Blood Glucose, MGUS, Metformin and Myeloma: Part 2

 Metformin as a Possible Treatment for Myeloma?

I first heard about metformin as a possible treatment for multiple myeloma from Dr. Robert Orlowski with MD Anderson, a myeloma specialist, who was a co-author of  a paper on the topic published in The British Journal of Cancer. Generally, as with other cited evidence, the BJC paper indicated worse outcomes for diabetic myeloma patients, but also showed that treatment of such patients with metformin was associated with better results. Beyond that there was other evidence that persons who had myeloma and were taking metformin regularly seemed to experience disease progression more slowly than others. Data shows that myeloma patients with diabetes, are associated with shorter survival, although research by Wu et al. (2014) seems to indicate that metformin ameliorated that risk. There is also recent research showing that metformin may have potential therapeutic use in treating myeloma. Recent data from  Zi et al. (2014) showed a direct effect of metformin against myeloma in vivo with Dexamethasone. There is even recent research suggesting Metformin increases the effectiveness of Bortezomib (Velcade) as recently described in research summarized by Jagganathan et al. (2015).

Metformin and Ritonavir as Potential Therapeutic Agents

As we described last time, there is some evidence (albeit inconclusive) that metformin may slow progression of MGUS and myeloma with conventionally used agents such as Dexamethsone and Bortezomib (Velcade).  However, there is also intriguing data over the last few years showing that metformin when matched with another drug, ritonavir, routinely used to treat HIV, may have beneficial anti-myeloma impacts. In 2012, Dr. Steven T. Rosen, then at Northwestern University was working towards a clinical trial to test this drug combination. And the research paper describing the rationale for the trials is here. And more recently, Dalva-Adyemir et al. (2015) – with Rosen one of the authors-- again showed research suggesting possible effectiveness of ritonavir and metformin along with strong justification for its mode of action. Ritonavir capitalizes on a key myeloma plasma cell malignancy characteristic: that of elevated glucose utilization which is intrinsic to the survival and proliferation of myeloma cells. Many myeloma patients who have had a PET (positron emission tomography) scan are aware that radioactive glucose is used in the test as the plasma cells have an elevated glucose uptake and may then become visible to sensitive whole body scans for concentrations of radioactivity. But unlike healthy cells, myeloma cells depend strongly on certain types of glucose uptake. Myeloma researchers have determined that myeloma clones depend heavily on glucose transporter-4 (GLUT4) for supporting their gluttonous glucose habit. This is where FDA approved protease inhibitor ritonavir comes in: it elicits a selective inhibitory effect on GLUT4. Metformin, on the other hand, inhibits mitochondrial complex 1 which GLUT4 impaired plasma cells seek to exploit to survive in the presence of ritonavir. When subjected to both therapies in combination, the hope is that myeloma cells will be killed outright (apoptosis) or otherwise severely inhibited. The combination of metformin and ritonavir becomes a sort of 1-2 punch to starve myeloma from its mode of unrestrained replication. Dr. Rosen has now filed a patent on GLUT4 inhibitors for blood cancers including multiple myeloma. So what to make of all this?  Should myeloma patients be running out to start taking metformin? No. We embrace evidence-based medicine.  The evidence is not yet conclusive. Within treating myeloma, the medical research community seeks to protect us from flawed and ineffective treatment as well as over treatment. Approved medical treatment for myeloma needs to be based on the proven ability of treatments to help us more than they might harm us. And this needs to be proven in randomized clinical trials in a statistically convincing fashion, ideally replicated in different settings, patient populations and by different researchers. This is the foundation of evidence-based medicine. And as myeloma patients, we should be very grateful to the tireless genetic scientists, myeloma researchers and oncologists who seek to bring its power and safety to our treatment. For a moment, let’s go back to the compelling research from the Chang et al. (2015). This work shows an almost undeniable association in the difference in the progression of diabetic MGUS patients to myeloma depending on whether they are taking metformin or not. However, a key thing about MGUS patients is that this problem is common whereas only about 10% of these patients will develop myeloma over their lifetime. Remembering the Hippocratic Oath—do no harm-- the risk to treat such a massive population, often unnecessarily, could far outweigh the benefits. On the other hand if one is an MGUS patient with high serum blood glucose, then seeing an endocrinologist to prescribe metformin might be a reasonable course of action—particularly if the MGUS was classified as the high risk variety. However, to recommend taking metformin as a high risk MGUS patient would require rigorous clinical trials and not just cohort studies or case-control evaluations of the type I have cited in preceding weeks.

