The Treatment Ends, But Does the Cellular Impact?
But what happens inside our cells after all of that?
The melphalan leaves the body fairly quickly. That doesn't
necessarily mean every biological effect starts and disappears just as quickly.
That is where mitochondria become interesting.
First, What Does Melphalan Actually Do?
Before an autologous stem cell transplant, patients usually
receive high-dose melphalan, a powerful chemotherapy drug. I like to explain
its job simply: melphalan destroys the myeloma cells and severely damages the
bone marrow, and then our stem cells come back in to rescue us. Melphalan
damages DNA and kills rapidly dividing cells, but healthy cells can also be
affected. That's why we may experience hair loss, mouth sores, stomach
problems, and extremely low blood counts. On transplant day, our previously collected
stem cells are returned to us and eventually begin rebuilding the bone marrow
and producing new red blood cells, white blood cells, and platelets. We call it
a stem cell transplant because those stem cells are transplanted back into our
bodies, but their real job is to rescue our bone marrow after the high-dose
chemotherapy.
The Drug Leaves. What About the Damage?
Mitochondria are like tiny power stations inside our cells,
helping produce the energy our bodies need. Melphalan damages cells and can
disrupt their mitochondria, potentially triggering cell death. That's exactly
what we want it to do to myeloma cells. Unfortunately, healthy cells can get
caught in the crossfire too.
Melphalan itself doesn't stay in the body very long, but
that doesn't mean all of its effects disappear when the drug does. Think of a
sunburn. The sun exposure may have ended hours ago, but the damage to your skin
remains. Chemotherapy is much more complicated, but the idea is similar.
Some damaged cells die, while others survive but may not
function as well as before. Researchers call one of these changes cellular
senescence, where a cell remains alive but no longer grows or functions
normally. Scientists are also studying how chemotherapy affects our
mitochondria and whether these cellular changes may play a part in why some
people feel like treatment aged them.
This doesn't mean every transplant survivor has permanently
damaged mitochondria. It simply means that what happens to our cells during
treatment may last longer than the chemotherapy itself.
Why am I still so tired?
Not two weeks after transplant.
Not two months.
Sometimes years later.
If mitochondria aren't working efficiently, cells may have
more difficulty producing and managing the energy the body needs. Mitochondrial
dysfunction has therefore become one area researchers are investigating in
cancer-related fatigue and survivorship.
But we have to be careful here.
We cannot say that mitochondrial damage from melphalan is the
reason someone is fatigued years after transplant.
Post-transplant fatigue can have many causes, including
anemia, medications, chronic inflammation, pain, poor sleep, hormonal changes,
loss of muscle mass, deconditioning, infection, nutritional problems, the
underlying cancer, and other medical conditions.
Mitochondrial dysfunction may be one piece of a much bigger
puzzle.
Mitochondria and Our Muscles
Mitochondria are particularly important in muscle because
muscles require a tremendous amount of energy.
When mitochondrial function is impaired, it can be
associated with things like reduced endurance, exercise intolerance, muscle
weakness, and slower physical recovery.
Sound familiar?
Again, that doesn't prove melphalan caused someone's muscle
weakness years later. There are plenty of other possible causes, but it does
help explain why researchers are interested in mitochondria when studying
long-term cancer-treatment fatigue and physical decline.
"I feel like treatment aged me."
There may actually be some science behind that feeling.
Intensive chemotherapy creates enormous stress on the body.
It damages rapidly dividing cells, forces tissues to rebuild, and can
contribute to processes associated with biological aging, including cellular
senescence and changes in mitochondrial function.
Researchers are beginning to look more closely at whether
cancer treatment can actually accelerate the body's aging process. That doesn't
mean receiving melphalan suddenly makes you ten years older, but intensive
chemotherapy puts an enormous amount of stress on our cells and tissues. This
may help explain why some people come out of treatment feeling as if their
bodies have aged much faster than the calendar suggests they should have. So,
when a patient says, "I feel like treatment aged me," there may
actually be some science behind that feeling.
What About the Long-Term Risks We Already Know About?
High-dose melphalan has known potential late effects. One of
the most serious is the increased risk of secondary blood cancers, particularly
myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). These can
develop years after treatment.
Some patients can also experience prolonged or persistent
problems with blood counts or organ function after intensive therapy, although
the cause may involve more than melphalan alone.
Melphalan can also affect other parts of the body. In rare
cases, it has been linked to lung damage, while kidney and liver function are
usually monitored closely during treatment and afterward. Neuropathy is a
little different and worth explaining because although it is common among
myeloma patients, melphalan may not always be the cause.
Numbness, tingling, and burning in the hands and feet are
certainly familiar to many myeloma patients, but melphalan isn't usually the
first drug we blame. Other myeloma treatments—particularly drugs such as
bortezomib—are much better known for causing peripheral neuropathy. The disease
itself and other medical conditions can also contribute.
When we've been through several different drugs plus a
transplant, figuring out exactly which treatment caused a symptom isn't always
easy.
But Aren't Mitochondria Able to Repair Themselves?
Thankfully, our cells have ways of cleaning up and
recovering from some of this damage. One of those natural processes is mitophagy,
the cell's own housekeeping system. It recognizes mitochondria that have become
damaged or aren't working properly and removes them, helping the cell get rid
of what is no longer useful or healthy.
