ASH Day 2: Which CAR to Hitch a Ride with?

ASH Day 2: Which CAR to Hitch a Ride with?

December 12, 2021 – Today began with watching a few presentations that focused on the epidemiology of myeloma patients. For example, abstract 400 examined COVID-19 vaccine effectiveness for multiple myeloma (MM) patients associated with the VA. They examined nearly 7,000 MM patients and compared COVID-19 results with vaccinated and unvaccinated patients, as well as compared these with non-MM patients. Not surprisingly, they concluded that vaccines were an effective strategy for preventing COVID-19, but less so for MM patients.

Abstract 402 examined racial and ethnic differences in MM patients. The presenter, Dr. Nancy Gillis (Moffitt Cancer Center – Florida) remarked that “Blacks are getting one-half the benefit of improved survival outcomes compared with whites. However, similar access to care results in similar outcomes.” As a society, we need to do more to accrue a diverse population in our clinical trials and then provide better access to new treatments.

I always appreciate it when negative trial results are presented. These are trials where the suspected benefit hypothesis is not met.  Abstract 466 compared Ninlaro® (ixazomib) added to Revlimid® (lenalidomide) + dexamethasone (IRd) maintenance versus (Rd) alone and concluded that the Ixa arm did not result in improved progression free survival (PFS).  And abstract 486 concluded that the addition of Empliciti® (elotuzumab) to Revlimid, Velcade® (bortezomib), and dex (ERVd) induction/consolidation and Rev maintenance did not result in improved PFS or overall survival (OS).

Other abstracts showed the benefit of adding either Darzalex® (daratumumab) or Sarclisa® (isatuximab) (both CD-38 monoclonal antibodies) provides benefit when considering outcomes such as responses, minimal residual disease (MRD) rates, PFS, and or OS. Example include Abstracts 463 (Isa + RVd induction), 464 (dara + IxRd induction), and 465 (dara + CyBorD + Rev (5 drugs!) for ultra high-risk MM).

Another important study, Abstract 467 examined the impact of chromosome 1 gain (3 copies), amplification (>3 copies) and deletion, conferring inferior PFS compared with standard risk patients. Kyprolis® (carfilzomib), Revlimid, and dex (KRd) may overcome negative OS for gain1 and del1 but not necessarily amp1, however more follow-up needs to be done for this particular mutation.

And speaking of chromosomes, 17p deletion is long-considered to be a high-risk factor. But how is the clone size (17del seen in >60% plasma cells) impacted by a tandem transplant?  Abstract 460 demonstrated tandem transplant compared with a single transplant improves outcomes but clone >60% may negatively impact outcomes. However, there were a couple of audience questions about biased results, such as tandem patients being more fit than single transplant patients.

I want to now share what I consider today’s most impactful presentations. All of the CAR T’s presented below have an additional focus of lengthening the persistence (survival) of the CAR T cells in order to increase PFS times.

CAR’s and more

  • CT103A CAR T from China demonstrated (N=79) 95% ORR with 58% CR with mPFS of 25 months.  The first enrolled patient is still in stringent complete remission (sCR) for 34 months. And for 13 patients who had previous CAR T, ORR was 77% and CR 39%.  [547]
  • bb21217 CAR T for N=72 included 40% HR and 22% EMD patients. Results include 69% ORR (inc 28% CR) and mDOR of 2 yrs. [548]
  • CARTITUDE CAR T updated results after 2 yrs follow-up for N=97. ORR 98%, CR 83%; 2-yr PFS and OS were 61% and 74% respectively and even higher for those with sustained MRD-. [549]
  • ARI0002h CAR T appears unique because some of a patient’s CAR T cells are given up front and then a booster dose is subsequently given. For N=30, ORR=100 and CR=60% and the mPFS is estimated to be 18 months. 
  • Master Trial: Dara-KRd -> SCT -> D-KRd -> D-KRd -> R maintenance. MRD is tested after each treatment and 2 successive MRD- at 10-5 results moves the patient into a MRD-SURE category to stop treatment (observation only) with continued MRD surveillance. Results were presented for SR, HR and UltraHR (>1 HR factor) patients. 2-yr PFS and OS were in the 90%+ for SR and HR but only 58% and 76% respectively for UHR pts. And 84 pts (72%) achieve MRD-SURE. [481]
  • In abstract 551, an oral Gamma Secretase Inhibitor to increase BCMA expression may be used in the future with BCMA-directed therapies.

