Post-ASH Reflections

Post-ASH Reflections

The ASH21 Meeting of blood diseases is in the books. What I can share with patients, care partners, and all who are interested is that the myeloma research world is on fire! There are so many new questions for new and veteran researchers, so many creative possible solutions were a part of this annual meeting with a usual attendance of 30,000 health professionals with interests in hematology. 

I wanted to share the many advancements being made in the myeloma world – to be able to communicate hope for treatment options and high hopes for a cure for multiple myeloma (MM). There was something new at every level of myeloma treatment — from the newly diagnosed to those who are considered to have relapsed/refractory multiple myeloma (RRMM).

There were an incredible 879 myeloma-related abstracts submitted to the conference — a compelling evidence of increasing interest and progress in this rare cancer by researchers from all over the world. This was a huge increase compared to the number of myeloma abstracts during my first ASH conference 7 years ago in 2014.

The science was sometimes difficult for me to follow, but I knew I would have several opportunities, including leaning on team members to try to understand the mechanisms of new therapies. I knew that I should not get distracted by trying to follow p-values, levels of significance or by understanding the intricacies of targeted therapies. These targeted therapies are moving us closer to precision or personalized medicine. I could gain better understanding of the biology of multiple myeloma and the new strategies to control it.

Some outstanding advances included the seeming omnipresence of the monoclonal antibody, daratumumab, in many therapies – both front line and after three or four therapies. Daratumumab was approved by the FDA in 2015 along with three other drugs. It is interesting to see it taking center stage in combination with various other drugs. The evidence of several clinical trials shows that there may be a change from the current “gold standard” of newly diagnosed myeloma therapy —from three drugs to four drugs.

Population Studies and Biologic Determinants of Myeloma Control

There were several important progress reports on two population studies, one of which is the iStopMM Study (Iceland Screens, Treats, or Prevents Multiple Myeloma) —a part of the Black Swan Research Initiative (BSRI) of the IMF. In this innovative nationwide, randomized clinical trial (RCT), approximately 80,000 adults over 40 years of age who consented to participate were screened for the myeloma precursor monoclonal gammopathy of undetermined significance (MGUS). There were an impressive eight presentations from this clinical trial, including four oral and the remainder poster presentations. One of the significant results is the occurrence of MGUS, expected in the general population as they increase in age. Smoldering multiple myeloma (SMM) incidence was higher than expected. Observations have determined that the use of mass spectrometry versus Serum protein electrophoresis (SPEP) should be used to determine myeloma protein levels. 

Because of this unique longitudinal trial, there is genetic sequencing information on all volunteer participants. Finding SMM during screening can allow earlier intervention. The question arises as to whether widespread screening is advisable. The ethics of screening without having an appropriate treatment plan needs to be considered. The results of the studies that come from this trial are highly significant, but come with the limitation of being a homogeneous, virtually all-white population.

Early results from another population clinical trial called the PROMISE Study were presented. In contrast to the demographics of the iStopMM study, the PROMISE Study enrolled myeloma patients 40 and over who self-identified as African American or Black and patients of any race who had a family history of myeloma.

Over 7,200 were screened using SPEP and mass spectroscopy. Overall, MGUS was detected in 10% of volunteers using mass spectroscopy, 6% using SPEP. Some subgroups showed even higher prevalence of MGUS, like African Americans over age 50 with 17% MGUS using mass spectrometry. Clearly, these population studies with different demographics —age, race/ethnicity, geography, genetic sequencing, etc.— will help us unravel the many mysteries of myeloma. 

New Approaches to Myeloma Control

Other study results focused on immunotherapy called CAR T therapy, including ABECMA® (idecabtagene vicleucel). On March 26, 2021, the FDA approved idecabtagene vicleucel (also called ide-cel), which targets B cell maturation antigen (BCMA) protein that lives on the myeloma cell. There has been so much work since this therapy was first introduced to reduce major side effects and the expense of CAR T as major barriers for access to this therapy. 

The reported outcomes demonstrate remissions that are deeper and last longer, allowing patients and their families a longer period of no treatment. With these advances, there was discussion among some scientists that someday CAR T therapy might replace stem cell transplant as a consideration for earlier therapy than after four prior treatments.

