Debate: Early Intervention for Smoldering Multiple Myeloma (SMM) — A Summary
One of the most relevant sessions for those interested in smoldering myeloma was a Spotlight Session called “Smoldering Myeloma: A Case for Early Intervention?” presented by Maria-Victoria Mateos, MD, PhD, and Karthik Ramasamy, MD, PhD. The seventy-five-minute session featured a two-sided debate on whether early intervention is appropriate for smoldering myeloma. Dr. Mateos argued in favor of early intervention, while Dr. Ramasamy presented the opposing perspective.
Before presenting their arguments, important points about diagnosing and monitoring SMM were emphasized:
- Rule out other conditions: Diseases like diabetes, hypertension, and vitamin deficiencies can mimic signs of myeloma.
- Confirm the diagnosis: Doctors should check for the presence of the M-protein. They should also ensure there is no anemia, kidney issues, or high calcium levels, and repeat these tests at least once to confirm stability.
- Conduct a full evaluation: Tests like free light chain (FLC) assessment, MRI, and bone marrow biopsy help ensure no active myeloma-defining events (MDEs) are present.
Assessing the risk of SMM progressing to active myeloma is critical for providing the right care. Risk models estimate the chance of progression, typically identifying patients with a 50% risk of developing myeloma within two years. Ideal models combine clinical, biological, and dynamic markers. Examples include:
- The Pethema model
- Bence Jones proteinuria (protein in urine)
- Evolving M-spike patterns or changes in M-spike and hemoglobin levels
- PET-CT imaging
- The PANGEA model
(Note: The “20-2-20” model, widely used in the U.S., was not presented.)
Dr. Mateos began with the question, “Smoldering Myeloma: A case for early intervention?” Her position was clear: early treatment offers the best chance to cure myeloma. However, she noted that “cure” must be carefully defined. She referenced a 1963 definition of cure: after a decade or two, patients are disease-free and have a similar life expectancy to the general population.
She outlined the challenges of achieving a cure:
- Myeloma is a complex and diverse disease, not a single condition.
- Treatment should be personalized: frail patients or those with high-risk features need different approaches than fit, low-risk, or asymptomatic individuals.
Dr. Mateos supported her argument with studies showing promising results for early treatment:
- Aquila study
- GEM-CESAR trial
- ASCENT trial
- Immuno-PRISM and CAR-PRISM studies
She concluded:
- Results from these studies are encouraging, but they need longer follow-up to confirm if early treatment leads to a lasting cure.
- Treating high-risk SMM (HR-SMM) with therapies used in active myeloma may offer a curative option.
- Patients with newly diagnosed myeloma (NDMM) and no high-risk features may also achieve cure-like outcomes.
A key point here is that the main difference between HR-SMM and NDMM is the absence of myeloma-defining events (MDEs) in HRSMM.
Dr. Ramasamy countered Dr. Mateos’ position by stating: “Early intervention only adds costs and toxicity unless we treat the right patient, at the right time, with the right goal.”
He highlighted the complexities of SMM:
- Myeloma remains incurable despite advances.
- SMM is a heterogeneous disease—not all patients progress in the same way.
- Patients have different priorities and expectations for treatment.
- Effective therapies already exist to treat active myeloma, and earlier use can be studied further.
- SMM is a large population—how many patients would truly benefit from early treatment?
Dr. Ramasamy then asked: “Under what conditions is early intervention valid?” He proposed five criteria:
- SMM cells are sensitive to treatment.
- Treatment happens before the disease evolves further.
- Treatment is tailored to individual patients.
- Early intervention prevents life-altering complications during monitoring.
- Early treatment improves survival.
He compared SMM and NDMM studies to examine treatment response:
- In transplant-eligible patients, response rates (VGPR or better) were similar for SMM and NDMM.
- In transplant-ineligible patients, NDMM studies showed better responses than SMM studies.
Dr. Ramasamy then laid out the pros and cons of treatment approaches in SMM. The following table is a reproduction of one of his slides:
| Prevent/Delay Active Myeloma | Functionality Cure Myeloma | |
| Pros | Low-intensity approach Relatively fewer side effects Applicable to the majority of SMM patients | High potential for treatment-free period Deep responses |
| Cons | May require further therapy Lower response rate Lack of deep responses | High-intensity approach Higher risk of adverse events Applicable for a smaller proportion of patients Risk of multidrug resistant clones |
Dr. Ramasamy pointed out challenges with current SMM trials:
- Changing definitions of high-risk SMM (HRSMM) and NDMM complicate results (e.g., SLiM CRAB criteria, Mayo “20-2-20,” and IMWG criteria).
- Lack of survival data: Only the DETER-SMM trial measures overall survival as an outcome.
- Toxicity concerns: Some trials report side effects and reduced quality of life for patients receiving early treatment.
Dr. Ramasamy suggested next steps:
- Better monitoring tools: Improve risk models, use whole-body MRI for imaging, and follow care standards.
- Patient involvement: Include patient preferences in research, explore barriers to treatment, and set toxicity limits in trials.
- Refine treatment approaches: Develop personalized treatments tailored to individual patients.
- Cost-effective therapies: Recognize the financial burden on patients, including treatment costs, managing side effects, and lost productivity.
Dr. Ramasamy’s final points included the following:
- Enhance monitoring tools alongside early treatment models.
- Prioritize patient involvement in research.
- Focus early treatment trials on patients at the highest risk of progression.
- Design trials to reduce short- and long-term side effects.
- Ensure trials measure clinically meaningful outcomes.
- Develop affordable treatment strategies to maximize accessibility.
Conclusion
The debate between Drs. Mateos and Ramasamy highlighted the uncertainties surrounding early intervention for SMM. Mateos argued that early treatment offers hope for a cure, especially for high-risk patients, while Ramasamy emphasized caution, patient priorities, and the need for refined, cost-effective approaches.
For those with SMM, it’s essential to carefully consider the risks and benefits of early treatment. Discuss all options with your doctor, evaluate your personal risk tolerance, and consider your long-term goals before making a decision. Research is advancing, but there are still more questions than answers in this complex space.
