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 

‘Extra’ is Not Always Better

‘Extra’ is Not Always Better

The diagnosis of multiple myeloma is just that — “multiple.” There are so many manifestations of this one diagnosis that you could have 10 people with multiple myeloma in a room and you could hear 10 different versions of their diagnosis and treatment.  

Modern treatment options continue to improve progression free survival (PFS) and overall survival (OS). This was nicely reviewed by Dr. Bharat Nandakumar (Mayo Clinic —Rochester, MN) in his Paper Number: 119: Mortality Trends in Multiple Myeloma after the Introduction of Novel Therapies in the United States

All patients with multiple myeloma (MM) diagnosed between January 1, 2004 and December 31, 2018 seen at MAYO and followed in SEER (18 registry research data 2000-2018, November 2020 submission) were included in the study.

Patients were grouped into three 5-year groups based on the year of diagnosis:

  • 2004-2008
  • 2009-2013
  • 2014-2018

For the estimation of relative survival, patients alive at the end of 2019 were censored to align with the published United States general population rate tables. 

Overall survival (OS) estimates were calculated by Kaplan and Meier method. 

  • Steady improvement in OS in both populations with time.
  • Steady decrease in early mortality in both populations with time.
  • Improvements in survival across all risk groups with time.
  • Older patients (>65 years) with favorable disease characteristics experienced survival outcomes comparable to US general population – ‘Functional cure.’
  • Are patients seen in community settings lacking behind in the adoption of available therapies or lack access to them? 

However, effective treatment options remain very limited for high-risk variants (HRV) of myeloma such as extramedullary disease (EMD), especially with organ manifestation, and 1q+ and 1q amplification.  There is increasing interest in addressing this unmet need. I will share a few of the abstracts that looked at these HRVs. 

Paper No: 485: Characteristics and Outcomes of Newly Diagnosed Multiple Myeloma Patients with and without Extramedullary Disease after Autologous Transplant and Maintenance Therapy: A Study from the Cmwp-EBMT.  Dr. Nico Gagelmann (University Medical Center Hamburg-Eppendorf — Hamburg, Germany)

EMD is when myeloma cells develop in tissues outside of the bone marrow and can happen at diagnosis or as part of relapse/progression. EMD is less common in IgA MM, but more common in ISS (International Staging System) Stage III.  Use of post-transplant maintenance was the focus for this subgroup analysis. In short, PFS and OS was shorter in this subgroup of organ involved EMD regardless of choice of maintenance with thalidomide, lenalidomide or bortezomib.  

The effects of the addition of daratumumab are yet to be analyzed.  EMD, especially organ involved, remains an area of unmet need where further investigation into effective therapies for PFS and OS is needed. 

Paper No: 467: Impact of Chromosome 1 Abnormalities Among Patients with Newly Diagnosed Multiple Myeloma: A Subgroup Analysis from the Endurance (ECOG-ACRIN E1A11) Trial, Dr. Timothy M. Schmidt (University of Wisconsin —Madison, WI)

77 In Multiple Myeloma, High-Risk Secondary Genetic Events Observed at Relapse Are Present from the Diagnosis in Tiny Undetectable Subclones – Herve Avet-Loiseau, MD, PhD, (Universite Paul Sabatier —Toulouse, France)

Dr. Avet-Loiseau asked the following questions: Are abnormal clones present earlier than currently identified?  Do these minor subclones impact clinical evolution?

The progression free survival (PFS) and overall survival (OS) were essentially the same for those who did not present but had 1q+ at time of relapse. It is believed this subclone already had an impact on outcome. The significance is that we need to look for this subclone at time of diagnosis to address proper therapy at time of diagnosis.  

There are many unmet needs in myeloma therapy. These HRVs are just a couple.  Having “extra”-medullary disease or “extra” copies of chromosome 1 are not favorable.  

Each year I attend the ASH meeting, I am inspired and thankful there are so many scientists and clinicians that work extra hard to improve diagnostic testing, develop new drugs and combinations of therapies.  In this respect, “extra” is important. 

I want to send an “extra” thank you to the researchers, the research coordinators, the clinicians, and the patients for their “extra” contribution that will help us one day find a cure for myeloma.  Without the “extra” effort by so many, we would not be where we are today in improving survival.  But we are not done, and we need to go the “extra” mile(s) to get there.  

