Friday was a light day, program-wise. Even so, I was immersed quickly into the bright lights of ASH. I learned a lot by attending an excellent symposium, Adapting Clinical Practice to a Rapidly Changing Therapeutic Landscape in Multiple Myeloma, moderated by Dr. Brian Durie (IMF & Cedars-Sinai), and including myeloma specialists Dr. Jesus San-Miguel (University of Navarra, Spain), Dr. Philippe Moreau (University Hospital of Nantes, France), Dr. S. Vincent Rajkumar (Mayo Clinic, Rochester), and Dr. Thomas Martin (UCSF). This program detailed various case studies along the myeloma continuum.
The first dealt with smoldering multiple myeloma (SMM), which I’ll be focusing on: Evidence for Treating High Risk Smoldering Multiple Myeloma. The definition of high-risk smoldering myeloma (HRSMM) was reviewed, and the details of a case study were outlined. The experts weighed in on whether to treat or not, and if so, how? Interestingly, there wasn’t a consensus about treating, which highlights a challenge those with smoldering myeloma may face. Those who are high-risk can enter treatment through a clinical trial, and possibly off-trial, too, and thus clear-cut decision points don’t exist. The experts highlighted that the rationale for early treatment is either to delay progression or to cure the disease.
Discussion ensued, and it was really interesting to follow along with these specialists as they considered key data points and rationales for one approach over the other. In the end, I came up with these takeaways:
Patients with HRSMM should be followed very closely, approximately every two months, as progression consists of an evolving pattern of change.
Use SLiM CRAB for treatment guidance, as the goal is to treat before active CRAB symptoms are evident.
Progression is hard to capture at the moment, as it happens between visits (see #1 above).
Dr. San-Miguel predicted that the 2 in the 20/2/20 risk progression model may be replaced with .2 in the future.
Although not discussed, the question about who decides treatment in HRSMM arose. Specifically, how much input should patients have, or should the physician decide exclusively? I wish they discussed this.
Dr. Thomas emphasized the importance of gathering and observing trends in key myeloma markers; he wants to see “the movie,” versus individual snapshots.
December 11, Saturday
As the first official day of ASH 2021 began, I had the opportunity to sit in at the International Myeloma Working Group breakfast, where investigators shared some research highlights. This was fascinating as the best in the myeloma world asked questions and discussed recent findings…wow!
I also attended a variety of other presentations. A couple of key points that I’d like to share are as follows:
Results from the iStopMM (Iceland Screens, Treats, or Prevents Multiple Myeloma) project are coming out. If you don’t know about this project, it is really quite amazing! Iceland has been able to screen about half of its adult population (40+ years old, over 75,000 people) for MGUS and SMM, via M-protein and abnormal FLC ratio. The prevalence of SMM in the total population is estimated to be about .5%, with prevalence increasing with age. Of those with SMM, about a third were considered to have intermediate or high risk SMM. Risk was assessed with both the Mayo 20/2/20 model and the Spanish model, which resulted in 55% agreement. They concluded that a need for improved risk stratification exists. A future direction with this data is to continue to follow these individuals, as well as to explore the possibility of familial connections, correlations with autoimmune issues, and psychological outcomes related to knowledge of having SMM.
Early research is looking at the possibility of following smoldering myeloma via liquid biopsies (i.e., from plasma) versus bone marrow biopsies (BMB). BMBs, which are currently the “gold standard,” are invasive and often painful, and thus, are done at diagnosis and then later when other labs show that progression may be occurring. They also tend to be “patchy,” meaning that results are somewhat sample-dependent. Two papers (Garces and Dutta) highlighted the possibility of liquid biopsies, comparing results to BMB. The early work looks promising, so we’ll have to stay tuned in the coming few years on this front.
I’m not finished with Day 1 yet, as I’ll be attending one more oral session and then, at least six poster presentations. My general impressions are that ASH certainly brings the best and brightest together as they shine light in the myeloma space. I’m taking in as much as I can, and I hope that what I share is of interest and value to you!
The first official day of ASH activities started at 6:30 a.m. with the International Myeloma Working Group (IMWG) Breakfast Meeting. The IMWG is exactly that — a working group of myeloma experts from across the world, who come together periodically to investigate and create new guidelines for everything myeloma. They form different subgroups to review, collaborate, and make recommendations for new, up-to-date guidelines on many topics.
What a blessing it is to be in a room with this much talent and passion for myeloma! I feel very honored to have been given this opportunity to experience such collaboration and cooperation between experts for the good of myeloma patients all over the world.
