Multiple Myeloma

For many years, the fight against multiple myeloma unfolded like a siege—slow gains measured against painful losses.

Now, researchers like Rafat Abonour, MD, speak optimistically about what the future holds. “A lot of us are bold enough to say we can cure multiple myeloma with the treatment we provide,” said Abonour, who oversees the myeloma program at Indiana University Melvin and Bren Simon Comprehensive Cancer.

Since 2013, eight therapies have gained federal approval, including second-generation proteasome inhibitors and newer immune-based options like bispecific antigens. Those advances have provided oncologists with a deeper bench of options for patients whose disease requires second or third options. For some, care for managing myeloma resembles managing a chronic condition.

Yet researchers still tackle thorny problems.

Why do some patients with precursor conditions like smoldering multiple myeloma or monoclonal gammopathy of undetermined significance (MGUS) eventually progress to full-blown cancer? Why does myeloma surge back–even if immunotherapy wipes it out? What genetic factors power hyper-aggressive disease?

At the IU Simon Comprehensive Cancer Center, we are striving to find those answers. Our physicians and researchers work at the cutting edge, using the latest advances in genomic sequencing, machine learning and drug discovery. They also lead clinical trials for the newest options in immunotherapy.

Our progress against multiple myeloma is also made possible by generous donors like you.

“Donors have helped us build a strong program,” Abonour said. “It’s given us opportunities to be bold. We can ask big questions. Sometimes, doing that means you won’t get funded through traditional sources.”

Philanthropy will allow the IU Simon Comprehensive Cancer Center to continue to recruit talented scientists. It will underwrite collaborations with the Brown Center for Immunotherapy, turning newly discovered targets into immunotherapies manufactured at IU. And it can fund trials offering new therapies through IU Health’s statewide network.

Together, we can reach the ambitious goal of curing myeloma. Here is a look at our progress and what supporters make possible.

Telling the Story of Myeloma

Understanding any form of cancer starts at the same place: studying cells to see what’s gone wrong.

But often, those cells lack diversity. They come from patients whose cancer is highly aggressive. A patient’s age, gender, or racial background can also be critical factors in progression. And as genomic analysis has improved, we’re learning no two patients confront the same disease.

To make progress, researchers need a broad array of patients and samples taken as myeloma unfolds.

It’s why IU established the Indiana Myeloma Registry.

Since the registry came online in 2018, nearly 1,000 patients have enrolled, each providing tissue samples, medical history, and access to their treatment history. It is the mechanism for writing the history of each patient.

Saliva samples are the source of DNA samples parsed for genomic data that can help us understand how each patient’s myeloma developed. Meanwhile, blood and bone marrow samples taken during therapy can be analyzed to track how the cancer evolves and responds to different types of treatment.

For example, we don’t know the events unfolding for patients whose smoldering multiple myeloma—one of two precursor conditions—becomes cancer. If we understand those mechanisms, could we prevent myeloma? Or, at the very least, identify people at the highest risk and potentially start treatment earlier?

Once diagnosed, watching myeloma unfold in real-time is key for laboratory researchers. “You’re not inferring relationships,” said Brian Walker, PhD, a professor of medical and molecular genetics. “You can see exactly what the changes are, how the cells behave, and what the biology actually is.”

Along the way, we can get better insights into why many myeloma patients see their disease return or multiple treatments fail over time. Pairing a patient’s treatment history with tissue samples can lend critical context researchers lack.

Tracking patients throughout their care is also essential to understand how therapies perform in the real world. “Clinical trials are not always representative of the patients we see,” said Abonour.

Having that data helps physicians create better classifications for regimens. Over time, drug companies can partner with IU, knowing it has a diverse pool of patients to participate in clinical trials.


Finding the Next Generation of Insights

Brian Walker, PhD
Daniel and Lori Efroymson Professor of Oncology

Two questions continue to gnaw at researchers. Even as we learn more about myeloma, we still don’t know why less than 1 percent of patients with precursor conditions ultimately develop cancer. And even as therapies improve, we don’t understand why many patients see their disease eventually roar back.

Next-generation sequencing, which allows us to analyze DNA better, will help us answer those questions.

Using samples from IU’s myeloma registry, Walker and his team are revealing the cancer’s slow-motion evolution. In a condition like MGUS, for example, there are fewer genetic mutations or abnormalities.

The lab found one gene that might play a leading role. It guards the cell’s genome, making sure copying unfolds without a hitch. But when absent, errors pile up, and some pieces of code get misplaced. In samples taken from patients at regular intervals, Walker has found their frequency ramps up, allowing myeloma to emerge and crowd out normal cells rapidly.

