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Discussion about multiple myeloma treatments, stem cell transplants, clinical trials, alternative medicines, supplements, and their benefits and side effects.

Wondering about 21 day lenalidomide

by suzierose on Fri Mar 23, 2012 2:44 pm

I was sitting here pondering the dosing schedule for lenalidomide. Given we have front page stories on alternating weeks with thalidomide along with the SPM labelling change the thought occurred to me...

How was it determined that lenalidomide should be given for 21 days? Could it be given for 7 days, skip a week, 7 more days, skip a week, 7 more days...vs. 21 consecutive days and skipping a week?

I am wondering this based on the alternate thalidomide week trial dosing as well as how patients went from taking 80mg dex per week to 40mg dex per week with the same efficacy outcomes in another trial.

Celgene set up that alternating thalidomide weekly with lenalidomide which of course allows for enhanced revenues particularly as they doubled the dose of lenalidomide and propped up lagging thalidomide sales.

It would not be revenue enhancing to give alternate week lenalidomide as patients would be taking 14 caps per month vs. 21 caps per month...however, it might have the same efficacy, perhaps it would require dosage titration depending on the patient response, i.e. 10-25mg doses could be administered.

Can any of the Beacon Advisors address this? Is lenalidomide 14 caps a month as effective as 21 caps a month, were there any trials that did comparsion efficacy dosing for maintenance or acute therapy?

If I recall correctly the reason 'lo-dose' Dex came about was serendipitous as patients were having side effects, same thing with sub-q bortezomib.

Perhaps, 14 caps monthly of lenalidomide is sufficient for acute and chronic treatment of multiple myeloma and could lower the risk of SPM.

Name: suzierose
When were you/they diagnosed?: 2 sept 2011

Re: Wondering about 21 day lenalidomide

by suzierose on Fri Mar 23, 2012 9:46 pm

Ahhhh, they have done alternate day lenalidomide trials:

"In this limited retrospective study, we demonstrate that the alternate day dosing schedule of lenalidomide is likely to have equivalent efficacy to the standard schedule (MM009/010 trial patients at second relapse)
• There was a total saving of £464,322 ($725,704.64) which is equivalent to £11,905.69 ($18,607.81) per patient treated
• Cost effectiveness analysis estimated the Cost per QALY (ICER) to be £25281 compared to the original Celgene submission (as recalculated by ERG/ NICE) of >£47100
• This ICER is comparable to the final NICE accepted Celgene submission (£24600) that included a price cap at 26 cycles and an increased QALY value for final years of life. Our model did not incorporate this.
• The ICER for this schedule is below the threshold of £20,000-£30,000 set by NICE for drugs to be approved within the UK. Probability 76% at £30,000; 82% at £40000
• We recommend this schedule to be investigated prospectively"

Name: suzierose
When were you/they diagnosed?: 2 sept 2011

Re: Wondering about 21 day lenalidomide

by Dan D on Sat Mar 24, 2012 2:51 pm

Interesting -- to say the least.!

And like you, I wonder whether alternate day dosing -- in addition to meaning less gouging of patients -- would also translate to fewer sife effects and perhaps longer efficacy in a relapse or frontline setting.

Keep advocating!!! I hear you.

Dan D

Re: Wondering about 21 day lenalidomide

by TerryH on Sat Mar 24, 2012 6:03 pm

Thanks for bringing this study to everyone's attention, suzierose.

It may seem like semantics, but it's really misleading to call this study a trial. The researchers retrospectively reviewed patient records from a single treatment center in Britain and identified patients who had been treated with alternate-day dosing Revlimid (almost certainly as a cost-saving measure). They then summarized the results and compared them to published results from a major prospective trial.

I'm fairly certain the results of this trial basically guarantee you won't see alternate-day dosing of Revlimid in the U.S. The key results of the British study that you failed to mention are the overall survival numbers. Median overall survival in the alternate-day dosing group was 26 months, and it was 36 months in the regular dosing group.

If you consider the possibility that patients who got the alternate-day dosing schedule may have been "lower-risk" patients who doctors thought might not need regular dosing, then the British results look even less compelling.


Re: Wondering about 21 day lenalidomide

by suzierose on Sat Mar 24, 2012 7:30 pm


Thanks for highlighting that oversight.

It is a retrospective analysis vs a clinical trial.. far more pharmacoeconomics than clinical. the Brits were certainly looking for cost reduction when it comes to lenalidomide therapy.

It's possible I was too far down in the rabbit hole on this one, looking for comparison of alternate dosing schedule..looked right over the overall survival.

When it comes to OS, and looking further at the alternate dose I can't tell if those were relapsed patients as well vs the regular dosing.

I should probably put this irksome idea on hold for steroid free days, I was just so disturbed by these new trial designs with higher doses and known greater toxicities that I wanted to find out if anyone one had done the opposite. After all...they used 80mg dex for decades subjecting patients to the horrors of high dose steroids until last year, when they finally designed a lo-dose dex trial and found it was comparable.

