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Dosing Myeloma Chemo
How do clinical trials figure out the dosing of myeloma chemo regimens? This may seem like a silly question but the answer is anything but silly.
Clinical trials rely on a concept called maximum tolerated dose. Meaning, give MM patients as much of a given chemotherapy as they can tolerate.
Further, for newly diagnosed myeloma patients (NDMM), it is not the dose of one’s induction therapy that governs the patient’s response. Some NDMM patients achieve MRD – after only a few rounds of induction therapy while many others many never reach complete remission (CR).
What are some common short, long-term and late stage side effects of chemotherapy?
Short-Term Side Effects
Short-term side effects occur during or immediately after chemotherapy and can include:
- Fatigue: A common and persistent feeling of tiredness.
- Nausea and Vomiting: Often managed with antiemetic medications.
- Hair Loss (Alopecia): Hair loss from the scalp and other parts of the body.
- Anemia: Low red blood cell count, causing fatigue and weakness.
- Infections: Increased risk due to a lower white blood cell count (neutropenia).
- Bruising and Bleeding: Lower platelet counts can lead to easier bruising and bleeding.
- Mouth Sores (Mucositis): Painful sores in the mouth and throat.
- Loss of Appetite: Changes in taste and appetite.
- Diarrhea or Constipation: Gastrointestinal disturbances.
- Skin Changes: Dryness, rashes, and changes in skin color.
Long-Term Side Effects
Long-term side effects are those that persist for months or years after treatment ends. They can include:
- Cognitive Changes (“Chemo Brain”): Problems with memory, attention, and executive function.
- Peripheral Neuropathy: Numbness, tingling, or pain in the hands and feet.
- Cardiovascular Issues: Heart problems, including weakened heart muscles and increased risk of heart disease.
- Pulmonary Issues: Lung problems such as fibrosis or reduced lung capacity.
- Kidney Damage: Impaired kidney function or failure.
- Hearing Loss: Especially related to high-frequency sounds.
- Bone and Joint Pain: Chronic pain in bones and joints.
- Endocrine Disorders: Hormonal imbalances, including thyroid dysfunction and early menopause.
Late-Stage Side Effects
Late-stage side effects might develop years after chemotherapy has been completed. These can include:
- Secondary Cancers: Chemotherapy can increase the risk of developing another type of cancer later in life.
- Cardiomyopathy: Long-term heart muscle damage.
- Chronic Fatigue: Persistent fatigue that does not improve with rest.
- Infertility: Damage to reproductive organs can result in permanent infertility.
- Liver Damage: Long-term liver dysfunction or failure.
- Cognitive Decline: Continued or worsening cognitive issues.
- Psychological Effects: Long-term psychological issues such as anxiety, depression, and PTSD.
My point is that the dose of the FDA approved, standard-of-care NDMM induction therapy probably isn’t the reason why he or she achieved one response or another.
This SOC is prescribed to ALL NDMM patients regardless of their age, stage, symptoms, or goals.
As the article below explains, maximum tolerated dose may just lead to short, long-term and late-stage side effects, not a long overall survival.
I am a long-term MM survivor and cancer coach. Years of research and listening to MM patients has taught me that the article below is long overdue. Dosing requirements should be reviewed and reduced in many cases.
In the meantime, NDMM patients must work with their oncologists to balance the damage done my the patient’s MM and the patient’s toxic therapies in order to manage both quality and quantity of life.
Are you a newly diagnosed MM patient? If you’d like to learn more about both conventional and non-conventional MM therapies email me a David.PeopleBeatingCancer@gmail.com
David Emerson
- MM Survivor
- MM Cancer Coach
- Director PeopleBeatingCancer
Spurred by Survivors, Researchers Are Revisiting Cancer Drug Doses
“In 2019, after Kimberly completed her second round of radiation therapy for metastatic breast cancer, her oncologist put her on a daily dose of 125 mg of the targeted drug palbociclib (Ibrance), which was the recommended dose.
Over the next 8 months, Kimberly experienced debilitating fatigue and other side effects, including diarrhea and an anal fissure. She dropped from 120 pounds to just 95 pounds…
She pleaded with her oncologist to reduce her dose to see if that would help ease the side effects. But her oncologist insisted that the full dose was needed to keep the disease at bay.
Undeterred, Kimberly continued insisting on a dose reduction, and eventually her oncologist relented, reducing the dose to 100 mg. Kimberly felt better almost immediately; her energy returned and the gastrointestinal issues subsided. She then pressed her oncologist to reduce the dose even further.
Kimberly has now been on 75 mg of palbociclib since 2020, and, for the time being, has no evidence of active cancer. She’s returned to living a full life—traveling to developing countries for her job, practicing yoga, and advocating for others living with cancer. And last year, she even achieved a personal goal of climbing to the top of the Swiss Alps.
“If I had stayed on the 125-mg dose, it would have broken me. I would have had to try a different drug,” which may have led to a different outcome, she said.
Driven by experiences like Kimberly’s, researchers have been rethinking the traditional paradigm of identifying the best dose of cancer drugs to use in patients.
For years, that process has been largely unchanged, its goal being to determine the “maximum tolerated dose”—that is, the intersection of where a drug inflicts the most harm on tumors while not causing side effects that are intolerable to patients…
But newer treatments, such as immunotherapies and targeted therapies, generally don’t take this indiscriminate approach, and their ideal dose, researchers are realizing, may actually be lower than the highest dose that a patient can tolerate.
