Home » News

Broad Range Of Kyprolis Studies Presented At ASH 2013

18 Comments By
Published: Jan 28, 2014 7:12 pm

The 2013 annual meeting of the American Society of Hematology (ASH), which took place last month, featured many oral and poster presentations about Kyprolis, one of the newest drugs to be approved for the treatment of multiple myeloma.

The drug continues to be tested in various combinations in both newly diag­nosed and relapsed/refractory multiple myeloma patients, as well as in patients with the myeloma precursor disease smoldering myeloma.

In most trials, Kyprolis (carfilzomib) was combined with dex­a­meth­a­sone (Decadron) and a third drug, some­times even a fourth drug, such as Revlimid (lena­lido­mide), thalidomide (Thalomid), cyclo­phos­pha­mide (Cy­toxan), or clarithro­mycin (Biaxin).

Most of these combinations are ones in which Kyprolis replaced Velcade (bortezomib) in a regimen that has already been shown to be highly effective.  Kyprolis and Velcade belong to the same class of drugs called proteasome inhibitors.

Across all different patient populations, Kyprolis continues to show strong results, with overall response rates ranging from 100 percent in smoldering multiple myeloma patients, to the 90 percent range in newly diagnosed (symptomatic) myeloma patients, and to the 60 to 70 percent range in relapsed patients.

Where comparisons can be made, Kyprolis-based combinations appear to have higher response rates, or deeper responses, than the equivalent Velcade-based combinations.

Kyprolis In Newly Diagnosed Myeloma Patients

Kyprolis-Revlimid-Dexamethasone Plus Revlimid Maintenance

Dr. Neha Korde from the National Cancer Institute and the National Institutes of Health presented updated results from a Phase 2 trial of Kyprolis, Revlimid, and dex­a­meth­a­sone followed by Revlimid maintenance therapy for newly diagnosed myeloma patients (abstract).

Among the 43 patients included in the study, 98 percent responded, with 51 percent achieving a stringent or com­plete response, 16 percent a near complete response, 21 percent a very good partial response, and 9 percent a partial response.

Among all the patients who reached at least a near complete response, 100 percent of those tested were negative for minimal residual disease.

The one-year progression-free survival rate was 97 percent.

Dr. Korde also reported that the regimen was an effective and tolerable regimen for older patients.

Comparisons to Velcade-Revlimid-dex­a­meth­a­sone for newly diagnosed myeloma are not simple, in that most studies of the Velcade-based regimen allowed patients to undergo stem cell transplantation or Velcade maintenance therapy, while patients in the Kyprolis study received Revlimid maintenance therapy.

The studies show that response rates are nearly 100 percent for both the Velcade- and Kyprolis three-drug regimens, with around 40 percent of patients receiving the Velcade-based regimen also undergoing stem cell transplantation.

However, two studies of the Velcade-based regimen show that 75 percent to 84 percent of patients treated with the regimen responded within four cycles, while the Kyprolis study showed that 98 percent responded in just two cycles.

Kyprolis-Cyclophosphamide-Dexamethasone Plus Kyprolis Maintenance

Dr. Sara Bringhen from the University of Torino in Italy reported results from a Phase 2 study evaluating Kyprolis, cyclo­phos­pha­mide, and dex­a­meth­a­sone as initial therapy for older, newly diagnosed multiple myeloma patients (abstract; presentation [pdf] courtesy of Dr. Bringhen).  After initial therapy, patients re­ceived further Kyprolis maintenance therapy.

Overall 96 percent of study participants responded, with 64 percent reaching a complete or near complete response, 12 percent a very good partial response, and 20 percent a partial response.

The two-year progression-free survival rate was 76 percent, and the overall survival rate was 87 percent.

According to Dr. Bringhen, Kyprolis-cyclophosphamide-dex­a­meth­a­sone therapy compares very favorably to other treatment options for older patients, both in terms of efficacy and safety.

Several previous studies have shown that the Velcade-based version of this induction therapy (commonly referred to as VCD or CyBorD) is highly effective for newly diagnosed myeloma patients.  One study demon­strated the combination’s efficacy and safety specifically in older patients; however, the study did not include maintenance therapy.  Given that response rates prior to maintenance therapy were not presented for the current study, it is difficult to make direct comparisons between the Kyprolis- and Velcade-based cyclo­phos­pha­mide and dex­a­meth­a­sone regimens for older myeloma patients.