Much of this data is new, but in time, it could pave the way for biomarkers oncologists use to keep tabs on patients. By understanding the cellular mechanics at work, Walker hopes we could single out at-risk individuals.

The lab also sequences samples based on the treatment a patient receives. Studying genetic changes over time might help us understand why some therapies, like newer proteasome inhibitors, fail. “There’s no point in treating patients with an ineffective therapy,” Walker said. “They could move on to other options.”

Slowing Myeloma’s Metabolism

Kelvin Lee, MD
Director, IU Melvin and Bren Simon Comprehensive Cancer Center
Associate Dean of Cancer Research

What cancer craves is control, and myeloma is no different.

To survive, it needs to gain control of its surroundings and how it interacts with other cells in the bone marrow. Treatments will be more effective once we understand how myeloma asserts that power.

Lee’s lab probes for those vulnerabilities and has discovered one way myeloma protects itself. The lab studies a gene that helps stabilize a protein responsible for correctly replicating its own DNA. Targeting that gene might disrupt the cancer’s ability to copy itself so quickly.

But there’s also another weak point.

A receptor on the surface of myeloma cells acts as a weather gauge, collecting information and environmental readings. Slowly, it also reprograms a cell to use fat instead of sugar for energy. Fat is easier to burn, allowing myeloma cells to function more efficiently–and resist chemotherapy.

These insights are invaluable in developing more refined therapy, like exploring whether that stabilizing gene could be targeted with immunotherapy.

Giving Immunotherapy a Gentler Touch

Attaya Suvannasankha, MD
Associate Professor of Clinical Medicine

Over the past several years, immunotherapy has shown promise in treating myeloma. Yet those treatments aren’t always durable–and still pose the risk of harsh side effects.

One solution might be bispecific antigens, cells retrofitted to identify a target on the surface of a myeloma cell and draw immune cells to take them out.

This past year, Suvannasankha led a clinical trial for a drug called linvoseltamab, which was effective in 90.3 percent of patients. Aside from the results, the therapy was also noticeable for milder side effects—making it easier to administer to older patients.

The treatment is unique because the antigen binds “gently” to the target and T cells, decreasing the workload to destroy myeloma. It also keeps the immune system from overdrive, lowering the risk of a cytokine storm. And most importantly, 78 percent of patients whose earlier therapies had failed remained in remission after a year.

To Suvannasankha, it’s early evidence that you can create more tolerable therapies without sacrificing effectiveness. “In this very difficult-to-treat group, where remaining options are so limited, to say that remission may continue at one year at such a high rate is pretty phenomenal,” she said.

Helping the Body Reinforce Bone

G. David Roodman, MD, PhD
Associate Professor of Clinical Medicine

Myeloma is more than a blood cancer. It’s also marked by painful and crippling bone disease, which afflicts up to 80 percent of patients.

It’s the result of cancer hijacking the environment inside bones to survive. Throughout our life, marrow produces a set of cells to keep our bones healthy and stable. One set chews up old bone while the other replaces it.

Yet each develops from the same type of stem cell, and as they evolve, proteins and growth factors are released. Some of them help myeloma cells grow and take over.

Slowly, cancer tilts the balance, favoring bone-eating cells. Eventually, painful lesions form and go unrepaired.

Roodman’s lab looks for ways to block those interactions, which would halt myeloma and help bones repair themselves. It identified a gene myeloma relies on to communicate with the microenvironment and tamp down the production of bone-repairing cells. There’s also a platform on the surface of myeloma cells where two complexes come together, releasing factors acting as handbrakes.

Yet the lab, in partnership with the University of Pittsburgh, found a molecule that might block the gene’s expression. So far, it’s shown promise in cell and animal models at slowing down myeloma’s growth and allowing bone-building cells to form.

If development reaches a clinical trial, Roodman thinks the resulting drug would be used in combination therapy for patients whose cancer sloughed off standard treatment. And it could be the first drug intended to treat bone disease.


Improving Immunotherapy

Travis Johnson, PhD
Agnes Beaudry Professorship in Myeloma Research

 The best way to imagine cell sequencing is to think of a TV.

When next-generation sequencing arrived almost a decade ago, it allowed researchers to see genetic changes in high definition. Now, the arrival of single-cell sequencing is something like 4K, allowing scientists to analyze the profiles of individual cells from an entire group.

