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Smoldering Multiple Myeloma Treatment Risks-

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The opinion article below conveys a fascinating perspective of smoldering multiple myeloma treatment risks. In a day when more and more oncologists are encouraging SMM patients to undergo active therapy, it is refreshing to read Manni Mohyuddin’s perspectives.


What are the pros and cons of active treatment of smoldering multiple myeloma?

Pros

  1. Delay in Disease Progression:
    • Reduction in progression to symptomatic MM: Early treatment can potentially delay the progression from SMM to symptomatic MM, which is associated with more severe symptoms and complications.
    • Improved survival rates: Some studies suggest that early treatment might improve overall survival and progression-free survival.
  2. Prevention of End-organ Damage:
    • Avoidance of complications: By treating SMM early, there is a potential to prevent complications such as bone fractures, kidney damage, anemia, and infections, which are common in symptomatic MM.
  3. Reduced Tumor Burden:
    • Control of disease: Early intervention can help in reducing the tumor burden, making the disease easier to manage in the long run.
  4. Psychological Benefits:
    • Patient reassurance: For some patients, knowing that they are proactively managing their condition can provide significant psychological comfort and reduce anxiety related to disease progression.

Cons

  1. Risk of Over-treatment:
    • Unnecessary exposure to side effects: Not all SMM patients will progress to symptomatic MM. Treating patients who may never develop symptomatic disease exposes them to the risks and side effects of treatment without clear benefits.
    • Impact on quality of life: Early treatment can negatively affect the quality of life due to the side effects and complications associated with MM therapies.
  2. Development of Resistance:
    • Drug resistance: Early and prolonged use of treatments could potentially lead to the development of drug-resistant disease, complicating future treatment options when the disease becomes symptomatic.
  3. Economic and Resource Considerations:
    • Cost of treatment: The financial burden of early treatment can be significant, both for healthcare systems and patients, especially if the benefits of early intervention are not clearly established.
    • Resource allocation: Allocating resources to treat SMM might divert attention and resources from patients with more advanced and symptomatic disease.
  4. Uncertain Long-term Benefits:
    • Lack of consensus: There is still a lack of consensus in the medical community regarding the clear benefits of treating SMM early. The risk-benefit ratio is not well established for all patients.
    • Variable disease progression: SMM is a heterogeneous condition with variable progression rates, making it challenging to identify which patients will benefit most from early treatment.

Dr. Mohyuddin’s essay touches on, what I consider the most important reason not to begin active therapy for the SMM patient. And that reason is three part-

  1. When diagnosed with SMM, the patient should begin Pre-habilitation– anti-MM nutrition, supplementation and lifestyle therapies shown to enhance the efficacy of active treatment if it does begin someday. 
  2. If the SMM patient ever does progress to full MM, they will be early stage aka stage 1. This being the case, their prognosis is much better, and they will respond better to therapy.
  3. Lastly, taken together- pre-habilitation and stage 1 MM, the SMM patient has a much better chance of active treatment resulting in MRD and therefore a longer overall survival.

I am a not any sort of medical professional. I am a long-term MM survivor. I view treatment decisions from a patient’s perspective as opposed to an oncologist’s perspective. I understand from personal experience that smoldering multiple myeloma treatment risks are not to be taken lightly.

Are you a SMM patient? If you would like to learn more about anti-MM nutrition, supplementation and lifestyle therapies email me at David.PeopleBeatingCancer@gmail.com

Good luck,

David Emerson

  • MM Survivor
  • MM Cancer Coach
  • Director PeopleBeatingCancer

Do No Harm: What Smoldering Myeloma Teaches Us

“Smoldering multiple myeloma (SMM), a potential precursor to multiple myeloma (MM), has become a controversial topic. Some people diagnosed with SMM will live their whole lives without ever developing MM, while others will develop it quickly.

My approach to treating SMM takes into account what its history can teach us about

1) how advancements in imaging and diagnostic reclassifications can revise the entire natural history of a disease and

2) how evidence generated by even the best of studies may have an expiration date.