Until next year, when we learn the newest updates at the 64th annual American Society of Hematology meeting, please stay safe, stay hopeful and be good to yourself and others.  

Teresa Miceli, on Twitter @IMFnurseMYELOMA 

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

Mental Health and Myeloma Research

Mental Health and Myeloma Research

As I mentioned in my previous blog, “What are You Going to Fill Your Glass with?” I reviewed a variety of sessions dealing with various aspects of mental health. Almost all of them were poster sessions, which I personally like because they have such a different feel from oral presentations (at least in my field; I imagine it’s the same at ASH). 

In poster sessions, posters are placed in aisles, and you get to walk around a large room with the presenters standing nearby. You can stop and chat with the presenters to ask questions and make comments. The experience is much different from the typical 3-minute Q&A session done in oral presentations. 

However, virtual poster sessions consist of poster images along with submission abstracts — there wasn’t any opportunity to engage with the researchers. Nonetheless, there were some interesting projects and I’m going to highlight some of those findings in this blog. 

One interesting study examined psychological distress and quality of life, along with prognostic awareness, by line of therapy in those with multiple myeloma. Regardless of the line of therapy, about a quarter of all patients demonstrated clinically significant levels of anxiety, depression, and post-traumatic stress disorder (PTSD).

While a quarter doesn’t represent a majority, it is still a high number. Furthermore, the study did not report the overlap (or lack thereof) among patients. For example, 25% of the patients could have reported all three; 25% could have reported anxiety; while a different 25% could have reported depression, etc. 

This study also looked at prognostic awareness. They found that over 90% of patients felt like prognostic information was helpful in making decisions about treatment. Over 85% said that prognostic information helped with coping, as well as making future plans. While 85% indicated that their oncologist told them that their myeloma was incurable, only 42% thought it was incurable; 30% reported that they had a terminal illness. 

These patients reported significantly higher depression, anxiety, symptom burden, as well as lower quality of life. The authors concluded that intervention is needed to help patients reduce distress, improve quality of life, and develop various coping strategies that can be helpful over the multiple myeloma disease pathway. 

Another project explored interest in and feasibility of a lifestyle intervention program for those with myeloma. These researchers intentionally sought a diverse sample: the 38 myeloma participants consisted of 54% White, 46% Black, 54% Female, and 46% Male. The majority (55%) have not received lifestyle counseling from their healthcare team, but almost 90% were interested in a lifestyle program. Specific areas of interest included social support, guided/personalized exercise, meal preparation support, and flexibility. These results also revealed a significant gender difference in perceived emotional support, informational support, instrumental support (i.e., tangible support, like mowing the lawn or other physical tasks), and companionship, with females reporting higher support in all these areas. 

Taking this intervention program support a step further, another study is in process, and is looking at the effectiveness of digital life coaching during the autologous stem cell transplant (ASCT) process. This study focuses on a specific event in the myeloma pathway (SCT) and thus has a more focused time point. 

Based on a pilot, which consisted of life coaches meeting with patients digitally and connecting every 5-7 days, they are now launching a phase II trial looking at a digital life coaching program compared to typical SCT care. An interesting element of this study is that one of the outcome measures will be the use of sedative-class PIMs, such as lorazepam, temazepam, and similar medications. They will also compare patient-reported outcomes (PROs) including quality of life, emotional distress, and sleep disturbance. 

The last project I want to highlight also doesn’t have results yet but has garnered a lot of attention during ASH – the iStopMM project. This project will be reporting on mental health correlates and outcomes in the future, and that data will be highly anticipated, I think!

Mental health is important. It influences how we handle stress, how we make healthy choices, how we think and feel about our lives and our relationships, and how we rely on our ability to adapt to changes and cope with challenges we encounter in everyday life. It’s encouraging to see research addressing mental health among myeloma patients!