Kyprolis Plus Melphalan And Prednisone

Results were also presented from a Phase 1/2 study of Kyprolis in combination with melphalan (Alkeran) and prednisone for older newly diagnosed myeloma patients (abstract).

Overall, 91 percent of patients responded, with 55 percent achieving at least a very good partial response.  The median event-free survival was 22 months, and the two-year overall survival was 84 percent.

This combination appears to compare favorably to Velcade plus melphalan and prednisone for older newly diagnosed myeloma patients.  A previous study showed that the overall response rate for this combination was 79 percent, with 47 percent achieving at least a very good partial response.

In addition, only 6 percent of patients treated with Kyprolis-melphalan-prednisone developed moderate or severe peripheral neuropathy (pain, tingling, or loss of sensation in the extremities), making it a safe and effective option for older patients.  Similarly, 8 percent of patients treated in a previous study with the Velcade-based combination developed moderate to severe peripheral neuropathy.

Kyprolis Plus Cyclophosphamide, Thalidomide, And Dexamethasone

A poster presented at ASH summarized the final results of a Phase 1/2 study of Kyprolis plus cyclo­phos­pha­mide, thalidomide, and dex­a­meth­a­sone – a combination therapy known as “CYCLONE” – in newly diag­nosed myeloma patients (abstract).

According to the researchers, the combination is highly efficacious.  After four treatment cycles, 91 percent of patients responded, with 76 percent achieving at least a very good partial response.

The two-year progression-free survival was 77 percent, and the two-year overall survival was 98 percent.

Kyprolis Plus Dexamethasone, Followed By Revlimid-Clarithromycin-Dexamethasone Consolidation and Revlimid Maintenance

Another poster summarized results of a study that investigated a sequential approach of upfront Kyprolis plus dex­a­meth­a­sone, followed by consolidation therapy with Revlimid, clarithromycin (Biaxin), and dex­a­meth­a­sone, and finally Revlimid maintenance as first-line therapy for newly diagnosed myeloma patients (abstract).

Overall, 83 percent of patients responded to Kyprolis-dex­a­meth­a­sone induction (9 percent stringent com­plete response, 39 percent very good partial response, and 35 percent partial response).  According to the researchers, these response rates compare favorably to similar studies using Velcade-based com­bi­na­tions.

The researchers point out that responses deepened with consolidation and maintenance therapy (13 per­cent stringent com­plete response, 48 percent very good partial response, and 26 percent partial re­sponse for an overall response rate of 87 percent).

Kyprolis In Relapsed And Refractory Myeloma Patients

Weekly High-Dose Kyprolis

Results from a Phase 1 study of once-weekly (rather than twice-weekly), high-dose Kyprolis plus dex­a­meth­a­sone for relapsed or refractory myeloma were summarized in a poster presented at ASH (abstract).

Eighteen patients, with a median of one prior treatment regimen, have been enrolled and treated in the study thus far.  The patients were given Kyprolis infusions once a week for three weeks out of each four-week cycle.  After an initial starting dose of 20 mg/m2, patients subsequently received doses of Kyprolis ranging from 45 to 88 mg/m2.

Patients also were given 40 mg of dex­a­meth­a­sone once every week.

Thus far, two-thirds of the patients have achieved at least a partial response to the weekly high-dose Kyprolis and dex­a­meth­a­sone therapy.  This compares favorably, the investigators note, to the 55 percent to 60 percent response rate seen in a separate study using twice-weekly Kyprolis.

The median time to response was one month, which the investigators described as rapid.

Kyprolis In Smoldering Myeloma Patients

Kyprolis-Revlimid-Dexamethasone Followed By Extended Revlimid

Another poster summarized results from a pilot study of Kyprolis in combination with Revlimid and dex­a­meth­a­sone followed by extended Revlimid dosing for high-risk smoldering myeloma (abstract; full poster [pdf] courtesy of Dr. Ola Landgren).  Earlier results from the study were presented at the International Myeloma Workshop in April 2013 (see related Beacon news).

Among the 12 patients evaluated for response, all achieved at least a near complete response.  In addition, 92 percent had no minimal residual disease detected.

For more information, please see the Beacon’s ASH 2013 Myeloma Gateway.

Tags: Multiple Myeloma, Carfilzomib, Kyprolis, ASH 2013 Meeting

Photo by José Goulão on Flickr – some rights reserved.
Tags: , , , ,


Related Articles:

18 Comments »

  • Multibilly said:

    So amazingly encouraging!

    Beacon Staff, I always do find it frustrating to try to pull data from earlier studies for comparison given that many also include SCTs as part of the study.