Now, on to the oral presentations. Some highlights from Day 1 include:
Exciting information coming from the most recent update of the Griffin Study. This study is looking at Dara plus RVd in patients with ASCT eligible Newly Diagnosed MM and updated analysis includes subjects after 24 months maintenance treatment. It appears that the quad therapy yielded 81% MRD negative subjects vs the 44% with only the triplet VRd therapy. We know that sustained MRD Negativity is more important than one snapshot, but so far, 6-month and 12-month MRD negativity remain improved with quad therapy. Will this study further direct quad therapy as SOC in induction therapy and then dual therapy in the maintenance phase?
Also, final analysis of the BELLINI study supports a biomarker-driven approach in the current Venetoclax development program in t (11;14) RRMM. Consistent results from this study are showing improvement in PFS and OS in patients with t (11;14) or BCL2 high expression.
Liquid biopsies are gaining strength in research! Will checking circulating plasma cells in initial workups of patients and monitoring throughout disease management be the new standard, rather than serial bone marrow biopsies?
For many studies, one of the AIMS is to eliminate dexamethasone from the commonly used regimens. This is good news when it comes to quality of life for myeloma patients. In the future, we may be able to remove this drug that, while effective, causes many patients so many side effects that affect quality of life.
Bispecific antibodies are up and coming! Different targets are being researched including BCMA and GPRC5D, among others. Promising data from Phase I studies, doses are being escalated and safety profiles are being identified.
iStopMM is a screening that is an unbelievably HUGE undertaking, giving endless amounts of data and assuredly, for years to come! Symptomatic screening for MGUS hasn’t been studied before, and the study’s aim states to determine if early detection can lead to the possibility of cure. Less than 2-6% of myeloma patients are diagnosed at precursor states. So how can we find them early? This Icelandic study had around 150,000 subjects show interest, with about 75,000 screened in the study. Of this group, 3,725 patients were found to have MGUS. Then this group blindly randomized into 3 arms: Arm 1 (current standard of care), Arm 2 (current IMWG guidelines), and then Arm 3 (more intensive follow-up). Initial findings are promising, but no recommendations are to be made until further research continues. Additional study looked into MGUS and COVID-19. Of 72,000 eligible subjects, 32,000 were tested. Results show that MGUS does NOT increase risk of contracting COVID, nor does it make the effects of the virus more severe, if infected. GOOD NEWS! Ideas for future research on this study population include evidence of chronic allergies/auto immune diseases/familial linkage —an important and expansive research!
Reports given for dose expansion phase of iberdomide — a novel IMiD therapy, like Rev/Pom, but big differences exist. Iberdomide is tumoricidal, while Rev/Pom are not. Also, side effect profiles are completely different, as iberdomide appears to be more easily tolerated, with typical IMiD-related events like GI effects, rash, and fatigue not noted. This is exciting news, again, for quality of life!
Final thoughts of the day: new and upcoming promising therapies are simply not cost-efficient or accessible for most patients. How do we improve access to these new therapies that can offer so much hope? For some patients that do not have access to large academic centers with myeloma specialists actively involved in their care, will these therapies remain unreachable to them? How do we bridge the gap? Food for thought!
Also, I am grateful that so many studies have a focus of improving quality of life for patients. This should ALWAYS be the AIM. Some thoughts from an oncology nurse, who is passionate about myeloma and from our 10-month-old, 110-lb. Newfoundland puppy, Bean, who just wants to have some attention today.
In my scientific career as a protein scientist studying protein misfolding, I’ve always been a little protein-centric in my view of biology. It’s a bit ironic because I work at an academic institution that is an RNA mecca, where many of my colleagues are doing amazing research understanding the role of RNAs in biology.
Simplistically, proteins do all the work in the cell. DNA gets all the glory, but RNA is the master regulator controlling the fate of each cell. How exciting it was for me to see proteins (specifically antibodies) playing such a major role in myeloma treatment on this first day of #ASH21!
One of the biggest take-home lessons for me today: Darzalex® (daratumumab) is the current “darling” of myeloma treatment strategies. Maybe I’m being biased because I love proteins, but it was awesome to see proteins as powerhouses of therapy in myeloma. There were many talks that discussed clinical trial data showing daratumumab and other CD38+ antibodies’ increased progression-free survival when added as a 4th agent to standard triplet regimes in newly diagnosed patients or when included as part of a new triplet regimen for relapsed myeloma.
During the International Myeloma Foundation sponsored session on “Adapting Clinical Practice to a Rapidly Changing Therapeutic Landscape in Multiple Myeloma”, there was a related thought-provoking discussion led by Dr. S. Vincent Rajkumar (Mayo Clinic – Rochester, MN) on the importance of shared decision-making between myeloma patients and their myeloma specialists when making decisions about next steps in treatment because of the complexity of issues that each patient faces.
