The Neglected Common Thread: Malaria Drugs As Potential Myeloma Therapies
Published: Jul 12, 2014 2:41 pm
One of the first recorded cases of multiple myeloma in the modern era was that of Thomas Alexander McBean.
McBean was a well-to-do grocer in London who, in 1844, developed a condition which at the time had no name and no known cause.
It is now known, however, that what McBean had was multiple myeloma. This has been determined, in part, through work done by Dr. Henry Bence Jones in analyzing a sample of McBean's urine -- work which led to the identification of what is now described as Bence Jones protein.
McBean lived a bit more than a year after first exhibiting serious symptoms of multiple myeloma. Initial attempts to relieve his symptoms with various traditional therapies were only mildly successful. However, his symptoms dissipated almost entirely for several months after one of his physicians treated him with a combination of steel (yes, steel) and a promising new drug.
That promising new drug was quinine, and physicians at the time were testing it as a potential treatment for a range of different diseases. Quinine's original use, however, was as the first effective treatment for malaria.
Was it a coincidence that a malaria drug showed signs of anti-myeloma activity when it was used to treat Thomas McBean's multiple myeloma?
Recent research suggests not.
The Neglected Common Thread
In just the past several months, two journal articles have been published with results suggesting that two different malaria treatments may have anti-myeloma activity. Also, in 2010, a study presented at the American Society of Hematology (ASH) annual meeting reported similar findings for yet another anti-malarial.
In addition, there is evidence from at least one large study conducted in the 1990s that quinine itself has anti-myeloma activity.
Somehow, however, the common thread connecting these different studies – that they all involve treatments for malaria – seems to have been either neglected or completely overlooked.
The two recent research papers investigating the anti-myeloma activity of different malaria treatments, for example, make no mention of other research into the potential use of such treatments in myeloma.
Indeed, one of the two papers describes the drug investigated by the researchers as a treatment for autoimmune disorders. That is a valid description. But the drug's original use was as an anti-malarial.
It seems time, therefore, to highlight the fact that there is this common thread -- that, for whatever reason, researchers keep finding signs that drugs intended to treat malaria, a parasitic infection of the blood, may also have anti-myeloma activity.
Why Is The Common Thread Important?
Shining a light on this common thread serves several purposes.
First, it may encourage researchers to search for some shared way that these treatments combat multiple myeloma. If successful, such research might, in turn, lead to new therapies that are better at exploiting the newfound mechanism for treating myeloma.
Second, it calls attention to the individual therapies that have been investigated thus far, which, in turn, may encourage further research into the potential anti-myeloma activity of these drugs.
The malaria treatments which thus far have been investigated as potential myeloma therapies are all old drugs. They are therefore inexpensive, and their side effects are well understood. They are, as a result, comparatively easy for enterprising researchers to investigate further in either preclinical or clinical studies.
The rest of this article outlines some of the evidence that has been published thus far about the anti-myeloma activity of several different malaria treatments.
That evidence, it should be emphasized, is still immature. In addition, there is no sign at this point that any of the therapies discussed below are likely to have dramatic anti-myeloma activity.
What there is, however, is a consistent set of signals that these therapies may, for example, improve the effectiveness of existing myeloma therapies. And that, for the reasons just described, suggests that the therapies deserve greater attention -- individually, and as a group.
Myeloma specialists in the last 20 or 30 years have not overlooked the potential lesson from Thomas McBean's reaction to the quinine-containing "doublet" he received for his myeloma.
In the 1990s, for example, a large clinical trial was fielded that tested whether there was any benefit to adding quinine to a relatively standard chemotherapy regimen ("VAD-P") for newly diagnosed multiple myeloma patients. There were two groups of patients in the trial. One group was treated with the VAD-P regimen. The other received VAD-P and quinine (VAD-P/Q). Neither group of patients received stem cell transplants after completion of the initial treatment regimen, but many patients went on to receive maintenance therapy with prednisone.
Progression-Free Survival (top) and Overall Survival (bottom)
Note: Line styles for the regimens differ between the graphs.
(click on image to view a larger version of it)
The results of the so-called "SWOG-9210" trial showed, on the one hand, that there was no significant difference in the response of the patients who received the two slightly different upfront treatment regimens.
There was, on the other hand, a trend to improved progression-free and overall survival among the patients who received the regimen containing quinine (see the accompanying graph on the right with the trial survival results, and the full trial results as published in the journal Blood [full text]).
Since the SWOG-9210 trial, little or no additional research has been done to investigate further the potential anti-myeloma activity of quinine.
This may be due to the fact that, in another trial also conducted with newly diagnosed myeloma patients in the 1990s, adding quinine and the heart medication verapamil to a chemotherapy regimen led to a substantial increase in side effects. The increase was substantial enough, in fact, to cause investigators to halt testing of the regimen that included quinine and verapamil (see the related article in the Journal of Clinical Oncology [abstract only]).
The lack of additional research related to quinine, however, means that it has not yet been tested in combination with any of the new myeloma therapies introduced in the past 15 years, such as Revlimid (lenalidomide) and Velcade (bortezomib). It is therefore an open question whether quinine might do more, or less, to improve the efficacy of these newer agents compared to what it did in combination with the older, chemotherapy-based regimen, VAD-P.
