Multiple Myeloma Treatment: Individualizing The Dosing
When taking a pill, receiving an injection, or being infused through a catheter, every multiple myeloma patient or their caregiver has been told to check two simple things: that the name on the medication is correct and that they know what the medication is supposed to do.
Rarely does a patient ask the question, “How much medication are you giving me, and why so much?” If they did, they might be shocked by the answer from the clinician or the oncologist, “That’s how much we give everybody that weighs as much as you do.”
The multiple myeloma patient might then come back with the next obvious question, “Do all people with my weight get the same cancer response and experience the same side effects?” The answer would be, “No.”
In fact if the physician were totally forthright, they would have to admit, “We are not really sure how you will respond to this dosage, but we will monitor you and see what happens. If you experience severe side effects, we will probably decrease the dose. If your response is low and you have no side effects, we will probably increase the dose.” This is called “titrating” the patient. I call it treating the patient as a cancer experiment.
I am a visiting professor of industrial engineering at Purdue University. I am also a multiple myeloma patient. Since being diagnosed with myeloma last year, I visited oncologists for second and even third opinions, attended patient seminars, and read the technical literature about the various cytotoxic agents, corticosteroids, and novel agents that are available to treat my disease.
Being a scientist, worse an engineer, I was transformed into the dreaded “Internet patient,” one of a class of patients who are the bane of most oncologists-hematologists because of the time they consume in answering various questions relative to prognosis and treatment.
I learned there is an enormous ongoing research effort “searching for a cure” for multiple myeloma. That is wonderful. I also learned that there is much less effort focused on the best way to treat an individual who has the disease, like me. That is terrible. I and 19,999 other individuals were diagnosed with myeloma this past year. We can’t wait for “the cure.” We have to be treated now with the best available agents, using the best dosage regimen possible.
To illustrate the problem, consider the determination of the “standard dose” for the proteasome inhibitor Velcade (bortezomib). In a recent issue of Blood (see related Beacon news), the results of a Phase 3 randomized clinical trial involving 511 patients showed that administering Velcade once per week instead of twice weekly did not change the efficacy of the treatment, but the side effects were dramatically reduced. Specifically, severe peripheral neuropathy was reduced from 28 percent reported in the group with twice a week treatment to 8 percent in the group with once a week treatment, while 85 percent of the patients obtained at least partial response in both groups.
The results raise two immediate questions?
- Why did it take us so long to find this result? Surely, many patients have taken Velcade and are probably suffering needlessly because they were overdosed.
- If cutting the dose from twice weekly to once per week gave the same efficacy with fewer side effects, why not consider reducing it further to say once every two weeks or once every ten days? In fact, why aren’t these dose responses better characterized before a drug is released on the market?
The reason is apparent. Randomized clinical trials are currently used to compare the efficacy and toxicities of various dosages and combinations of treatment agents. They have major drawbacks (see a related Wall Street Journal article). They require long time frames and are expensive. Further, with a rare disease like myeloma, there are insufficient patients in the same stage of the disease, with the same pretreatment exposures and even with the same form of myeloma.
Given these limitations of clinical trials, it is not surprising that there is a lack of agreement within the myeloma medical community, not only on dosage regimens but also on how to treat myeloma, i.e., aggressively, moderately, sequentially, or, if asymptomatic, watch and wait. In this opinion piece, I will address only the dosage regimen issue.
As patients, our goal is a dosage regimen that will maximize the effectiveness of treating “our” cancer, while minimizing “our” toxic side effects. The key word is “our,” since each of us responds differently to the treatments.
I have not met an oncologist who does not think that a personalized dosage regimen is a great idea. What I also found among them was a good deal of skepticism that it could be done efficiently without jeopardizing the patient further.
I believe it can be done. The method I am suggesting rests on one basic assumption; there is a relationship between the concentration-time a drug is in the peripheral blood and the efficacy of treatment and toxicities in the patient. It is called pharmacokinetics and is fundamental to the pharmacological basis of therapeutics.
Why would this not apply to multiple myeloma?
We know that myeloma is in the bone marrow. Drugs find their way into the blood either directly through a catheter or, when taken orally, absorbed from the stomach. The drug or its metabolites are then transferred to the bone marrow microenvironment, where they attack the cancer cells directly (chemoagents) or change the environment to suppress myeloma growth (novel agents). Unfortunately, they are also distributed throughout the body, where they encounter non-diseased tissues and organs, resulting in toxicities.