    Do you know when we will be seeing the results of VRd studies without an SCT component, similar to what we are seeing here with the Kyprolis studies? While not quite apples to apples, I believe there were some Vd and Rd studies without SCT that were presented at ASH 2013 that may be good to compare to these studies.

    Seems like the medical industry must also be frustrated by these same sorts of inconsistencies between various trial results.

  • nancy shamanna said:

    Thanks for this interesting article, Maike! Kyprolis looks to be a really good drug, and another weapon against MM. Note that on the CYCLONE study, one of the Beacon’s advisers, Dr. E. Libby, is one of the coauthors. i hope that soon an application will be made to Health Canada for the approval of Kyprolis here.

  • Multibilly said:

    Nancy,

    It must drive you nuts seeing Canada being behind the USA in adopting new treatments. I’ve wondered the same thing about Europe (who I used to think was more liberal than the USA in approving new drugs…but maybe that was just a false impression).

    Is this a question of Canada being more conservative and cautious than our FDA in the USA, or is it more of an economic issue with the cost of the drugs in a socialized medicine environment? Or is it that Canada just needs to do their own tests and that they don’t trust non-domestic trial results?

  • Beacon Staff said:

    Thanks, Multibilly and Nancy for your comments.

    In reply to your questions, Multibilly, there are a couple of studies, one of which is completed and should be reporting results soon, that may help in the comparison of Velcade-Revlimid-dexamethasone (VRd) and Kyprolis-Revlimid-dexamethasone (KRd).

    The following study is comparing Rd and VRd in newly diagnosed patients not intending to undergo immediate transplantation. One notable difference, though, between this study and the KRd study is that the patients participating in the VRd study received Rd maintenance, while the patients participating in the KRd study only received Revlimid maintenance. This study is completed, so results should be reported in the near future.
    http://clinicaltrials.gov/ct2/show/NCT00644228

    The study that is going to be quite interesting is one that is directly comparing VRd and KRd. This one is not expected to be completed until 2016, but hopefully we will see some preliminary results presented at one of the upcoming meetings.
    http://clinicaltrials.gov/ct2/show/NCT01863550

    We could compare KRd to Rd to make sure Kyprolis enhances the efficacy of Rd without adding significantly more side effects, which it does. In the study that you mention, the overall response rate among patients treated with Revlimid-dexamethasone was 72 percent (compared to 98 percent for KRd). Comparable progression-free survival and overall survival data were not provided for the two studies. There are some differences, though, in treatment protocols for these two studies.

    However, Velcade also enhances the efficacy of Rd. Therefore, it’s important to know how VRd and KRd compare.

    In general, it is best to compare two-drug regimens to two-drug regimens, three-drug regimens to three-drug regimens, and so on, since efficacy typically increases as more drugs are added to the regimen.

  • nancy shamanna said:

    Hi Multibilly, Thanks for your comment! I think that the answer to your question would be ‘all of the above.’ Of course, the underlying assumption here also is that the most recent drugs are coming in from other countries , which seems to be mostly the US.

    It doesn’t so much ‘drive me nuts’, as makes me sad. i personally knew people with myeloma who have passed away now. The newer drugs might have helped them to survive. Of course, we are working on a continuum in myeloma. Compared to a decade ago, there are better treatments than there were before. I imagine that all of us who have survived thus far for a few years or more can look on with amazement as newer and better treatments become available for NDMM patients. I count myself very fortunate indeed to have been able to take the ‘novel agents’. Even the ASCT was a treatment only available in the last 20 years or so I think, and I was provided with that therapy also. Just think of all the millions of people who suffered from myeloma throughout human history, who had no effective treatments. Even today, in many parts of the world, adequate treatments for myeloma are not available.

    So I am keeping an eye on all of this, since I work for ‘advocacy’ on behalf of my local support group, with Myeloma Canada. We are ‘watching and waiting’ for the new drugs to come in so that, if necessary, we can advocate to our national and provincial health authorities for their inclusion into our publicly funded health care system! wE are hoping that will be soon also! I know that the drug companies are working on this issue.

    So, I will climb down off of my soap box now!!!

  • Mark said:

    Hi Multibilly and Beacon Staff,

    Many doctors including Dr. Rajkumar of Mayo go out of their way to warn patients that we should not compare the toxicities/outcomes of short term Phase 1 and Phase 2 trials. Only randomized Phase 3 trials can do that. As the Beacon Staff points out drugs like Kyprolis can have long term side effects that are not seen in short term studies like the ones mentioned above. Take note in the small smoldering study 1 out of 12 patients (8%) had heart failure and 2 (17%) had acute kidney damage. It is unknown if this could lead to serious long term issues in these patients. IMO that is fairly toxic triplet for a patient with smoldering to be using.

