In presenting "What is myeloma" to newly diagnosed patients, Dr. Morie Gertz uses the comparison of myeloma to "weeds" in a garden, which in this case is the bone marrow microenvironment.  A recent book, Weeds: in defense of nature's most unloved plants, by Richard Mabey, provides wonderful insights into the analogy of myeloma cells as weeds.  

So what is a weed?  The first aspect is that it is not intentionally planted- so it is not a "plant" (or flower/tree/bush) which you wanted.  Certainly, this applies to myeloma cells nobody wants them.  There are truly intruders.  Other aspects which apply are: aggressive, resilient- hard to get rid of and spreading in an unwanted fashion.  What is the driving force behind all this?  Why do weeds keep popping up?

 The answers are interesting and important.  Weeds love "disturbed ground": areas recently dug up, bulldozed, abandoned, or contaminated with toxic waste.  Classic sites for weeds were bomb sites in London during the blitz of the Second World War.  Weeds unseen for generations, suddenly grew in profusion.  The weeds started a process of environmental healing: transitioning to new urban countryside.  So weeds function in a restorative fashion.

So what is myeloma?  Local sites of myeloma in damaged tissues do occur rarely but are quite remarkable.  For example, a gentleman struck by lightning on his leg bone went on to develop myeloma at that site.  Other examples include myeloma growing in the pocket for a cardiac pacemaker which became infected and myeloma growing alongside leaking silicone breast implants.  So the point is a disturbed, activated, and damaged microenvironment can enhance myeloma growth.

Weeds also outgrow new favorable environments.  If conditions are right, weeds can overtake any garden.  Myeloma cells do the same and continue to grow when conditions favor antibody production or production of the "monoclonal spike" in an effort to combat infection.  A "positive feedback loop" can be established whereby the disturbance, activation, or damage is not corrected (for example, breast implants are leaking and are not removed) and a favorable growth environment persists.  The myeloma monoclonal protein (or antibody) cannot do its job: the local situation is not corrected.  It is amazing to see the impact of what happens when the situation is corrected   with immune modulating agents such as thalidomide, Revlimid, and Pomalidomide.  The microenvironment is stabilized: growth slows or stops.  There is an opportunity for abnormal cells to be eliminated.  But, like weeds, myeloma cells are remarkably resilient.  We need ways to wipe out every last cell and/or keep the microenvironment hostile for new growth.

In nature, mature forests teach us many lessons.  Trees and shrubs dominate some weeds, those which are light dependent die off, others are not able to compete with large trees that change the soil chemistry.  So re-achieving balance is a natural strategy.  This provides hope and the expectation that correct maintenance strategies can work long term, if crafted with the aim of achieving the best immune and chemical balance. As we are learning from our fields and gardens, using stronger and stronger weed killers may not be the way to go.  So let's keep an eye on the weeds and see what more they have to teach us and help us in the search for the cure.

As Dorothy so correctly exclaimed, "There's no place like home." After a good night's sleep needed to catch up from an extraordinarily busy ASH, I thought I'd provide some final thoughts.

I've always said the good news about being diagnosed today with Myeloma is that there are so many more treatments available than when I was diagnosed in 1995. And it's never been truer after seeing more options presented at this year's ASH. Of course, the "bad news" about being diagnosed with MM today is there are so many treatments without knowing which works best for you. There's lots of overall statistics with details about responses according to different MM risk groups and other factors but nothing that says "this is the best treatment for you". However, the good news is that if a treatment is going to work, patients typically will show a response in 1-3 mos (cycles). If you're non-responsive, then try another treatment...i.e. manage your disease.

While it's believed that deeper responses lead to longer progression -free survival and overall survival, that's again part of "overall averages." I had a near complete response from an old induction treatment called VAD and a complete response from a tandem auto transplant...however, the response only lasted 18 months, after which I relapsed. Stay educated and try to consult with an MM expert whenever possible.

What I saw at this year's ASH was a better understanding of why patients either relapse (treatment stops working) or are refractory (treatment never worked). Even though Velcade and Revlimid protocols show high response rates, most patients still relapse. This year's meeting had several presentations identifying resistance mechanisms and pathways associated with these drugs. That's why Vorinostat plus Velcade might work in a patient refractory to Velcade. Or why R/R MM patients respond better to Elotuzumab plus Revlimind plus Dex than R/R MM patients respond to Rev plus Dex alone. Or why adding Perifosine to Velcade plus Dex shows responses in patients refractory to Velcade. It's all about "synergy" of drugs combinations used to treat MM, where combining drugs produce better responses than the sum of responses each drug yields.

