[AlanB]

How best to improve response to Kyprolis, Revlimid & dex?

by AlanB on Sat Oct 07, 2017 8:41 pm

I have a 75-year-old friend with multiple myeloma. We want to see her obtain a deeper response during first-line therapy. She has had 3 cycles of Kyprolis, Revlimid, and dexamethasone (KRD) so far, and is also on Zometa. She has tolerated the regimen, staying on an even keel, and all her lab numbers look good. Our plan is to go for a stem cell collection at some point between cycles 4 and 7. For a variety of reasons, we need to postpone an autologous stem cell trans­plant for now.

Her dose of Kyprolis is standard (36 mg/m2). From the outset, she was started on lower-than-usual doses of Revlimid (15 mg/day) and dexamethasone (20 mg/week), just to reduce her risk of side effects.

Over 3 cycles, her M-spike has dropped from 4.3 g/dL (pre-treatment) to 1.1 - 0.5 - 0.3 g/dL. I know the VGPR (>90% drop) gives us a lot to be thankful for. But the graph of her M-spike thus far (see below) suggests a plateau is coming up, rather than a further decline to our short-term goal of 0.

As I see it, if we want to obtain an early, significantly deeper response, our options are:

1. Giving it more time (the graph suggests this will not work well)
2. Going for early autologous stem cell transplant (not a good option for us right now)
3. Increasing the dose of Revlimid and dexamethasone for Cycle 4, and then seeing how things go from there.

We are primarily wondering which of the two options in (3) to pursue, and would appreciate input on them, as well as other thoughts or other perspectives on our situation.

3-Cycle M Spike 2.jpg (23.27 KiB) Viewed 1394 times

[Cheryl G]

Re: How best to improve response to Kyprolis, Revlimid & dex

by Cheryl G on Sun Oct 08, 2017 1:27 pm

Hi Alan,

I'm sorry to hear about the concerns you have regarding your friend's response to her KRD treatment.

I would not assume that your friend's response to her treatment is close to plateauing. I suspect she will see further decreases in her M-spike, and increased normalization of her free light chain levels, with additional cycles of KRD. Responses can continue to deepen even after 6, 9, or even 12 or more cycles of treatment. You can't really say that the response has plateaued until you've actually seen proof there's a plateau.

I'm not a doctor, but if I had to choose between increasing the Revlimid dose and increasing the dexamethasone dose to get a deeper response, I'd probably explore the Revlimid option first, assuming nothing is standing in the way of a higher Revlimid dose at this time.

Another option would be to add Biaxin (clarithromycin) to the treatment regimen. This combination has been described as "Car-BiRD". The Biaxin seems to potentiate the effect of the dexamethasone, and it also may have an anti-myeloma effect of its own. You can find some research out there that reports on the regimen in newly diagnosed patients. See, for example, these two abstracts:

Mark, T, et al, "Car-Bird [Carfilzomib, Clarithromycin (Biaxin), Lenalidomide (Revlimid), Dexa­metha­sone) For Newly-Diagnosed Multiple Myeloma," ASH 2013 annual meeting abstract #3216

Forsberg, PA, et al, "Carfilzomib Induction with Lenalidomide and Clarithromycin Consolidation and Lenalidomide Maintenance (CarBiRD) for Multiple Myeloma" ASH 2016 annual meeting abstract #4518

Just as an aside, 36 mg/m2 is not the approved dose of Kyprolis when it's given together with Revlimid and dexamethasone. The approved dose is 27 mg/m2. See Table 1 in the the pre­scrib­ing information for Kyprolis for more information on the approved dosing:

Also, please be sure your friend's heart function is checked regularly while she is on the KRD regimen. One of the reasons the regimen is not used so frequently in newly diagnosed patients is because of its potential heart-related side effects.

Best wishes,
Cheryl

[stefania888]

Re: How best to improve response to Kyprolis, Revlimid & dex

by stefania888 on Sun Oct 08, 2017 3:09 pm

I would personally give the current regimen another cycle to work. Plateaus aren't necessarily bad. Stable is better than an increase! Initially I had the same goal as your friend; to get as close to a 0 M-spike as possible and potentially avoid a stem cell transplant for awhile. (Spoiler alert: KRD only worked for me for 4 cycles, got my M-spike down to 0.4, it climbed while we tried another cycle, I switched to Darzalex and Velcade, went on to to have a failed stem cell transplant, had numbers climb again going back on Darzalex and Velcade, and am now getting good results with Pomalyst, Ninlaro, and dex, at least for now.)

If it plateaus or even rises slightly, your friend probably has the option to bump up the Revlimid, if it's tolerable. That was my least favorite drug in terms of side effects, but everyone's different. However, the Revlimid bump would probably be more effective against the myeloma than a bump in the dex.

Please keep us updated!

[AlanB]

Re: How best to improve response to Kyprolis, Revlimid & dex

by AlanB on Fri Oct 13, 2017 4:57 am

Cheryl, adding the Biaxin (clarithromycin) directly to Kyprolis, Revlimid, and dexamethasone (KRD) is a very interesting idea. And to both you and Stefania, thank you for your replies. They are so very helpful. You have given me a lot to think about.

