The ASCENT trial (Aggressive Smoldering Curative Approach Evaluating Novel Therapies) is evaluating the effectiveness and safety of the combination of Darzalex® (daratumumab) + Kyprolis® (carfilzomib) + Revlimid® (lenalidomide) + dexamethasone in high-risk smoldering multiple myeloma (HRSMM). We hope to learn whether starting treatment early substantially improves outcomes, leads to a higher level of undetected minimal residual disease (MRD), sustained remissions, and potential cure.

Shaji K. Kumar, MD (Mayo Clinic) and I are Principal Investigators for the trial, which is sponsored by the IMF as part of the Black Swan Research Initiative. The trial sites include: Mayo Clinic (Rochester, Minnesota); Indiana University Simon Cancer Center (Indianapolis); University of Maryland; MD Anderson (Houston); Swedish Medical Center (Seattle); Emory University (Atlanta); University of Chicago; Cornell University (New York City); University of North Carolina; Columbia University (New York City); University of Wisconsin; and University of Kansas. (Locations and contact information can be found at the ASCENT trial page on clinicaltrials.gov.)

Cure Trial Program

This is the second of three of what we are calling “CURE” trials. The first, the CESAR trial, is ongoing in Spain with Professor Maria Victoria Mateos as the Principal Investigator. CESAR uses the combination of Kyprolis + Revlimid + dexamethasone (KRd)+ ASCT in the same setting as ASCENT. With a median follow-up of 28 months, 94 percent of patients are in remission, with 62 percent having undetected MRD at the 10-6 level (zero out of a million cells). It is hoped that the addition of daratumumab in the U.S. ASCENT trial will enhance the undetected MRD level among patients to approximately 80 percent (at 10-6 level). The CESAR trial has been well tolerated, thus, there is great optimism moving forward.

The same “CURE” concept—early, aggressive treatment—is also being evaluated as part of the IMF-funded iStopMM  project in Iceland. In this setting, Kyprolis + Revlimid + dexamethasone (KRd) is being offered to patients with smoldering multiple myeloma (SMM), and to patients with active multiple myeloma (MM). Patients also have the option for autologous stem-cell transplant (ASCT). The important aspect of this project is that we can directly compare outcomes in the very early intervention in SMM to outcomes using the identical therapy at the point of development of active myeloma.

Criteria for Smoldering Myeloma

The International Myeloma Working Group (IMWG), the research arm of the IMF, has been evaluating the criteria for both active multiple myeloma and smoldering multiple myeloma for the past several years. With S. Vincent Rajkumar, MD, as the first author, a key manuscript in this inquiry was the New Diagnostic Criteria for Myeloma. This 2014 paper introduced the concept of MDEs (Myeloma Defining Events), based on:

1. Plasma cells in the bone marrow at 60 percent or more
2. sFLC ratio at 100 or more
3. MRI focal lesions at more than one, and/or
4. Evidence of deteriorating renal function

Because of these new diagnostic criteria, patients with what used to be called “ultra-high-risk smoldering multiple myeloma“ are now classified as having active myeloma, since there was found to be a high likelihood of progression to active myeloma within 18 to 24 months (confirmed in at least two studies).

The next question for researchers was, “Which of the remaining patients are at a high risk of progression?” (It should be noted that a high risk of progression from SMM to active MM is NOT the same as what is commonly called “high risk” – a classification that refers to patients who have active myeloma with abnormal chromosome findings, including 17p-; t[14;16]; t[4;14], and 1q+. These findings correlate with a likely shorter remission with standard myeloma therapies.)

Mayo Clinic and the IMWG have been investigating patients at high risk of progression.  An initial answer was published by the Mayo team earlier this year. New criteria for HR [of progression] SMM were:

1. Myeloma protein spike of 2 grams or more
2. sFLC of 20 or more
3. Bone marrow plasma cell (BMPC) of 20 or more

These three factors comprise the new “2/20/20” criteria. The IMWG is completing an analysis of more than 2,000 patients to confirm this finding. Preliminary results confirm the Mayo criteria, with full results likely available in the coming months. For the time being, these are the criteria being used in the ASCENT trial.

Strategic Priority to Seek Potential Cure

It is important to emphasize that the CURE trial program is, indeed, a trial program. These pilot studies are designed to investigate the current potential of the most promising available therapies. It is highly likely that sustained benefit will occur for about half the patients, and maybe more. The focus of the IMF Black Swan Research Initiative is to identify and characterize the patients achieving undetected MRD status, which is sustained long-term, as well as those patients for whom new options in therapy are certainly required. Characterizing these patients with positive MRD/resistant disease is a key objective. Once that occurs, the next generation of therapies can be offered to them, informed by detailed studies of residual disease.

Excitement for the Future

The initial results with the CESAR, ASCENT, and iStopMM trials are very encouraging! We understand that it will take time to confirm the long-term benefits—including quality of life, which is all-important. However, with our increasing knowledge of the pattern of genetic mutations, which dramatically increase over time, it seems that early intervention is the correct strategy. The challenge is to both identify the best therapies and administer them in a safe fashion to the most appropriate patients.

Different Strategies for Smoldering Disease

Preliminary findings from E3A06, the ECOG randomized clinical trial comparing placebo versus Revlimid (lenalidomide) alone for patients with HR SMM, have just been released. The PFS (Progression-Free Survival or length of remission) was prolonged with the Revlimid therapy. This delay in the development of active myeloma is important. Unlike the CURE trial approach, the strategy here is to control the disease rather than attempt to achieve deep response and cure. The long-term benefits with each approach will emerge over the coming years.

The opportunity to intervene aggressively early with the ASCENT trial therapy is a tantalizing approach to manage the disease before sequential resistant mutations develop. Conversely, there is a concern that lesser therapy, such as with Revlimid alone (as in the E3A06 trial), will prolong initial remissions, but allow subsequent resistant mutations to still emerge and cause problems later. Only time will tell which strategy produces the superior outcomes. 

 

---

Dr. Brian G.M. Durie 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®.