[TerryH]

Revlimid 3-drug regimens no better than Revlimid-dex

by TerryH on Thu Mar 03, 2016 9:44 pm

The "in" thing these days is to claim that "more is better" when it comes to treating multiple myeloma. Use more drugs at the same time, people say, and you'll get better survival.

A new study was just published that suggests that, at least when it comes to Revlimid, this isn't always true.

The study was carried out in older newly diagnosed multiple myeloma patients. More than 600 patients took part in the trial. The patients were randomly assigned to get one of three treatments as their initial therapy:

• Revlimid and dexamethasone (Rd)
• Melphalan, prednisone, and Revlimid (MPR)
• Cyclophosphamide, prednisone, and Revlimid (CPR)

Patients received 9 28-day cycles of treatment regardless of which treatment regimen they received.

After the initial 9 cycles of treatment, patients were then randomly assigned to receive either Revlimid maintenance, or Revlimid and prednisone maintenance.

You can check out the results yourself, but, statistically, there was no difference in either progression-free survival or overall survival between the three initial treatment regimens.

Statistical significance is not always the best way to evaluate results, so I strongly suggest looking at the survival graphs. When you eyeball them, you'll see that MPR may provide slightly better progression-free survival than RD and CPR. But there is really no difference in overall survival between the three treatment regimens.

Here is a link to the study, which came out today in the journal Blood:

V Magarotto et al, "Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma", Blood, March 3, 2016 (full text of article - HTML; full text of article - PDF)

I think there are a number of interesting aspects and implications of this study that are worth discussing.

(The dose of Revlimid that was used was lower, it should be noted, in the MPR and CPR regimens – 10 mg for 21 out of 28 days, versus 25 mg for 21 out of 28 days. Also, the dex dosing in the Rd regimen was hardly easy-going – typically 40 mg once a week, each week of the cycle.)

[TerryH]

Re: Revlimid 3-drug regimens no better than Revlimid-dex

by TerryH on Fri Mar 04, 2016 9:53 am

I mentioned the survival curves and how I think they could be worth discussing. I'm attaching a file with them.

SurvivalRates.jpg (58.69 KiB) Viewed 1094 times

I'm also attaching a file with the response rates for all three regimens.

ResponseRates.png (34.76 KiB) Viewed 1094 times

[Multibilly]

Re: Revlimid 3-drug regimens no better than Revlimid-dex

by Multibilly on Fri Mar 04, 2016 11:40 am

Nice post Terry,

I think it's important to also point out the recent results of the SWOG S0777 study (RVd versus Rd), when talking about Revlimid triplets. This report generated a lot of discussion at ASH 2015. Progression-free survival and overall survival graph comparisons are included in the link below.

"Bortezomib, Lenalidomide and Dexamethasone Vs. Lenalidomide and Dexa­metha­sone in Patients (Pts) with Previously Untreated Multiple Myeloma without an Intent for Immediate Autologous Stem Cell Trans­plant (ASCT): Results of the Random­ized Phase III Trial SWOG S0777[/url]," 2015 ASH annual meeting abstract #25 (abstract with graphs)

[faithoverfear]

Re: Revlimid 3-drug regimens no better than Revlimid-dex

by faithoverfear on Fri Mar 04, 2016 1:48 pm

Averages can hide a great deal of meaningful information. Unless the difference between options is overwhelming, the chance of an individual having the same result as the average is not great. It could be much better or much worse.

After going through the mill, I would try the less toxic option first and only go more toxic if the less toxic option does not work well.

I'm fairly new to this forum, so I would like to hear other points of view.

Let your faith be greater than your fear.

[TerryH]

Re: Revlimid 3-drug regimens no better than Revlimid-dex

by TerryH on Fri Mar 04, 2016 3:06 pm

Multibilly - Thanks for bringing up the SWOG study. I figured it would come up in this discussion, and it absolutely deserves to be part of the conversation.

Prior to the SWOG study, I would have expected there to be a difference in progression-free survival between the two arms of the that study, but not necessarily a difference in overall survival. So the overall survival results are important. To me, they suggest that there is a synergy between Revlimid and Velcade that allows them to get a deeper response, and improved OVERALL survival, compared to what would happen if you gave the treatments to a patient sequentially -- one during induction, and the second later at relapse.

That said, I'm waiting to get a more detailed look at the SWOG results once they are published.