Much of what we know about SMM today dates to a pivotal study by Robert A. Kyle, MD, and colleagues, published in 2007. That inspirational team of investigators followed people diagnosed with SMM from 1970 to 1995 and established the first natural history of the condition. Their monumental effort and the data and conclusions it generated (eg, 10% risk annually of SMM becoming MM for the first 5 years) are still cited today in references, papers, and slide sets.

Despite the seminal importance of this work, from today’s perspective the 2007 study might just as well have been describing a different disease. Back then people were diagnosed with SMM if their blood work detected a monoclonal protein and a follow-up bone marrow biopsy found at least 10% plasma cells (or a monoclonal protein exceeding 3 g/dL). If there were no signs of end-organ damage (ie, no anemia or kidney problems) and an x-ray showed no fractures or lesions in the bones, the diagnosis was determined to be SMM.

What’s different in 2024? First and foremost: Advanced, highly sensitive imaging techniques. MRIs can pick up small lytic lesions (and even the precursor to lytic lesions) that would not appear on an x-ray. In fact, relying solely on x-rays risks missing half of the lytic lesions.

Therefore, using the same criteria, many people who in the past were diagnosed with SMM would today be diagnosed with MM. Furthermore, in 2014 a diagnostic change reclassified people’s diagnosis from the highest risk category of SMM to the category of active MM.

Due to these scientific advances and classification changes, I believe that the natural history of SMM is unknown. Risk stratification models for SMM derived from data sets of people who had not undergone rigorous advanced imaging likely are skewed by data from people who had MM. In addition, current risk stratification models have very poor concordance with each other. I routinely see people whose 2-year risk according to different models varies by more than 30%-40%.

All this information tells us that SMM today is more indolent than the SMM of the past. Paradoxically, however, our therapies keep getting more and more aggressive, exposing this vulnerable group of people to intense treatment regimens that they may not require.

Therapies tested on people diagnosed with SMM include an aggressive three-drug regimen, autologous stem cell transplant, and 2 years of additional therapy, as well as more recently CAR T-cell therapy which so far has at least a 4%-5% treatment-related mortality risk in people with myeloma and a strong signal for secondary cancer risk. Other trials are testing bispecific therapies such as talquetamab, a drug which in my experience causes horrendous skin toxicity, profound weight loss, and one’s nails to fall off.

Doctors routinely keep showing slides from Kyle’s pivotal work to describe the natural history of SMM and to justify the need for treatment, and trials continue to use outdated progression prediction models.

In my opinion, as people with MM keep living longer and treatments for MM keep getting better, the threshold for intervening with asymptomatic, healthy people with SMM should be getting higher, not lower.

I strongly believe that the current landscape of SMM treatment exemplifies good intentions leading to bad outcomes. A routine blood test in a completely healthy person that finds elevated total protein in the blood could culminate in well-intentioned but aggressive therapies that can lead to many serious side effects. (I repeat: Secondary cancers and deaths from infections have all occurred in SMM trials.)

With no control arm, we simply don’t know how well these people might have fared without any therapy. For all we know, treatment may have shortened their lives due to complications up to and including death — all because of a blood test often conducted for reasons that have no evidentiary basis.

For example, plasma cell diseases are not linked to low bone density or auto-immune diseases, yet these labs are sent routinely as part of a workup for those conditions, leading to increasing anxiety and costs.

So, what is my approach? When treating people with SMM, I hold nuanced discussions of this data to help prioritize and reach informed decisions. After our honest conversation about the limitations of SMM models, older data, and the limitations of prospective data studying pharmacological treatment, almost no one signs up for treatment.

I want these people to stay safe, and I’m proud to be a part of a trial (SPOTLIGHT, NCT06212323) that aims to show prospectively that these people can be watched off treatment with monitoring via advanced imaging modalities.

In conclusion: SMM teaches us how, even in the absence of pharmacological interventions, the natural history of a disease can change over time, simply via better imaging techniques and changes in diagnostic classifications. Unfortunately, SMM also illustrates how good intentions can lead to harm.

Dr Mohyuddin is assistant professor in the multiple myeloma program at the Huntsman Cancer Institute at The University of Utah in Salt Lake City.

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