Doing so allows researchers to isolate cells with markers of high-risk melanoma, but other insights are buried in an avalanche of data. And Travis Johnson, PhD, an assistant professor of bioinformatics, uses powerful tools like machine learning to find them.

Unlike some cancers, where one mutation drives the disease, myeloma relies on multiple changes playing out. “It’s multifaceted on a scale the human mind can’t comprehend,” Johnson said. “It’s a bad disease, and its complexity makes it a fascinating problem to work on.”

Using existing tools and algorithms, Johnson hunts for patterns in data from a small group of patients and compares it to other datasets available to researchers. That way, he sees if trends scale up. He can also add other variables–like risk profiles for certain patients—and see if others emerge.

Often, Johnson focuses on copying errors for genes linked with more aggressive forms of myeloma. He passes his findings along to Brian Walker, PhD, a professor of medical and molecular genetics, whose lab tries to validate them at the lab bench. For his part, Walker provides feedback that helps Johnson make tweaks.

Together, Johnson and Walker could discover genetic markers for high-risk myeloma or hint at a substantial likelihood of recurrence. Genomic testing would allow oncologists to identify and track patients most at risk. Patients can start treatment and halt myeloma’s return when they show the marker.

Charitable support is essential for researchers like Johnson, who are in the early stages of their careers. A generous estate gift from Jim Beaudry, PhD, lets Johnson carve out time to focus on myeloma projects and pay for a graduate student to assist with analysis. His data helps peers at IU and can pave the way for large grants from the NIH.

Improving Immunotherapy

Julia Reinke, PhD candidate
John and Cindi Young Myeloma Research Fund

While immunotherapy can wipe out myeloma, remission is frustratingly short. Often, cancer roars back within two years; by that point, a patient has exhausted their treatment options.

Sometimes, myeloma proves cunning enough at manipulating its environment to shut out immune cells—even those specifically designed to hunt it down.

Reinke, who works in Dr. Kelvin Lee’s laboratory, might be able to tell us why thanks to work supported by the generosity of the Young family.

T cells must rapidly divide and scale up their numbers to power their pursuit. Fueling that process requires those cells to degrade an enzyme called tryptophan in the bone marrow. Yet myeloma can cut off that supply and lock out cancer-killing cells.

It’s also a potential reason immunotherapy comes up short.

Reinke’s research tries to explain the cellular processes cancer uses to achieve that goal. Her findings might also lead to a target that could be used to design more-efficient CAR T cells. Getting there, however, starts with amassing exploratory data that can lead to more considerable grant funding.

Cindi Young waged a 14-year fight against myeloma but died before immunotherapy treatments were available to her. Her family chose to honor her memory by investing strategically in work that could help other patients–and families–prevail.

Enhancing Patient Care

Maci Cox and Ke Yang

Most days, Maci Cox’s job as a social worker supporting myeloma patients is about stacking small gestures: handing out a business card, arranging transportation, lining up lodging, or helping someone navigate an insurer’s website.

“It’s solution-based,” Cox said. “When a patient has a problem, my brain just starts going.”

It’s also a helping hand made possible by Miles for Myeloma funding directed to enhancing patient care through the IU Health Foundation.

Along with Ke Yang, a nurse practitioner, Cox ensures patients receive care that treats the whole person and enhances their quality of life. They work out of an office tucked away on the second floor of the IU Melvin and Bren Simon Comprehensive Cancer Center just steps away from infusion rooms.

They meet with myeloma patients who have completed induction therapy and are preparing for a bone marrow transplant. Yang addresses any medical questions they might have about the procedure, its side effects, and outcomes. Meanwhile, Cox helps guide patients in the weeks and months afterward.

That includes administering a psychological assessment. During that meeting, Cox also learns where a patient is working, the status of their family, and what support system they might have. It helps her ascertain what’s needed to ensure the patient stays on track with follow-up care.

Often, a patient’s needs are practical. If they need lodging in Indianapolis, Cox can connect them with community foundations that offer it. For transportation she might be able to obtain a gas card from a social service agency.

“It sounds really simple,” said Cox, who sees up to 15 people each week, “but it’s just hearing patients and making sure they feel supported.”

Cox’s aspiration to work with cancer patients started as an intern with a support group while she earned a master’s degree at the University of Southern Indiana. So far, the reality has been everything she wanted.

“Everyone is just so grateful to be here–the staff in the clinic, the doctors, and the nurses,” she said. “The gratitude patients show confirms my decision to do this.”


For information on how you can help support myeloma research at Indiana University Melvin and Bren Simon Comprehensive Cancer Center, please contact Meghan McFadden Forestal at


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