Alternating Revlimid And Thalidomide Is As Effective As Either Drug Alone In Newly Diagnosed Multiple Myeloma Patients
Results of a small Phase 2 study show that newly diagnosed multiple myeloma patients achieve similar response rates with alternating weeks of Revlimid and thalidomide in combination with dexamethasone as patients receiving Revlimid with dexamethasone or thalidomide with dexamethasone.
The study investigators point out that the alternating regimen was well tolerated even though Revlimid was administered at a higher than usual dose of 50 mg per day. However, the regimen was not, as they had hoped, more effective than either Revlimid (lenalidomide) or thalidomide (Thalomid) alone in combination with dexamethasone (Decadron).
They therefore conclude that Revlimid with low-dose dexamethasone remains one of the standards of care for newly diagnosed multiple myeloma patients.
“It is unlikely that this regimen will be utilized to treat myeloma patients. However, the study does show that Revlimid may be administered safely at higher doses,” said Dr. Madiha Tufail, the study’s lead investigator from the John Theurer Cancer Center in Hackensack, New Jersey.
Dr. Tufail suggests alternative dosing schedules may lead to more promising results.
“This pilot trial may lead to a trial of more intense Revlimid therapy with 50 mg administered in the standard of 21 successive days (instead of every other week), which may result in higher response rates. In addition, it may be of interest to administer thalidomide and Revlimid concurrently instead of the alternating week schedule to see if high response rates may be achieved,” she explained.
Revlimid and thalidomide belong to a class of drugs called immunomodulatory agents. Even though they belong to the same class of drugs, they are associated with different side effects. Thalidomide leads to high rates of peripheral neuropathy (pain or tingling in the extremities due to nerve damage), while the most common side effect of Revlimid is low blood cell counts (see related Beacon news).
In this Phase 2 trial, Dr. Tufail and her colleagues alternated the weeks in which they administered Revlimid and thalidomide. They hypothesized that this schedule would reduce side effects associated with each drug, which in turn would increase schedule adherence and decrease the need for dosage reductions. By maintaining effective doses of each drug, the researchers hoped to see an improvement in response rates without increasing the side effects.
Between November 2009 and January 2011, 22 newly diagnosed myeloma patients with a median age of 62 years were enrolled in the study. The patients received four 28-day cycles of induction therapy with Revlimid, thalidomide, and dexamethasone followed by an autologous stem cell transplant.
In each cycle of therapy, patients received 200 mg of thalidomide daily during the first and third week. Revlimid was administered at 25 mg daily during the second and fourth week of the first cycle; if Revlimid was well tolerated during the first cycle, the dosage was increased to 50 mg in subsequent cycles. Additionally, the patients received 40 mg of dexamethasone once peer week throughout each treatment cycle.
Patients received a median of 3.5 cycles of therapy. Eighty-six percent of the patients received the escalated dosage of 50 mg Revlimid during the second cycle; however, 24 percent later reduced their dosage back to 25 mg due to low blood cell counts.
The overall response rate after the induction therapy was 68 percent, with 4 percent achieving a very good partial response and 64 percent a partial response. Additionally, 23 percent of patients achieved a minimal response.
According to the study investigators, the overall response rate is identical to that which has been observed with Revlimid plus dexamethasone or thalidomide plus dexamethasone alone after four months of treatment in similar patients.
Severe side effects included low white blood cell counts (14 percent), low red blood cell counts (14 percent), constipation (14 percent), and rash (9 percent). One early death occurred due to pneumonia. No severe rates of peripheral neuropathy or blood clotting were observed.
“The toxicity profile in our study was better than reported in the literature,” explained Dr. Tufail. “Clinically significant neuropathy was not observed - probably due to the alternating weekly schedule. [Low blood cell counts] were minimal, even at double the standard dose of Revlimid.”
For more information, please see the study in Clinical Lymphoma Myeloma and Leukemia (abstract).