Likewise, it is not known what impact quinine, without verapamil, would have on treatment tolerability when used with newer agents.
Recent Studies Involving Anti-Malarials
Although quinine has not been investigated in recent years as a potential myeloma therapy, other malaria treatments have.
A recently published article by researchers at the University of Arkansas, for example, reports results of preclinical research into the anti-myeloma activity of artesunate, which is currently recommended by the World Health Organization as a first-line treatment for malaria (article in the journal Oncotarget [full text]).
The authors note at the beginning of their article that there has been recent research suggesting that drugs similar to artesunate may have activity against cancer in general. Interestingly, the paper makes no mention of research into the anti-myeloma activity of malaria treatments, even though an earlier draft of the paper – presented as a poster at the the 2012 American Society of Hematology annual meeting (abstract) – explicitly describes such research as motivating the authors' study.
During their investigations of artesunate, the Arkansas researchers found that the drug induced cell death in several different treatment-naïve and drug-resistant multiple myeloma cell lines. In particular, artesunate was able to overcome resistance in both Velcade- and dexamethasone (Decadron)-resistant myeloma cells.
In addition, the researchers found that artesunate may act synergistically with Velcade and dexamethasone as an anti-myeloma agent.
Based on their findings, the researchers recommend that artesunate be investigated further to establish its therapeutic potential in multiple myeloma.
Shortly after the publication of the Arkansas study, researchers from the University of Pennsylvania reported on the results of a Phase 1 trial testing hydroxychloroquine (Plaquenil) combined with Velcade in patients with relapsed/refractory multiple myeloma (article in the journal Autophagy [full text]).
Hydroxychloroquine is often used to treat inflammation associated with autoimmune disorders such as rheumatoid arthritis. When it was first marketed in the 1950s, however, it was used to treat malaria.
The Phase 1 trial testing the combination of hydroxychloroquine and Velcade included 25 myeloma patients who had received a median of three prior therapies. Almost two thirds of the patients had been previously treated with Velcade.
Six different Velcade and hydroxychloroquine dosing schedules were tested in the trial, and, among the six patients who received the highest dose of hydroxychloroquine, 33 percent responded, with all responsse being very good partial responses. Among patients in the trial who had not been previously treated with Velcade, 38 percent responded, and again, all responses were very good partial responses.
The researchers describe the two-drug combination as "well tolerated" and believe the dosing schedule involving the highest dose of hydroxychloroquine should be the preferred dosing schedule.
Although the investigators appear to have expected somewhat higher response rates than were observed during the trial, they conclude that combining hydroxychloroquine with Velcade is "feasible and a potentially useful strategy for improving outcomes in myeloma therapy." They recommend that further research investigate hydroxychlorquine in combination with drugs in the same class as Velcade. One such drug would be Kyprolis (carfilzomib).
Hydroxychloroquine is currently being tested in a second clinical trial with relapsed multiple myeloma patients that is still ongoing (see related Beacon news). The drug also was tested in another University of Pennsylvania clinical trial with myeloma patients that is now complete.
At the 2010 ASH annual meeting, Canadian researchers gave an oral presentation describing research they carried out focused on the malaria treatment mefloquine (Lariam), which is chemically related to quinine (abstract).
In particular, the Canadian researchers conducted several different preclinical tests of the anti-myeloma and anti-leukemia activity of mefloquine. In one series of tests, for example, they introduced the drug into cultures of a number of different leukemia and myeloma cell lines. In all cases, the drug demonstrated activity against the cultured cells.
The researchers also found that mefloquine substantially delayed tumor growth in mice injected with different human leukemia and myeloma cells.
The investigators next conducted several additional tests to determine the mechanism by which mefloquine may cause myeloma and leukemia cells to die.
Based on the results of these tests and the earlier testing they carried out with cell cultures and mice, the researchers conclude that mefloquine "displays preclinical activity in leukemia and myeloma" and, "given its prior toxicology and pharmacology testing, mefloquine could be rapidly advanced into clinical trial for patients with leukemia and myeloma."
For more on the history of multiple myeloma – including further details about Thomas Alexander McBean – see this article published in the journal Blood in 2008.
Quinine is available not only as a prescription drug but also in low doses as the key ingredient that gives tonic water its distinctive taste. Indeed, because quinine also can relieve and prevent muscle cramps, it is not uncommon for tonic water to be recommended as a household remedy for cramps.
The FDA, however, several years ago warned against the off-label use of prescription-strength quinine for muscle cramps and restless legs syndrome, citing a number of cases where such use led to serious side effects. These side effects often involved low platelet levels and serious blood-related problems.
Readers therefore should avoid self-medicating with quinine in any way without first discussing the possibility with their physicians.
- Beacon NewsFlashes – October 1, 2012
- Common Solvent Appears To Have Anti-Myeloma Activity
- Researchers Determine Outcomes For Myeloma Patients Who Have Failed To Respond To Novel Agent Therapies
- Regardless Of Prior Therapies, Velcade Is Superior Over Dexamethasone In Relapsed Multiple Myeloma Patients
- New Myeloma Drugs Target Different Mechanisms: Signaling Pathways