Each of us has a unique concentration-time or pharmacokinetic profile. By knowing what it is, we can start to determine the best dosage regimen for us.
What would be involved in getting this pharmacokinetic information? Based on our research at Purdue (published in Computers & Chemical Engineering), it would require only one, or at most two, blood samples taken at a specific time following administration of a drug. Ideally, these samples would be taken from the patient after receiving an early non-toxic dosage in order to determine his or her pharmacokinetic profile. From these samples and additional data reported to the U.S. Food and Drug Administration by the pharmaceutical manufacturers, a truly “patient-specific” dosage regimen could be calculated before long-term treatment is started.
Why is it not being done today? The approach has not been demonstrated convincingly enough to the multiple myeloma medical community. It apparently would require a major clinical study from a respected medical group committed to finding the best way to administer drugs to the myeloma patient population. Unfortunately, the “Search for the Cure” is getting most of the research funding, relegating “Individualizing the Dose” for us existing patients to a lower priority.
I hope you will join me in encouraging the myeloma medical community to help refocus these priorities so that we can control our myeloma without needless suffering.
Gary Blau currently holds the position of Visiting Industrial Professor of Chemical Engineering at Purdue University. Gary is also a multiple myeloma patient.
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Hi Gary
Your article is right on.
Fortunately with myeloma, we have several excellent tests which will tell you within a month or so whether the dose you're taking is correct.
Using freelite and electrophoresis assay results, we were able to lower my dose of Dex to 10mg/wk, and rev to 15 mg, which were much more tolerable. Then, after a year of treatment, when m-spike and light chains "plateaued", apparently due to tolerance, they resumed their downward trend when we adjusted dex to 2x/wk and rev to 30mg on dex days.
Frank
Hi Gary and Frank
This was also the case for me. 40mg of Dex a week to 8mg worked just fine prior to my stem cell transplant. They never tried to lower the Velcade.
After transplant both do not work. Alot of work needs to be done on this problem.
Greg
Dear Frank and Greg:
Thank you for sharing your "tiration" results. They are consistent with what I have learned in the waiting rooms of the medical centers I have visited. We can do something about this using clinical pharmacokinetics. The challenges are either to get the pharmaceutical companies to include measured pharmacokinetics of the patient not just weight or surface area in determining their recommended dosage regimen or to have the oncologists demand the pharmacokinetics of the individual and calculate an individualized regimen before the start their titration. In both cases we need to get closer to the non toxic yet efficacious dose "before" the oncologists starts tweeking the dose and save us a lot of suffering and more effective treatment.
Gary
Gary, does the Block Center (http://www.blockmd.com/) manage chemo differently than other centers? I recently discovered their services. They mention that they use "Chronotherapy --- Chemotherapy Administered in Sync with Your Personal Biological Clock". Further in they mention that they can then administer higher doses at times when the patient can better tolerate it.
So I wondered if you know whether they do genetic testing to confirm which chemo is best suited, at what times of the day, and what amounts.
Your article is bang on. I feel, based on what I've been learning since diagnosis, that we are basically one big experiment. We are "unregistered" clinical trials.
Hannao. I know little about the Block Center beyond what appears on their web site. I remain sceptically that they can provide the same level of care as a MM familiar cancer center. In contrast to what I am suggesting, they respond to relieving toxicities after they occur from a standardized dosage regimen. I propose that we individualize the dosing "before" treatment is started so that we won't have to deal with toxicities at all.
I like your term "unregistered" clinical trials. One of my colleagues suggested "guinea pigs" but that seems a little harsh.
Gary
Gary, thanks for your response.
I am actually thinking of contacting them to clarify. Web sites are too generic. I only recently ran across them so I wasn't sure if you were familiar with them.
If I discover anything new, I'll be sure to post it. For now I am pleased to report that I remain in remission, but I want all my research in place so I know what my options are in future.
