[darnold]

Re: NEJM article on transplantation & Revlimid maintenance

by darnold on Sun Sep 07, 2014 3:12 pm

Very interesting discussion, and I hope the current research into genetic changes and drugs will help to provide a better picture on which line of drugs makes sense for each of us.

I was on a maintenance dose of Revlimid for two years after my SCT. I had a bad time with it, and eventually developed a low level M-spike. My oncologist took me off of it, and I was drug free for a wonderful year. Last June, my lambda count leaped up, so I took three cycles of Velcade over the summer. I'll see my oncologist this week and see if he wants me to take more cycles or switch to maintenance. I'm pretty sure he is thinking about Velcade for maintenance -- in part because I responded well to it during the three cycles (i.e., mainly fatigue, no neuropathy other than occasional tingles in my arms) and in part because I had a hard time with Revlimid.

More food for thought -- if others have problems with Revlimid, even at low doses, like I did, doesn't that suggest looking at Velcade or another alternative for maintenance?

Dana A

[coachhoke]

Re: NEJM article on transplantation & Revlimid maintenance

by coachhoke on Sun Sep 07, 2014 4:52 pm

Multibilly, Mark 11, and Darnold,

I'd love to take a year off from my Revlimid maintainance, for QOL reasons; but as Multibilly and Mark suggest, I'm afraid to.

Coach Hoke

[Multibilly]

Re: NEJM article on transplantation & Revlimid maintenance

by Multibilly on Sun Sep 07, 2014 5:15 pm

Nancy,

Regarding your comment

Unfortunately, 'maintenance' is not recognized as a status for treatment in Canada, although of course, relapse or drug resistance (to change drugs) is. So, our oncologists have to work around these definitions for treatment of patients. Myeloma Canada is tackling the issue of 'maintenance' now actually, as an advocacy issue.

You probably already know this, but in the USA, none of the NCCN-preferred maintenance drugs like Revlimid, Velcade or thalidomide are actually approved by the FDA for multiple myeloma maintenance. So, technically, they are prescribed off-label for maintenance in the USA. So, it's not exactly a perfect situation here either.

Good luck with the advocacy battle.

[Nancy Shamanna]

Re: NEJM article on transplantation & Revlimid maintenance

by Nancy Shamanna on Sun Sep 07, 2014 5:54 pm

Thanks MultiBilly, I am sure that as time goes on and more studies are done, the situation of 'continuous maintenance' will be addressed. I went to a lecture from Dr. Leuleu, a myeloma expert from France, and he was saying the same thing, especially wanting to have that available for 'high risk' patients. He wanted the EU or his country (can't remember) to approve 'maintenance'. so I guess this is one of those as yet unresolved issues of myeloma treatment. However, that does not take away from the fact that we do have better drugs available than previously were available, and anyone who has relapsed, or never got to a CR in the first place, is probably on treatments.

I feel rather fortunate not to have been on any drugs for almost 3 1/2 years now. It has given me a chance to recuperate a lot. I may be back on treatment again, but that would not be 'maintenance', just treatments for myeloma.

But my question was just if there are some studies done that show that long term maintenance, as opposed to one or two years of treatment with low dose Revlimid, are superior for OS. I think we already know that one or two years of Revlimid maintenance is a good thing.

[Mark11]

Re: NEJM article on transplantation & Revlimid maintenance

by Mark11 on Sun Sep 07, 2014 6:32 pm

Hi Nancy,

Dr. Bergsagel from the Mayo Clinic wrote an interesting paper about myeloma survival last year. He brought up an interesting point about many studies on main­te­nance therapy.

A major focus of research has been on the prolonged use of subtherapeutic doses of an active drug in the absence of observable benefit to the patient, called 'maintenance.'

Maintenance with melphalan, cyclophosphamide, interferon-alpha, thalidomide, lenalidomide, and bortezomib have all been shown to be more toxic than placebo, to consistently prolong progression-free survival, but not in general overall survival. In most of the studies, only about one half of the placebo group received thera­peutic doses of the novel drug at relapse, so that in effect one is comparing a group that all receive the novel drug, to one in which only half of the patients do.

Given this inherent bias, it is surprising that a more consistent survival benefit is not seen, and the absence of which suggests that continuous, chronic, subtherapeutic dosing is likely inferior to intermittent therapeutic dosing. Recent genomic studies have identified a high degree of clonal heterogeneity in multiple myeloma that is dynamically modulated under sequential therapeutic pressure. Future therapeutic strategies will need to be designed taking this heterogeneity into account.

L Bergsagel, "Where We Were, Where We Are, Where We Are Going: Progress in Multiple Myeloma," ASCO 2014 Education Book.

I think most patients assume that all patients in the placebo group get access to the experi­mental drug at relapse when that is not the case in all of the studies.

