Extinguishing Smoldering Myeloma?

For patients with smoldering myeloma – a precursor stage of multiple myeloma (MM) – the standard approach for years has been “watch and wait,” based on the desire to avoid unwanted toxicities with unnecessary treatment.

“Smoldering myeloma is an older term,” Joshua Richter, MD, myeloma specialist and assistant professor at the Tisch Cancer Institute, Division of Hematology and Medical Oncology at Mount Sinai Hospital in New York City, tells ASH Clinical News. “Some groups, including the Mayo Clinic, have pushed to define this state as ‘asymptomatic myeloma,’ which is probably a better term. Basically, it means myeloma that we need to monitor but not to actively treat.”

But, according to Dr. Richter and other myeloma specialists interviewed by ASH Clinical News, the way clinicians are viewing so-called smoldering myeloma is changing. With data from several trials suggesting that early intervention treatment may prevent progression to symptomatic MM, there is now a debate among experts about who to treat, when to begin treatment, and which drugs or combinations of drugs to use.

Expanding the Definition of Multiple Myeloma

MM is the result of progression through two prior clinical states, a pre-malignant state known as monoclonal gammopathy of undetermined significance (MGUS) and an intermediate stage between MGUS and MM known as smoldering myeloma. However, progression from MGUS to symptomatic myeloma is not on a continuous spectrum. Most patients with MGUS never go on to develop symptomatic myeloma. Those with smoldering disease have only a 10% risk per year of disease progression for 5 years, then a 3% risk per year for the subsequent 5 years, followed by a 1% risk per year.

For years, MM was defined by the presence of four features, all of which are indicative of the clonal progression to symptomatic myeloma, known as CRAB:

  • hypercalcemia (C)
  • renal dysfunction (R)
  • anemia (A)
  • bone lesions (B)

Patients with smoldering myeloma, on the other hand, have no CRAB features. That changed in 2014, when the International Myeloma Working Group (IMWG) updated the diagnostic criteria for MM, adding additional specific biomarkers to patient evaluation criteria for those who did not display CRAB features. These included level of serum or urine monoclonal protein (serum ≥3 g/dL or urinary monoclonal protein of ≥500 mg/24 hours), percentage of clonal bone marrow plasma cells (≥10%), and serum free light chain ratio (involved to uninvolved ratio of > 100).1 In addition, the IMWG, including clinicians at the Mayo Clinic in Rochester, Minnesota, and the Centro de Investigacion Medica Aplicada in Pamplona, Spain, recommended the use of MRI imaging to detect the presence or absence of focal lesions. These updated criteria, known as “SLiM CRAB,” identify a new group of patients whose disease features now warrant treatment, rather than the traditional “watch and wait” approach. “SLiM” refers to three factors: ≥60% (S) plasma cells by flow cytometry on clonal bone marrow plasma cells, kappa-to-lambda or lambda-to-kappa light chain (Li) ratio of >100, and ≥1 focal lesion on MRI (M).

“These criteria expanded our definition of multiple myeloma to include patients who were previously diagnosed with smoldering myeloma but now are considered to have symptomatic myeloma,” said Sagar Lonial, MD, myeloma expert and Professor and Chair of Hematology and Medical Oncology at the Emory University School of Medicine and Winship Cancer Institute in Atlanta. Dr. Lonial also served on the IMWG committee that published the updated diagnostic criteria. “These biomarker-driven criteria have been widely adopted around the world,” said Dr. Lonial. “This system allows us to identify those patients who have an 80% risk of progression to symptomatic myeloma within 1 year, and to intervene early with treatment.”

According to Shaji K. Kumar, MD, who treats patients and conducts research at the Mayo Clinic in Rochester, Minnesota, about 7% and 10% of patients who were previously labeled as having smoldering myeloma are now classified as having MM based on these criteria. Despite the acceptance of these new criteria, Dr. Richter highlighted some caveats in the data from the IMWG. For example, the research supporting the changes used data from patient aspirate samples to estimate the percentage of clonal plasma cells.