    A classic example of this is long term Revlimid use. I have seen numerous patients in forums mention that they can no long fight infection due to low blood counts from long term Revlimid use. I am sure they were not warned about that when starting out on never ending cycles of Revlimid. I also saw a video where Dr. Barlogie mentions that he thought never ending cycles of Revlimid would lead to less MDS (secondary cancers) when in reality it seems to lead to more.

    As far as other countries not having all the “latest and greatest” drugs take note of this comment in Dr. Durie’s blog on October 10, 2013:

    “Rather remarkably, the outcomes in Asia and Latin America are quite good, and have survival rates comparable to those in the US and Europe, despite much later diagnosis and considerably reduced access to the newer IMiDs and proteasome inhibitors. Revlimid is still not approved in Korea and Brazil, for example, and there is extremely limited access to Pomalidomide and Carfilzomib, both approved by the FDA in the US.”

    Just having access to the latest drugs is not enough. The docs need to learn how to use them properly and not just keep prescribing them “until you relapse” which leads to less quality of life for the patients and from what the studies show a very limited or no overall survival benefit.

    Mark

  • Multibilly said:

    Beacon Staff, thanks for the update/details on the other studies. You guys rock.

  • Multibilly said:

    Thanks for the comments Mark. Good food for thought. For me, given my lifestyle and loves in life, the issue of avoiding PN in a course of treatment is paramount. So, the thought of being on an earlier gen drug like Thalidomid or Cytoxan would scare me to death (I went to my first and last MM support group meeting and talked to a lot of of folks that were experiencing PN first hand as a result of earlier gen drug treatments).

    But your points are well taken and the potential side effects of the latest gen drugs are not to be taken lightly (i.e. is having PN really an issue if your kidneys don’t work or your heart gives out?).

    The choices are never easy…but I will always welcome more choices rather than fewer.

  • Terry L. said:

    I was one of the patients in the NIH carfilzomib trial for newly diagnosed at the NIH outlined in the article. Dr. Landgren and Dr. Korde are my doctors and I think the world of them. I am glad to have participated and helped science and, of course, myself in the process.

    I never felt like a test subject or “guinea pig”, although I guess I was … LOL. I wanted to try something different and am fortunate I had a great response and never developed any PN or other bad side effects. I personally know several of the other participants in the NDMM and SMM carfilzomib trials at the NIH and they feel the same.

    Mark makes some valid points. Each therapy is a double edged sword. In the end, I thank God I got the slot in the trial. Perhaps, some of the others who participated can chime in. Thanks to the MB for this article. Terry L. Haddonfoeld, New Jersey

  • Joe Courtney said:

    I was most struck by results of the study revealing that once weekly carfilzomib produced better results than the more standard twice per week infusion. I don’t understand the dose comparisons (total mg. per week), but this seems like a wonderful result. Much like finding out that once per week Velcade works just as well as twice per week. Or that low-dose dex is better than high dose. I was dreading the prospect of going on carfilzomib because of the twice per week infusions. Am I missing something?

  • Beacon Staff said:

    Thanks, everyone, for all your comments and feedback about the article.

    Mark – You are absolutely correct that it is important to be cautious about comparing results of clinical trials. Even comparing results between Phase 3 trials is dangerous. Different trials will inevitably have different patient populations, and there also are bound to be differences in rules about how long therapy is given, dosing, and other important details.

    Ideally, you want a Phase 3 trial that directly compares alternative treatment regimens, so at least the patient populations can be roughly similar. However, even results from comparative Phase 3 trials have to be treated carefully. It is not too hard to “load the dice” in a comparative trial through decisions about, for example, dose levels, dosing frequency, and route of administration.

    In the end, however, physicians (and patients) have to make treatment decisions based on the information that’s available — as imperfect as it is. And that often means having to make comparisons across trials, bearing in mind that the comparison will be flawed in many ways.

    At The Beacon, we do comparisons across trials when we think it will be helpful to our readers, but only if the comparison seems legitimately “apple-to-apples.” It should be clear from the above article that, when an apples-to-apples comparison wasn’t possible, we chose not to make it.

