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Pomalyst-Based Combination Regimens Presented At ASH 2013

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Published: Feb 10, 2014 3:38 pm

At the 2013 annual meeting of the American Society of Hematology (ASH), which took place in December, there were many oral and poster pre­sen­ta­tions about Pomalyst, the newest drug approved in the United States and Europe for the treatment of multiple myeloma.

Many of the presentations were about studies of Pomalyst (poma­lido­mide, Imnovid) and dex­a­meth­a­sone (Decadron) in combination with a third drug, such as Velcade (bortezomib), Kyprolis (car­filz­o­mib), cla­rith­ro­my­cin (Biaxin), cyclo­phos­pha­mide (Cytoxan), or Doxil (doxorubicin lipo­somal), for relapsed and refractory myeloma.

Several of the other presentations were about the Phase 3 clinical trial that found Pomalyst plus low-dose dex­a­meth­a­sone significantly im­proved overall survival of relapsed and re­frac­to­ry myeloma pa­tients compared to high-dose dex­a­meth­a­sone alone (see related Beacon news).  This is the study that led to the ap­prov­al of pomalidomide in Europe, where it is marketed under the brand name Imnovid (see related Beacon news).

There were also several preclinical studies of Pomalyst that were presented at the meeting.  A list of all Pomalyst-related abstracts from the ASH meeting can be found here.

This ASH update – the last The Beacon will publish related to the 2013 ASH meeting – summarizes the findings from the presentations about Pomalyst-based three-drug combinations.

A previous Beacon article summarized findings about Pomalyst plus dex­a­meth­a­sone for the treat­ment of relapsed and refractory multiple myeloma (see related Beacon news).

Overall, Pomalyst-based three-drug combinations are showing promising results in relapsed and refractory multiple myeloma patients.

In particular, Pomalyst-Velcade-dexamethasone appears to have a higher overall response rate than Revlimid (lenalidomide)-Velcade-dexamethasone.  Longer follow-up time will be needed, though, to see how progres­sion-free and overall survival for the two regimens compare. Pomalyst is the newest drug that belongs to the same class of drugs as Revlimid, called immunomodulatory drugs.

It is anticipated that Kyprolis-Pomalyst-dexamethasone will further improve efficacy vis-à-vis both Pomalyst-Velcade-dexamethasone and Revlimid-Velcade-dexamethasone.  Kyprolis is the second drug to be approved in the United States that belongs to the same class of drugs as Velcade, called proteasome inhibitors.

The results presented at ASH for a study investigating the Kyprolis-Pomalyst-dexamethasone combination in relapsed patients attracted significant attention, as the combination achieved substantial response rates in a heavily pretreated group of patients.

Comparisons between Kyprolis-Pomalyst-dexamethasone and Velcade- or Revlimid-based regimens cannot be made, however, precisely because the participants in the Kyprolis-Pomalyst-dexamethasone trial were more heavily pretreated than those in comparable Velcade- and Revlimid-based studies.

Results from one of the studies presented at ASH also show that the addition of clarithromycin to Pomalyst plus dexameth­a­sone doubled the overall response rate and progression-free survival compared to the two-drug regimen.  Overall survival was also noticeably longer with the addition of clarithromycin.

Kyprolis-Pomalyst-Dexamethasone

Dr. Jatin Shah from MD Anderson Cancer Center in Houston presented updated findings from a Phase 2 trial investigating a combination of Kyprolis, Pomalyst, and dexamethasone for the treatment of relapsed and refractory myeloma (abstractpresentation [PDF] courtesy of Dr. Shah).

The study included 79 heavily pretreated patients with a median age of 64 years and who had received a median of five prior lines of therapy.  Among those patients, 70 percent responded to Kyprolis-Pomalyst-dexamethasone therapy, with 27 percent achieving a very good partial response and 43 percent a partial response.

The median progression-free survival was 9.7 months, and the median overall survival was not yet reached at 18 months.

One aspect of the study results that drew particular attention was the fact that outcomes for study partic­i­pants with high-risk chromosomal abnormalities were at least as good as those seen in patients without such abnormalities.

Similar results were seen in other studies presented at ASH that involved Pomalyst in the treatment of relapsed pa­tients.  Together, the results suggest that Pomalyst may be able to overcome the negative im­pact of certain (typically) high-risk chromosomal abnormalities in relapsed myeloma.

The most common severe side effects in the Kyprolis-Pomalyst-dexamethasone trial were low white blood cell counts (29 percent of patients), low red blood cell counts (18 percent), and low platelet counts (14 per­cent).