Gary,
the points in your article are right!!! Thank you for you article. One could assume, that after ASH 2010 there's more pressure behind it with revlimid perhaps doing secondary cancers in myeloma patients. The dosage itself could be fatal at the end. In an article I got from a friend, I learned, that combination therapy is the most advanced and difficult process to do in research. But dosage and combination together will be the key for therapy. Please look at the matrix for development cycles:
http://bloodjournal.hematologylibrary.org/cgi/content/full/116/4/510
As to speak for me, I don't see a way to get influence on these capital-intensive markets on my own. Without being a conspiracy-guy, I understand, that there's only sometimes a link between drug companies with their enormous investments and some clinical facilities.
As patients the only way to act in a powerful manner is, to do work (as long as it is possible) in the organisations like IMF and MMRF and get our arguments heard. Perhaps raise money for tests. But - what do you think, how could we get more pressure on your point? It would be very kind, if you could give us some hints how to act effectively?
Thank you.
Peter
I believe Revlimid doses start too high as well, Gary. Very helpful article. Thank you! Pat
Pat: I really enjoy your column. The latest on nutritional supplements was particularly well researched. In our work on Individualizing the Dosing at Purdue we have obtained some interesting retrospective results with one of the drugs you are taking for peripheral neuropathy, Gabapentin. From pharmacokinetic data collected on 28 patients we were able to show that using the standard dosing regimen three patients were getting ineffective treatment (not within the therapeutic window) and several were getting only marginal treatment. By adjusting the amount and timing of the dose we were able able to come up with a regimen that would guarantee, with 99% confidence, that these patients would be treated properly. You seem to have backed into you own therapeutic window by a self titration strategy. We will get our results published in the scientific literature. Then we will need to do a prospective randomized trial to get the prescribing docs aboard. We are also working with the IU medical center to raise the funding to apply the same approach to MM compounds. It is a long process. We need a way to get individualized dosing ideas with chemo agents into the hand of the prescribing physicians faster.
Hi Gary, as one who has PN as the primary MM symptom, I am very interested in better relief. Can you provide more info on the Gabapentin dosing you mentioned??
regards,
scott
Hi Gary,
My husband was diagnosed with MM Mar '08 through a routine physical (no symptoms, slight increase in protein in urine, & slight decrease in white count. He has only had a very low M spike, & still has no bone or kidney damage, so only way to determine if cancer is back is through bone marrow biopsy). He started revlimid, 8 months later has autogolous stem cell transplant resulting in CR. 8 months later kappa light chain started increasing so his doc put him back on revlimid; despite my constant badgering of his doctor to do a biopsy, he didn't have one until 1 1/2 yrs later, results showing 30% plasma cell count. He was then put on Velcade (had trouble with lower platelet counts), biopsied after 2 mos., results at 50%. His doc now wants to put him on cytoxan only(I'm thinking because of platelet problems he had); I'm hearing that combination therapy has the best results. What are your thoughts? We see his doc tomorrow, if possible, could you respond asap? Thanks, Linda
Hi Gary, thanks so much for your careful and informative article. My wife has had 12 infusions of Velcade with Dex and 4 of aredia. All is based on her height and weight. She is experiencing some hair loss and a very itchy scalp. Everyone claims that velcade does not cause hair loss, but I think your article hints at the fact that in her case she needs a more personalized dosage based on pharmokinetic profile. I would love to hear from you to discuss this further. Thanks again for your enlightening article. Edward
Hi Gary
Excellent article.
I suspect that the professionals who would be most likely trained, at the current moment, to implement this are Oncology Pharmacists. They are the ones trained in pharmocokinetics of dosing and have the skill set to dose the chemotherapy by the patients invidivual distribution, metabolism and elimination kinectics.
In fact pharmacists do this very thing for a number of drugs presently, such as aminoglycosides, which are known to be toxic to renals and cause deafness unless they are carefully monitored and titrated into a very tight dosing schedule that minimizes peaks and troughs of the drugs.
It would seem to be that what needs to happen, independent of the mfgr of the drugs, in that every office needs to have an oncology pharmacist where that is there specific job, just as there are many other professionals such as nurses, med technologists and phlembotimists at the cancer care centers along with the hematologist oncologist and radiologist.
Perhaps, that is what patients want to champion. The professional group with the skill set is already there..you just need to move them into the clinical setting. It isn't difficult to do..anymore so that drawing blood for any other tests they choose to do.
And it would certainly cut down on toxicities, overdoses and obese patients being overmedicated due to the lipophilicity of many of the agents.
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