Proving Anti-Myeloma Drugs Work: Why it’s so Hard

Nature does not give up its secrets easily. This is particularly true with complex systems. What’s a complex system?  That person in the mirror: a human being. As many of you know, I have spent many hours looking at cohort, meta-analysis and case-control studies looking at all kinds of issues associated with diet and myeloma. These data are sparse enough and hardly rigorous. I know the dangers so these studies and at least try not to cherry pick them.  I’m not interested in pseudoscience, nor should you be. The anti-vaccination movement tills that territory. A big difference for me and my examination of  influences of diet and myeloma: you remain a flexible attitude towards evidence in lieu of definitive clinical trials. And you know that while you are trying to exploit beneficial associations in the existing data, you can’t be sure of whether the recommendations will help. “The science is soft,” as Dr. Jeff Wolf, my myeloma specialist says. However, I still believe it is still useful to try to exploit evidence on how we might help ourselves. Most often, such studies are all we have.  And it is quite true that I tend to pay attention when there are multiple studies pointing to the same factors (cruciferous vegetables, ursolic acid-rich foods and fish appear helpful to the reducing chance of developing myeloma, while sugar and butter do not). Of course, we hardly know if the same factors might be useful for people that already have myeloma Today we hear the repeated warning to would be data miners: correlation does not imply causality. And that caution is pounded into the skulls of budding statisticians in graduate schools everywhere. I heard it plenty too-- and it is fair warning. But one also does well to listen to the sage advice of Edward Tufte: “Correlation is not causation,” he counsels,” but it sure is a hint.” In other words, more studies and independent reviews of the same phenomenon by multiple sources showing correlation is a powerful hint that there may be causality lurking about.  But while correlation is necessary for causation, the opposite is not true. Still, consistent evidence of correlation with studied variables versus a parameter of interest compels us to look further. And we should look if maintaining a skeptical stance. And even well-trained doctors and diagnostic experts can be swayed by large numbers of cohort studies and a consistent chain of evidence. Back when I began to work on this series, I spoke with Dr. Vincent Rajkumar, arguably one of the preeminent myeloma researchers today.  As a cautionary tale, the good doctor told me about work he did back in 1997 where he and colleagues had many studies showing the hormone replacement therapy looked to be helpful for women to reduce their chances of cardiac events. He and colleagues composed a paper based on the cutting edge research were they recommended such therapy be routinely recommended for post-menopausal women. They were confident the recommendations would help and potentially save lives. But they were wrong. Completely wrong. A follow-up randomized study by the Women’s Health Initiative not only showed hormone replacement therapy was not helpful to reduce cardiac events, but, in fact, the opposite was true.  It was unhelpful. Only a true randomized trial was able to reveal that bias in the opportunity samples was hiding the truth of the matter. I was impressed by Dr. Rajkumar’s candor and my enthusiasm for showing the link between blood glucose, metformin and myeloma greatly slowed the composition of this series. Why? While the evidence on blood glucose, diabetes and metformin is intriguing, it is hardly definitive. There might be other hidden factors at work. What to do? On this, statistician George Box was aptly paraphrased: “The only way to find out what will happen when a complex system is disturbed is to disturb the system, not merely to observe it.” Randomized clinical trials where the treatment is disturbed relative to the group receiving it and lurking confounding variables are randomly distributed across groups So, how to establish causality in a sea of cohort and case control studies? While there are now several studies pointing to metformin having large potential impacts on MGUS or myeloma, although intriguing they are not definitive. I think we can readily agree that the human body is a complex system, so the recommendation is to carefully design experiments and randomize subjects so that the influences are randomized in a particular way so that we can find out what effects are truly caused by the factors of interest. And then to also use some of the other means to combat statistical bias: randomized studies conducted by other researchers and on different populations and with good sample sizes. Will metformin help with efficacy of our conventional treatments such as Dexamethasone and Velcade? And will metformin and ritonavir turn out to be another treatment in the growing pharmacological arsenal against myeloma? Or another failed drug combination of many to have not been proven in the difficult arena of rigorous clinical trials? We can’t know. I just wanted those of us in the myeloma world to understand the difficult challenge our doctors and medical researchers face. Thank them, would you?

What to do While we Wait?

What to do while we wait for more definitive data on whether metformin or ritonavir might be possible treatments for us? Firstly, we watch and use the other FDA approved drugs becoming available under guidance of our doctors to help ourselves. But clearly, from my perspective, it seems prudent for myeloma patients to watch their blood glucose carefully—and to keep an eye on clinical trials and other developments regarding metformin and myeloma. If your blood glucose is high and you have myeloma or MGUS, it might be advisable to see an endocrinologist. You can also help yourself without metformin: none of your doctors will complain about your personal efforts to control your blood glucose through diet and exercise.  Even if not a magic bullet, there is ever more data showing that this is likely a good idea for those of us suffering multiple myeloma. Indeed, it is a good idea for just about everyone on the planet in the Western World where the risk for obesity and Type 2 diabetes seems to grow each year. In particular, recent rigorous clinical trials published in the Lancet  have shown that individuals embracing a Mediterranean diet, with foods such as olive oil, whole grains and leafy vegetables and fruits, have a lower risk of developing diabetes. In the study, complex carbohydrates foods such as oat cereal, yogurt and low-fat dairy products, green leafy vegetables, grapes, apples, blueberries and walnuts and limited alcohol consumption were associated with reduced diabetes risk. Drinking coffee and even decaffeinated coffee were also associated with lower type 2 diabetes risk. And the unhelpful foods?  Sodas and other sugary drinks, red and processed meats and refined carbohydrates.  Candy, ice cream and pastries. And particularly bad would be heavy carbohydrates and sugars eaten on an empty stomach. Disaster for breakfast? glazed donuts…or pancakes with lots of syrup And there is a lot of data to suggest that exercise is important in helping to control blood sugar as experienced within Type 2 diabetes.  I just picked out a recent meta-study.  There are many. The main enemy?-- sedentary lifestyle. More important than the type of exercise appears to just be the choice of exercise versus surrender to the coach potato life. So, not only watch your diet, but in consultation with your doctors, get out and move! Me?  Walking is always good-- fresh air and a new perspective. And, while I haven’t seen a study yet (it’ll be coming), I’d bet daily walkers have better mental health too… Oh, it has been done! Spanish office workers who are regular walkers report better sense of well-being: Who could be surprised? Be well everyone. And thanks for your patience and attention while I try to make my case that blood glucose could be important to us.