The Case for Waiting

ON A SUNDAY MORNING in February 2020, 56-year-old Jim Pass was lying on the floor in his home in the northern Chicago suburb of Winnetka when he found himself unable to move.

Pass, now 62, doesn’t remember much after an ambulance rushed him to the hospital. He woke up the next day at Kellogg Cancer Center in Evanston, Illinois, and learned he had multiple myeloma, a type of blood cancer that had caused a tumor to develop in his spine and temporarily paralyze him. After receiving immediate radiation therapy to shrink the tumor on his spine, Pass had to make a choice. One option was to receive an autologous stem cell transplant (ASCT). He would start induction treatment with a three-drug regimen. After having his stem cells collected and frozen, he would go into the hospital to receive high-dose chemotherapy followed by an infusion of his stored stem cells.

His other option was to enroll in a clinical trial testing the effectiveness of four drugs that are often used as part of induction therapy before ASCT. If the drug combination put the cancer into remission, he could delay the stem cell transplant for as long as the myeloma remained at bay.

Pass was 56, which was a decade younger than when most people who have multiple myeloma are typically diagnosed with the disease. His cancer did not have any chromosomal abnormalities that suggested it was aggressive. Given the timing of his diagnosis with the start of the COVID-19 pandemic, Pass, who was a financial portfolio manager, was also concerned about the hospital stay that would be needed if he received a stem cell transplant.

“If I did the clinical trial, I could keep working, and I’d still have the option of a stem cell transplant if I needed it later,” Pass says.

Stem cell transplant remains a cornerstone of multiple myeloma treatment for those who are eligible for the procedure. However, the drugs used in induction therapy prior to transplant are often effective at eliminating the disease—a status known as minimal residual disease (MRD) negativity. Thus, many researchers are questioning whether it’s safe to delay a stem cell transplant—an option that some patients are also considering.

When it comes to treatment for multiple myeloma, “one size does not fit all,” says Saad Usmani, a myeloma specialist at Memorial Sloan Kettering Cancer Center in New York City.

Standard Treatment With ASCT

Up to 50% of people with multiple myeloma will receive ASCT as part of their treatment. To prepare for ASCT, patients begin treatment with induction therapy with three to four drugs over four to six months. The aim of the induction treatment is to reduce the extent of the disease as much as possible. Then, doctors collect stem cells from the patient’s blood or bone marrow to be frozen for later use.

To prepare the body to receive these cells, the patient typically goes into the hospital to receive high-dose chemotherapy with melphalan, in a process called conditioning. This chemotherapy wipes out multiple myeloma cells as well as healthy cells from the bone marrow. The treatment eliminates the immune system and makes the person vulnerable to infections and illness. Next, the stored stem cells are infused back into the person’s body. The stored cells then make their way through the blood stream into the bone marrow. In this process, the hope is the stem cells will begin to make new healthy blood cells free of myeloma.

ASCT is intense, and full recovery can take a few months. “Most patients are 80% to 90% back to normal within three months,” says hematologist-oncologist Sagar Lonial, chief medical officer of Winship Cancer Institute of Emory University in Atlanta.

ASCTs have led to long-lasting remissions, says Lonial, who was a researcher for a clinical trial called DETERMINATION. This study, published in 2022 in the New England Journal of Medicine, compared a standard triplet therapy alone to triplet therapy plus ASCT. Researchers found that patients who had stem cell transplants had remissions that lasted an average of 67.5 months. Those who received the triplet therapy alone had remissions lasting 46.2 months. But patients in both groups lived about the same time: between six and seven years after treatment.

But even with more time in remission, stem cell transplants can come with trade-offs, especially with the conditioning agent used right before the transplant.

“High-dose melphalan is derived from phenylalanine mustard, which in its original form was soluble mustard gas,” says Paul Richardson, a hematologist-oncologist at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston, who was the principal investigator on the DETERMINATION trial. “Not that melphalan chemotherapy itself is excessively toxic, and it clearly has value. But it can be challenging both in terms of acute and long-term toxicity.”

The conditioning agent that wipes out the immune system right before the stem cell transplant impedes the body’s ability to make blood cells, which means patients need to be closely monitored in the hospital. The treatment also carries long-term risks, including secondary cancers like leukemia. Undergoing this treatment sooner rather than later may amplify that risk, Richardson says. “The strategic view is that if you’re using a treatment as toxic as this, only use it when you have to,” he says.

But there’s also a case to be made for throwing everything available at multiple myeloma right up front, says Lonial. “We know that the disease is never more sensitive to treatment than it is at the time of initial diagnosis,” he says. “Every time you treat it, it’s developed new mutations, and it’s more resistant than it was before. Our approach has been to do whatever we can to maximize the first remission.”