Another major area of research and hope for those who have already been heavily treated for myeloma is the research of bispecific antibodies – an emerging immunotherapy. Bispecific T-cell Engagers (BiTEs) are antibodies that simultaneously target BCMA or other proteins, GPRC5D, and FcRH5 and immune effector cells (like T-cells). Research on all these therapies is ongoing with reports especially on working to decrease side effects like cytokine release syndrome (CRS), cytopenia, and infections.

Social Determinants of Health

I was excited to witness more attention being given to the equally important Social Determinants of Health (SDoH). With all the bench research, and phases I-IV of clinical trials, translating that research to delivery of results to patients and communities must also take center stage. I was encouraged to see the Anti-Racism Studio as a part of the daily agenda at ASH. I believe this heightened awareness of the need for diversity in clinical trials and suggestion from the audience could move the inclusion of diversity in research to a policy level at these scientific sessions. We have to include community engagement in the recruitment of “partners or participants,” not “subjects” to clinical trials. We have to learn from studies like iStopMM and take the clinical trial to the community to remove barriers to participation, such as transportation. We need to consider institutional racism and unconscious bias on the part of providers to be successful in equitable access to care. We should find ways to ensure that all myeloma patients will have access to newly discovered therapies —removing yet another potential barrier to participation. Acknowledging and monitoring for health equity is essential.

Final Note

I am honored and humbled to be a member of this patient advocate team. It still melts my heart each time I see and hear a researcher-presenter include patients and participants in their acknowledgments. I extend my sincerest appreciation to the IMF and all the sponsors who supported our attendance at this very important annual ASH meeting.

Gail McCray, on Twitter @IMFgailMYELOMA 

Post-ASH: Seeing in the Sand

Post-ASH: Seeing in the Sand

“Any fool can turn a blind eye but who knows what the ostrich sees in the sand.” – Samuel Barclay Beckett

Colon cancer screening has been shown to reduce the incidence of colon cancer in the general population by identifying premalignant lesions in the colon and treating them. Can screening for elevated blood proteins impact a specific blood cancer? Multiple myeloma (MM) evolves from monoclonal gammopathy of undetermined significance (MGUS) which is completely asymptomatic.

In an attempt to cure or prevent MM, a massive screening study, the Black Swan Research Initiative (BSRI), was undertaken in Iceland. The BSRI was established by International Myeloma Working Group (IMWG) in 2012 to find a cure for MM. The study was given the acronym iStopMM (Iceland Screens, Treats, or Prevents Multiple Myeloma) and was supported by the International Myeloma Foundation (IMF).

The study initiated by Dr. Sigurdur Kristinsson (Professor of Hematology — University of Iceland) involved over 75,000 patients.  Everyone over the age of 40 was recruited to participate in the study which included 140,000 individuals in Iceland. Dr. Kristinsson tasked a team of 20 investigators to screen for MGUS, smoldering multiple myeloma (SMM). Those who were diagnosed as either having MGUS or SMM would be randomized in a clinical trial to find an appropriate follow-up to determine if screening can prevent multiple myeloma and its ravaging symptoms. The iStopMM study is a randomized controlled study of identified MGUS or SMM individuals that have been grouped either by clinical monitoring or with lab monitoring to evaluate their progress. A third group will be monitored more aggressively, with more invasive tests to establish a pattern of the development of multiple myeloma.

Another study presented at ASH, known as the PROMISE study, is evaluating screening to reduce the incidence of multiple myeloma and to prevent late complications of bone and kidney disease. The PROMISE study, coordinated by Dr. Irene Ghobrial (Director, Clinical Investigator Research Program, Dana-Farber Cancer Institute — Boston, MA), looks at high-risk individuals. High-risk individuals are defined as being first-degree relatives of patients with blood cancers or African Americans who have 2-3 times greater risk of developing MM. The goal of this study is to evaluate the prevalence of MGUS in this high-risk group. In a cohort of 2,960 high-risk individuals screened, the prevalence of MGUS was found to be significantly increased.

These studies are being conducted to determine if, in the future, watchful monitoring, or offering earlier and more aggressive therapy — based on screening for MGUS, SMM, or early MM — could lead to prevention or a possible cure for multiple myeloma. What one “sees in the sand” by screening may change the course of the disease, like it has been shown for other screening initiatives.

