Good morning, myeloma world.

Have you ever gone for a walk on a hot summer day, with birds singing and insects buzzing and the sound of children and traffic in the distance, and all of a sudden you notice that all of the sounds that were there before aren't there any more, and it's really, really quiet? Like, scary quiet?

Well, that's how we feel right now here at Myeloma Morning Headquarters, be­cause we don't have a single new myeloma-related research study or business news item to report about.

Nada. Zilch. Zero.

This, of course, makes us worried that we'll be hit with a tidal wave of new studies and other news later this week.

We'll just have to see.

In the meantime, we do have a few things we want to mention.

First, there's the sort of buzz you would expect when a billionaire donates hundreds of millions of dollars to immunotherapy research (Reuters ^[1]; USA Today ^[2]; related Beacon forum discussion ^[3]). Our take: We look forward to summarizing results of the funded research once there actually are results to summarize.

We also will mention that there are definitely strings attached to the donated money, and strings usually complicate and bog things down. One news report, for example, notes that “Each of the cancer centers in the consortium agrees it will send top scientists to join the Parker Institute and relinquish considerable control over their research.”

Second, if German happens to be your native tongue, please note that select editions of Myeloma Morn­ing are being translated into Deutsch. You can find the translations – and all German translations of select Beacon articles – at this link ^[4]. Kudos to our collaborator Sabine Schock and colleague Maike Haehle for the hard work they do on the translations.

Third, for those of you who are really interested in early-stage research into potential new myeloma ther­a­pies, we have some additional information about the preclinical drug CCF642.

We first discussed a study with preclinical research results for CCF642 in the April 8 edition of Myeloma Morning ^[5]. Then, in yesterday's edition of Myeloma Morning ^[6], we published comments about the study by Dr. Leif Bergsagel of the Mayo Clinic.

Today, we have some feedback from the lead author of the CCF642 study, Dr. Frederic Reu of the Cleveland Clinic. He responds to questions we sent him about the study and also to some of Dr. Bergsagel's comments.

Dr. Reu told us:

“CCF642 inhibits the enzyme (called PDI) that folds certain proteins so that they can be secreted. Myeloma cells secrete substantially more such proteins than other cells, which probably explains why doses of CCF642 that were well tolerated by normal bone marrow cells and mice resulted in rapid accumulation of misfolded proteins and programmed cell death in myeloma cells.

“I fully agree with Dr. Bergsagel that more work needs to be done before the concept of PDI inhibition may be applied to patient care. We are currently pursuing several avenues to develop an op­ti­mized PDI inhibitor.

“On the one hand, we are trying to define the interaction of CCF642 with PDI further by obtaining crystal structures of the PDI/CCF642 complex and through additional studies aimed at clarifying target sites in PDI. Aided by computational modeling and medicinal chemistry, this may allow us to develop an op­ti­mized PDI inhibitor based on the CCF642 scaffold.

“On the other hand, we are also performing computational (“in silico”) screens for a theoretically ideal PDI inhibitor that we will then synthesize, test, and refine as we do for CCF642. When we have op­ti­mized a lead PDI inhibitor, we plan to test it in Dr. Bergsagel’s myeloma mouse model (which Dr. Bergsagel has already kindly agreed to provide for our PDI research).

“It will also need to undergo formal safety testing before it can be translated into patient care but I think pharmacologic transient partial PDI inhibition has a good chance of not affecting healthy tissues much while rupturing an Achilles heel of myeloma.

“As far as the assay that led to the discovery of CCF642 is concerned, the main novelty or advantage compared to other tests is that it simulates several key barriers to in vivo success of myeloma drug candidates in one relatively simple assay. Like the assay developed by Dr. Mitsiades group at Dana Farber (McMillin DW et al. Nat Med 2010 ^[7]), it employs a bone marrow stromal cell line that, just as the normal bone marrow, can make myeloma more resistant to drugs. In addition, it tests whether drug candidates can withstand liver enzymes, diffuse well through tissues, and whether they can work in the context of relatively rapidly decreasing levels as often occurs after single doses in humans due to clearance by kidneys and other mechanisms. All this can be tested separately, but other investigators may find it helpful as a screen for in vivo promise of drug candidates.”

Quickly Noted

• A new participant in the Beacon's forum is looking for feedback from people who have been on their own – without a caregiver – after a stem cell transplant (link to discussion ^[8])
• A discussion in the forum about fluctuations in free light chain levels has been active since it was started last month, and it now includes some useful information posted last night by forum regular MikeB (link to discussion ^[9])
• Debbie is now at Day 26 after her stem cell transplant, and she is wondering when it will be safe for her to go out walking and biking (link to discussion ^[10])
• There are some incredibly creative and funny people on the Internet, aren't there? While posting to the Beacon's Google Plus page ^[11] earlier today, we came across this collection of amusing photos ^[12] (yes, it is safe for work). This photo ^[13], in particular, struck us as both particularly funny and particularly well executed.