Key Takeaways from the 2022 American Society of Hematology (ASH) Conference
What myeloma patients and family and friends need to know
I am pleased to share with readers of Myeloma Today an overview of the top abstracts of interest presented during myeloma sessions at the 64th Annual Meeting & Exposition of the American Society of Hematology (ASH) in December 2022. Impressively, more than 1,000 abstracts presented at ASH were related to myeloma, demonstrating important developments for the myeloma community. Each year, different patterns of importance emerge, with bispecific antibodies becoming an area of great excitement at ASH 2022, with results from many clinical trials reported.
Talquetamab is an investigational, off-the-shelf (ready to use), bispecific T-cell engager antibody. It targets both GPRC5D (a novel target on myeloma cells) and CD3 (a target on T cells), activating the body’s immune system to fight myeloma. Abstract #157 oral presentation drew such interest that attendees spilled over to five extra rooms. The overall results clearly impressed the ASH participants. Talquetamab demonstrated robust efficacy and manageable safety in patients with heavily pretreated relapsed refractory multiple myeloma (RRMM). A video presentation by Dr. Ajai Chari is available on the IMF website. To view any of the IMF’s videos from ASH 2022, follow these steps: go to videos.myeloma.org and click on the “ASH” tab, then enter the abstract number or presenter name into the “search” bar.
Teclistamab, the bispecific monoclonal antibody recently approved by the U.S. Food and Drug Administration (FDA) and branded as Tecvayli™ was the focus of correlative analyses in Abstract #97. Abstract #160 discussed the results of the MajesTEC-2 clinical trial of Tecvayli in combination with SQ Darzalex® (daratumumab) + Revlimid® (lenalidomide). A video presentation by Dr. Emma Searle is available on the IMF website.
Other results with bispecific antibodies
Abstract #1919 presented a first-in-human study of Abbv-383 as monotherapy in patients with RRMM. Abstract #4555 updated safety and efficacy of REGN5458 in a first-in-human study in patients with RRMM. Abstract #158 demonstrated that elranatamab induces durable clinical and molecular responses for patients with RRMM – a video presentation by Dr. Noopur Raje is available on the IMF website.
Abstract #162 presented results from a first-in-human study of alnuctamab in patients with RRMM. Abstract #567 presented data that pretreatment with tocilizumab prior to the bispecific cevostamab in patients with RRMM showed a reduction in cytokine release syndrome (CRS) incidence and severity. Abstract #161 discussed the T-cell engaging bispecific antibody RG6234 as being highly effective in patients with RRMM – a video presentation by Dr. Carmelo Carlo-Stella is available on the IMF website.
CAR T-cell therapy in the frontline setting
A new approach to CAR T-cell therapy in the frontline setting became notable. Abstract #366 was presented by Dr. Juan Du. This phase I study for transplant-eligible, newly diagnosed high risk myeloma found the BCMA-CD19 dual FasTCAR-T therapy (GC012F) to have a safe profile and high efficacy, with a 100% overall response rate (ORR) and 100% negativity for minimal residual disease (MRD). The manufacturing time for GC012F is 22–36 hours, much faster than the standard approaches, while producing a good quality T-cell product. A video presentation by Dr. Juan Du is available on the IMF website.
The IMF’s iStopMM (Iceland Screens Treats or Prevents Multiple Myeloma) project is a population-based screening study for monoclonal gammopathy of undetermined significance (MGUS) led by Dr. Sigurður Kristinsson (University of Iceland, Reykjavík). iStopMM is looking at the population of Iceland, where everyone over the age of 40 was invited to participate in the study and more than half of this population volunteered. The many diverse outcomes from iStopMM will benefit not only Iceland but the myeloma community around the world. A total of 10 abstracts were invited for presentation at ASH 2022.
Four oral iStopMM abstracts
Abstract #103 demonstrates that while prevalence of MGUS is high in the iStopMM study, the prevalence of IgA MGUS does not increase with age in the way other immunoglobulin subtypes do. Abstract #105 showed that SARS-Cov-2 vaccinations do not lead to progression of MGUS – a video presentation by Dr. Róbert Pálmason is available on the IMF website. Abstract #967 looks at the epidemiology, causes, and the impact of using mass spectrometry in the detection and identification of M-proteins. The notion that the development of a new M-protein can be either temporary or transient was assessed as related to low-level proteins detected using mass spectrometry. This video presentation by Dr. Róbert Pálmason is also available on the IMF website.
Abstract #107 discusses the development of a multivariable model to predict the risk of ≥ 10% bone marrow plasma cells, which changes the diagnosis from MGUS to SMM, which in turn carries a greater risk of progression to myeloma. This received some of the greatest attention from ASH attendees. The need for upfront bone marrow sampling in individuals with MGUS was based on four predictors: MGUS isotype (IgG, IgA, biclonal), M-protein concentration, free light chain ratio, and total concentrations of IgG, IgA, and IgM. Using this risk model, it became possible to avoid bone marrow sampling in 36.1% percent of patients.
From a screened cohort of 75,422 persons age ≥ 40 years (51% of the Icelandic population), MGUS has been identified in 3,358 cases, of which 2,542 were randomized to active follow-up. A calculator app has been developed and can be accessed at istopmm.com/riskmodel. Patients’ laboratory results can be entered to obtain an output of the predicted percent of plasma cells in the bone marrow. Patients and treating doctors can use these results to decide the best approach for each individual patient while considering factors such as age, cost, and preference.