John DeFlice, on Twitter @johnde1MYELOMA

ASH 2021 Day 1: From Iceland to Bispecifics

ASH 2021 Day 1: From Iceland to Bispecifics

Dec 11, 2021 – The day began at 3:30 a.m. PST for the privilege of being able to attend the International Myeloma Working Group (IMWG) meeting. The IMWG has over 250 myeloma specialists who meet twice a year. The agenda included a review of current projects and a discussion of possible proposals to specifically produce guidelines for myeloma treatment. For example, in 2021, guidelines were produced for redefining plasma cell leukemia as 5% circulating plasma cell, infection prevention (very timely during this pandemic), bone disease, and the role of mass spectrometry. Ongoing projects include the management of renal failure, CAR T, and smoldering multiple myeloma (SMM) guidelines.  

Then it was off to “virtually” attend a number of first-day oral abstract presentations.  The format of these 15-minute talks is for the primary investigator to present their slides for 10 minutes and allow 5 minutes for questions. The hybrid nature of this year’s ASH — where facilitators, presenters, and the audience is a blend of in-person and virtual— made this quite a challenge. This format worked better as the day went on but did cause some information to be missed, if you attended virtually.  [On the other hand, it snowed in Atlanta 2 years ago and I missed some information while being there in-person.] 

These are my highlights from today’s presentations: [Abstract#] 

Iceland 

There were at least 3 studies presented from the iStopMM project, which is in its 5th year. If you’re not familiar with this project and its potential importance, check out Dr. Brian G.M. Durie’s recent blog video.  

One essential question asked was whether or not we should screen for monoclonal gammopathy of undetermined significance (MGUS). Other diseases offer early screening, resulting in the improvement of overall survival so why shouldn’t this be true for MGUS, a possible precursor to myeloma? Over 75,000 individuals were screened with nearly 4,000 MGUS patients found and after 3 years of follow-up some have become SMM and myeloma patients. [156] 

While this is a long-term study, several interesting outcomes have already been determined: 1) SMM occurs in 0.5% in persons 40 years or older but according to today’s risk stratification, only 1/3 of these SMM patients are considered intermediate or high risk; [151] 2) There is no relationship between MGUS and the susceptibility of either getting COVID-19 or the severity of it. [154] 

Bispecific Antibodies 

There were several updates provided on bispecific antibodies with more to come on Sunday and Monday.  The Bispecifics often use 1-2 “step-up” doses (start with lower amounts) to mitigate potential cytokine release syndrome (CRS). Today, abstracts provided results for:

1) Cevostamab (FcRH5 marker on the MM cell x CD3 on the T cell) given every 3 weeks to n=161 patients (pts) heavily pre-treated (including prior BCMA) resulted in ORR of 57% and mDOR of 11.5 mos for dosing 132-198mg via IV; [157]

2) Talquetamab (GPRC5D x CD3) given SubQ to N=55 pts resulted in ORR 67-70%; [158]

3) And when talquetamab is combined with dara N=21 showed an ORR 77-85% (no dara within prior 90 days); [161] 

4) REGN5458 (BCMAxCD3) N=73 provided ORR = 75% at the combined 200-800mg dose levels. [160] 

Other Studies 

  1. An update with a 2-year follow-up was provided for the Griffin study: [Dara]RVd -> SCT -> [D]RVd -> [D]R maintenance (2 yr). Dara arm results in superior outcomes after 2-year follow-up: MRD- (10-5) 64% vs 30%, CR 82% vs 61%, and MRD- >12 mos durability 44% vs 13%. [79] 
  1. Iberdomide (a CELMod) + dex demonstrates efficacy in triple-refractory patients, including those 100% refractory to IMIDs, ORR 26% N=26 and pts with previous BCMA, ORR 25% N=24. [162] 
  1. The PROMISE study examines potentially high-risk individuals, specifically Black/AA (N=2439) and those with first degree relative dx with hema malignancy or precursor to MM (N=3866). MGUS screening via both SPEP (6%) and Mass Spec (13%) confirmed both higher rates and increased sensitivity with Mass Spec. [153]  

That’s it for tonight.  While my first meeting tomorrow isn’t until 6:30 a.m. PST, one benefit of a virtual ASH is that many sessions are recorded and available for replay (just in case I oversleep).   

Be your own best patient advocate. 

Jack Aiello, on Twitter @JackMAiello