Faithoverfear - Welcome to the forum. I would agree with you that, if two approaches to treatment give similar overall survival results, the treatment that offers a better quality of life is definitely more desirable. I also agree that individual experiences can be very different than average, or median, responses.

I don't feel, however, that we should just ignore statistics. Yes, my own experience will be unique, but I need to make a decision about treatment based on something, and looking at trial results is one way to inform my decision.

[DallasGG]

Re: Revlimid 3-drug regimens no better than Revlimid-dex

by DallasGG on Fri Mar 04, 2016 7:56 pm

One study with the following options for treatment only proves that those combinations have similar results.

• Revlimid and dexamethasone (Rd)
• Melphalan, prednisone, and Revlimid (MPR)
• Cyclophosphamide, prednisone, and Revlimid (CPR)

So, yes, if those are your options, I agree that less might be better. But I don't think you can use this ONE study to make the conclusion that less is always better. With all the drugs available to treat multiple myeloma now, it will probably take some time to come up with the most optimal combinations. And what works for one individual might not work so well for someone else. Hopefully as time goes on and we learn more about the different types of myeloma, each person can be treated with the best option for them. For some people, "more" might be better.

[TerryH]

Re: Revlimid 3-drug regimens no better than Revlimid-dex

by TerryH on Sat Mar 05, 2016 9:00 am

Hi Kent,

Thanks for your comments.

I'm not really trying to use the results of this study to argue "less is more". I'm just trying to show that there are good data that do not align with the common assumption these days that "more is better".

One part of the "more is better" assumption is that taking more drugs at one time is better than than taking fewer drugs. This study shows that isn't true for these three treatment regimens.

Another part of the assumption is that you should go with treatments that have the highest share of patients reaching very good partial response (VGPR) or better.

This study also shows that isn't always true.

If you look at the response rates I posted earlier, the RD regimen actually has the highest share of patients achieving a VGPR or better (34% versus 26% for MPR versus 20% for CPR). Yet overall survival for the RD regimen is no different than overall survival for the other regimens.

People in the "more is better" camp also say that treatments that have better progression-free survival usually lead to better overall survival. Again, this study shows that's not true. The MPR regimen qualitatively has better progression-free survival than the other treatments, but there's no real difference in overall survival.

I think the way to look at this study is that it affirms the view that, if myeloma patients have access to basically the same drugs, and can take them for as long as they need to be taken, it doesn't really matter what order the drugs are taken, or how many of them are taken at one time. The key thing for survival is how many different (effective) treatments there are, and that patients be able to take the drugs for as long as they are effective.

This study made sure all the patients had access to Revlimid, and they had access to it for extended periods of treatment – something that isn't always true in many countries. The patients all probably had access to Velcade to a similar extent, and also to all the older, cheaper drugs , like dex, prednisone, and doxorubicin.

So, big surprise – the patients all have basically the same overall survival, regardless what treatment they got right after being diagnosed.

(I should add one clarification: What I've written above doesn't apply if we're talking about treatment prior to an allo stem cell transplant. It is my understanding that, in that case, studies suggest it is best to get as deep a response as possible prior to the transplant.)

[JPC]

Re: Revlimid 3-drug regimens no better than Revlimid-dex

by JPC on Mon Mar 07, 2016 2:57 pm

Good day:

Just to add a quick comment here. Terry, your article and your comments are certainly very valid, and makes some strong research-based points, and define a scenario where Rd beats (or arguably is the equal of) the other 3-drug regimens.

The target population in that study, however, would be the older, transplant-ineligible patients. In that group, there is the issue (or at least the concern) of frailty, and inability to tolerate the drugs. In the SWOG study cited by Multibilly, that was for patients intending to go on to transplant – the younger, so-called "fit" patients. That is a different group, and in that group, 3 drugs were much better than the two drugs.

So I do not think it's an issue of "More" or "Less", its an issue of right-sizing for the given group, and both studies provided good data on the population under study, to that end. This relates to the complexity of multiple myeloma, and as we have all said you need a specialist that has seen all the various "flavors" before.

On an individual basis, you do not know going in whether you could get away with the lower level of treatment, in hindsight, you might have a clue, after the fact. If you are in the younger, fit category, and you are dealing with the treatments, I think that I have seen a reluctance to cut back. So I think there is an aspect of this where you do not know that "More is better", but recognizing that, you might think that "More is safer".