Comparisons of this regimen to Pomalyst-Velcade-dexamethasone or Kyprolis-Revlimid-dexamethasone are not possible at this time because patients in the current study were more heavily pretreated than pa­tients in similar Revlimid- and Velcade-based studies.

Pomalyst-Velcade-Dexamethasone

Two studies of Pomalyst in combination with Velcade and dexamethasone for relapsed or refractory myeloma were presented during a poster session at ASH.

One of the studies is a Phase 1/2 clinical trial that included 25 patients who had received a median of three prior lines of therapy.  The overall response rate was 92 percent, with 40 percent achieving a complete response, 24 percent a very good partial response, and 28 percent a partial response (abstract).

The other study is a Phase 1 clinical trial that included 28 patients who had received a median of two prior lines of therapy.  Among the patients for whom mature response data were available, the overall response rate was 71 percent, with 5 percent achieving a complete response, 38 percent a very good partial response, and 29 percent a partial response (abstract; poster [pdf] courtesy of Dr. Paul Richardson).

Several combinations of doses were tested in the Phase 1 study and many patients received less than the Phase 2-recommended dose, which may explain why the response rates in this trial were less than those from the Phase 1/2 trial.

This Pomalyst-based regimen appears to compare favorably to Revlimid-Velcade-dexamethasone.  A Phase 2 clinical trial tested the Revlimid-based regimen in 64 relapsed and refractory myeloma patients who had been treated with a median of two prior lines of therapy.  Overall, 64 percent of study participants responded, with 18 percent achieving a complete or near complete response, 11 percent a very good partial response, and 34 percent a partial response.  The median progression-free survival was 9.5 months, and the median overall survival was 30 months.

Indeed, the 92 percent overall response rate seen in the first Pomalyst-Velcade-dexamethasone study described above would be considered a substantial response rate in a study involving newly diagnosed myeloma patients.  In the Pomalyst-Velcade-dexamethasone study, however, the patients had received a median of three prior therapies, and response rates in such patients are typically noticeably lower than in newly diagnosed patients.

This makes the 92 percent response rate reported for the study all the more noteworthy.

Pomalyst-Clarithromycin-Dexamethasone

Another poster summarized results from a Phase 2 study of Pomalyst in combination with clarithromycin and dexamethasone, commonly referred to as ClaPd, for heavily relapsed or refractory myeloma.  The study participants had received a median of five prior lines of therapy (abstract).

Overall, 61 percent of study participants responded, with 4 percent achieving a stringent complete response, 1 percent a complete response, 15 percent a very good partial response, and 41 percent a partial response.  Among the patients previously resistant to both Revlimid and Velcade therapy, 56 percent responded to ClaPd.

The median progression-free survival was 9 months, and the median overall survival was 19 months.

These results show that the addition of clarithromycin doubled the overall response rate and progression-free survival compared to Pomalyst plus dexamethasone alone.  Overall survival was also noticeably longer with the addition of clarithromycin.

In the Phase 3 study of Pomalyst plus dexamethasone, in which the median number of prior therapies was also five, the overall response rate was 31 percent.  Specifically, 1 percent achieved a complete response, 5 percent a very good partial response, and 26 percent a partial response.

The median progression-free survival for the two-drug combination was 4 months, and the median overall survival was 13 months.

Pomalyst-Cyclophosphamide-Dexamethasone

Another poster presented the results of a Phase 2 trial in which half of the patients were treated with Pomalyst plus dexamethasone and half also had oral weekly cyclophosphamide added to their regimen.  The study participants were all heavily relapsed and refractory myeloma patients.  They had received a median of five prior lines of therapy and all were refractory to previous Revlimid therapy (abstract).

Of the 66 patients evaluable for response, which includes those treated with Pomalyst-dexamethasone as well as those treated with Pomalyst-cyclophosphamide-dexamethasone, 49 percent responded, with 2 percent achieving a complete response, 15 percent a very good partial response, and 32 percent a partial response.  The median progression-free survival was 6.4 months.

Since these aggregated results are better than those for Pomalyst plus dexamethasone alone, it suggests that the addition of cyclophosphamide improves response rates and progression-free survival.

The efficacy of the Pomalyst-cyclophosphamide-dexamethasone regimen appears to be similar in efficacy to the regimen of Revlimid plus cyclophosphamide and prednisone.  A small study tested the Revlimid-based regimen in 14 patients with a median of six prior lines of therapy and all of whom were refractory to Revlimid and dexamethasone.  The results showed that 49 percent of patients responded, with 14 percent achieving a complete response, 21 percent a very good partial response, and 14 percent a partial response.