Related Articles:
- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients
- Nelfinavir-Velcade Combination Very Active In Advanced, Velcade-Resistant Multiple Myeloma
- Adding Clarithromycin To Velcade-Based Myeloma Treatment Regimen Fails To Increase Efficacy While Markedly Increasing Side Effects
- Stem Cell Transplantation May Be Underutilized In Multiple Myeloma Patients In Their 80s
- Revlimid, Velcade, and Dexamethasone, Followed By Stem Cell Transplantation, Yields Deep Responses And Considerable Overall Survival In Newly Diagnosed Multiple Myeloma
Delighted to read that Dr.Tufail recognizes that alternative dosing schedules may lead to more promising results. However, I am concerned that her approach is to increase the dosing to a daily high dose regimen of Revlamid without trying to "individualize" the dosing to the patients. She still plans to treat the patients as if no inter patient variability exists in the absorption, distribution and elimination of the agents despite strong evidence to the contrary.
I find this trial design disturbing. What was the point of it?
For Celgene to increase sales of thalidomide which has more severe neuropathy and sedation than lenalidomide and is no longer the drug of choice in the newly diagnosed MM patient ...as it shouldn't be?
Why didn't they just alternate every other week dosing with lenalidomide? Oh, that's right...reduced sales..revenues& profits.
Instead they DOUBLE the dose of lenalidomide, to make more profits and ensure that the trial outcome had a statistically significant outcome for the patients given that they already knew from other trials that lenalidomide has greater PFS than thalidomide.
All of which is why I find the trial design disturbing. Heck they already know the half-life for lenalidomide and could have simply dosed it every other week.
And higher doses virtually always mean higher AE's.
aaarrrgh
I have to agree with both Gary and suzierose above. There does not appear to be any advantage of this alternating regimen over now standard Revlimid (25 mg po for two out of three weeks regimen with Dexamethazone) induction therapy. The side effects are actually greater, and there were NO complete response rates! There is now good evidence for better lenalidomide (Revlimid) efficacy with fewer side effects than thalidomide (Thalomid); alternating these agents makes no sense to me. I would like to know why Dr. Tufail makes the conclusions she makes.
Can anyone tell me about the article written in the Beacon regarding Antabuse and a study that was done in Italy regarding its findings? If I remember correctly the drug Antabuse (Disukfiram) was found to be effective in killing Myeloma cells while causing no injury to normal cells.That is huge and yet I've heard nothing more about it since last month. I'm taking Rev and just finished my first 21 days today. I am also taking Dex 80mg once a week. My first Zometa IV is set for this coming Tuesday. I also read that 20 mg of Dex was found to be more effective than 40 and I have been prescribed 80. I have questions for my doctor when i see him Tuesday. I need to know some answers and I need to ask what I perceive to be tough questions. It's my life, my disease and I want to know. I did write to one of the contributors of the Italian Research team but haven't heard back. Let's see, Revlimid at $8000 per month or Antabuse at $400 per year. I wonder.
Hello Ed,
The Myeloma Beacon article that you are referring to is this one:
http://www.myelomabeacon.com/news/2012/02/20/beacon-newsflashesfebruary-20-2012/
See, in particular, the third item in the list of Newsflashes.
Please note that the study discussed in the Newsflash does NOT involve testing of disulfiram (Antabuse) in a clinical trial with myeloma patients. Instead, cells taken from myeloma patients were exposed in a laboratory testing to disulfiram, and the researchers then observed the impact of the drug on the cells and reported these results.
Thus, although these initial tests seem promising, we don't yet know what sort of response disulfiram generates when actually administered to myeloma patients.
This doesn't mean you shouldn't discuss disulfiram with your physician. We just want you to be aware of what sort of evidence is actually available thus far for the drug.
In regard to high-dose dex vs. low-dose dex, yes, there is evidence that Revlimid with low-dose dex is associated with better outcomes than Revlimid with high-dose dex in newly diagnosed myeloma patients. Here is the Beacon article on the subject:
http://www.myelomabeacon.com/news/2009/10/27/study-shows-higher-survival-with-revlimid-and-low-dose-dexamethasone-than-revlimid-and-high-dose-dexamethasone-in-multiple-myeloma-patients/
It is worth mentioning, however, that in this study -- which generally is considered very important in the myeloma field -- all patients took 40 mg dex on any given day they took the drug. However, the patients on the "high-dose" schedule took 40 mg on on days 1-4, 9-12, and 17-20 of a 28-day cycle, while those on the "low-dose" schedule took it on just days 1, 8, 15, and 22 of a 28-day cycle.
Good luck!
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