As we prepare for the 63rdAmerican Society of Hematology (ASH) Annual Meeting in Atlanta, Georgia, December 11-14, serious concerns have emerged this week about the new COVID-19 Omicron variant. It is very important to balance the very real new anxieties about the implications of Omicron for the myeloma community and the major progress that will be illustrated by presentations at the upcoming ASH meeting.
ASH 2021: Game-changing observations about early disease
This year, the top abstracts come from Iceland and the iStopMM project of which I am a part (full disclosure) and have written about several times. Launched in 2016, iStopMM (Iceland Screens, Treats, or Prevents Multiple Myeloma) is the first population-based screening study for MGUS, said principal investigator, Dr. Sigurdur Y. Kristinsson of the University of Iceland. The study also includes a randomized trial of follow-up strategies.
The key points from the four oral presentations to be given at ASH are:
- Screening and identification of monoclonal proteins early (Abstract 156). Population-based screening versus chance detection at other medical check-ups can lead to much improved outcomes. The precise value will be evident from comparisons in the three arms of the randomized trial: detailed testing and early intervention versus not. If screening for monoclonal proteins becomes the standard of care, this changes the whole structure of myeloma care.
- The iStopMM study screening (Abstract 151) revealed a higher-than-expected occurrence of smoldering multiple myeloma (SMM) than expected (as well as undetected active myeloma), with an opportunity for earlier intervention before symptoms emerge.
- The observation that COVID-19 infections (Abstract 154) did NOT occur more frequently among the MGUS patients is extremely important and relieves some anxiety in this patient group.
- New reference levels for serum Free-Light chain levels in patients with renal (kidney) impairment (Abstract 542) is a very helpful guideline.
In addition, two iStopMM abstracts presented as posters illustrate the role of monitoring circulating plasma cells (Abstract 2645) and the prior bias in assessments of individuals with MGUS (Abstract 1618) due to underlying medical issues brought the patients to medical attention.
Overall, the presence of all of this research at ASH represents quite a tour de force by the Icelandic team led so ably by Dr. Sigurdur Kristinsson. Much more is to come in the next few years as other results emerge.
A related and very important Abstract (541) from the Spanish team (senior author Bruno Paiva) outlines the use of flow cytometry to identify MGUS patients versus SMM or active myeloma patients. Based on data from 5,114 patients in the Spanish databases, just three parameters allow the “MGUS phenotype” to be derived and broadly applied. This is a very important practical algorithm or tool to classify patients.
Another related project (PROMISE study, Abstract 152) assesses the occurrence of MGUS (specifically the heavy-chain type) in older Black individuals with first-degree relatives with MGUS or myeloma. There is a high prevalence of MGUS in such individuals, again supporting the notion of the value of precise screening approaches.
Important treatment results
Abstract 79 provides an update after 24 months of maintenance in the GRIFFIN trial, which compares Dara VRd versus VRd in newly diagnosed myeloma. For the first time there is a trend to PFS (progression-free survival) benefit at the 36-month cut-off, with rates of 88.9% (for Dara VRd) versus 81.2 % (for VRd). MRD (minimum residual disease) at a 10 to minus 6 threshold is assessed. After 24 months of maintenance, an impressive 64.4% of Dara VRd patients achieved MRD negativity (versus 35.8% for VRd alone). The role of quads or four-drug regimens in the frontline depends on the ongoing follow-up results in this trial, as well as, for example, the CASSIOPEIA trial (Dara VTd versus VTd), also reported at ASH (Abstract 82).
Abstracts reporting the results of trials with bispecific monoclonal antibodies are my fifth selection. Several abstracts collectively indicate the potential for bispecifics:
- Abstract 821: reporting good outcomes for triple-class refractory patients
- Abstract 161: illustrating the way forward with excellent result and tolerance with talquetamab (anti-GPRC5D) plus daratumumab
- Abstract 896: follow-up with anti-BCMA teclistamab, again, with promising results
- Abstract 157: follow-up results with cevostamab (anti-FcRH5) bispecific, showing clinically meaningful results and acceptable tolerance
These very encouraging results point to an emerging role for bispecific therapies.
The Omicron crisis
This past week the news has been full of reports about what the World Health Organization (WHO) has characterized as a “Variant of Concern” (VOC) called Omicron. The word Omicron was a surprise because working through the alphabet from Alpha to Beta, Gamma, then Delta, the next variant should have been Nu and after that Xi. Both were rejected because Nu is too much like new and Xi is part of the name of China’s top leader, Xi Jinping. Next is Omicron.
Why the concern?
The new variant, B.1.1.529, was identified in Gauteng region of South Africa and linked to a local technical university called TUT. The earliest cases probably date back to October, but the alarm went off when the results of sequence analyses came in showing a huge number of new mutations, including 30 in the all-important spike protein region alone.
This, combined with a very sharp increase in cases from a few hundred to a few thousand, contributed to the WHO TAG (Technical Advisory Group) recommending the VOC designation on November 26.
The other concern is the infections were occurring among those previously infected or fully vaccinated (two shots, mostly without a booster), called “re-infections” or breakthrough infections. This immediately raised the question of whether or not current vaccines will work well against the omicron variant. In addition, some of the many mutations indicated that this new variant might also evade the cellular (T cell) responses against COVID-19.
The first case in the U.S. was documented in San Francisco on December 1, a mild case in a fully vaccinated, healthy individual. The full scope of occurrence in the U.S. will emerge in the coming weeks.
Some good news
We must be very grateful that high throughput sequence analyses are available in South Africa, which led to the precise identification of this new variant as soon as the concern arose about rapidly increasing cases. We already have some information about the patients, as well.
In the young student population, the infections have been frequently mild. However, we do not know what happens in older and/or vulnerable groups such as myeloma patients. Will omicron be dangerous or maybe even more dangerous than then Delta variant? It is too soon to know.
What we do know is that we have so many newer tools to fight this new variant including:
- Very effective vaccines, particularly after booster shots
- Knowledge that masks really do protect
- Several treatment options that are available or emerging, including monoclonal antibodies and new anti-viral agents from both Merck (already approved) and Pfizer (on a fast track for approval with reported 89% efficacy!)
- The availability of rapid COVID testing. Apparently, such testing will be made available free of charge via “at-home kits.” The rapid testing is essential because the anti-viral treatments all work best at the point of early infection.
The Bottom line
Despite the pandemic, ASH illustrates that a huge amount of important research is continuing. And, although the Omicron variant is a setback, we really do have the tools and strategies to get through this potential surge and hopefully stay safe.
It is SO important to get that booster shot, wear your mask in situations of risk and use common sense precautions.
There undoubtedly will be ongoing updates through the holiday season to advise what additional measures can be recommended.
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