What were the myeloma-related "hidden gems" of the recent American Society of Hematology (ASH) annual meeting, which ended two weeks ago?

The Beacon asked exactly this question of its Medical Advisors -- the myeloma specialists who generously share their knowledge and expertise in the Beacon's myeloma discussion forum.

And the responses from the Advisors were surprising.

Surprising, because they were so similar.

The three Advisors who responded to the Beacon's question indepen­dently picked the same "hidden gem" -- specifically, the research presented at the meeting showing that the protein known as "cereblon" affects whether or not myeloma patients respond to certain myeloma treatments.

These findings were mentioned in the Beacon's update for the second day of the ASH meeting.  The findings indicate that myeloma patients with high levels of cereblon in their bone marrow respond better to the class of drugs known as immunomodulatory agents ("IMiDs") than myeloma patients with little or no cereblon in their bone marrow.

The IMiD class of drugs includes thalidomide (Thalomid), Revlimid (lenalidomide) and the potential new myeloma treatment pomalidomide.

The rest of  this article passes along the feedback the Beacon received from its Medical Advisors about the ASH meeting's "hidden gem."

A related article published last week here at The Beacon presented the Advisors' thoughts regarding the top myeloma-related research findings of the ASH meeting.

Dr. Peter Voorhees from the University of North Carolina at Chapel Hill:

A target has finally been established for the IMiDs!

Investigators had previously published findings showing that the binding of thalidomide to a protein called cereblon was necessary for its teratogenicity [tendency to cause birth defects].

Now, Dr. Keith Stewart and his colleagues at the Mayo Clinic in Scottsdale, Arizona, have discovered that Revlimid and pomalidomide must bind to cereblon to achieve their anti-myeloma effect (abstract).

In fact, when cereblon levels are low in myeloma cells, the drugs do not work as well.

With this new information, we can better determine how these drugs work in myeloma, study the basis of resistance to this class of drugs, and develop novel therapies that can restore sensitivity to the IMiDs.

Dr. Adam Cohen from the Fox Chase Cancer Center in Philadelphia:

I think one of the most important research findings, reported by Dr. Keith Stewart and colleagues from Mayo Arizona and two other groups at this year’s ASH meeting, involves a protein called cereblon and its potential ability to predict responsiveness to IMiDs such as thalidomide and Revlimid.

First identified as the primary target protein through which thalidomide causes teratogenicity, cereblon has now been shown to be activated in myeloma cell lines and in primary patient myeloma samples, and the level of activation seems to correlate with whether the cells can be killed by thalidomide or lenalidomide.

Much more research needs to be done to understand the exact function cereblon plays in myeloma and how its binding by IMiDs leads to myeloma cell death, but its discovery offers the tantalizing possibility of a predictive biomarker for IMiD sensitivity that could help guide the choice of therapy, bringing us closer to truly personalized therapy for our patients.

Dr. Ken Shain from the Moffitt Cancer Center in Tampa:

I feel that one of the topics in myeloma research that deserves a lot of attention was the conversation around the potential IMiD target cereblon.

I am not sure where or what the role of cereblon will be in the future of myeloma therapy.

However, building on the seminal 2010 article (abstract) by Ito et al. published in the journal Science  -- a piece of work that initially identified cereblon as a potential teratogenic target of thalidomide -- Dr. Keith Stewart and colleagues from the Mayo Clinic in Scottsdale, Arizona, further demonstrated that cereblon activation was also important for the effects of the thalidomide derivatives Revlimid and pomalidomide.

The authors demonstrated that cereblon activation was associated with sensitivity to Revlimid and pomalidomide in myeloma cell lines.

The specific role of cereblon was examined using shRNA technology to chronically decrease the activation of cereblon.  This down regulation correlated with resistance to both IMiDs.

These findings may have significant applications to the treatment of myeloma and possibly other tumors.

The possibility exists that patients with high activation of cereblon are more sensitive to thalidomide, Revlimid, or pomalidomide and that patients with low activation may be less sensitive or resistant.  As such, cereblon may be an important marker for a patient-specific, personalized treatment paradigm.

A rationale was further highlighted at the ASH meeting by the work presented by Heintal et al. (abstract).  These authors begin to address the issues of levels of cereblon activation and response to IMiD therapy by examining the activation of cereblon in 44 myeloma samples treated with Revlimid and dexamethasone (Decadron) relative to normal bone marrow samples.

The authors demonstrated that increased cereblon activation (relative to normal bone marrow) correlated with a significantly better response to Revlimid and dexamethasone (minor response or better).  In patients with stable or progressive disease, cereblon activation was less than normal in the bone marrow.

These data, again, provide significant rationale for the further study of cereblon in myeloma and perhaps other Revlimid, pomalidomide-, and thalidomide-sensitive diseases.

However, it is important to note that these were lab studies and need to be further developed in patient specimens and incorporated into clinical trials to correlate with outcomes (response, progression-free and overall survival, etc.) before we can state anything definitively about a role for cereblon in myeloma or other diseases.

For the short term, more study is needed and I don’t see any direct impact on myeloma patients today.  Hopefully, with more examination it will impact how we approach patients in the future.

I think that there is a reason for excitement in this line of research.  However, as always, our enthusiasm needs to be tempered until supportive data is presented.

Furthermore, with history as a guide, drug target activation does not always correlate with response, especially drug targets that do not appear to facilitate disease progression.

Note: The Advisor responses summarized above have been edited slightly for length, flow, and adherence to Beacon conventions (regarding, for example, drug names).