“We’ve got a real mess here, where patients are being overdosed,” said Mark J. Ratain, M.D., of The University of Chicago, who has been studying the drug dosing issue for decades…
“We want to live as long as possible, but not at any price,” said Julia Maues, who has metastatic breast cancer and is a founding member of the Patient-Centered Dosing Initiative, a patient-led advocacy group that promotes a more personalized approach to drug dosing for patients with metastatic breast cancer. “What we want is to balance treatment with quality of life.”
The Food and Drug Administration
The Food and Drug Administration (FDA) is also getting into the act. In 2021, the agency launched an initiative called Project Optimus to change how researchers select which dose of new drugs to test in cancer clinical trials…
Guided by Project Optimus, for example, researchers recently reported on a clinical trial involving the experimental targeted therapy camonsertib. In the 119-patient study, they compared two different doses given via different treatment schedules—that is, the specific days and frequency when the drug should be taken.
Each dose and treatment schedule had similar effects in terms of shrinking patients’ tumors. But one was clearly safer, specifically with regard to inducing dangerously low red blood cell levels (anemia). Although it used the higher of the two doses tested, it also included a one-week treatment break, often called a holiday, every fifth week. Based on the findings, this dose and schedule will be used in larger clinical trials.
The researchers also noted that, although the trial was small, their careful cataloguing of side effects may, in the future, help clinicians “tailor both dose and schedule for patients.”
What about doses of existing cancer drugs?
Some researchers interested in dose optimization are coming at the issue from the other end of the drug development spectrum.
Over the last decade, for example, Dr. Ratain and his colleagues have focused much of their research on determining the most effective and safe doses of several cancer drugs that are already in wide use.
For example, they conducted a clinical trial testing two different doses of one of the most commonly used drugs to treat prostate cancer, abiraterone (Zytiga). In addition to dose, however, there was another difference: how the drug was taken.
Giving patients one-quarter of the standard 1,000-mg dose with a low-fat meal had a similar effect on reducing prostate-specific antigen levels—a commonly used marker of whether a drug is shrinking prostate tumors—as giving them the full dose on an empty stomach, which is how it was given in the clinical trials that formed the basis for abiraterone’s approval in 2011.
This reduced dose, taken with food, also costs patients 75% less and is now listed as an alternative to taking abiraterone on an empty stomach in widely used cancer treatment guidelines.
Researchers are also exploring the possibility of using lower doses of immune checkpoint inhibitors, which have rapidly become standard treatments for many cancers. Other studies have analyzed if, under certain circumstances, giving these immunotherapies at their usual dose but less frequentlyExit Disclaimer is a viable treatment approach.
Dr. Ratain pointed out that it’s critical to re-evaluate the dosages of already approved drugs because many are being combined with other, often experimental drugs in clinical trials. If the dosage of the approved drug is not optimal, that may affect both its efficacy and safety when used along with other drugs.
“The majority of drug therapy for the next decade is going to be with drugs that are already approved, not drugs that haven’t been approved yet,” Dr. Ratain said. “If you don’t fix the dosing of drugs already on the market, patients are going to continue to get overdosed even when you add a new drug [in combination].”
Dr. Ratain and his colleagues have been reviewing data on every FDA-approved cancer drug to determine which ones might be the most important to study in what are often called post-market optimization studies.
They are also developing a website to share potential dosing strategies for many approved cancer drugs, starting with the oral drugs and then moving to the intravenous drugs. By doing so, they hope to encourage researchers to perform dosing studies on these drugs to determine whether lower doses might be just as effective and potentially safer.
“The reason people are afraid of [cancer] treatment is because of the perception that … it’s no pain, no gain,” Dr. Ratain said. “I want to change that. I don’t think people need to have side effects to have effective treatment.”
Meanwhile, FDA has launched another initiative, called Project Renewal, that aims to update the dosing of some existing cancer drugs. In December 2022, the agency approved the option of a lower starting dose of the chemotherapy drug capecitabine (Xeloda) for patients with metastatic breast cancer—the first dosing update under Project Renewal.
Fighting for a better quality of life
Maues, who herself is on a reduced dose of a cancer drug, said she’s optimistic that change is beginning to happen but that patients need to continue advocating for themselves.
“Yes, we want to change things at the core, but all of that is slow. People right now are dying of side effects or going to the emergency room because the medication that’s supposed to be saving them is actually hurting them,” Maues said. “We can empower patients to speak up.”
And they may well find a receptive audience, according to another recent survey conducted by the Patient-Centered Dosing Initiative.
That survey found that 85% of oncologists did not believe that a higher dose of a cancer drug is always more effective than a lower dose, and 97% said they would be willing to discuss flexible dosing with their patients.
Maues noted that the organization has developed fliers and other educational content to help guide patients in their conversations with their doctors about drug dosingExit Disclaimer.
As for Kimberly, she said she feels much more empowered in her treatment journey.
“It was the right decision for me,” she said of the dose reduction. “I can still do things and live my life. If you live your life, then you feel like you want to live. Otherwise, you’re just waiting to die, and I don’t want to live that kind of life.””