That’s it for today.  Tomorrow’s sessions include IMWG Conference Series from ASH 2021. IMF Chairman Dr. Brian G.M. Durie, Dr. Maria V. Mateos (University of Salamanca — Salamanca, Spain), Dr. Thomas Martin (UCSF Helen Diller Family Comprehensive Cancer Center — San Francisco, CA) and MM Nurse extraordinaire Beth Faiman PhD, RN, MSN, APRN-BC, AOCN (Cleveland Clinic Taussig Cancer Institute — Cleveland, Ohio) distill, debate, and discuss the latest news and trends in the treatment of multiple myeloma from this 63rd Annual ASH Meeting. Check out the IMF website for replays.

Be your own best patient advocate.

— Jack Aiello, on Twitter @JackMAiello

I Hope Myeloma BiTES the Dust

I Hope Myeloma BiTES the Dust

The last few years, I have been interested and hopeful in the number of types of immune therapies. Immunotherapies aid our own immune systems to help fight infections and attack cancer cells.  We want our immune systems to function as normally as possible to find and destroy abnormal cells to possibly prevent or slow the growth of many cancers, including myeloma.  

However, we all know that myeloma is smart and tricky. Myeloma cells have ways to avoid the immune system’s ability to destroy them due to genetic changes that make myeloma cells less visible to the immune system.

Dr. Mikhael has created a series of videos to help us better understand:

  • What is B-cell maturation antigen (BCMA)
  • What are Antibody Drug Conjugates (ADCs)
  • What is CAR T-Cell Therapy
  • What are Bispecific Therapies

You can view these helpful videos HERE.

Harnessing the power of our own immune systems to work best and help it to do what it’s supposed to do is smart science!  Bispecifics act as the bridge connecting the T-cells to the myeloma cell.  The T-cell then kills the myeloma cell, as it recognizes it as an abnormal cell.  These bispecifics are what are sometimes referred to as “off-the-shelf.” This is different than the CAR T immune therapies, whereby a patient’s own T-cells are harvested and then sent to a lab to be re-engineered and then given back to the patient.  

This process takes time and the challenge of what does a patient do while waiting for treatment, plus can a patient even get CAR T?  We have heard that cancer centers only have a certain number of spots for patients waiting for CAR T.  Hopefully, this shortage of spots opens soon to enable more myeloma patients to have access to CAR T.

On Saturday afternoon, we listened to Abstract 161 on “Phase 1b Results for SubQ Talquetamab Plus Daratumumab in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)” by Dr. Ajai Chari (Mount Sinai — New York).  This bispecific is a little different because instead of targeting B-cell maturation antigen(BCMA), it targets G protein-coupled receptor, class C group 5 member D (GPR5CD).  This is important for patients who have already had multiple BCMA targeted therapies, because it’s a different target to go after besides BCMA. More Targets = More Hope!

Here are a few slides on SubQ talquetamab plus dara: 

The title of today’s blog is “I Hope Myeloma BiTES the Dust” and here’s my song for you to enjoy by Queen:

Michael Tuohy, on Twitter @IMFmikeMYELOMA

The Day of Symposiums

The Day of Symposiums

Hybrid Meeting Format  

As with previous years, the International Myeloma Foundation (IMF) held its signature satellite symposium during that 63rd annual meeting of the American Society of Hematology (ASH). It featured Drs. Brian G.M. Durie (IMF Chairman of the Board), S. Vincent Rajkumar (Mayo Clinic — Rochester, MN), Tom Martin (UCSF Helen Diller Family Comprehensive Cancer Center — San Francisco, CA), Jesus San-Miguel (Clinica Universidad de Navarra — Navarra, Spain), Philippe Moreau (University Hospital — Nantes, France). Absent this year was Dr. Shaji Kumar (Mayo Clinic — Rochester, MN).   

The symposium flow included a hypothetical case presentation, followed by how you treat questions and audience vote, the speakers’ case for why they voted the way they voted, and then audience polling to see if the speakers changed any audience minds.   

The case studies and presentations ranged from smoldering myeloma to relapsed/refractory myeloma, approved drugs, drug combinations, and drugs in the pipeline.   

I noted on the disclosure slides the only one that did not have ANY disclosures was Dr. S. Vincent Rajkumar. Does it mean the others are conflicted, and you should consider their discussions to be biased? Well, NO! I invite you to read this Twitter thread to see why not.   

The significant benefit of treating high-risk SMM patients in myeloma is high, noted Dr. San-Miguel, up to 7 years of progression-free survival (PFS) before the smoldering myeloma progressed to full-blown myeloma. Not only was the progression delayed, but the risk profile post-progression was similar to those on the wait-and-watch approach. Dr. Rajkumar indicated the wait-and-watch experiment has failed for high-risk smoldering myeloma patients.    

The speakers noted the features that made SMM high risk (seen below), where the presence of these features indicated an up to 50% chance of progressing to myeloma in two years.    