Mark

Moderator's Note: A myeloma survival graph in the article by Dr. Bergsagel that Mark mentions is discussed in this forum discussion: "Multiple myeloma survival in 2014" (discussion started May 22, 2014)

[Nancy Shamanna]

Re: NEJM article on transplantation & Revlimid maintenance

by Nancy Shamanna on Sun Sep 07, 2014 6:51 pm

Thanks Mark, that's interesting.

The 'key points' in the article you cited:

• multiple myeloma survival has improved over the last 50 years with the introduction of four active classes of drugs: DNA alkylators, glucocorticoids, IMiDs, and proteasome inhibitors.
• The genetics of are multiple myeloma divided between recurrent IgH translocations and hyperdiploidy, with frequent dysregulation of MYC.
• Tumor genetic heterogeneity is a major cause of treatment failure.
• Current therapeutic approaches are exploring various combinations, sequences, and duration of active drugs.
• Future approaches will incorporate novel forms of immunotherapy.

Probably patients did not take the drug in the experiment after relapse because it was not approved where they live. Clinical trials are conducted in many countries, and some patients sign up just to get access to a drug they wouldn't have a chance to take otherwise.

[Multibilly]

Re: NEJM article on transplantation & Revlimid maintenance

by Multibilly on Sun Sep 07, 2014 7:31 pm

Intriguing post Mark. In searching for other articles by Dr. Bergsagel on this topic, I picked up on an ASH 2013 abstract that also underscores one of his same points that you shared.

"Lenalidomide Maintenance Therapy In Multiple Myeloma: A Meta-Analysis Of Randomized Trials," ASH 2013 abstract 407.

Conclusions from the above abstract:

"Meta-analysis of RCTs (randomized control trials) demonstrates significant improvement in PFS and modest improvement in OS with LM (lenalidomide maintenance). There is an increased risk of grade 3-4 adverse effects, including SPMs (second primary malignancies) with LM. Substantial heterogeneity for estimate of OS among protocols is a limitation of this analysis. Lack of uniform access to lenalidomide upon disease progression in the placebo/no maintenance arms of the constituent studies should be taken into account while interpreting aggregate effect estimates for OS in this meta-analysis."

[Beacon Staff]

Re: NEJM article on transplantation & Revlimid maintenance

by Beacon Staff on Sun Sep 07, 2014 8:07 pm

Since this discussion is becoming heavily focused on maintenance therapy, we thought we would point out a few links here at The Beacon related to maintenance therapy:

Maintenance therapy news articles at The Beacon
Maintenance therapy abstracts from the 2013 ASH meeting
Maintenance therapy discussions here in the Beacon forum

[coachhoke]

Re: NEJM article on transplantation & Revlimid maintenance

by coachhoke on Sun Sep 07, 2014 8:17 pm

Wow, Mark. Now I really think I should take a holiday from my Revlimid maintenance.

Thanks,
Coach Hoke

[Mark11]

Re: NEJM article on transplantation & Revlimid maintenance

by Mark11 on Tue Sep 09, 2014 7:11 am

I saw this a New York Times article today that made me think of Multibilly's comment above,

On a slightly different note, the drug companies must also be incredibly excited about the prospect of having continuous maintenance become a more common recommendation for multiple myeloma patients. I have to imagine that would result in an unbelievably huge increase in sales for them, perhaps even more than having an altogether new multiple myeloma drug approved?

The doctors that recommend maintenance therapy may be excited as well as their "consulting fees" could get larger from the drug companies for recommending such a profitable course of therapy for patients. This New York Times article discusses doctors being paid as consultants or being on drug companies "advisory boards" seems to really be influential on what drugs they vote for approval. This could influence on if they think maintenance is necessary. Here's a quote from the article:

She found that over all, committee members had a 52 percent chance of voting in favor of a sponsor of a drug. But members who had financial interests in only the company whose product was under deliberation were more likely to vote for its approval, with a probability of 63 percent.

If members served on advisory boards for only the company whose product was up for review, then the chance they would vote in favor of it shot up to 84 percent. (Members who had financial interests in, or served on advisory boards for, both the company whose product was being reviewed and at least one of its competitors were not more likely to vote in favor of any particular company’s drug, however.)

It’s hard to look at data like this and not be concerned about conflicts of interest. There’s a reason that 10-cent coupons exist; it’s because they work. Financial interests absolutely do influence our decision making. Since 2008, the F.D.A. has worked to reduce the number of committee members with financial conflicts of interest; the Pham-Kanter study indicates that this effort has met with significant success. Other conflicts of interest, like professional or ideological ones, can also influence our behavior, but these have not been as well studied. And the F.D.A. is not the only place where financial conflicts of interest are a concern.

Financial relationships between doctors and industry are not uncommon. In 2007, research showed that 94 percent of physicians in the United States had such relationships. More than 80 percent of doctors had accepted gifts, and 28 percent had received payments for consulting or research. Sixty percent of those physicians were in medical education, and 40 percent were involved in writing practice guidelines.