Risk-Stratifying Smoldering Myeloma

The reshuffling of patients from “smoldering” to “symptomatic” based on the 2014 update resulted in the need to redefine “high-risk” smoldering myeloma with the highest risk of progression to MM. “There was a prior risk stratification tool from 2008, but we found that we had to go back to the drawing board and figure out a new risk stratification model with different risk cutoffs,” Dr. Kumar recounted.

Addressing this issue, in 2018, Dr. Kumar and colleagues published a revised risk stratification strategy that clinicians have dubbed the ”20/2/20” criteria.2 Analyzing 421 patients with smoldering myeloma, the researchers were able to categorize patients as having low, intermediate, or high risk of progression based on three features: presence of >20% bone marrow plasma cells, a serum M protein spike of >2 g/dL, and a free light chain ratio of >20. Each factor is an independent predictor of a shorter time to progression. The low-risk group, with none of the features, had a 5% risk of disease progression at 2 years. Intermediate-risk patients had at least one of these features and a 17% risk of progression, while high-risk patients had at least two features and a 46% risk of progression.

“For patients who have a risk of progression of 50% at 2 years, as a community, I think we are comfortable about discussing the potential for early interventions with those patients,” Dr. Kumar explained.

“This tool is a way for us to provide a prognosis of which patients fits into the highest-risk smoldering category, but who do not meet the criteria for symptomatic myeloma,” Dr. Lonial commented.

“It’s a great bedside tool through which clinicians count the number of risk factors present to identify those at higher risk for developing symptomatic disease,” added Dr. Richter.

How to Prevent Progression

Equipped with criteria to help answer the question of who to treat, the next question becomes what to treat them with. Researchers have two basic hypotheses about early treatment for those with high-risk smoldering myeloma, Dr. Kumar said: “The first is whether treatment can improve overall survival and the second is whether an early intervention could potentially cure some patients.”

Thus far, two phase III studies have demonstrated that early treatment can delay the development to symptomatic myeloma. The first, published in 2013 by the Spanish Myeloma Group, randomized 119 patients with high-risk smoldering myeloma to observation or early induction treatment with lenalidomide plus dexamethasone. Compared with observation, treatment delayed progression to active disease (not reached vs. 21 months), increased overall survival (94% vs. 80%), and did not compromise the efficacy of subsequent therapies.3

However, the regimen has not been adopted widely because of several issues with the trial. First, the patients were risk-stratified using a flow cytometry technique that is not easily executed at all treatment centers. The second, according to Dr. Kumar, is that patients were not diagnosed using modern imaging techniques such as MRI and PET. In retrospect, using the 2014 staging criteria, about one-quarter of patients on the trial actually may have had MM and not smoldering myeloma. “All of these issues mean that the results may not be applicable to current practice,” he said.

The second trial, completed in 2019, used the 2018 risk stratification criteria and MRI imaging to identify 182 patient with intermediate- and high-risk smoldering myeloma and randomized them to receive lenalidomide monotherapy or observation.4 Again, treatment reduced the risk of progression: The risk was 78% lower for all patients and 90% lower for patients with high-risk smoldering myeloma. One- and 3-year progression-free survival in the lenalidomide arm were 98% and 91%, respectively, compared with 89% and 66% in the observation arm. The patients are still being followed for overall survival.

For Dr. Richter, the trial is a success for those patients for whom lenalidomide alone can prevent the progression to symptomatic myeloma. But, because the trial includes a heterogeneous group of patients, there also are likely patients with more biologically aggressive disease for whom lenalidomide alone is likely not enough. And, unfortunately, the exposure could lead to resistance to the drug later on, he told ASH Clinical News.

