Long-Term Revlimid-Clarithromycin-Dexamethasone Is Effective And Safe In Newly Diagnosed Myeloma Patients
The results of a recent retrospective analysis show that long-term treatment with the combination of Revlimid, clarithromycin (Biaxin), and dexamethasone – commonly abbreviated "BiRd" – is effective and safe in newly diagnosed myeloma patients.
Furthermore, the study did not find any significant association between long-term Revlimid (lenalidomide) therapy and an increased risk of developing secondary cancers.
“We did expect these results. It was our sense from following patients who have been treated with lenalidomide [Revlimid] long-term and have not received any genotoxic therapy that we did not see increased rates of second primary malignancies,” said Dr. Ruben Niesvizky from Weill Cornell Medical College and one of the study investigators.
Dr. Niesvizky added that the emergence of secondary cancers might be related to the sequential or concurrent use of Revlimid with chemotherapy drugs such as melphalan (Alkeran) or doxorubicin (Adriamycin), rather than long-term exposure to Revlimid itself.
In the current study, none of the patients who received high-dose melphalan followed by a transplant were given Revlimid maintenance therapy after their transplant.
The authors of the current study point out that it does have some limitations, including its retrospective nature and the relatively small number of study participants. They also believe that further evaluation of the relationship between long-term Revlimid therapy, treatment with alkylating agents such as melphalan, and the development of secondary cancers is still needed.
Revlimid has proven effective in both previously untreated and relapsed/refractory myeloma patients. The addition of clarithromycin (Biaxin), an antibiotic used to treat bacterial infections, to Revlimid has been shown to improve response rates and survival times. Clarithromycin also has shown promising results when combined with Pomalyst (pomalidomide) and dexamethasone (Decadron) for relapsed/refractory patients (see related Beacon news).
However, some studies investigating long-term Revlimid therapy have raised concerns of a possible relationship between long-term Revlimid usage and increased rates of secondary cancers (see related Beacon news articles).
In the current follow-up analysis, researchers from Weill Cornell Medical College in New York City sought to investigate the effects of long-term treatment with Revlimid in previously untreated myeloma patients.
The Phase 2 trial that yielded the data for this study enrolled 72 newly diagnosed myeloma patients between December 2004 and November 2006.
Patients in the study received 25 mg of Revlimid on days 1 to 21, 500 mg of clarithromycin twice daily, and 40 mg of dexamethasone weekly on a 28-day treatment cycle. Patients could choose to receive an autologous stem cell transplant after reaching a maximum response, or to continue with the combination regimen.
Patients who opted for a stem cell transplant did not receive any maintenance therapy after the transplant.
The initial study results published in 2008 showed that 90 percent of the patients achieved a partial response or better, compared to 79 percent of patients in a comparable study where only Revlimid and dexamethasone were the treatment regimen.
After a median follow-up of 6.6 years, 14 percent of patients were still receiving Revlimid; 65 percent had relapsed and gone on to receive second-line therapy.
Approximately half of the study participants (46 percent) elected to have a stem cell transplant, followed by observation only.
Patients who chose to have a stem cell transplant received a median of 10 cycles of Revlimid, clarithromycin, and dexamethasone, compared to 26 cycles for patients who received continuous therapy of Revlimid, clarithromycin, and dexamethasone with no transplant.
The overall response increased to 93 percent after a median of 6.6 years of follow up.
At the time of the analysis for the current study, the median progression-free survival time across all patients in the trial was 4.3 years, and the median overall survival has not been reached. The five-year overall survival rate was 75 percent.
The current analysis also showed that the patients who elected to have a stem cell transplant (with no follow-up maintenance therapy) did not experience any survival improvement versus the patients who did not have a transplant and continued with their therapy.
In fact, patients who received a transplant had a median progression free survival of 47 months versus 60 months for the patients who opted, instead, for continuing treatment with Revlimid, clarithromycin, and dexamethasone.
The five-year overall survival rate, however, was 75 percent for both groups of patients.
The researchers found 12 cases of secondary cancers (16.7 percent) among the study participants. The types of secondary cancer include skin (6), colon (2), prostate, pancreas, metastatic melanoma, and lung carcinoid. There were no secondary cancers that were blood cancers, such as myelodysplastic syndromes or acute myeloid leukemia.