Treatment with melphalan may increase the mutational load to an even greater degree than initial treatment with induction therapy alone. “The data show,” Richardson says, “that when you have myeloma, you have about 7,500 mutations on diagnosis. When you relapse after melphalan, it goes up to about 14,000. It doubles. If you relapse after triplet induction therapy, it goes up by about 1,500.”

A stem cell transplant as that first approach might lead to more lasting remission, but it could also make it harder to treat multiple myeloma later. The choice to delay stem cell transplant is not black and white, but it’s a question that researchers are exploring and patients may want to consider.

Quadruplet Therapy Alone

In addition, the three-drug regimen has expanded, including a fourth drug that inhibits CD36 proteins on multiple myeloma cells, which is driving even deeper responses. Thus, more people may be faced with the choice to go at the disease with everything available all at once or to approach it with one treatment option at a time.

Recent studies that have incorporated the newer four-drug regimens suggest deep molecular responses to treatment using sensitive tests that detect MRD. For example, the MIDAS trial, published June 3, 2025, in the New England Journal of Medicine, enrolled more than 800 people with newly diagnosed multiple myeloma. All of them received six cycles of quadruplet induction therapy with Kyprolis (carfilzomib), Sarclisa (isatuximab), Revlimid (lenalidomide) and dexamethasone—a regimen called Isa-KRd. After the initial six cycles, they underwent MRD testing.

Those who tested MRD negative at 10^-5—a sensitivity that indicates the absence of a single multiple myeloma cell per 100,000 normal cells—were randomized to receive either ASCT plus two more rounds of Isa-KRd or six more rounds of Isa-KRd without ASCT.

After the respective treatments were complete, researchers assessed MRD in patients again, says Philippe Moreau, one of the trial investigators and a hematologist who specializes in multiple myeloma at the University Hospital of Nantes in France. MRD negativity rates at 10^-6—that’s sensitive enough to detect one cancer cell per 1 million normal cells—were nearly the same in those who received ASCT and those who didn’t.

Based on these results, Moreau says, “for MRD-negative patients, we believe that we don’t need, at any cost, to perform an autologous stem cell transplantation, which is potentially associated with significant toxicity.”

Moreau adds, “This is not the final word. We need longer follow-up. We are following the patients in both arms of the study to make sure that the results will continue to be identical over a longer period of time.”

As part of his treatment in a different clinical trial, Pass received a four-drug regimen called Dara-KRd: Darzalex (daratumumab), Kyprolis, Revlimid and low-dose dexamethasone. Like so many in the MIDAS trial, Pass also achieved negative MRD status at 10^-6. He’s been in remission since August 2022.

It’s too soon to tell how long he and other clinical trial participants who put off a stem cell transplant will be able to delay it.

Pass has quarterly blood draws and annual scans and bone marrow tests to check that his cancer is still in remission. Should he ever need an ASCT, his stem cells were banked after he began induction therapy with Dara-KRd.

The Evolution of Treatment

ASCT is still a mainstay of multiple myeloma treatment. But many people, including those with high-risk myeloma, are not candidates to delay stem cell transplant.

“There are certain genetic abnormalities in myeloma cells that tell us there’s a higher chance of it coming back,” Usmani says. “Certain presentations are also more aggressive, like myeloma showing up in organs outside the bones.” When this happens, it most commonly arises in the lymph nodes, spleen, liver or kidneys.

But even for those with high-risk disease, the treatment recommendation may not be cut-and-dried. “We’ve realized that ‘high risk’ is a relative thing,” Richardson says. “There are some patients who have t(4;14) translocation, a high-risk genetic abnormality, who clearly benefit from early transplant, and there are others who do not.”

Age also guides who might be eligible for ASCT. “There is no age limit or cut off for stem cell transplant, but our preference is mostly for patients who are up to the age of 70,” Usmani says. After that, a person may be too frail for the intense treatment.

“The potential challenge comes if I’m having that discussion with someone who is 68 or 69, and they’re asking if they can just push it off,” Usmani says. “By the time it comes back, you’re in your mid-70s. The discussion becomes very individualized.”

In the same way that Pass decided to delay ASCT so he could keep working and avoid hospitalization during a global pandemic, individual preference, especially in those whose cancer doesn’t have any high-risk abnormalities, can come into play.

Now three years into remission, Pass accepts the scans and blood work as a part of life. He admits he sometimes gets anxious before these tests, but day to day, he says, “I lead my life how I did prior to getting sick. I play golf quite a bit. I’m athletic. My kids keep me busy, and I’m obviously healthier.”

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