Pomalyst-Dexamethasone-Doxil

Another poster presented results of a Phase 1/2 trial of Pomalyst, dexamethasone, and Doxil in heavily relapsed and refractory myeloma patients.  The study participants had received a median of five prior lines of therapy, and all were refractory to Revlimid (abstract).

Of the 32 patients evaluable for response, 31 percent of patients responded to treatment with a partial response.  The median progression-free survival was 3.1 months.

Researchers observed high rates of low white blood cell counts at the initial 4 mg daily dose of Pomalyst. The Pomalyst dose was lowered to 3 mg, and no additional cases of low white blood cell counts were observed.

In comparison to treatment with Velcade-dexamethasone-Doxil, response rates for the Pomalyst-based regimen may be a little lower.  However, the Pomalyst-based regimen may be a good option for patients who are refractory to or cannot tolerate Velcade.

Results from a study of the Velcade-based regimen in myeloma patients who had received a median of five prior lines of therapy showed that 44 percent of study participants responded, with 4 percent achieving a complete response, 11 percent a very good partial response, and 29 percent a partial response.

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

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4 Comments »

  • Eric said:

    What mechanism is postulated for the use of antibiotic clarithromycin? How does it improve the results? Could myeloma be linked to underlying bacterial infection, noting that the antibiotic is normally used for dental issues and pneumonia ?

  • Eric Hofacket said:

    Good question, what is the mechanism clarithromycin? Progression free survival increased from 4 months to 9 months, overall survival from 13 months to 19 months. This is really good results from adding a cheap antibiotic to Pomalyst. And these people had an average of 5 prior lines of therapy. Are similar results seen from people in induction therapy? Why does this help? Does it only work with Pomalyst? What about Revlimid or even Velcade? Or does it only help with the Pomalyst, Revlimid, thalidomide class of drugs? Is there a down side or risk to long term use of clarithromycin? If not given its low cost why not start everyone on Pomalyst and even Revlimid on it now? What about those on maintenance Revlimid?

    So many questions but if this really does work this well I am sure there are lots of people on Pomalyst and Revlimid who would like to start using clarithromycin now if it can show these kind of results.

  • Myeloma Beacon Staff said:

    Thanks for the questions, Eric and Eric.

    The first studies testing clarithromycin (Biaxin) as a potential anti-myeloma agent were initiated more than 15 years. Since then, there has been rather consistent evidence that the drug improves response rates when it is combined with a steroid (particularly dexamethasone) and an immunomodulatory agent such as Revlimid, Pomalyst, or thalidomide.

    You may recall having heard of the “BiRd” regimen. Well, that’s clarithromycin (Biaxin) combined with Revlimid and dexamethasone.

    Although clarithromycin may have some anti-myeloma activity on its own, the primary way it is believed to improve response rates when combined with other drugs is by increasing the potency of the steroid that’s included in the combination.

    For many myeloma specialists, this raises the question: If the main thing the clarithromycin does is heighten the effect of the steroid in the regimen, why not just up the dose of the steroid and leave out the extra drug (clarithromycin)?

    The way clarithromycin yields a higher response rate also raises questions about whether those response rates lead to longer survival. Recall that Revlimid combined with low-dose dexamethasone was shown, in a key trial several years ago, to have better survival outcomes than Revlimid combined with high-dose dexamethasone, even though the high-dose dex combination had a higher response rate.

    Also, as Beacon Medical Advisor Dr. Peter Voorhees points out in this posting in the Beacon’s discussion forum,

    http://www.myelomabeacon.com/forum/multiple-myeloma-igd-t1767.html#p9799

    there are concerns that using clarithromycin in regimens that include Velcade could lead to more frequent Velcade-related side effects.

    These questions and concerns seem to be the main reason that clarithromycin is not more widely used in the treatment of myeloma.

    It is fair to wonder, however, whether recent research suggesting a closer connection between infection and myeloma will lead to more frequent use of clarithromycin as an anti-myeloma agent.

    This paper,

    http://bloodjournal.hematologylibrary.org/content/111/3/1101.long

    has some information on the BiRd regimen when used in the treatment of newly diagnosed myeloma patients. It also includes a brief description of how myeloma specialists believe clarithromycin may improve response rates when added to other anti-myeloma agents, particularly steroids.

    Also, here is a list of four abstracts from the recent ASH meeting that summarize research at least somewhat related to clarithromycin in the treatment of myeloma:

    http://www.myelomabeacon.com/tag/ash-2013-clarithromycin/

  • Phil Kur said:

    Greetings: I have been taking Pomalyst and will be adding Cytoxan IV next week. My oncologist would like to build up my WBC’s with Neupogen but I developed Sweet’s syndrome the last time I self-injected Neuopogen. Any suggestions? Thank you.