The median time to secondary cancer diagnosis was 35 months.
The development of secondary cancers was not associated with chromosomal abnormalities, the number of Revlimid treatment cycles, treatment with a stem cell transplant, or disease stage.
Furthermore, the investigators pointed out that the rate of secondary cancers observed in this study (2.85 percent per year) was not significantly different from the rate expected for similarly aged individuals without myeloma (2.1 percent per year).
For more information, please see the study in the journal Blood (abstract).
Related Articles:
- Adding Clarithromycin To Velcade-Based Myeloma Treatment Regimen Fails To Increase Efficacy While Markedly Increasing Side Effects
- Could A Decades-Old Antibiotic Have Anti-Myeloma Activity?
- Revlimid, Velcade, and Dexamethasone, Followed By Stem Cell Transplantation, Yields Deep Responses And Considerable Overall Survival In Newly Diagnosed Multiple Myeloma
- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients
- Sustained Complete Response To Initial Treatment Associated With Substantial Survival Benefit In Multiple Myeloma
That is so interesting about the BIRD treatments...Do the authors offer any explanation as to why the use of Biaxin improves the efficacy of Revlimid? (or Pomalidomide). Do you know whether there is comparable data for patients who were simply on Rev/Dex, for comparison purposes?
(1) I find the following particularly intriguing and disturbing for overzealous advocates of transplants:
In fact, patients who received a transplant had a median progression free survival of 47 months versus 60 months for the patients who opted, instead, for continuing treatment with Revlimid, clarithromycin, and dexamethasone. (Survival was the same)
(2) I am also not sure how to reconcile the 60 month period for those receiving no transplant versus a median number of 27 treatment cycles for those receiving no transplant. Does that mean that after 27 cycles, these receiving no-transplant went on revlimid? Or nothing at all?
And as always, what was the impact of low-risk versus high-risk characteristics?
Thank you for this excellent review of a timely study. Now that we are hopefully nearing the approval of pomalidomide (Pomalyst in US), I wonder if it would lead to even better response rates, with fewer side effects (especially neutropenia) instead of Revlimid in the BiRD regimen. The study referenced in the article using this for released MM seems to indicate that. The addition of a saccharomyces probiotic (Florastor) due to the prolonged antibiotic use is certainly warranted, with several other supplements, for better tolerance and hopefully efficacy.
The next big breakthrough is likely to be the addition of a monoclonal antibody (like elotuzumab) to the regimen. However, even this is unlikely to be curative. A vaccine or a targeted immunotherapy is likely to be the only hope for a permanent remission (other than some cases of allo transplants).
Nancy, my understanding of the pharmacology of clarithromycin (Biaxin) is that the mechanism this macrolide antibiotic in the BiRD (or BiPD) regimen is a prolongation of the half life of both the Imib's and the dexamethasone due its P450 hepatic metabolism. That is why it doesn't work alone.
Joey, I would not give up on the benefit of ASCT in certain cases. It does deepen the response (up to doubling the PFS and OS) in some cases, especially high risk cytogenetic MM (like my case!).
Now for the synchronicity: today is my first anniversary of my auto transplant! I celebrate Candlemas, Imbolc (Celtic Midwinter) and Groundhog Day today along with a deep gratitude for my blessings and the loved ones in my life. And, I just started the BiRD regimen this week due to an early diagnosis of relapse. We'll see how it works in the next few months. So life goes on, and every day is a gift. That is why we call it the present! Thank you all, Jan
Thanks for all the comments, everyone.
Nancy - Our impression from discussions we've had with various myeloma specialists in regard to Biaxin (clarithromycin) is that the exact way in which the antibiotic improves the efficacy of the Revlimid (or Pomalyst) and dexamethasone is not known. However, it is thought to intensify the efficacy of primarily the dexamethasone in these regimens, although it may also intensify the efficacy of the Revlimid or Pomalyst.
And the way in which it "intensifies" the efficacy of these agents may be through the mechanism that Jan just mentioned in his comment. (Thanks Jan!)
Here is a link to the abstract for a journal article that compares the results of the BiRd clinical trial for data from a similar patient population treated with only Revlimid and dexamethasone:
http://onlinelibrary.wiley.com/doi/10.1002/ajh.21777/abstract
The text of the full article that reported on the initial results of the BiRd clinical trial can be viewed here:
http://bloodjournal.hematologylibrary.org/content/111/3/1101.long
Joey - Regarding the median length of therapy for the patients who did not get a transplant, their therapy stopped if they had to switch to another treatment due to disease progression or if they could no longer tolerate the treatment.
