What Is the Best Approach for Patients with Smoldering Myeloma?

The recent publication of the ECOG trial evaluating lenalidomide (Revlimid) treatment versus observation for patients with smoldering myeloma has prompted considerable discussion about the current recommendations for treatment. That discussion has largely been triggered by the study’s closing summary, which indicates that the data “support early therapy [with lenalidomide] as a standard of care in high-risk SMM (HR-SMM).”

Is lenalidomide truly a new standard of care for HR-SMM?

For many physicians and patients, the answer is either “no” or “we are really uncertain,” based on:

• The numbers of patients with HR-SMM treated in the ECOG trial
• The criteria to be used for HR-SMM criteria
• The toxicities and treatment details in the ECOG trial
• The lack of longer-term outcomes information
• The availability of more than 50 trials globally to assess management of SMM.

Of the 180 patients in the ECOG trial, only 14 with HR-SMM received treatment with lenalidomide. Though their outcomes were improved versus observation alone, this is an extremely small number of patients as a basis for a “standard of care.”

In addition, the remaining patients (the vast majority of them) were those with lower-risk SMM, and they did not achieve benefit with treatment. This is important on many levels, not least because the criteria for the diagnosis of HR-SMM are currently in flux. 

Does a patient have HR-SMM or not? This is a key question, and for practicing clinicians and patients, the answer is often unclear. The fact that lower-risk patients do NOT benefit from the lenalidomide treatment heightens the need to have a definitive diagnosis before embarking on treatment for potential HR-SMM patients. 

The results of the ECOG trial are supported by results of the prior Spanish trial, which compared treatment with lenalidomide and dexamethasone to observation. In each case, the risk of progression has been significantly reduced. However, the Spanish trial researchers used their own system for HR-SMM classification. 

Criteria for HR-SMM

New models for the identification of HR-SMM have been introduced in the past two years. The 2/20/20 model proposed by the Mayo team uses serum M-component level (2 grams per deciliter—g/dL-- or more); bone marrow plasma cell percentage (20% or more); Freelite ratio (20 or more) as the classification tool. This is quite good as a tool and has been validated by a more recent IMWG retrospective analysis. These IMWG analyses have also produced a more refined scoring system, which assigns points based upon levels of the same factors, with the option to add in poor-risk chromosome abnormalities, such as 17p- and 1q+ (which increase the score). An app is in development by the IMF to simplify the use of the scoring system.

The bottom line: these systems are just at the point of release for general use and are not integrated into “standard of care” algorithms or plans as of now. They are, as yet, not well known in the community setting. Newer classification systems are being sought, including so-called dynamic systems, which encompass serial evaluations to assess changes over time as a basis for decision-making.

Treatment details from the ECOG lenalidomide trial 

Among treated patients, 40% came off treatment due to toxic adverse events. This is important in itself, but also because the duration of treatment is limited by these toxic events. The open question remains: what is the recommended duration of treatment?

Based upon available results, shorter and longer treatment produced equivalent results (median duration of treatment was 23 cycles). An important summary point is that cumulative risk of progression for the treated patients was 7.3% at 3 years (versus 31.6% in the observation arm of the study). This reduced risk of progression is the key benefit supporting the value of treatment versus no treatment. But reduced risk of progression must be balanced against the toxicities of therapy and, of course, costs.

It is important to note that lenalidomide is currently approved for the treatment of myeloma, not SMM. Thus, reimbursement for the cost of medication by health insurance companies could be an issue. In addition, there are sequential difficulties with disease assessment and management with treated SMM patients. If a patient with SMM progresses, what is that? Is it myeloma? Maybe, maybe not. In reality, it is previously treated, early myeloma. Is “prevention” a line of therapy? The semantics become very challenging, as does the eligibility for alternate treatment strategies. 

So, what should a patient do right now?

• Considering all the elements and details noted above, my recommendation is that lenalidomide is not yet a routine standard of care for HR-SMM. 
• Detailed discussions with your doctor are essential to determine your risk status and review the potential options, including observation; lenalidomide or lenalidomide+dexamethasone; or potentially, more aggressive so-called “Cure” approaches.
• If discussion with your doctor leads to a decision to closely observe without treatment, it is extremely important to establish a clear protocol for regular monitoring to detect any early indications of disease progression.
• In these discussions, the question of “what is SMM?” needs to be addressed. Patients with HR-SMM basically have early, active myeloma. The criterion of HR-SMM based upon a more than 50% (or 70-to-80% risk with the new scoring) likelihood of progression in 18 months to 2 years is similar to the already-accepted new criteria for active myeloma using plasma-cell percentage in the bone marrow, Freelite, and MRI findings. Thus, if treatment is to be given for HR-SMM, it is logical to treat it as one would treat myeloma. Conversely, patients with lower-risk SMM—especially with true, low-risk SMM—should NOT be treated with myeloma-type therapy, since they do not benefit from lenalidomide.

The final question is: if HR-SMM is really like early myeloma, is gentle (lenalidomide-type) treatment the answer? Or is more aggressive treatment warranted? 

In a new ECOG trial, the value of lenalidomide versus daratumumab+len+dex is being assessed — an important comparison.

More aggressive approaches are being assessed in the “CURE” trials (KRd or dara KRd +/- ASCT). The longer-term benefit of aggressive treatment versus gentler approaches remains to be seen. Clinical trials are the only way to have clear answers, and I strongly advocate for continuing to conduct trials in the SMM setting, as well as offering patients options after careful individual discussions.