“My issue is that this is still a homogeneous approach for a heterogeneous disease,” he said. “I am not a fan of single-agent trials to prevent progression because there should be a line in the sand that delineates patients with a relatively benign neoplasm that does not need to be treated from patients who are likely to progress and should be treated to prevent myeloma-related end-organ damage,” Dr. Richter continued. “The current standard is a three- or four-drug regimen; giving a single agent is undertreating someone who is likely to progress – and overtreating those who likely will never progress.”

Dr. Richter added that he is awaiting results from the phase II ASCENT trial, which is evaluating whether the combination of carfilzomib, lenalidomide, daratumumab, and dexamethasone could potentially cure high-risk smoldering myeloma, before patients start to develop symptoms.5

The phase II GEM-CESAR trial, also from the Spanish Myeloma Group, also is testing a combination regimen (carfilzomib, lenalidomide, and dexamethasone), followed by high-dose therapy and autologous hematopoietic cell transplantation, in younger patients with high-risk smoldering myeloma.6 After a median follow-up of 32 months, 93% of patients had disease in remission; 56% of patients who completed induction therapy and underwent transplant have no detectable measurable residual disease.

An ongoing phase III trial from the ECOG-ACRIN Cancer Research Group, also in patients with high-risk smoldering myeloma, is evaluating whether the combination of daratumumab, lenalidomide, and dexamethasone can prevent progression to MM.7

What’s Next?

A pressing question on myeloma specialists’ minds is whether long-term therapy might affect patient’s stem cells that could be needed for a transplant down the line. “This is a concern, and we certainly need to be thinking about collecting and storing patients’ cells before they get too many cycles of treatment,” said Dr. Kumar. For example, in the ECOG-ACRIN trial, patients were recommended to have stem cells collected following four cycles of therapy to preserve the ability to receive an autologous transplant in the event of later disease progression.

Another goal is to define patients with high-risk smoldering myeloma with greater accuracy. “We would like to identify the genomic and immunologic factors associated with high-risk disease to create a computational model that can identify patients who will not need treatment and those that do,” Dr. Richter said. “The future for smoldering myeloma is shifting the focus from clinical features to understanding and using the biology of the disease to help our patients.

“This new risk stratification system is good, but it’s not perfect. Some patients might look like they have high-risk disease but will not progress, and some patients who are classified as low risk might progress faster,” he added. “We still have work to do to improve the risk stratification, using the information about the genetics of the patients’ myeloma cells. That might take us to predicting progression at 5 years with an accuracy of about 90%.”

All three clinicians who spoke with ASH Clinical News emphasized that it may be as important to not treat some patients as it is to treat others. Still, Dr. Richter said, “that can be a difficult conversation to have with a cancer patient: We think you shouldn’t get treatment right now but should be monitored carefully.” —By Anna Azvolinsky


  1. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538-e548.
  2. Lakshman A, Rajkumar SV, Buadi FK, et al. Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria. Blood Cancer J. 2018;8:59.
  3. Mateos MV, Hernandez MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med. 2013;369:438-447.
  4. Lonial S, Jacobus S, Fonseca R, et al. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2019 October 25. [Epub ahead of print]
  5. ClinicalTrials.gov. Aggressive smoldering curative approach evaluating novel therapies and transplant (ASCENT). NCT03289299. Accessed February 7, 2020, from https://clinicaltrials.gov/ct2/show/NCT03289299.
  6. Mateos MV, Martinez-Lopez J, Otero PR, et al. Curative strategy (GEM-CESAR) for high-risk smoldering myeloma: carfilzomib, lenalidomide and dexamethasone (KRd) as induction followed by HDT-ASCT consolidation with KRd and maintenance with Rd. Abstract #781. Presented at the 2019 ASH Annual Meeting, December 8, 2019; Orlando, FL.
  7. ClinicalTrials.gov. Lenalidomide, and dexamethasone with or without daratumumab in treating patients with high-risk smoldering myeloma. NCT03937635. Accessed February 7, 2020, from https://clinicaltrials.gov/ct2/show/NCT03937635.