Six poster iStopMM abstracts
Abstract #3188 investigates determining hemodilution in diagnostic bone marrow samples in myeloma and its precursors by next-generation flow (NGF) cytometry. Abstract #4455 looks at circulating tumor plasma cells in the screened smoldering multiple myeloma (SMM) cohort of iStopMM with the aim of giving clinical care and treatments to those who benefit the most from them, while limiting interventions in those who do not need them. Abstract #4504 looks at MGUS with multiple paraproteins.
Abstract #4507 found that for screened individuals who had no known illness prior to testing, there is no correlation between underlying autoimmune diseases and MGUS. This calls into question prior linkage of M-proteins as possible causes of autoimmune problems. Abstract #4537 presents that hypercalcemia, particularly isolated hypercalcemia, is not a strong indicator of MGUS progression. Lastly, Abstract #4541 finds no association between MGUS and chronic kidney disease.
Icelandic screening datasets
I recommended that you review all abstracts from the iStopMM study. Collectively, these abstracts point to many new paradigms in the evaluation and management of M-protein disorders, and many more new observations are forthcoming. This is the beginning of a new era in the study of early disease entities which can be precursors to myeloma or other lymphoproliferative disorders. Visit myeloma.org/black-swan-research-initiative/istopmm to learn more about the iStopMM study.
Potential curative approaches
The IMF Black Swan Research Initiative® (BSRI®) is funding CURE clinical trials in the U.S. and abroad. The ASCENT and the CESAR studies use a curative strategy that aims to treat myeloma early and aggressively. The curative approach is at the heart of the BSRI pathway to a cure for myeloma. Effective new multiple myeloma therapies are driving longer remissions, and “cure” is coming into focus in three different ways:
- Functional cure is when a patient is in a prolonged remission, while testing can still detect that a small amount of myeloma is present.
- Normal relative survival is when a patient is in a prolonged remission and has reached a point where their survival is equal to or better than another person of the same sex and age.
- True cure is the goal of the CURE trials. It is the most difficult to confirm, no matter how sensitive the testing.
CURE trials presented at ASH 2022
Abstract #757 presented data from the ASCENT clinical trial of fixed-duration aggressive induction therapy for high-risk SMM with the combination of Darzalex + Kyprolis® (carfilzomib) + Revlimid + dexamethasone (D-KRd) for two years of therapy. Eighty-seven patients were enrolled in the study, with 31% still receiving active treatment at this time. Best ORR thus far is 97%, with only 3 patients progressing. Bone marrow MRD negativity was achieved by 84% of patients. The median time for MRD negativity was 6.6 months with 53 cases occurring at the end of induction, 16 at the end of consolidation, and 4 at the end of maintenance. This means that more MRD negativity will be achieved as patients complete the planned therapy. Therapy was well-tolerated with no unexpected toxicity signals. There is great optimism about the potential for long-term MRD negativity, with the possibility of “cure” for some patients.
Abstract #118 presented the post-hoc analysis of sustained undetectable MRD in the GEM-CESAR clinical trial of high-risk SMM, the longer-term follow-up from the companion study of Kyprolis + Revlimid + dexamethasone (KRd) with an autologous stem cell transplant (ASCT) rather than Darzalex. The results were similar to the ASCENT study – 63% of patients achieving MRD negativity after maintenance. After 70.1 months of follow-up, 94% of patients are still in remission, with 6 patients having progressive disease. Thus far, 7 patients have died, meaning a 6-year survival rate that’s also in the 90% range. A video presentation by Dr. María-Victoria Mateos is available on the IMF website. Longer follow-up is required for both ASCENT and CESAR trials, but it is reasonable to anticipate excellent long-term benefits.
MRD testing approaches
Abstract #865 presents ultrasensitive assessment of MRD in peripheral blood used to enhance the NGF method to increase sensitivity to a level of 10-7 or 10-8 by the “BloodFlow” method, which shows great promise to reduce the need for bone marrow sampling. A video presentation by Dr. Laura Notarfranchi is available on the IMF website.
Abstract #866 discusses the clinical impact of NGF in bone marrow vs. mass spectrometry in peripheral blood to assess MRD. Bone marrow NGF and blood mass spectrometry testing gave similar predictive information. It seems that newer blood testing approaches have the potential to substantially reduce the need for bone marrow sampling. This is a very promising trend both for patients and for the efficiency of clinical trials. Longer follow-up is required for both trials, but it is reasonable to anticipate excellent long-term benefits. A video presentation by Dr. Noemí Puig is available on the IMF website.
Abstract #569 presented an efficacy and safety analysis of the IFM2017-03 phase III clinical trial. This became a point of considerable interest for its non-aggressive approach in frail or elderly patients with newly diagnosed myeloma. The Revlimid + dexamethasone (Rd) regimen was compared to the dexamethasone-sparing Darzalex + Revlimid (DR) regimen. Although more deep responses occurred with the Rd regimen, the DR regimen had excellent results without long-term dexamethasone and was well-tolerated, becoming an option for frail or elderly patients.
Important work in myeloma research is continuing. The reports presented at ASH 2022 are very exciting, with numerous new observations and great hope for the immediate future. For more detailed discussions, I invite you to view the many IMF video recordings with ASH 2022 abstract presenters at videos.myeloma.org, as well as to replay two archived IMF webinars, “Top Myeloma Research Presented at ASH 2022” and “Making Sense of Treatment”.
(This article was published in the 2023 Winter Edition of the IMF's quarterly publication, Myeloma Today. Read the full publication here.)