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In 2014, the International Myeloma Working Group (IMWG) – a change that has had a profound effect on the concept of early treatment of patients with smoldering multiple myeloma.

The diagnosis of multiple myeloma traditionally required the presence of end-organ damage known as the CRAB criteria (increased calcium level, renal dysfunction, anemia, and destructive bone lesions). The IMWG update added three biomarkers that can be used to diagnose multiple myeloma in patients who do not have CRAB features:

• Clonal bone marrow plasma cells of 60% or more

• Serum free light chain (FLC) ratio of 100 or greater, involved FLC level is 100 mg/L or higher

• More than one focal lesion on magnetic resonance imaging

"So the overall risk of that group of smoldering multiple myeloma patients changed because of the removal of this extremely high-risk group from that population," explained Shaji Kumar, MD, of the Mayo Clinic in Rochester, Minnesota. This also meant that changes were needed on how high-risk smoldering multiple myeloma is defined.

"This was done over the past 2 or 3 years, during which two different efforts came to the same conclusion, that a risk-stratification model referred to as the 20/2/20 criteria could be used to risk stratify patients at diagnosis," he said.

In a study published in , Kumar and colleagues analyzed 421 patients with smoldering myeloma and were able to categorize patients as having low, intermediate, or high risk of progression based on the presence of 20% or more bone marrow plasma cells, a serum M protein spike of greater than 2 g/dL, and a free light chain ratio over 20 -- hence the term "20/2/20."

The team determined that the presence of at least two of these risk factors identified patients at a distinctly higher risk of progression compared with other patients.

In another study in , Kumar and a co-author found that based on the presence of two or three of the 20/2/20 factors, a subgroup of smoldering multiple myeloma patients could be identified by who had a 50% risk of progression 2 years from diagnosis.

This development of a more accurate risk-stratification model has enabled researchers to pursue the concept of early intervention for high-risk patients, Kumar said. "Nearly half of patients with smoldering multiple myeloma will get myeloma within the first 5 years of diagnosis. So there has been a lot of interest in pursuing early intervention."

The idea is not only to see whether these patients can be prevented from progressing to myeloma and the significant end-organ damage that comes with it, but also to determine whether the disease could actually be cured, said Brian Durie, MD, chairman of the International Myeloma Foundation (IMF). "That patient with advanced disease is going to be more difficult to cure. And your best chance to achieve a cure is to start early."

Added Kumar: "In order to spur this research we needed a risk-stratification criteria that accurately identified the people at the highest risk, because we certainly don't want to intervene in people with the lowest risk, where the risk-benefit ratio may not be favorable."

The initial trials in this area were aimed at exploring the concept of delaying the progression of smoldering multiple myeloma to active myeloma through early intervention.

"The focus there was to use something simple in order to reduce the risk of toxicity, because the overriding concern when starting to do research in smoldering multiple myeloma is that we could not end up harming the patient," Kumar explained.

A randomized 119 patients with high-risk smoldering multiple myeloma to either observation or treatment with a combination of lenalidomide and dexamethasone, and showed that early intervention could delay progression to active disease and improve overall survival.

Kumar noted, however, that most of the patients in the trial did not undergo advanced imaging, and that about a quarter of patients actually had myeloma instead of smoldering multiple myeloma -- "so that did decrease the overall value of the study."

A y asked the same question, but used lenalidomide as a single agent. The results also indicated that early intervention with lenalidomide in patients with intermediate- or high-risk smoldering multiple myeloma delayed progression to symptomatic multiple myeloma, as well as the development of end-organ damage.

While lenalidomide-based therapy appears to be able to prevent progression and improve survival, is it also possible to actually achieve a cure through early, aggressive treatment with multidrug combinations?

The Black Swan Research Initiative, an IMF project focused on finding a cure, is conducting trials in this setting.

The phase II enrolled 90 patients with smoldering multiple myeloma at high risk of progression who were treated with a combination of carfilzomib, lenalidomide, and dexamethasone, followed by autologous hematopoietic cell transplantation and consolidation therapy. The goal was potential cure, defined as sustained minimal residual disease negativity at 5 years after high-dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT).

A total of 56% of patients who completed induction and HDT-ASCT achieved minimal residual disease negativity. "That's quite a high level of initial success," Durie said. "We're now out in the 4- to 5 -year time range, and a majority of those patients are still coming along with no evidence of recurrent disease. While we're not calling that a cure yet, we feel like we're making headway in that direction."

Kumar and Durie are also leading the multicenter phase II , which is evaluating the same combination of carfilzomib, lenalidomide, and dexamethasone, but with the addition of daratumumab in patients with high-risk smoldering multiple myeloma.

As for the suitability of this early treatment approach for the clinic, Kumar said that is a conversation worth having with high-risk patients.

"Based on what we know about high-risk smoldering multiple myeloma, many of us feel comfortable doing something for these patients," he said. "Our preference is to put them in clinical trials, but if someone doesn't want to go into a trial, I do think we want to show these patients the data showing the improvement in survival from the two [lenalidomide-based] studies, and I would certainly consider using -- at a minimum -- lenalidomide-based treatment. If, however, the patient does not feel ready to start therapy, but would rather stay with observation, I think that is reasonable, too."

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