In our final blog entry on the key clinical developments presented at the International Myeloma Workshop (IMW) held in early September in Vienna, Austria, we focus on strategies for identifying patients with smoldering multiple myeloma (SMM) who are at the highest risk of progressing to active MM and report on the special “Hot Topics in Myeloma” session that focused on COVID-19 and how myeloma patients have fared following vaccination.
Smoldering Multiple Myeloma: Will Assessment of Bone Marrow Plasma Cells Be Replaced by Assessment of Circulating Tumor Cells for Periodic Risk Assessment?
Patients with SMM are typically monitored without therapeutic intervention until there is evidence of disease progression. However, there is a subset of SMM patients that exhibit disease features that put them at high risk of developing active MM relative to patients who do not exhibit these features. New stratification models have been developed to identify which patients are likely to progress to active MM slowly—if ever—and which patients are likely to progress quickly.
The 2/20/20 model is a validated risk-scoring tool that is used to categorize patients with SMM into low-, intermediate-, or high-risk groups depending on whether they have any of the following measurements: (a) >2 g/dL M protein, (b) >20 free light chain ratio, or (c) >20% bone marrow plasma cells. The addition of cytogenetic analysis (by fluorescence in situ hybridization [FISH]) refines the risk groups. Data presented at IMW focused on strategies for improving the identification of patients at risk of progressing to active myeloma.
In the first presentation, researchers assessed how well the Mayo 2018 and International Myeloma Working Group (IMWG) 2020 clinical models predict progression to active MM over time in 704 patients with SMM. The predictive ability of these models is important, because the risk of progression decreases over time, and both models were developed for use at diagnosis. The results showed that both models can reliably provide prognostic information about the risk of progression for patients with SMM up to 4 years post initial diagnosis. Also, patients who migrate to a higher risk category over this time have an increased risk of progression; these patients need to be carefully monitored, as they may be candidates for early treatment intervention.
In the second presentation, European clinicians investigated the value of measuring circulating multiple myeloma cells (CMMC) every 6 months in 150 SMM patients as a predictor of disease progression. The investigators also looked at the profile of the immune cells collected from the blood of these same patients. Patients with low CMMC levels (≤0.73 cells/μL) had a lower risk of progression than patients with high levels (>0.73 cells/μL) (15% vs 67% progressed at 2 years). Median time to progression for patients with high levels was 17.5 months. Certain T cell subsets from the blood samples were associated with a shorter time to progression and a higher risk of transformation to active myeloma.
These data are interesting in that this new, minimally invasive measure using CMMC in the blood may have the potential to replace measurement of plasma cells from bone marrow biopsy samples—potentially changing the 2-20-20 model to a 2-20-0.7 model—to assess risk in SMM patients.
The ability to identify SMM patients with high-risk disease periodically and easily will aid in the development of appropriate interventional studies to prevent the development of active MM in these at-risk patients.
COVID-19 Vaccination in Myeloma: Suboptimal Antibody Response
Clinicians at the Massachusetts General Hospital and the Dana-Farber Cancer Institute presented data on whether MM patients are able to mount a sufficient response to either of the available COVID-19 vaccine types, mRNA vaccines (Pfizer and Moderna) or adenovirus vaccine (J&J). In this study of 91 vaccinated MM patients, 91% had a spike protein antibody response. These responses varied based on which vaccine was used (74% with Moderna vaccine, 51% with Pfizer vaccine, and 20% with J&J vaccine). Only 56% of patients achieved a spike protein antibody response >100 U/mL (45% of patients with progressive disease achieved this level). The investigators concluded that MM patients have an impaired response following COVID-19 vaccination and that being in remission is associated with an improved spike protein antibody response.
Clinicians at the Icahn School of Medicine at Mount Sinai reported their experience with the response to a two-dose regimen of a mRNA vaccine (Pfizer or Moderna) administered to 320 MM patients. The results showed that 81.3% of patients had a spike-binding antibody response >10 days after the second dose. In a control group of age-matched health care workers, antibody levels were significantly higher. Patients who had prior COVID-19 infection had antibody responses 10-fold higher than patients without prior COVID-19 infection.
Interestingly, MM patients on active treatment had lower antibody levels than did patients not on therapy. Approximately 16% of patients failed to develop a detectable spike-binding antibody response; of those patients, 58.5% were on an anti-CD38 antibody, 31.7% were on an anti-BCMA bispecific antibody, and 9.8% were on CAR T-cell therapy (>3 months after the therapy).
As with the study from Massachusetts General Hospital, the data from Mount Sinai suggest that MM patients mount a suboptimal response after vaccination. Furthermore, two similar studies that were presented—one conducted in the United Kingdom and one in Germany—also concluded that the response to vaccination is lower in MM patients, especially after the first dose.
For further review and discussion of the information presented at IMW, please check our additional blog post here, here, and here.
Support for this activity has been provided through a donation from Amgen; educational grants from GlaxoSmithKline, Karyopharm Therapeutics, and Oncopeptides; and a sponsorship from Johnson & Johnson Health Care Systems, Inc.