For patients who are refractory to immunomodulators, proteasome inhibitors, and CD38+ antibodies, clinical trial data reported showed BCMA-targeted therapies to be very promising, with response rates of >60% in heavily pretreated myeloma patients. These therapies include FDA-approved CAR T cells and the antibody drug conjugate Blenrep® (belantamab mafodotin), which has a manageable ocular toxicity. Additionally, several bispecific T cell engagers (BiTEs) are anticipated to obtain FDA approval in the next few years. These BCMA-targeted therapies are changing the treatment landscape for relapsed/refractory myeloma and providing new hope.
I found myself thinking a lot about shared decision-making between a myeloma specialist and a patient whenever there is a progression of disease. Making a next therapy decision is a very personal decision — influenced by toxicities, comorbidities, cost, access to care and so many other things. For me, I tend to want to focus on hitting my myeloma hard to prevent the development of drug-resistant clones so I can be around long enough to see my four kids become thriving adults.
I’m grateful that I moved to a combination CD38+ antibody/immunomodulator/steroid therapy line at the very first hint of relapse, right when the pandemic started. I am so grateful for my myeloma specialists, Dr. Muthalagu Ramanathan (UMass Memorial Health Care – Worcester, MA) and Dr. Giada Bianchi (Dana-Farber Cancer Institute – Boston, MA) who have helped me navigate my own therapy decisions.
I enjoyed following the #ASH21 meeting on Twitter, including attending my first @TwitterSpace today hosted by Dr. S. Vincent Rajkumar. I also smiled when I read this tweet about a talk by Dr. Nina Shah(University of California – San Francisco, CA) :
I’m glad that my myeloma specialists and I are “cool,” as I am using daratumumab for a 2nd line. I’m also excited about all these other key points about treatment options for relapsed/refractory myeloma, and I am looking forward to learning about other new targets in the pipeline, like CELMoDs and other immunotherapies in the days ahead.
Today, I heard data that made me even more confident about my decision to start a new line of therapy 21 months ago. I learned that circulating tumor cells predict risk of progression for smoldering myeloma patients. I also really enjoyed a talk by Dr. Giada Bianchi which discussed the role of the tumor microenvironment in the progression from MGUS to SMM to myeloma. I enjoyed thinking about how changes in the bone marrow milieu can influence progression of myeloma, and it was striking to me that changes in both protein and miRNA levels were playing a role in this interaction between the bone marrow components and the plasma cells in a way that leads to progression.
Specifically, bidirectional exchange of exosomes (vesicles that deliver lipids, proteins and nucleic acids) between myeloma plasma cells and components of the bone marrow niche supports pathogenesis. As a scientist, it makes sense to me to hit my myeloma hard to limit the development of new myeloma clones, and I’m so grateful that I, so far, have been able to manage the side effects of treatment and to continue teaching that I love.
It seems like proteins are indeed becoming powerful players in the development of new therapies, and new technologies like single-cell RNA sequencing will also help develop new biomarkers and therapies for myeloma patients with aggressive disease.
The Friday before the official start of ASH is always considered as Symposium Day. Symposiums typically last a couple of hours and involve several myeloma expert doctors discussing patient cases and various treatment options. Patient cases can vary from smoldering to newly diagnosed, to early and late relapse, and along with them — the consideration of risk factors and comorbidities.
These meetings are sponsored by advocacy organizations: the International Myeloma Foundation, Healthtree Foundation, Research To Practice, as well as Pharma companies. While they don’t include new information that will subsequently be presented at ASH, they provide treatment suggestions currently approved by the FDA as well as consideration of ongoing clinical trials.
In particular, my goal was to listen for insights provided by the specialists and to offer those takeaways in this blog.
After attending 3 symposiums, here’s what I heard:
At an Education Program discussing high-risk MM (HRMM), Dr. María V. Mateos (University of Salamanca – Salamanca, Spain) remarked: “While there’s no specific treatment for HRMM, our goals should be to provide continuous therapy and focus on getting MRD (minimum residual disease) as low as possible.”
Dr. Suzanne Lentzsch (Columbia University Medical Center – New York) noted an important study from Dr. Rafael Fonseca (Mayo Clinic, Rochester, MN) which showed “that 57% of non-transplant eligible patients only get 1 Line of Therapy, so many patients are not getting newer treatments.” [Personally, I’m trying to track down this report.]
