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%. 
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. 
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-. 
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. 
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.
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:
I’m very encouraged by all the abstracts related to bispecifics because they offer a unique way to attack myeloma. As we all know, myeloma is very smart and sly. It continually changes to evade the current treatment and can become more high-risk over time which complicates things even more. Finding new ways to outsmart myeloma becomes ever important as the number of relapses increases.
Ultimately, you never want to run out of lily pads to jump to and this requires novel methods of treatment. Developing new treatments takes years of research and trials before approval is granted.
Bispecifics are one of the most promising new ways on the horizon to fight myeloma. They attack myeloma cells in two ways. First, they identify an antigen expressed on myeloma cells, like BCMA. Secondly, they engage your circulating T cells. All this leads the drug into the malignant myeloma cell resulting in cell death. I first remember a large amount of attention on bispecifics at ASH 2018 and all the buzz was on using the BCMA antigen on the myeloma cells.
Moving forward to 2021, BCMA bispecifics are moving forward and there is also a focus on bispecifics that use different antigens, such as GPRC5D, CD3, and FcRH5, and looking at using bispecifics in combination with existing therapies like Darzalex® (daratumumab). Regardless of the antigen, it needs to be widely expressed on myeloma cells and not on your healthy cells.
There is the promise that in 2022, we will see the Federal Food & Drug Administration (FDA) approval of at least one bispecific. Bispecifics, like all treatments, do come with side effects. We’ve all experienced the typical side effects like fatigue, GI issues, and low blood counts, but bispecifics have a side effect most may not be familiar with — Cytokine release syndrome (CRS). CRS is a syndrome that results from the immune cells being activated and releasing large amounts of cytokines into your body. Cytokines are small proteins that help direct your body’s immune response and large numbers of them increase inflammation in the body. Much has been learned about the treatment of CRS and it has shown to be successfully controlled with medications as needed.
Years 2020 and 2021 were certainly filled with both unexpected challenges and silver linings for the entire world. I prefer to focus on the positive and when I think about time, I think of how lucky I am to be here. I was diagnosed in September 2000 so I am now a 21-year survivor, or should I say a Myeloma Warrior? It hasn’t always been easy, but with the milestones I’ve reached with my family and the research I’ve benefited from, living with myeloma has kept me grounded, humble, and grateful.
In 2000, I was 36 and our children were 2 and 7 years old. Back then, treatment options were extremely limited. We were told to be prepared and to write our will. Today, we have an armamentarium of options. Each one comes with great hope for longer remissions, fewer side effects, and a better quality of life.
There are multiple novel agents that are now available to treat newly diagnosed and relapsed/refractory myeloma. Depending on how you count the treatments and combinations, there are currently 15 FDA-approved treatments for myeloma with more coming!
The question that I will be focusing on at ASH: How do we sequence and strategize therapies to ensure the best outcomes? It’s certainly a hopeful time.
If you have read my blogs from previous ASH reports, you probably noticed that because of my love for music, I’ve made it a tradition to include rock songs in my blogs.
Songwriter and former member of The Band, Robbie Robertson recently did a remake of the song “The Wait” with musicians from all over the world. Indeed, music has the power to break down boundaries and to bridge the distance between people.
We are seeing global research and collaboration come together at ASH.
“It Makes No Difference” from The Last Waltz by The Band takes on a special meaning, as we “wait” for better treatments and a cure. It’s a sad song with threads of hope coming from Garth Hudson’s masterful saxophone-playing, Robbie Robertson’s lead guitars, and from the heart-wrenching vocals of Rich Danko.
I’m honored to participate virtually in this year’s #ASH 21 conference! I am excited to learn about all the latest and greatest advances in myeloma therapies and treatments. My goal is to share that information with myeloma patients and their caregivers, especially those who have young children, to encourage and empower them on their myeloma journey.
In addition, I feel so thankful and blessed that the virtual format is still being utilized. It allows me to participate in a safe environment as well as manage my energy levels. We can still learn so much virtually! Thank you, IMF for not only allowing me to participate, but for keeping it virtual as well! #IMFASH21