Jessie Daw, on Twitter @Daw6Jessie 

#ASH21 Trial Design Acronyms

#ASH21 Trial Design Acronyms

I was going to write something insightful – my biggest takeaways – from the last two days of the 63rd annual meeting of the American Society of Hematology (ASH) meeting. I started saying that: 

  • the MASTER trial was very patient-centric; it had over 23% African Americans enrolled in the trial, the MRD response adopted treatment secession strategy is innovative, the trial enrollment was enriched and powered for high-risk patients, and the MASTER-2 trial design is future-looking, the result of 
  • the GRIFFIN trial could be setting quadruplet (dara-RVd) standard of care for high-risk patients in those countries where dara is approved and can afford it
  • the near 100% ORR, deepening stringent complete response (sCR) at year 2, results of CARTITUDE-1 are going to be game-changing and an indicator that myeloma has indeed entered the era of immunotherapy 
  • the OPTIMUM data showed the benefit of adding a CD38 to a quadruplet for those prospectively identified as having ultra high-risk disease by gene expression profile (GEP) 

Then I said, what were the drugs in the GRIFFIN trial again, and what are the randomization criteria for those trials with one?  That is when I pivoted to collecting the trial design in one place for some of the clinical trials presented or referenced at #ASH21.  Below is a non-exhaustive list of trial designs for us clinical trial mortals. In no particular order: 

OPTIMUM [Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, Dexamethasone (Dara-CVRd), V-Augmented Autologous Stem Cell Transplant (V-ASCT) and Dara-Vrd Consolidation in Ultra-High Risk (UHiR) Newly Diagnosed Myeloma (NDMM) and Primary Plasma Cell Leukemia (pPCL) Compared with Myeloma XI/XI+ Trial Treatment for Uhir MM: The UK Optimum/Muknine Trial (Clinically Relevant Abstract)]

MASTER [Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone (Dara-KRd), Autologous Transplantation and MRD Response-Adapted Consolidation and Treatment Cessation. Final Primary Endpoint Analysis of the Master Trial] 

CASSIOPEIA [Daratumumab (DARA) with Bortezomib, Thalidomide, and Dexamethasone (VTd) in Transplant-Eligible Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM): Analysis of Minimal Residual Disease (MRD) Negativity in Cassiopeia Part 1 and Part 2]

MAIA [Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): a randomized, open-label, phase 3 trial]

Forte [Evaluation of the Safety and the Efficacy of Carfilzomib Combined With Cyclophosphamide and Dexamethasone (CCyd) or Lenalidomide and Dex (CRd) Followed by Autologous Stem Cell Transplant (ASCT) or 12 Cycles of Carf Combined With Dex and Len for Patients Eligible for ASCT With Newly Diagnosed Multiple Myeloma] 

GRIFFIN [Study Comparing Daratumumab, Lenalidomide, Bortezomib, and Dexamethasone (D-RVd) Versus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Subjects With Newly Diagnosed Multiple Myeloma]

GMMG-HD6 A Phase III Trial on the Effect of Elotuzumab in VRD Induction /Consolidation and Lenalidomide Maintenance in Patients With Newly Diagnosed Myeloma (GMMG-HD6)

GMMG-HD7 Trial on the Effect of Isatuximab to Lenaliodomide/Bortezomib/Dexamethasone (RVd) Induction and Lenalidomide Maintenance in Patients With Newly Diagnosed Myeloma (GMMG HD7)

CARTITUDE-1 A Study of JNJ-68284528, a Chimeric Antigen Receptor T Cell (CAR T) Therapy Directed Against B-Cell Maturation Antigen (BCMA) in Participants With Relapsed or Refractory Multiple Myeloma. Please note there are now CARTITUDE-2, 3, 4, and 5 in progress. You can read about them at clinicaltrial.gov site 

CC-220-MM-001 [Iberdomide (IBER) in Combination with Dexamethasone (DEX) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Results from the Dose-Expansion Phase of the CC-220-MM-001 Trial]

Bb21217 [Study CRB-402 a BCMA-Targeted CAR T Cell Therapy, bb21217 is a 2-part, non-randomized, open label, multi-site Phase 1 study of bb21217 in adults with relapsed/refractory multiple myeloma (MM). KarMMa is the bb2121-MM-001, the original bb2121 study]

MajesTEC-1 (Phase 1/2 Study of Teclistamab, a B-Cell Maturation Antigen x CD3 Bispecific Antibody, in Relapsed/Refractory Multiple Myeloma)

iStopMM [A Nationwide Phase 2 Trial of Patients With Smoldering and Active Multiple Myeloma (MM) (iStopMM)]

I hope this list of clinical trial design in one place will be helpful for patients, advocates, and those who don’t always speak myeloma. 

Sharing The Hope!  

Yelak Biru, on Twitter: @NorthTxMSG