And the other thing I learned is that not all IMIDs (Thalidomide, Rev, Pomalidomide), Proteasome Inhibitors (Velcade, Carfilzomib, Marizomib), HDAC Inhibtors (Vorinostat, Panobinostat), etc are alike even though they fall within the same category of drugs. As such, one could be R/R to Velcade but Carfilzomib may work...and I presume the reverse could also be true. There are different underlying cell interactions in these drugs even though they fall in the same general category.

Finally, treatment phases of induction (first-line treatment/s), SCT transplant (or not, early or late), consolidation (or not) and maintenance (if so, how long) all continue to be areas of study for newly diagnosed patients. Clinical trials typically begin with R/R patients and then move towards newly diagnosed patients. I think it's so important to enter a clinical trial if you have the opportunity. Typically a trial (especially phases II or III) offers you the best treatment, medically you're monitored very closely, and perhaps it's actually more affordable. Most important, it's the way we advance treatment options for ourselves and future MM patients.

I hope I get a chance to blog from next year's ASH in Atlanta. In the meantime, I'm spending most of the next 2 days pulling together all of my notes for presentation to our SF Bay Area MM Support group. If you want a copy, just reply to the blog with your email information or contact me through the IMF.

Thanks for reading,

Jack Aiello

It was a long day today with meetings beginning at 7am and ending at 6pm. There were a couple of 1-2 hr breaks in the middle that provided me time to check out posters. And then tonight I attended a Journalist Workshop where MM experts Drs. Durie, Moreau, Richardson and Orlowski presented ASH highlights to the US and International Press that was translated real-time into 4 other languages and also streamed on-line. So let me provide some of today's results working my way backwards.

At the press meeting, the doctors were asked about the most significant announcements at ASH. The various drugs getting the most attention (and well-deserved) were Carfilzomib and Pomalidomide. Maybe you've heard of these and the hope is they'll receive FDA approval in 2012. However, you may not have heard of Elotuzumab (humanized monoclonal antibody) or MLN9708 (oral proteasome inhibitor) which also received positive marks.

Dr. Durie also noted that the treatment paradigm has changed since 10 years ago when novel drugs such as Thalidomide and Velcade started appearing. In the past a patient would receive a limited cycle of drugs, get a transplant or not, and see how they do. Today continuous therapy (at least fairly long-term) is becoming the model. A patient receives induction therapy, a transplant or not, possibly consolidation treatment followed by maintenance. And while it's not known how long maintenance should last, trials are being done for 1-yr, 2-yrs, 3-yrs or even "time to progression" (till your MM becomes active again).

Some exciting trial results presented today include:

• The oral proteasome inhibitor MLN9708 in Relapsed/Refractory MM pts in a Phase I trial showed about a 13% ORR (<= Partial Response) and 60% stable disease as a single agent.
  
  
• Elotuzumab, which doesn't really have much MM activity on its own, is combined with Rev-dex in a Phase II trial of R/R MM pts and shows a 92% ORR (14% CR) whereas Rev-dex alone showed about 60% ORR for the same type of patients.
  
  
• In the completion of a Phase III trial, Melphalan+Prednisone+Rev followed by Rev maintenance for newly diagnosed older (non SCT eligible) pts showed ORR of 79% and after 4 years, the median Overall Survival (OS) has not yet been reached. Remember, this is an older patient base.
  
  
• BTW, in the same elderly population, Vel-Thal maintenance after VMP or VTP showed 46% CR and median OS not yet reached at 5 years.
  
  
• Several Carfilzomib (Cfz) studies were presented:
  
  
  • CfzRd for newly diagnosed showed ORR = 100% after several cycles;
  • Cfz-only for R/R MM pts (not having taken Velcade) showed ORR 42-52%
    
• Several Pomalidomide (Pom) results were also presented:
  
  
  • Pom-Cytoxin-Prednisone for R/R MM pts showed ORR 66%;
  • Pom-Biaxin-Dex for R/R MM pts showed ORR 60%;
  • Pom-Dex for R/R MM pts (75% refractory to both Vel and Rev) showed 32% ORR with little difference among various refractory groups

And still there was more with drug such as Perifosine, Panobinostat, Vorinostat as well as other combinations.

That's it for Monday's sessions highlights from my perspective. The show ends tomorrow and I'll try to put up one final post after I return home.