The 2021 International Myeloma Working Group Summit, held virtually June 22-23, provided a rare opportunity for over 100 of the top myeloma experts from around the world to actively discuss topics of the greatest current importance in myeloma. The participants took full advantage of the opportunity to have lively discussions and make plans for future research collaborations. Here are some of the key takeaways that will positively impact the future of myeloma:
Role of Immune Markers
In an effort to understand patterns of progression and relapse, much of the Summit discussion centered around immune regulatory mechanisms. Does myeloma progress because regulating T cells become exhausted? And if so, is there a routine way to track that?
Wise counsel was provided by colleagues from Spain (Salamanca and Pamplona) reminding the group that there are multiple, complex changes over time, and it will still take several careful studies to gather necessary data to make recommendations. There was particular interest both in patients with high-risk smoldering multiple myeloma (HR SMM) who progress (or not), as well as patients with low-level residual disease after therapy who remain stable or progress. Sophisticated 47-color next-generation flow cytometry (NGF) and single-cell studies are underway to help provide guidance.
A Need for a New Look at Patients with Early Disease
Tiny ‘spikes’ on mass spectrometry
Using mass spectrometry, tiny monoclonal proteins are detectable at a very early time point. As many as 30% of such tiny “spikes” can disappear over time, having been triggered by infection or some other immune reaction. What name should we use for such “pre-MGUS” patients? For patients who develop persistent MGUS, how should we classify those who are predicted to remain stable for 10 or 20 years using the new 2/20/20 SMM scoring system versus those likely to progress within 1 to 2 years?
The consensus at the Summit was that the latter group should be considered much more like myeloma and that early treatment of some sort should be offered, especially for ultra-HR SMM (2/20/20 score of at least 12).
What Treatment to Use for Early Disease?
At the Summit, the question then became “what type of treatment?” A minimum of lenalidomide (Revlimid) was recommended, with the idea that this should be “the control arm preventing or reducing disease progression” in planned randomized phase III trials. The alternate notion is to continue phase II trials to assess if more aggressive approaches can achieve cure for some patients. The strange paradox is that it will take so many years (most likely longer than 20 years) to confirm the value of triple or quadruplet combinations or more aggressive approaches in achieving long-term, disease-free remission or cure.
Sustained MRD negativity during remission provides an excellent indicator of long-term benefit, but truly only time will tell. We hope that using mass spectrometry (or other new and innovative testing) in this setting can become a reliable indicator of potential early relapse.
The Importance of Real-World Data
Access to trials in patients with advanced disease
Dr. Morie Gertz (Mayo Clinic, Rochester, MN) raised the question of how to manage relapsing patients in the real-world setting. Unfortunately, a majority of patients are not eligible for current clinical trials because a patient’s health status needs to be good (not the case for many patients) in order to assess potential toxicities of new/untested agents or combinations. So, how can we solve this problem?
Clearly, early, careful testing of new agents is required for safety reasons. But next-level trials can perhaps explore more challenging situations, such as those patients with very low blood-count levels or compromised kidney or liver function.
Including FDA and EMA Representative in Future Summit Discussions
IMWG researchers and our industry partners suggested that representation from the U.S. Food & Drug Administration (FDA) and European Medicines Agency (EMA) be considered at future meetings to help address these key clinical trial issues. There was enthusiasm to make this happen, along with the incorporation of much more real-world data outcomes analyses incorporating quality of life assessments. From these, better priorities can be established for drug selection and creation of optimal doses or schedules for emerging agents and combinations.
Disparities in Clinical Trials
At the Summit, myeloma researchers expressed great interest in addressing disparities in clinical trial access and accruals. There was an acknowledgement that currently existing major social disparities make this an especially difficult problem to solve. But there was a major impetus to seek changes to improve access for all disadvantaged groups.
Immune Therapies Registry and Virtual Tissue Bank
In the future, being able to measure the efficacies and toxicities that occur when various immune therapies are used sequentially is extremely important. The IMWG Immune Therapy Committee, chaired by Drs. Tom Martin (UCSF) and Yi Lin (Mayo Clinic), has moved quickly to establish a framework for an IMWG Immune Therapies Registry. The Registry will collect data in a serial fashion for patients receiving the new immune therapies, including those with BCMA as a target such as belantamab (Blenrep); anti-BCMA CAR T-cell therapies (ABECMA and cilta-cel); as well as several bi-specific antibodies currently in trials. We already know, for example, that bi-specifics can be effective after other BCMA-targeted therapies.
The full details of the Immune Therapies Registry, housed at UCSF, will be increasingly important in the coming years as more and more agents receive FDA approval and become widely used.
The virtual tissue bank
A Virtual Tissue Bank has been in development for some time as part of the Asian Myeloma Network (AMN), a research division and clinical trials group of the IMF. Dr. Wee Joo Chng (University of Singapore) has set up the system in which all participating centers are allowed to retain tissue samples at their home sites rather than sending for testing elsewhere. The system is essentially a computer network for data sharing. But beyond just data collection and sharing, standardization of tissue collection and analyses is encouraged to enhance collaborative efforts.
This system is now under development for the Immune Therapies Registry group and is now moving forward.
COVID-19 Vaccination for Myeloma Patients
Dr. Evangelos Terpos (University of Athens, Greece) delivered the Summit Keynote Lecture on COVID-19 vaccination for myeloma patients, which was greatly appreciated. There was much disappointment in learning that some of the newer immune therapies, such as anti-CD 38 and anti-BCMA approaches, really impaired neutralizing antibody responses required for immunity against COVID-19.
Discussion evolved to consider use of third “booster shots” for myeloma patients on such therapies and/or with low blood-lymphocyte levels (another risk factor). A trial to assess the value of the booster will begin very soon in Greece. Another potential trial will include the use of monoclonal antibodies against COVID-19 (such as a Regeneron product available in the U.S.) as an early intervention or even a preventative approach for those at highest risk of COVID complications.
Bottom Line for the 2021 IMWG Summit
The 2021 Virtual IMWG Summit was a resounding success. The open Zoom format allowed active discussions in a very intimate fashion. In closing, myeloma researchers from around the world expressed their appreciation for the opportunity to participate. Despite this success, everyone is looking forward to the return to our normal in-person gathering. The Robert A. Kyle Lifetime Achievement Award and Brian G.M. Durie Outstanding Achievement Award recipients (Dr. Nikhil Munshi and Dr. Shaji Kumar respectively) received heartfelt congratulations in this virtual space, along with celebratory photo montages of their lives. But we are all looking forward to next year’s Summit, when we can honor the 2020, 2021 and 2022 IMWG Award recipients with live musical accompaniment from our IMWG musicians Dr. Vincent Rajkumar and Dr. Philippe Moreau. Then we will feel we are really back to a new normal.