Jan - What a coincidence that you just started the BiRd regimen. Good luck with it!
Thanks Jan and Beacon Staff, I really appreciate your getting back to me about BiRD treatments. I think that the saccharomyces probiotic refers to prevention of yeast infections. I am filing all of this information for future reference, if needed. Congrats Jan on reaching the first anniv. of your transplant, and the other holidays you mentioned! The groundhog saw his shadow yesterday so I am sure that this means six more weeks of winter here...it would be anyways! I reached the third anniv. since transplant last month actually! it is a milestone of sorts, although I usually just count the time since my dx now!
Thank you, Beacon Staff and Nancy. FYI, saccharomyces boulardii was originally used therapeutically in France, and is now marketed in US (and Canada?) as Florastor. It is a yeast probiotic which does not get degraded with antibiotics, incl. clarithromycin, unlike acidophilus and bifidus. I recommend it for my patients to prevent dysbiosis (abnormal bacteria in the gut) following broad spectrum antibiotics. Since it stays in the gut, it does not affect metabolism of other medications. Dose is 250 mg po bid, usually for 10 days, but I am taking it concomitantly with Biaxin.
After much research, and input from my excellent hematologist, and naturopathic oncologist, I have chosen to supplement the BiRD regimen with curcumin (1 gram bid), Thymucin and astragalus (2 bid), green tea extract (2 bid), and inbetween I take Reishi and Coriolus concentrated mushroom extract (2 bid each) on an empty stomach. In addition I take ASA, 81 mg daily, B complex, fish oil bid, Coq10, 300 mg, vit. D3, 2000 IU, and a good multivit. I also have weekly acupuncture (very relaxing!), Bioenergy treatments and other energy healing techniques weekly, yoga and daily meditation for at least 20 minutes with my wife and soul mate (Anam Cara), and most important of all, a half liter of good beer daily: Pilsner Urquell from my home town, Pilsen, Czech Republic. Seriously, it is low in alcohol, yet full of nourishment; great hops! And of course good water, fresh air, quality nourishment, and outdoor exercise with sunshine! BTW, I still practice holistic women's health care and gynecology in Eugene.
So I share the details so that others may find the BiRd regimen better tolerated and effective. Of course, individuals need to check with qualified specialists regarding their unique situation. I hope to use Pomalyst instead of Revlimid soon as part of the regimen, since I surmise a more effective response rate. And then I surrender to the Spirit. As they say, let go, let God! Gratitude, intimacy and forgiveness for all is important. Namaste! Jan
Hi Jan, I like the recommendation of Pilsner Urquell! It's always been one of my favorite brews. I am partial to Belgian or German weiss beers as well. I drink a daily glass of kefir which is loaded with probiotic cultures and seems to be an immune system enhancer. I just hope it is "enhancing" the right cells! It contains several yeast probiotics in addition to yogurt lactobacilli. The kefir I buy is made by Polish immigrants. I know it is popular in Europe. Do you drink it? Thanks for your posts. I find them very informative. Terry L.
Thank you Terry for your kind comments. Due to lactose and casein sensivity, I must limit my intake of Kefir and yoghurt. I agree they are very healthy for most people. I do eat fermented food frequently. In addition to drinking my beloved beer, my wife makes great kimchi, and is hoping to make her own sauerkraut and pickles (must have live cultures though). Miso and tempeh, and ground flax seed as an anti inflammatory is very useful too. Everything in moderation though, including water! BTW, it is not just what we eat, but how we eat it. Taking time to savor a meal with your family and friends (last night we enjoyed lobster tails), is a great exercise in mindful eating. Mindfulness (AKA choice awareness), is an excellent exercise! Just some thoughts on Sunday morning... Jan
I have taken clarithromycin for some of my annoying ear infections. It worked for that, but the awful metalic taste coming out of my pores was very hard to tolerate plus my husband said I smelled like dirty pennies. I hope you are not bothered by that in your treatments!
I have experienced no such effect. I do find, however, that dexamethasone changes my taste buds for a few days.
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