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Thursday, May 31, 2012

Revlimid as Maintenance Therapy

Recently, I have been in contact with a fellow MM patient who has been following my blog.  Steve has suffered several bouts of cancer in his life, and was diagnosed with MM 5 years ago at the age of 51.  He is very interesting, because he and I have taken very different approaches to managing this disease.  Steve has always opted for conservative rather than aggressive treatments for all his cancers, opting for maximum quality of life up front as a primary goal.  Fortunately, this strategy has worked so far for him.

After his initial MM diagnosis, Steve went through an initial drug therapy which resulted in sCR, and then stopped all treatment for 2 1/2 years until relapse.  After 3 cycles of Rev/Vel/dex, he again went into remission and stopped further treatment until now.  While asymptomatic, his blood count numbers are on the rise and he will have to consider some sort of treatment again soon.

I recently sent Steve the writeup on my stem cell decision making process.  While his instinct is to avoid a stem cell transplant, he agreed that given my circumstances (age, etc.), he probably would have arrived at the same decision.  My treatment plan involves a consolidation phase followed by 3 years (at least) of maintenance with Revlimid.  However, both Steve and his oncologist are skeptical of any long-term maintenance therapy.

One of the more controversial issues in the MM community involves the question of long-term maintenance with Revlimid.  There have been 3 major Phase 3 clinical trials addressing this issue, all 3 of which were published in the May 10, 2012 issue of the New England Journal of Medicine (NEJM).  Steve was kind enough to forward me pdf files of all the articles, and he is interested in my take.  I was somewhat familiar with two of the studies: the French IFM study (Attal), and the CALGB study (McCarthy).  Dr. Richardson was an active participant in the latter.  Both of these studies involve stem cell transplants.  The 3rd study was Italian (Palumbo) and involved older patients not eligible for transplants.

All three of these studies showed dramatic improvements in median progression-free survival (PFS) with long-term Revlimid maintenance versus a placebo.  For the CALGB trial, the PFS was 46 months for the Rev vs. 21 months for the placebo.  These results were so dramatic that all 3 studies were unblinded, and the CALGB patients on placebo were given the option to switch over to Rev (most did).

However, there is a fly in the ointment here.  While the PFS numbers were dramatic, there was no corresponding increase in overall survival (OS) in two of the three studies!  Only the CALGB trial showed a modest improvement in the 3-year OS rate (85% for Rev vs. 77% for placebo).  It may be that longer followup times may yet establish an OS benefit to long-term Rev maintenance, but for now, these results are a bit troubling.

Most clinical trials use PFS as a desired end point, mainly because it takes much longer to establish median overall survival times.  However, many are now questioning the use of PFS as an end point in clinical trials if it doesn't lead to corresponding improvements in OS.

Another issue with Revlimid maintenance is the incidence of second cancers.  I have already blogged on this issue and discussed it with Dr. Richardson.  All the studies showed a somewhat higher incidence of second cancers in the Rev group vs. the placebo group.  In order to quantify this, a post hoc end point of event-free survival (EFS) was introduced, which added cancer events to the PFS.  For the CALGB study, the EFS was 43 mos., only 3 mos. less than the PFS, still a dramatic improvement over the placebo (21 mos.).  Therefore, the magnitude of benefit of Revlimid maintenance clearly seems to outweigh the risk of a second cancer.

The May 10 issue of the NEJM also published an editorial addressing these issues.  In addition to the issues I mentioned above, the editorial also addressed the cost question of long-term Rev maintenance.  At a list price of $450 per 10 mg tablet, the cost vs. benefit is a valid issue.  At what point could Rev maintenance be suspended while still giving a long-term PFS benefit?  While this is an important consideration globally, it doesn't affect me personally for now, since my Revlimid is being paid for by the clinical trial (thank goodness!).

Some of these questions may be answered in future clinical trials.  In the meantime, I am comfortable with the course of treatment I am taking, at least for now.  Even though an OS benefit hasn't been well established for long-term Rev maintenance, I would be very pleased to have an extended remission and not have to go back for relapse treatment any time soon. 

I have responded to Steve with my detailed comments on these articles, and I welcome the dialogue Steve and I have established on these issues.  It is helpful and instructive to listen to those who have chosen to take a different path.  I am always trying to learn more about this infernal disease.  I suspect there will be numerous decision points in my future, so I want to stay on top of all of this as best I can.

I hope this discussion hasn't bored you too much.  If it has, and you still read this all the way to the end, congratulations on your perseverance.

1 comment:

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