So that was what was fueling my interest.

When they are designing highly toxic trials with life-threatening AE's to put newly diagnosed patients on with 4 drug combos's, I submit chemo combos alternating lower doses merit testing as well.

Overall, thanks for the heads up!!

..note to self...slow down when on steroids...hmmmm is that possible?..doubtful

Name: suzierose
When were you/they diagnosed?: 2 sept 2011

Re: Wondering about 21 day lenalidomide

by Mark on Tue Apr 17, 2012 5:26 pm


I do not know why lenalidomide is dosed in 21 day cycles in the non-Allo setting. In the Allo setting we are most interested in its ability to increase NK cells. They try to time DLI's around this. The cytotoxicity of the NK Cells reach their height around Day 28-30 after a 21 day on 7 day off cycle. In the future, if some form of immunotherapy becomes available in the non-Allo setting or if a monoclonal antibody becomes FDA approved I am guessing they will try and time the highest blood concentration of the new therapy to this time period. If you are interested, there are slides of Page 5 of this presentation. The presentation is about Novel Agents and Allo transplants, so you may not have much interest.,%20Nicolaus_AlloSCT.pdf



Re: Wondering about 21 day lenalidomide

by suzierose on Wed Apr 25, 2012 12:09 pm

Hi Mark,

You always get hold of great slides!!!

You write:

"The cytotoxicity of the NK Cells reach their height around Day 28-30 after a 21 day on 7 day off cycle."

I think this is it. It makes sense. The slide on page 5 showed that clearly. I suspect that allo/auto has no real significant difference, rather it is the level of NK cells. Kinda makes me wonder even more why they alternated thalidomide with lenalidomide every other week, given lenalidomide is 50K times as potent as thalidomide...seems it was a purely revenue driven trial design.

The other slides were interesting, too.

There is a major difference in molecular response between allo vs auto on page one in patients with seemingly doesn't approach allo MR? If I read it correctly.

I could not quite understand what they were showing on page one ..with regard to trial design where patient gets allo then precedes to hi dose auto waits 2-3 months then has allogenic therapy?
DLI...adoptive immunotherapy? What is that or what are they showing there?

Again, great data on these slides.

Thanks for providing an answer to my pondering...I appreciate that..

Name: suzierose
When were you/they diagnosed?: 2 sept 2011

Re: Wondering about 21 day lenalidomide

by Mark on Sat Apr 28, 2012 11:12 am


lenalidomide's (LEN) ability to increase T and NK Cells is applicable to all patients - it does not matter if they did Auto, Allo, or no transplant. There have been small case matched studies (no randomized trials) that show relapsed/heavily pre-treated patients that did Allos get a better response to LEN than patients that did not. The thought is that the donor immune systems ability to identify the Myeloma as foreign means they will kill more Myeloma cells than a patient that did not do an Allo. LEN is being tested in blood cancer patients post-Allo that LEN does not show any direct ability to kill that cancer. Same concept - more T and NK cells should help the donor immune system kill more cells.

You question about the slide showing 50% of patients that do Allos getting an MR compared to 7% in one study and 16% in the other is related to the slide before it. The slide before it showed CR rates comparing tandem auto to tandem auto-allo RIC. He was trying to show how much deeper the responses likely were for the patients that did tandem auto-allo as opposed to tandem auto. Dr. Kroger is the Myeloma Doctor I read the most. He has been putting out research on MR’s since this Italian research was published in 2003:
“Of these 48 patients, 16 (33%) attained durable PCR-negativity after transplantation, whereas 13 (27%) remained persistently PCR-positive and 19 (40%) showed a mixed pattern. The cumulative risk of relapse at 5 years was 0% for PCR-negative patients, 33% for PCR-mixed patients, and 100% for PCR-positive patients. Within the group studied it was not possible to identify any clinical feature predictive of durable PCR-negativity. We believe that these findings could prompt the design of prospective studies to evaluate if the treatment of molecular disease can extend remission duration and survival.”

The other slide you are asking about just shows how the tandem auto-allo breaks up the high dose chemotherapy from the immunotherapy that used to be done together in a full Allo. That is too much for a patient to handle at once – hence the 30% TRM that Allos used to have associated with them. I actually do not see the need for the Auto if a patient can get a CR prior to Allo. If a patient feels the need to do an Allo that is younger and high risk (like me) there is really no need for the Auto prior to Allo. In a situation like mine I really liked my Doctors proposed strategy of getting CR from induction, doing a partially T Cell depleted Allo (takes away some of the immunotherapy but patients have a low probability of GVHD) and then following up with DLI if you did not get an MR from the Allo. If you think about it it saves a round of Chemo . The DLI comes in like a blood transfusion – the Allo RIC usually requires immunosuppression. You get PLENTY of that from the high dose Chemo.



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