The results of a small British study may lead to fewer myeloma patients suf­fer­ing from diarrhea while taking Revlimid.

In a short article published last week, researchers from the Royal Marsden Hospital in London report that a condition known as “bile acid mal­ab­sorp­tion” appears to be a frequent cause of the diarrhea experi­enced by some patients during treatment with Revlimid ^[1] (lena­lido­mide).

The researchers also found that the bile acid mal­ab­sorp­tion and re­sult­ing diarrhea in these patients can be addressed in two ways.

For some patients, reducing consumption of fatty foods can be enough to solve the problem.

For the rest, treatment with a class of drugs known as bile acid se­ques­trants will generally diminish or elim­i­nate the diarrhea associated with Revlimid.

Bile acid is produced by the liver, stored in the gall bladder, and released into the intestines to help with the digestion of dietary fat.

In some people, the body produces more bile acid than is needed, or the intestines do not adequately absorb bile acid, leading to higher-than-normal levels of bile acid in the intestines. This is the condition known as bile acid mal­ab­sorp­tion.

Bile acid mal­ab­sorp­tion is a recognized cause of chronic diarrhea, and is often treated with bile acid se­ques­trants. These drugs, which are often used as cholesterol-lowering medications, absorb (sequester) bile acid as they pass through the intestine.

Details Of The British Study

The Royal Marsden study involved 12 consecutive cases of patients who, between April 2011 and November 2013, were treated with Revlimid and developed diarrhea, or experienced a worsening of existing diarrhea, during treatment with the drug.

The 12 patients underwent testing for bile acid mal­ab­sorp­tion using a technique known as selenium homo­cholic acid taurine scanning.

All 12 patients tested positive for bile acid mal­ab­sorp­tion, with 75 percent of the cases being severe, 17 per­cent moderate, and 8 percent mild.

Based on the results of the testing, the patients were advised to reduce their dietary fat intake or were treated with a bile acid se­ques­trant, or both.

Two patients were able to resolve their diarrhea with dietary changes alone, while 10 patients were treated with the bile acid se­ques­trant Welchol (colesevelam, Cholestagel).

Overall, 50 percent of the patients reported a full normalization of their bowel movements. The re­main­ing pa­tients reported a reduction in stool frequency and/or improvement in stool consistency.

Most importantly, none of the patients needed a Revlimid dose reduction, or found it necessary to dis­con­tinue treat­ment with Revlimid, due to diarrhea associated with the drug.

According to the researchers, these responses confirm that bile acid mal­ab­sorp­tion was the likely cause of the diarrhea experienced by the patients.

Based on their findings, the investigators recommend that bile acid mal­ab­sorp­tion be investigated as the cause of diarrhea in patients who experience the condition while taking Revlimid, and that treatment with a bile acid se­ques­trant be used when necessary.

Prior Research And Related Treatment Guidance

According to Dr. Paul Richardson of the Dana-Farber Cancer Institute in Boston, who was not directly in­volved with the Royal Marsden study, the British research provides valuable support for findings first reported and discussed during an MMRF symposium at the 2010 American Society of Hematology annual meet­ing, as well as subsequently with various investigators, including the Royal Marsden team.

For several years, Dana-Farber myeloma specialists, along with gastroenterologists at the Brigham and Women’s Hospital in Boston and other researchers involved in several Revlimid clinical trials, had been ex­per­i­ment­ing with ways to address diarrhea being experienced by patients taking Revlimid.

By 2009, it was noticed that patients who experienced Revlimid-related diarrhea could be treated with 2 grams of Colestid (colestipol) up to three times a day before meals. This approach, Dr. Richardson told The Beacon, has a success rate of about 60 to 70 percent.

Like Welchol, the drug used by the British researchers in their study, Colestid is a bile acid se­ques­trant.

Currently, in patients taking 25 mg doses of Revlimid on a daily basis, Dana-Farber generally recommends reducing the dose to 15 mg a day if diarrhea becomes a significant problem. If the problem persists, Co­les­tid is prescribed in an attempt to address it, together with other anti-diarrheals.

In patients on maintenance-type doses of Revlimid (10 mg or 15 mg daily), Dana-Farber specialists will first use Colestid in an attempt to address chronic diarrhea occurring as a side effect, and will then reduce the dose of Revlimid if the Colestid does not fully address the problem.

These steps are accompanied by checks of stool samples and, as necessary, colonoscopies to rule out other potential sources of diarrhea being experienced by patients, as well as consultations with gastro­en­ter­olo­gists, if clinically indicated.

Dr. Richardson also noted that the Revlimid-related diarrhea he and his colleagues address as described above “occurs in a relatively small proportion of patients.” It is characterized, he said, “by gassi­ness, ur­gen­cy, and exacerbation with fatty meals.”

Myeloma patients who are considering treatment with a bile acid se­ques­trant to address Revlimid-related diarrhea should discuss with their physician exactly what times of the day they should take such med­i­ca­tions. The timing is important because the drugs, if taken at inappropriate times, could interfere with the absorption of Revlimid and other drugs the patient may be taking.

In the Royal Marsden study, for example, the researchers recommended patients take Welchol at least four hours before, or after, they took their Revlimid and “other dose-critical medications.”

The Beacon followed up with Dr. Charlotte Pawlyn, lead author of the British study, to find out more about the dosing recommendations she and her colleagues have for Welchol. "We normally treat patients in col­lab­o­ra­tion with the gastroenterology team," Dr. Pawlyn explained, "and I would recommend the patient should con­tact their hematologist and/or gastroenterologist for advice around their specific con­di­tion due to the fact they may be taking other myeloma or non-myeloma related medications that would require careful consider­a­tion. Colesevelam [Welchol] should be taken more than 4 hours apart from dose-critical medications to en­sure their absorption is not affected."

Dr. Pawlyn then went into more specifics. "In general, it is important to escalate the dose of [Welchol], i.e., start with one tablet a day and increase gradually by one tablet per day. In our experience, most patients end up taking 2-3 tablets twice a day. The six tablets can be split into 3 doses, but it's usually easier to take as two doses to avoid timings of other medications, including Revlimid."

She added that she and her colleagues "also perform blood tests to monitor trace elements, fat soluble vi­ta­mins, and triglycerides."

For more information on the Royal Marsden study, please see Pawlyn, C. et al, "Lenalidomide-induced diarrhea in patients with myeloma is caused by bile acid mal­ab­sorp­tion that responds to treatment," Blood, October 9, 2014 (full-text ^[2]).