The debate over when and how to treat high risk smoldering multiple myeloma patients (HRSMM) has heated up again at this year's ASH conference. HRSMM is defined as having at least a 50% chance of progressing to active myeloma within 2 years and 75% in 5 years. We'll review the basis of the current definition and recommendations, as well as several studies that are bringing us closer to finding more exacting individual genomic and immune parameters upon which to base the definition.
Based on the discussions below, we come to three important conclusions:
In a session "When Should High Risk Smoldering Be Treated?" led by Dr. Shaji Kumar along with seven other members of the International Myeloma Working (IMWG) group, they made the case for their conclusion that we have adequate evidence to recommend that HRSMM patients either receive treatment with lenalidomide only or add dexamethasone, or join clinical trials. This is captured in a proposed algorithm for 2021 by Dr. Vincent Rajkumar on behalf of the International Myeloma Working Group.
Evidence used to support this recommendation include the updated IMWG 2/20/20 criteria: >2 grams/deciliter of serum M-protein, >20% serum free light-chain ratio, and >20% plasma cells found by bone marrow biopsy. An IMWG Risk Score Tool was also developed which offers the incorporation of cytogenetics.
Important additional evidence comes from three studies:
This evidence shows an increase in progression free survival and a questionable increase in overall survival for early treatment. However, there are specialists who prefer to wait for genomic, kinetic and immune biomarkers that no longer assume "the disease" progresses in a linear manner, or even is one disease and will provide individualized data regarding risk of progression, before recommending early treatment which is accompanied by toxicities.
Here are three of the research studies on high risk smoldering myeloma I find incredibly exciting and for each I'll share why.
Dr. Benedith Oben of Belgium presented the first whole-genome sequencing (WGS) analysis of patients with monoclonal gammopathy of unknown significance (MGUS) and smoldering multiple myeloma (SMM) wherein they successfully identified two distinct mutational landscapes for stable precursors and progressive precursors.
Bone marrow samples of a total of 32 patients, 18 MGUS and 14 SMM were analyzed and compared to 80 myeloma patients with the following findings.
Here are Dr. Oben's conclusions:
Dr. Rosalinda Termini of University Clinic of Navarra, Pamplona, Spain who presented, said "New minimally-invasive methods should also monitor immune profiles, to identify patients with stable tumor/burden genetics but at risk of progression due to lost immune surveillance."
This research says it's not just about how aggressive or not the clones are, but about how well our immune systems monitor and respond to our abnormal plasma cells!
I love the topline goal of this trial which is to eventually use peripheral blood samples taken in the clinic to evaluate Circulating Tumor Cells (CTCs) and immune subsets to identify if you are at risk of progression to active disease.
Importantly, at interim analysis 8 of 18 patients who had progressive disease were not high risk smoldering myeloma (SMM) by the 20/2/20 model. Dr. Termini said they think Immunocell technology can be used to enhance the 20/2/20 model.
Specific aims were to:
Methods and Study design:
Her conclusions can be seen here.
Dr. Elisabet Manasanch of MD Anderson presented a third research study we should keep on our radar. What excites me most here is that she believes this research provides a rationale to halt progression of the disease with immunotherapy.
The basis for this research is that it is known that as early as MGUS, changes take place in immune cells and their function that result in reduced tumor surveillance.
The primary aims were to:
These slides capture the study design and conclusions.
Having reviewed the "what we know" and the "what we've yet to learn", my hope is that if you are a high risk smoldering myeloma patient making a treatment decision going into 2021, you will be introspective regarding your medical risk tolerance and combine this with thoughtful discussion with your myeloma specialist regarding the known details of your individual disease behavior and biology.
You will also need to select a specialist who has a treatment philosophy that aligns with your own. I truly believe knowledge is power, so please keep reading and learning.
about the author
Bonnie is a Myeloma Coach and the caregiver for her husband with Multiple Myeloma. They live at the foot of the Blue Ridge Mountains in Afton, VA with their 2 dogs and 2 cats.