This has been a busy few weeks, with many important items in the news. Perhaps the most prominent was the issue of smoldering multiple myeloma (SMM): how to diagnose it and how to treat it—or not.

Smoldering myeloma 
At the American Society of Clinical Oncology (ASCO) annual meeting in Chicago and the IMWG Summit in Amsterdam, both held this month, smoldering myeloma was the first item on the agenda. In Chicago, Dr. María-Victoria Mateos (University of Salamanca, Spain) presented a new scoring system for high-risk SMM (HR SMM). The system identifies patients most likely to progress to active myeloma at two years. The most predictive factors are the serum protein level, bone marrow plasma cell (BMPC) percentage, and Freelite ratio, as well as presence or absence of high-risk fluorescence in situ hybridization (FiSH) abnormalities. 

A preliminary system was called “2-20-20,” which referred to these simple cutoffs: 2 (serum protein g/dl); 20 (BMPC% in bone marrow); 20 (Freelite ratio). The new system takes the exact patient values (some being above or below the cutoffs) to give a customized prediction. The system identifies patients with a 70- to 80-percent risk of progression in the 2- to 3-year timeframe (true HR SMM), as well as patients with a 50 percent risk (high intermediate risk). An app is in development to make the use of this new scoring system as easy as possible.

Key questions about smoldering myeloma
Should patients with HR SMM be:

  • Observed?
  • Treated in a preventative fashion?
  • Treated as myeloma patients? 
  • Treated in an effort to achieve cure?

At ASCO, Dr. Sagar Lonial (Emory University, Atlanta) presented the results of the E3A06 ECOG trial in which 182 patients were randomized to either receive 25 mg of lenalidomide for 3 out of 4 weeks, or to be observed. Overall, the lenalidomide delayed progression versus observation, but this was only statistically significant for the small subset (29 patients) of true HR SMM patients, as defined by the system described above. This conclusion supported a similar conclusion from a prior randomized trial for high-risk smoldering myeloma that was conducted in Spain  (QUIREDEX), in which lenalidomide + dexamethasone was used.

What to do next is the question. Dr. Lonial suggested that the data are sufficient to recommend lenalidomide treatment for HR SMM. Reaction to this suggestion was quite mixed. Questions raised by myself and others about this approach included the possibility of developing resistance to suboptimal myeloma therapy, as well as concerns about side effects, costs, and the increased risk of second malignancies without the security of long-term benefits.

At the European Hematology Association (EHA) annual meeting, also this month, Dr. Mateos presented updated results of the Spanish CESAR trial for HR SMM. In this study, patients received attempted curative therapy with Kyprolis + Revlimid + dexamethasone + autologous stem-cell transplant (ASCT). At 30 months, 93 percent of patients are alive and 94 percent are in remission. Eighty-five percent of patients in the maintenance phase of the trial are in CR, with 68 percent MRD-undetected at 10-6 level. Obviously, deep MRD (minimal residual disease) negativity is strongly linked to long survival. Of note, no patients in the ECOG trial achieved MRD-undetected. 

The IMF-funded, ongoing ASCENT trial in the U.S., in which patients received Kyprolis + Revlimid + dexamethasone + daratumumab + ASCT in an effort to achieve cure, is already achieving MRD negativity. Initial results with the “cure approach” are very encouraging and support the underlying philosophy of our Black Swan Research Initiative.

A follow-on ECOG trial is starting in which lenalidomide as a preventative therapy will be compared with myeloma-type treatment (daratumumab + Revlimid + dexamethasone) in HR SMM patients. Results are eagerly awaited! It is likely that we will learn that “myeloma-type” triple therapy (dara + Rd) is superior. But as with the SWOG 0777 trial, although Velcade + Revlimid + dexamethasone triple therapy was superior, Revlimid + dexamethasone can be excellent for a subset of patients, including frail or elderly patients. 

In the interim, patients should discuss options with their personal physicians. For HR SMM patients, participation in a clinical trial is an important option. If treatment is not pursued, very careful monitoring (“observation”) is essential to detect any early progression.

Venetoclax update
There has been great excitement about the use of venetoclax (a BCL-2 inhibitor), which has been shown to be very active both alone and in combinations, especially in patients with the t(11;14) genetic abnormality, in whom BCL-2 production is enhanced. However, as I have discussed, unexpected deaths occurred in the BELLINI trial in which venetoclax was combined with Velcade + dexamethasone. An update on this trial was presented by Dr. Shaji Kumar (Mayo Clinic, Rochester) as a late-breaking abstract at EHA. The bottom line is that increased deaths were linked to both infection and progressive disease. However, in patients with t(11;14), there was still both PFS (remission duration) and overall survival benefit. Based upon this news, the FDA has reopened the CANOVA trial, in which venetoclax + dexamethasone is compared with pomalidomide + dexamethasone in t(11;14) patients. Very good news!

FDA approves expansion of daratumumab use
Today, the U.S. Food and Drug Administration (FDA) approved daratumumab in combination with lenalidomide and dexamethasone (Rd) for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant (ASCT). The approval is based on results from the phase III MAIA (MMY3008) clinical study, which showed that the regimen significantly reduced the risk of disease progression or death by 44 percent compared to treatment with Rd alone. Data from the study were recently published in The New England Journal of Medicine.

Celgene-Bristol-Myers merger
Talking about new drug development, there has been considerable interest in the planned merger of two major drug developers: Celgene and Bristol-Myers Squibb. The Wall Street Journal reported this week that the merger is on hold pending resolution of anti-trust concerns.   It seems that Celgene will need to separately sell off rights to its anti-inflammatory agent Otezla®, which generated $1.6 billion in global sales in 2018. Hopefully this can be resolved quickly to keep planned myeloma drug development on track.

9/11 victims funding
Federal funding to provide medical care to those exposed to toxins released by the 9/11 attacks is crucial. Without it, many first responders cannot get the monitoring and care they need and deserve. Former “Daily Show” host Jon Stewart’s passionate plea to extend victim compensation recently went viral. Then came the sad news that Luis Alvarez, the former New York Police Department detective and 9/11 responder who sat beside Stewart at the recent Congressional hearing, was entering hospice care. Myeloma is among the Ground-Zero-related cancers covered by the 9/11 funding. Congress responded to Stewart’s appearance by issuing assurances that funding would continue. It is a matter of decency that firefighters, police officers, and other first responders who bravely rushed to Ground Zero be given the medical care they so deserve. We will keep you posted. 
 


Image of Dr. Brian G.M. DurieDr. Brian G.M. Durie founded and now serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.

Previous Post
Prevention and the Search for a Cure Go Hand-in-Hand

Give Where Most Needed

We use cookies on our website to support technical features that enhance your user experience.

We also use analytics & advertising services. To opt-out click for more information.