    We agree with you, by the way, that efficacy shouldn’t be the only criteria when comparing treatment regimens. Safety also is very important. Generally, if we don’t mention safety issues when making comparisons, it’s because our review of the data led us to believe there wasn’t a significant difference on that front.

    Joe – It’s a bit too early to tell whether the results of the once weekly, high-dose Kyprolis study are as counterintuitive as the study investigators suggest.

    The comparison the investigators make to results of another trial, involving twice-weekly Kyprolis, are an example of the sort of comparisons Mark has warned about.

    In particular, the patients in the other trial were more heavily pretreated, having a median of four previous therapies (compared to just one in the new trial).

    In addition, the patients in the other trial were treated with rather high doses of Kyprolis — up to 56 mg/m2. (The FDA-approved Kyprolis dosing is 20 mg/m2 twice weekly for three out of four weeks in the first cycle, then 27 mg/m2 at the same dosing frequency for later cycles.)

    Still, we agree that it’s good that researchers are looking into the once weekly option for Kyprolis’s dosing.

  • Mark said:

    Hi Beacon Staff – You all are the best. You do an outstanding job of pointing out the limitations of the studies you write about. I would be nowhere near as informed of a patient without your site and the commentary you add to the studies you write about. You do a great job explaining things to “non-scientists” like me.

  • Beacon Staff said:

    Thanks for that very kind feedback, Mark. It’s much appreciated. And thanks, as well, for all your contributions in the Beacon’s discussion forum. We hope you know how helpful they are to everyone in the Beacon community.

  • Greg said:

    Have you heard of Kyprolis being considered for subcutaneous injection similar to how Velcade went from IV to sub cutaneous, minimizing neuropathy and vein damage?

  • Beacon Staff said:

    Hi Greg,

    We’re not aware of any studies being done to investigate administering Kyprolis subcutaneously.

    When Velcade is given intravenously, it’s given relatively quickly — the official prescribing information for Velcade says the IV injection can be done in 3-5 seconds. So it’s natural to consider doing the same thing, but just do the injection into the skin.

    This was then investigated and, as you mention, it was noticed that doing the injection subcutaneously seems to reduce how often patients getting the drug experience peripheral neuropathy.

    With Kyprolis, the recommended infusion time is 2-10 minutes, and it’s often done over an even longer period of time. It would be hard to inject the drug subcutaneously over a similar length of time. It’s also possible (we don’t know, though) that Kyprolis may irritate skin tissue more than Velcade.

  • Deb said:

    My husband is being treat with Kyprolis for relapsed MM. They have him on an escalating dosage schedule and is now taking 36 mg. I don’t see much of that on here and I am concerned about it. He is doing well with an excellent response. They did try to add the polamyst (sp) and he was so weak he couldn’t function so that has been stopped for now. I am scared about this treatment but he has had a BMT, Velcade, Revlimid, Cytoxan. Has anyone here known anyone who has had a transplant from a donor for MM. They have spoken to us about that but it doesn’t have very good odds of survival.

  • Christie May said:

    Hello,

    My husband saw his specialist today and was told the only alternative for him now is carfilzomib [Kyprolis] but it is only available in the US. We are in Sydney, Australia. He has had a stem cell transplant, thalidomide, Velcade and Revlimid. He is in good health other than low platelets. We are desperate for this new drug and he would be more than happy to take part in any studies. Happy to give you his doctors name and any other details you require. He is 63 years of age and was first diagnosed in 2008.

    Thank you, Christie

  • Silver Dollar Sam said:

    I do not know what treatment to choose now. I am a 10 year survivor and have been treated with Thalomid, dex, Revlimid, and PCI-32765 or Ibrutinib. I am relapsed and still work full time. My plate is full and I prefer to have a convenient treatment so I may continue my current lifestyle. I would rather have the cancer treatments work around my life’s schedule than for me to adjust my life for treatments.

    When on Revlimid, it worked great until I broke out in a rash, 4 times I was on then off, the rash would go away and then come back. I was finally taken off of Revlimid for good. Ibrutinib was my last treatment and it was convenient. Once a week orally with dex. This treatment failed to work and my numbers are going up. Tomorrow they will take me off the Ibrutinib study and put me on something else.

    I want to do the Pomalyst (pomalidomide), however my PA says not a good choice since I was on Revlimid before. They are suggesting Kyprolis (carfilzomib) / Velcade, which I know is IV infused. I also have a hard time putting a carcinogen into my body when I am already fighting cancer now.

    I do not know what to choose for my next treatment. I guess I will have to battle it out with the PA and doc. Thanks !!!!