7% in patients with EMD; 28.6% CRs. These responses were confirmed using whole body PET CT scanning to demonstrate the disappearance of multiple soft tissue lesions (plasmacytoma) throughout the body. Further studies are already planned for this important high-risk subgroup with an unmet need for active therapy .
This double targeting is a whole new way forward, which can apply to both bispecifics and CAR T approaches. With many early promising results, it is hard to say what can become the new Standards of Care (SOC) 5 years from now. The many new trials throughout the course of the disease will shed light on the best path forward.
Important Output from the 2023 IMWG Summit
The members at the 2023 IMWG Summit noted the numerous myeloma reports at 2023 ASCO and EHA. The considerable number of topics encompassed not just immune therapies but also the whole range of real-world study results, patient preferences, the importance of infections with new immune therapies and combinations and related quality of life issues (especially at EHA).
Follow-up studies with belantamab (DREAMM trials with Anti-BCMA drug conjugate; currently, belantamab is no longer approved in the U.S.), selinexor and cereblon E3 ligase modulatory drugs (CELMoDs) were presented, as well as newer and more unique approaches such as data related to arginine deprivation. There was much to think about and to discuss at the IMWG Summit.
High-Risk Smoldering Multiple Myeloma (HR SMM)
There were important discussions during the summit on new ways to improve the current 2/ 20/20 classification system based upon the level of myeloma protein (2 gms/dl) bone marrow plasma cell percentage (20%) and FREELITE ratio (20).
Looking at changes over time seems to be the most popular approach (dynamic model) with further studies planned. In addition, the most acceptable endpoints for trials are being re- considered since overall survival is such a difficult routine endpoint.
We need correlates, such as sustained MRD negativity which can be acceptable surrogates. Current status of reviewing MRD as a surrogate was also discussed. It is hoped that additional trials incorporating MRD testing that are now available can provide sufficient data in achieving the required levels of cross correlation between PFS and MRD negativity, in order to secure FDA approval.
The Role of Mass Spectrometry and Next Generation Flow (NGF) Testing
Mass Spectrometry—a very sensitive technique for measuring the level of myeloma protein—is moving forward to full commercialization. This entails knowing how to interpret results using this powerful new technology. Negative results, especially with the high-resolution method (versus the standard lower resolution method), indicate excellent response to treatment at a depth of response deeper than CR or sCR.
This is very helpful information. Sustained Mass Spec negativity can be especially good news for the patient and may mean that a follow-up bone marrow test can be delayed. Obviously, uses related to screening, diagnosis, monitoring, and relapse assessment are all under review. It is helpful that the cost of an individual test is low, although the cost of the initial outlay for equipment is high.
Next Generation Flow (NGF) MRD Testing
Next-Generation Flow (NGF) testing for MRD assessment is another powerful test which is also in the process of moving forward to full commercialization. Sensitivity can be at 10-5 level or greater and can strongly indicate an excellent deep response. As noted, the first step is to obtain FDA approval to utilize NGF (or Next-Generation Sequencing/NGS at similar sensitivity) for response assessment within clinical trials. This is under review at this time and the i2TEAMM is optimistic for a positive outcome.
In the meantime, there is considerable appetite for using MRD testing in clinical practice to document excellent deep response. Unfortunately, guidelines are urgently required to ensure that results provided to the clinician are reliable and accurate.
Standardization is required for the following: time point for testing; sampling method to avoid dilution of blood (versus bone marrow); transport of samples; laboratory reporting and interpretation. The IMWG Working Group is fully aware of these issues and guidelines will, indeed, be forthcoming in the near future.
Trend for the Future
With the introduction and assessment of new testing methodologies, as well as multiple and very active new therapies, it is crystal clear that 2023 moving towards 2024 and beyond has become a very exciting and rapidly changing time for myeloma management.
Talk to and work closely with your doctor to see what applies to your case or situation.
This is also the best time to contact the International Myeloma Foundation (IMF) to seek expert consultation. To achieve the best outcomes, get the very best advice possible and keep all options open for the exciting path ahead.