Our cells also have a way of making new mitochondria, called
mitochondrial biogenesis. In simple terms, the body can replace some of the
mitochondria that have been damaged with new ones. This means that
mitochondrial damage from chemotherapy doesn't necessarily last forever. Our
bodies continue working to clean up, repair, replace, and adapt long after
treatment is over. It may also help explain why recovery from a stem cell
transplant can take much longer than we expect. Even years later, the body may
still be adjusting and recovering from everything it went through.
Can We Improve Mitochondrial Health?
There isn't a magic "mitochondria reset button"
after transplant.
However, several things associated with overall metabolic
and mitochondrial health are also the same boring things our doctors keep
telling us to do.
When medically appropriate, they include:
- Gradually
increasing physical activity.
- Resistance
or strength exercise
- Eating
adequate protein and balanced nutrition
- Getting
good-quality sleep
- Managing
other health conditions
- Avoiding
smoking
- Discussing
persistent fatigue, weakness, or exercise intolerance with the medical
team
Exercise is particularly interesting because physical
activity can stimulate mitochondrial biogenesis and improve the body's ability
to produce and use energy.
Of course, "just exercise" isn't very helpful
advice when someone is dealing with severe cancer-related fatigue. Activity has
to match the person's health, abilities, blood counts, bone health, and
recovery stage.
And please be cautious with products marketed as "mitochondrial
support." A supplement labeled with the word "mitochondria"
on the bottle doesn't mean it has been proven to repair chemotherapy-induced
damage. Supplements can also interact with cancer treatments and other
medications.
Talk to your medical team before taking them.
What Researchers Still Don't Know
This may be the most important part of this entire
discussion.
We know quite a bit about how melphalan damages cells during
treatment.
We know mitochondria participate in some of those cellular
pathways.
We also know mitochondrial dysfunction, oxidative stress,
cellular senescence, inflammation, and biological aging are being studied in
cancer survivors.
What we don't yet know is exactly how much persistent
mitochondrial dysfunction from high-dose melphalan contributes to a particular
person's symptoms five, ten, or twenty years after transplant. That connection
is still being investigated, and I think that's an important distinction.
There is a difference between saying, "Scientists are
studying whether this contributes to long-term symptoms" and saying, "Melphalan
damaged your mitochondria, and that's why you're tired six years later."
Science isn't at the second statement yet.
Surviving Treatment Is Only Part of the Story
High-dose melphalan and a stem cell transplant have given
many myeloma patients years they may not have had otherwise. For some of us, it
has meant a long and deep remission and more time with the people we love. But
making it through transplant doesn't mean everything suddenly goes back to normal.
Treatment may be over, but our bodies can continue dealing with the effects
long after transplant day.
Cancer survivorship research also needs to ask what happens
to the body five, ten, fifteen, and twenty years after intensive treatment.
Why do some people bounce back while others struggle with
fatigue?
Why does one person regain their strength while another
never quite returns to their old baseline?
How much does it come from cancer?
How much does it come from chemotherapy?
How much comes from aging, inflammation, medications, immune
changes, mitochondrial health, or a combination of all of them?
We still don't have all those answers.
The melphalan may have left our bodies years ago. Our stem
cells rebuilt our bone marrow, our hair grew back, and our blood counts
eventually recovered. We went from counting the days after transplant to
celebrating the years since it happened. But that doesn't mean our bodies
forgot what they went through. Researchers are still learning just how long
some of the changes caused by such intense treatment may last and what they
could mean for us years down the road.
The treatment ends. Survivorship doesn't.
A Note About Research
Some of what we know about the long-term effects of
chemotherapy is well established, while research into mitochondrial
dysfunction, cellular aging, and long-term fatigue after cancer treatment is
still developing. This article is meant to help explain what researchers are
learning, not to suggest that mitochondrial damage is the cause of every
symptom someone experiences after a stem cell transplant.
Resources & Further Reading
National Cancer Institute (NCI)
International Myeloma Foundation (IMF)
Multiple Myeloma Research Foundation (MMRF)
Blood Cancer United
PubMed — National Library of Medicine
Research & Further Reading
Shafqat S, et al. “The Achilles' Heel of Cancer
Survivors: Fundamentals of Accelerated Cellular Senescence.” Journal of
Clinical Investigation, 2022. https://www.jci.org/articles/view/158452
Wang S, et al. “Accelerated Aging in Cancer Survivors:
Cellular Senescence, Frailty, and Possible Opportunities for Interventions.”
International Journal of Molecular Sciences, 2024.
https://pubmed.ncbi.nlm.nih.gov/38542292/.
Wang S, et al. “Cancer Treatment-Induced Accelerated
Aging in Cancer Survivors: Biology and Assessment.” Cancers, 2021.
https://pubmed.ncbi.nlm.nih.gov/33498754/
Filler K, et al. “Association of Mitochondrial
Dysfunction and Fatigue: A Review of the Literature.” BBA Clinical,
2014. https://pmc.ncbi.nlm.nih.gov/articles/PMC4136529/
Saligan LN, et al. “The Biology of Cancer-Related
Fatigue: A Review of the Literature.” Supportive Care in Cancer,
2015. https://pmc.ncbi.nlm.nih.gov/articles/PMC4484308/
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