Dr. Sigrun Thorsteinsdottir, MD, PhD, gave a comprehensive review of smoldering myeloma directed toward practitioners. The session was very informative and so I’d like to dedicate this blog to sharing this information from a patient’s perspective, as I’ll highlight various points made by Dr. Thorsteinsdottir.  

  1. Smoldering multiple myeloma (SMM) is a precursor condition that precedes multiple myeloma (MM). It is considered asymptomatic and is often diagnosed incidentally. Statistics show that 3-6% of myeloma patients previously had a known precursor condition.  
  1. In the iStopMM study, a study that has screened half of the adult population in Iceland, .5% of those 40 and older were found to have SMM, with rates slightly higher in males (.7%) compared to females (.4%). Other research conducted in the US shows that it is more common in Blacks than in other racial groups. The likelihood of being diagnosed with SMM increases with age.  
  1. When assessing the risk of progression to MM, cohort studies in the US estimate a progression rate of 10%/year for the first 5 years after diagnosis. After 5 years, the risk goes down to ~3%/year. It will be interesting to see what rates of progression emerge with time in the iStopMM study. 
  1. An interesting discussion is currently occurring in the field, as well as being studied: should SMM patients be treated? The standard of care currently is observation until progression. Recently, a number of experts have published their perspectives that they believe there is enough evidence that high-risk smoldering multiple myeloma (HRSMM) patients should be treated with lenalidomide or lenalidomide and dexamethasone. Other experts have also recently published that the current standard of care is still close surveillance outside of clinical trials and that the data published thus far doesn’t justify starting treatment. Last year, a European expert panel stated that perhaps treatment should begin in a selective group of very high-risk SMM patients, but they should receive treatment similar to MM patients. Those who are very critical of starting treatment say that the current recommendation based on recent trials to use lenalidomide poses the risk of over treating patients who do not need treatment and under treating patients who will get symptomatic MM.  
  1. Why do the experts disagree on this? One issue is that there is a lack of agreement regarding what constitutes HRSMM. Most experts agree that “high risk” is having a 50% chance of progression to MM within 2 years of SMM diagnosis, and a number of risk stratification models have been developed (e.g., Mayo Clinic model, PETHEMA model, IMWG 2020 model).  
  • The iStopMM study assessed 88 SMM patients diagnosed by screening, using the different models. They found an overall agreement of 52% between the models. 
  • To further address this issue, dynamic risk assessments are being developed. These take into consideration changes in key markers (M-protein spike, FLC ratio, etc) over time. While in development, these offer some hope for risk stratification in the future.  
  • Dr. Thorsteinsdottir also discussed the importance of defining what low-risk SMM is. One possible method is to evaluate circulating tumor plasma cells (CTCs) in peripheral blood by flow cytometry. This could possibly replace bone marrow biopsy at diagnosis, and the threshold of .015% CTCs could replace the >20% bone marrow plasma cells (BMPC) in the 2/20/20 model.  
  1. Another noteworthy question is: Does treatment benefit patients with HRSMM? Dr. Thorsteinsdottir noted that the conversation around this question is very interesting, even on Twitter. Dr. S. Vincent Rajkumar, MD, a myeloma expert from the Mayo Clinic, has shared that some people have asked him if they can follow closely instead of beginning treatment for HRSMM. He stated that doctors originally thought they could do this (i.e., follow closely), but in trying to do so, including following monthly, they failed to prevent end-organ damage with lenalidomide compared to observation in their random controlled trials.  
  • Those who are critical say that there are a number of reasons why SMM should not be treated. One reason is the risk of secondary cancers with lenalidomide treatment.  
  • There are two randomized phase 3 trials in SMM. One is the Spanish trial, where HRSMM patients (per the PETHEMA model) were treated with lenalidomide for 2 years. Results showed improved progression free survival (PFS) and overall survival (OS). The other is a United States study (Lonial et al., J. of Clinical Oncology, 2020) where patients were treated with lenalidomide alone. Results showed a response to therapy in 50% of the patients. PFS was significantly longer with lenalidomide versus those in the observation arm, but not OS. These included intermediate and HR SMM patients with abnormal FLC ratio.  
    • With these two trials, the definition of SMM is a little bit different because the SLiMCRAB criteria was used in the 2020 trial and only 25 patients were treated in the US study according to 2/20/20.  
    • There were toxicities in both of these trials, along with one treatment-associated death in both trials and more secondary cancers in the treatment arm in both trials.  
  • Several other trials are in progress, as well. Some research points to note are that in many, there are no control arms. Rather, some are pilots where all patients enrolled are given a treatment regimen and followed over time, while others include one treatment regimen is tested against another treatment regimen. These make it difficult to compare results to the standard of close observation.  
  1. Given what is known, how should physicians manage SMM? A thorough work-up at diagnosis is important, including complete blood count and all of the blood tests that are necessary, a bone marrow with FISH so that IMWG risk criteria can be used. Bone imaging is important, and if whole body low dose CT is negative, then a whole body MRI, MRI of the spine, or PET-CT can be used. Flow cytometry is possible, as well, if available.  
  • Using the data gleaned from these tests, patients should be risk stratified, and closely followed for the possibility of evolving disease.  
  • Other possible plasma cell associated conditions should be excluded.  
  • Hopefully, a dialogue occurs between the patient and the doctor, where the patient can share thoughts, goals, and perspectives on potential therapy. As a patient, you might consider examining your thoughts, goals, and perspectives between follow-ups, and if they change, be sure to communicate these changes with your doctor.  
  • With low and intermediate risk patients, if the disease appears stable, they can be seen a bit less frequently. But HR patients should be followed very closely, with clinical trials considered if there are some that seem to be a good fit. If a patient is both HR and has evolving biomarkers, starting treatment can be considered, although there are no approved drugs for this right now (in the US or Europe), but they might come very soon.  
  1. What are the remaining questions in SMM? 
  • Can validated risk stratification models that take into account evolving disease be developed? 
  • Can individuals who have a high risk of progression be correctly identified? If so, early treatment possibilities can be considered, and close observation is needed.  
  • Can those with low risk of progression (MGUS-like disease) be correctly identified? These patients should not be treated and should not be over-surveilled.  
  • When treatment is initiated, are short-term curative approaches or long-term less intensive treatments better?  

Dr. Thorsteinsdottir concluded this thorough review of SMM by again sharing that SMM is an asymptomatic precursor condition with a prevalence of .5% in those over 40 years of age. Previous treatment trials in SMM have used different diagnostic criteria and risk stratification models. Overall survival benefit has been demonstrated for treatment of asymptomatic patients, but researchers need to find out who exactly benefits. There are many unanswered questions regarding treatment in HRSMM. There is also a need for trials with overall survival and quality of life as primary endpoints, although this can be very difficult because the survival time can be very long, meaning the trials would take a long time (possibly 10 or 15 years or more…), but that would be optimal.  

I hope you’ve found this information beneficial. This session was packed full of SMM-related information, research, and perspectives, and I did my best to summarize them for you. The more educated patients can be, the better they will be able to advocate for themselves. Be well!