Dr. Noa Biran (Hackensack University Medical Center – Hackensack, NJ), when treating relapsed MM, suggested using the TRAP algorithm when making subsequent treatment decisions. T=Timing of relapse; R=Response from prior therapy; A=Aggressiveness of disease; and P=Performance status. This algorithm was reiterated by Dr. S. Vincent Rajkumar (Mayo Clinic, Rochester, MN).
Dr. Biran also noted that “triplets outperform doublets in early relapse.”
Dr. Philippe Moreau (University Hospital Hotel Dieu — Nantes, France) noted that an upcoming study for newly diagnosed MM will show no benefit of adding Ninlaro® (ixazomib) to Rev-dex maintenance.
For non-transplant eligible patients, Dr. Moreau noted: “I think DaraRd till progression [Maia study] is the best treatment for elderly patients. Dr. Rajkumar countered “But VRd for 6 months, then Rev maintenance is more cost-effective, easier on the patient, and also provides excellent results so either treatment choice is okay.”
Dr. Rajkumar’s principles for selecting treatments for relapsed MM: 1) use a triplet; 2) change 2 drugs; 3) consider a transplant; 4) consider a clinical trial.
Dr. Thomas Martin (University of California SF – San Francisco, CA) predicted: “Ultimately bispecifics will be used in all lines of therapy and CAR T will replace transplant.”
Dr. Morie Gertz (Mayo Clinic — Rochester, MN) “If Blenrep® is working, don’t give up due to ocular side effects. Rather, try dose adjustment, give less frequently, even adding prednisone has helped with eye effects…don’t give up.”
For triple-class refractory patients, both Drs. Martin and Gertz commented that the alkylating agent cytoxan should be considered if it hasn’t been previously used.
That’s it for tonight. My first meeting tomorrow is at 3:30am PST so it’s early to bed for Day 1 of ASH!
Wow, what an inspiring and exciting day! So much information was jampacked into a few hours! I attended the IMF/CCO Satellite Symposium entitled Adapting Clinical Practice to a Rapidly Changing Therapeutic Landscape in Multiple Myeloma.
A panel of experts discussed six different case studies, including the ability to vote for chosen treatment strategy prior to discussing the case study, and after. This type of approach made me realize how much I DO know about myeloma, because 95% of the time, I choose the treatment option that the majority of attendees choose. However, it also made me realize how much I DON’T know and how much there is still to learn!
The five expert panel members were Dr. Brian Durie (Cedars Sinai L.A.), Dr. Vincent Rajkumar (Mayo), Dr. Thomas Martin (UCSF), Dr. Phillippe Moreau (Nantes, France), and Dr. Jesus San-Miguel (Pamplona, Spain). What a powerhouse of knowledge and deep understanding of myeloma this group has! I was blown away — not just by their knowledge, but also by their ability to translate that knowledge to their audience. The differences between treatment strategies in the US vs Europe were also interesting to hear. The use of Melphalan is much more common there, as an induction drug and as part of a regimen at a lower dose, of course, than during transplant.
The expert panel discussed the risk stratification method to determine progression risk of sMM patients to myeloma. Factors include bone marrow plasma cell percentage, FiSH abnormalities, M Proteins, and FLC Ratio, but they proposed that circulating plasma cells should also be included in workup and risk stratification of sMM, rather than just bone marrow plasma cell percentages. Will this help improve quality of life in the future by not requiring as many serial bone marrow biopsies for patients? This remains to be seen — but anything to improve quality of life excites me!
In addition, there was a discussion about ASCT ineligible patients with myeloma with impressive PFS & OS data for DRd regimen until progression. This data was made even more impressive, as it included the frail elderly population as well.
An easy-to-remember and logical planning acronym for managing myeloma in first relapse was also shared by Dr. Rajkumar. TRAP (timing of relapse, response to prior therapy, aggressiveness of relapse, and performance status) are all factors to consider when making treatment recommendations for this population of patients. Sequential immunotherapies that have different targets were also discussed, i.e., BCMA, GPRC5D.
I am looking forward to the 24-month PFS data from the Cartitude trial that will be shared on Sunday. Data, so far, is undoubtedly positive which hopefully means good things in the future!
Time to reset, eat dinner, and spend some time with my family for the evening. Looking forward to what tomorrow brings! Knowledge is power and I can’t wait to continue to learn and grow so that I can pass that information along to my support group members. I can’t begin to express how grateful I am, both to the IMF and to our sponsors, Takeda, Karyopharm Therapies, and Bristol Myers Squibb for making my attendance and participation possible at ASH 2021. I even wore my GRATEFUL shirt! Until tomorrow…
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