Stefania, thanks for the personal feedback about Revlimid. That's good to know. Also, I will add my wishes that your current regimen has real and long-term staying power for you.

Cheryl, to my knowledge Biaxin+KRD hasn’t been previously reported, so you have a brand new idea. Instead, apparently, the studies on Car-BiRD split up the treatment as follows: first cycles are carfilzomib + dex (Car), followed by subsequent cycles of Biaxin + lenalidomide(Revlimid) + dex (BiRD).

I couldn't find any drug-drug interaction of Biaxin and Kyprolis, so at the very least I cannot see a problem in adding it to KRD directly. I will continue looking into this option.

Some of the reading I did suggests that Biaxin, in addition to potentiating the dexamethasone effect, seems to “smooth out” the high-and-low side effects of dexamethasone, so that would be helpful as well.

Alan

[Cheryl G]

Re: How best to improve response to Kyprolis, Revlimid & dex

by Cheryl G on Fri Oct 13, 2017 1:25 pm

Hi Alan,

Glad my comments were helpful.

Please be sure that your friend speaks with her doctor before adding Biaxin to her existing KRD regimen. In fact, I would try to consult with a myeloma specialist, or even some of the researchers who have investigated the regimens that include Biaxin, before adding the Biaxin to KRD, just to be sure there may not be any downsides to the approach.

I say this because it's possible that Biaxin, for example, could interfere with the metabolism of Kyprolis, affecting its efficacy and its side effects. There may be other potential negative interactions. Just because no one has published data suggesting negative interactions between the two drugs does not mean that such interactions won't occur. Kyprolis has not been FDA approved for all that long, in the grand scheme of things, and there have not been many opportunities to document how it interacts with drugs such as Biaxin.

In case you're interested, one forum member also shared his experience with another antibiotic, amoxicillin, and how it seemed to suppress his myeloma:

https://myelomabeacon.org/forum/revlimid-amoxicillin-anyone-t2294.html

Of course, this is just an anecdote, but I thought I'd point it out since it's related to the discussion we've had here about Biaxin.

Good luck!

[Kevin J]

Re: How best to improve response to Kyprolis, Revlimid & dex

by Kevin J on Sat Oct 14, 2017 8:39 am

I was in the clinical study for KRD (CRD back then) when first diagnosed in 2011, and had similar re­sponse. I started with an M-protein of about 3 g/dL (30 g/l), dropped to 0.1 g/dL by the end of cycle three, then stayed there until cycle 11 when I went to 0.0. This is typical of the way this treatment works, so it could take a while before you see additional reduction, particularly to get to complete response, even if you increase Revlimid or dexamethasone.

I'm currently in another clinical study, this time for Empliciti (elotuzumab), Pomalyst (poma­lido­mide), and dexamethasone, and in a stable response. From a purely personal empirical perspective, I have noticed that my IgA levels fluctuate as a function of the amount of sugar I consume (especially junk sugar). My levels tend to stay level or drop somewhat in cycles where I'm really good at avoiding junk food or processed sugars. Conversely, they tend to rise when I'm not so diligent. If you're look­ing for some short term improvement, this might help (and it certainly isn't going to hurt to avoid junk food).

Good Luck.

[AlanB]

Re: How best to improve response to Kyprolis, Revlimid & dex

by AlanB on Sun Dec 17, 2017 11:47 am

Hello again Cheryl, Stefania and Kevin,

I want to provide a follow-up, in case it is useful to you as well as to other patients. To recap, after Cycle 3, there seemed to be a mathematical trend that predicted a plateau in her M-spike. FYI, I rounded out the numbers in my first post, and I didn't write out the math behind the trend, but the plateau would have been around 0.23 g/dL (2.3 g/l).

We decided to leave aside the Biaxin, but push the accelerator to the floor with the full dose of Revlimid (25 mg) and dex (40 mg/week) after Cycle 3. The result was 0.24 g/dL after Cycle 4, and 0.18 g/dL after Cycle 5. I know these are small increments, but right now they mean a lot to us, because they could indicate a stronger response to therapy and a breaking-through of the theoretical plateau of 0.23 g/dL. Of course, we will never know whether this result would have happened with the lower doses anyway, but it is good at least to believe that we did something that helped!

Also, we had a consultation with a transplant doctor about the higher dose of Revlimid and its potential to impair stem cell collection. He said that the main concern about Revlimid is not the dose, but the number of months on Revlimid. So that was reassuring, and we are continuing the 25 mg heading into Cycle 6, with collection to follow.

Your collective feedback was extremely useful in helping me to think about the options that faced us, and to agree on a plan. Paraphrasing a post I read recently on this forum, one of the cruelest things about this disease is that it forces patients to make critical decisions about which even top experts in the field will disagree. This is difficult enough for me (as a caregiver), but it must be so much harder having to do this while under the effects of treatment. My hat is off to all of you.

I am very grateful to you, and to the Myeloma Beacon, for the opportunity to get such useful feed­back and help us guide our course.

Best wishes,
Alan