Factors Identifying 50% Risk of Progression at 2 Years 

Over the last two years, the researchers consider high-risk indicators have evolved. You may have heard the 2/20/20 model. They are now indicating the potential for the model to evolve to a 2/20/0.02% model allowing for frequent monitoring of the SMM patient and early warning system that the smoldering myeloma will progress to full-blown myeloma. Watch the studies in this area as research has indicated the importance of early intervention pre CRAB.    

Circulating Tumor Cells Predict Risk of Progress in SMM Patients 

Some exciting questions are being asked: Can CAR T replace upfront high-dose autologous stem cell transplant (ASCT)? Dr. Morreau indicated that a clinical trial is in the design phase in Europe.   

Dr. Martin’s wish list for future bispecific antibodies in relapsed/refractory myeloma included outpatient dosing with low cytokine release syndrome (CRS) and neurological toxicity, convenient administration (every 4, 6, 8 weeks). Dr. Martin had a similar wish list for BCMA CAR T cells, including faster manufacturing, better expansion, dual targeting, and outpatient administration.    

One of the highlights of the symposium was that all the bispecific antibodies for relapsed/refractory myeloma have a single drug overall response rate (ORR) of over 50%, some even 80%. This high ORR was unheard of in the chemotherapy era and even in the age of novel drugs such as Velcade® (bortezomib), Revlimid® (lenalidomide), Kyprolis® (carfilzomib), or Darzalex® (daratumumab).   

Summary of Bispecific Antibodies in RRMM 

Dr. Durie discussed the unmet need of triple-class refractory myeloma patients. Those patients, despite all efforts, their myeloma continue to progress and eventually die. He indicated the issue is even more exasperated with the withdrawal of melflufen and panobinostat from the market, and the limited use of venetoclax. 

The Unmet Needs of Triple Refractor Myeloma Patients 

And finally, Dr. S. Vincent Rajkumar of the Mayo Clinic unveiled his “Treatment Algorithm for 2020”. This algorithm embraces the principle of triplet preference, including at least two new drugs (not sure just drugs or if feasible drug classes), consideration of transplant in patients eligible for transplant. He said, “My preference is for people not to use this algorithm and urge patients to sign up to clinical trials.”   

During this symposium, I heard the phrases   

  • Flattening of the curve (the survival curve)   
  • Long treatment-free interval (drug holidays)  
  • Ease of administration (at home and subcutaneous administration, treatment intervals of >2 weeks)  
  • Fewer side effects   

There was an acknowledgment by the group that more needs to be done to bridge the gap between what the on-the-ground country by country reality is and the potential these new drugs offer.   

The IMF teams will be busy at ASH and will be facilitating either virtual or hybrid meetings:   

Yelak  

Sharing The Hope!  

Yelak Biru, on Twitter: @NorthTxMSG  

The Amazing Power of Proteins (and RNAs too)

The Amazing Power of Proteins (and RNAs too)

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.  

Yay Proteins! Yay RNAs too!  

Jill Zitzewitz, PhD, on Twitter @JillZitzewitz 

Symposiums Promise Many New Lily Pads

Symposiums Promise Many New Lily Pads

Today was filled with educational symposiums that offered medical professionals attending the 63rd American Society of Hematology (ASH) conference the opportunity to earn continuing education credits. 

For me, it provided a glimpse of what is to come this weekend and it reconfirmed that there are many more treatment lily pads that I can leap to in the future. Thanks to the International Myeloma Foundation (IMF) and our generous sponsors, this is my 9th year attending this conference. 

Every year offers great insight into the amazing research that is ongoing to find a cure for multiple myeloma. But some years, I feel like there are more leaps than others. I think 2021 will be one of those years pushing future treatment options to the next level. Bispecific antibodies and CAR T-cell therapies have been featured at previous ASH conferences, but the number of options is reaching a new level and new targets being studied provide more ways to outsmart our continually changing myeloma. 

With all this advancement comes more choices — another reason to be an informed patient. There will be a greater need to understand the sequence of treatments. For example, can you take a bispecific antibody before having CAR T-cell therapy if they target the same antigen on the myeloma cell? Recently approved new therapies and several on the verge of approval target BCMA. So, this is a question that will be widely discussed this weekend. And there is literally an alphabet soup of new targets being explored, so the options and combinations continue to explode. 

Saturday began at 6:30 a.m. (3:30 a.m. for our team members from the West Coast) with the International Myeloma Working Group (IMWG) meeting and was followed by a day filled with abstracts on all these amazing studies. 

Stay tuned to all the information our team will be sharing with you over the next few days. 

Linda Huguelet, Chattanooga Multiple Myeloma Networking Group 

Linda Huguelet, on Twitter: @LindaMYELOMA