Another item I would like to point out would be the debate (I daresay argument) regarding progression-free survival (PFS) and overall survival (OS) data. It is pointed out that one or another treatment has better PFS, but not proven OS benefit. I heard an interesting point on that recently from Dr. Polumbo. When doing a study, the data on the PFS is "under control" (for the most part). Once a relapse kicks in, the doctor and the patient throws the study out the window, and does what is best on an individual basis (i.e. real medicine what it is supposed to be). So the data (in many, but not all studies) on PFS is more valid than the OS data. There are other studies, that show for the most part, that better PFS does lead to better OS. So if there are two treatments being compared, and the PFS data is clear, but the OS is not, most doctors will go by the PFS results, and take that to be the better approach. An exception to this general rule is when you are simply timing or sequencing the treatments. In the early vs late ASCT scenario, it is roughly the same treatment in the end, just the timing is being studied.

Again, this all has to be tempered by good judgement, realizing that medicine is an art in addition to a science. Thank you for the interesting article.

[mikeb]

Re: Revlimid 3-drug regimens no better than Revlimid-dex

by mikeb on Tue Mar 08, 2016 11:37 am

Hi TerryH and others,

Thanks for the initial post, Terry. That's an interesting study and has generated an interesting discussion.

One point that hasn't been mentioned yet is that the study is comparing more than just 2 drugs vs. 3. In a way it is also comparing dexamethasone vs. prednisone because the 2 drug arm uses dex and both of the 3 drug arms use prednisone. So another way to interpret the results is that dex is equal to prednisone + melphalan and also equal to Cytoxan + prednisone (holding Revlimid as a constant in all arms).

In other words, experimentally there is a confound in this study that complicates understanding the results. It would have been much better if they had used dex in all arms or prednisone in all arms. Because they didn't do that, they are really comparing apples and oranges, unfortunately.

Mike

[DanielR]

Re: Revlimid 3-drug regimens no better than Revlimid-dex

by DanielR on Wed Mar 09, 2016 3:09 pm

Terry,

Thanks, this is indeed a thought-provoking issue. For me, two questions arose as I read your report and the thoughts of other responders to them: First, I am del(17p) and, as such, I find that I always read the results of any studies or trials with a wary eye. Don't get me wrong, it's not that I think the information is wrong or even misleading (though it certainly can be), but because there are so few studies and trials that differentiate between low risk and high risk (especially 17p) patients and their non high risk counterparts.

At best, 17p participants are relegated to a single line in an abstract that states that out of the 300 participants, 6 were 17p, or, worse yet, they get lumped together as 6 high risk participants. Normally, that's the extent of the differentiation. In other words, there really is no differentiation offered. Admittedly, when 17p accounts for only 7-15% (depending on the source) of all myeloma patients, they tend to get lost in the mix is understandable.

What little information is available specific to 17p demonstrates that they often respond very differently to drugs and drug combos than the average (mean). A case in point is the fact that post-ASCT maintenance, 17p patients respond much better to proteasome Inhibitors (PI) + dex (or prednisone), whereas their non 17p counterparts respond better to a combo, PI + IMiDs + dex. It has not escaped my attention that the entire point of your post is that this latter detail may be invalid, still, it remains consensus care.

What's particularly interesting to me is the fact that, as myeloma progresses within an individual, the percentage of 17p genetics increases, some reports contend to as high as 50%. So this undereporting will become increasingly important to all multiple myeloma patients as their disease progresses.

The second thought that this thread evoked for me is the general issue of "more is better", vs. "less is more" approaches to multiple myeloma care. I recently heard an interview with Dr. Berenson where he stated they have gotten dramatically better results with Darzalex (daratumumab), one of the 2 newly approved monoclonal antibody treatments for multiple myeloma, by cutting the initial protocol from 2x / week to 1x / week, a distinction that was never even explored in the trials. Since Darzalex was approved as a single agent, and at the risk of weakening my own argument, it does appear that the depth and duration of positive responses was substantially improved in the subsequent trials where multiple agents are being employed.

Here's the issue as I see it. Western medical protocol has always assumed that throwing every­thing you've got at a disease and then backing off those doses as the problem improves is prudent. Since no one can know ahead of time whether lower doses will be effective, this "more is better" approach is clearly justified. However, that fact does make the "more is better" choice the best option for you as an individual.

Clearly, neither the specialist, nor the individual can know ahead of time which approach will work best for them. To me that's why this line of query is so critical and it reinforces my con­viction that we must be active participants in our own care and protocol decision making. So Terry, while I may have gone a little off topic here, I again want to thank you for these thought provoking reports!

Aloha
DR.