Patients with non-secretory myeloma, a disease affecting a relatively small number of individuals, can face obstacles including difficulties in receiving a diagnosis, a scarcity of available clinical trials and a lack of connection with fellow patients.

About 98% of people with multiple myeloma have proteins in their blood that can be measured and followed over time, according to Dr. Sascha A. Tuchman, a hematologist and medical oncologist at the Lineberger Comprehensive Cancer Center at the University of North Carolina in Chapel Hill.

When doctors do blood tests for multiple myeloma, because the myeloma cells stay in the bone marrow, the tests can’t typically show the actual myeloma cells, Tuchman notes.

“However, in most cases, multiple myeloma conve­niently makes those immunoglobulin proteins that circulate in the blood,” he says. “We can measure those proteins and that enables us to track the disease. As levels go up or down, that typically tells us the myeloma in the person is growing or shrinking.”

However, that’s not the case for everyone with multiple myeloma, as 1% to 2% of patients with myeloma don’t secrete any proteins that can be measured in blood or urine.

“Non-secretory myeloma is not necessarily a separate disease,” explains Dr. Nisha Joseph, a hema­tologist and medical oncologist at the Winship Cancer Institute at Emory University in Atlanta, Georgia. “It presents differently in that when we are evaluating these patients either at diagnosis or relapse, we notice that they don’t secrete this abnormal paraprotein or monoclonal protein in either their blood or urine, which is an important part of our diagnostic workups.” (Paraprotein and monoclonal protein are other terms for immunoglobulin secreted by myeloma.)

According to Joseph, the definition of non-secretory myeloma is that the patient has a negative serum immunofixation (a test for specific proteins in the blood), negative urine immunofixation (a test for abnormal proteins in urine) and normal serum free light chain assay (a blood test for proteins made by plasma cells).

“These are three of the tests we use to detect the abnormal protein that myeloma cells secrete,” she says. “It is essentially a surrogate marker for how much myeloma there is in the body and, usually, the bone marrow.”

‘Something is Wrong.’

It’s been nearly 20 years since Vicki Jones was diagnosed with multiple myeloma, a cancer of the plasma cells. Much of her past two decades have revolved around monthly blood tests to monitor levels of a protein — in her case, immunoglobulin A lambda (IgA) — secreted into her blood by myeloma cells.

“For 17 years, IgA was a completely reliable marker,” Jones says. “We tested it every month and knew exactly whether chemo­therapy was working. I had a stem cell transplant in 2007 and was on many different chemotherapy types after that. I was never in a complete remission.”

Then, something changed. Jones, 71, of Spokane, Washington, says she was taking a three-drug combination to control the myeloma. She took Darzalex (dara­tumumab), a monoclonal antibody that blocks proteins fueling myeloma cell growth, as well as a corticosteroid drug called Revlimid (lenalidomide) and an immunosuppressant called dexamethasone.

Jones says her IgA levels had been consistent for several years. With her doctor’s blessing, she stopped her medication to get a COVID-19 vaccine. About a month later, her blood test showed her IgA levels had dropped. In fact, her numbers had improved so much that her doctor told her she could take a break from the drugs.

The next month’s regular blood test showed her IgA numbers had dropped again, this time to a level that was better than they ever had been, Jones says.

“That’s when I said, ‘That’s not the way things go for me,’” she says. “‘Miracles do happen, but I don’t think this is one. Something is wrong.’”

A bone marrow biopsy confirmed her instinct. “I had relapsed big time,” she says. “I had 80% myeloma cells in my bone marrow, which is huge. That number had always been about 15% at the most through the years.”

Her myeloma had become non-secretory myeloma, a rare condition in which myeloma cells don’t secrete or produce proteins. “I felt like I had been diagnosed all over again,” Jones adds. “On the outside, I was totally calm. But on the inside, I was scared to death.”

Understanding Non-Secretory Myeloma

Plasma cells located in the bone marrow under normal circumstances help a person’s immune system by making proteins called immunoglobulins (antibodies) that bind germs and viruses and kill them. But when plasma cells become cancerous, they grow too much, invade spaces they’re not supposed to be in and secrete abnormally high levels of one clone of antibody protein but at the expense of the normal diversity of antibodies made by the collective immune system. That’s multiple myeloma.

Myeloma can cause a shortage of different blood cell types and brittle bones that break easily. Myeloma can also cause problems with the kidneys, such as kidney failure, when the kidneys stop working entirely due to the toxic effects of the high clonal antibody load.

Typically, myeloma cells live in the bone marrow and don’t circulate in the blood, but myeloma secretes immunoglobulin proteins into blood, after which the proteins are cleared through the kidneys and excreted into urine. Hematologist oncologists rely on these proteins as markers of myeloma activity to determine if myeloma is stable, improving or worsening.

Non-secretors present a diagnostic challenge, according to Tuchman. He notes that hematologist oncologists may suspect myeloma if a person has low blood counts or high blood calcium levels. Doctors may also detect holes in the bones (bone lesions) when someone has an X-ray or other imaging test.

“Those findings often prompt bone marrow biopsy, which leads to a diag­nosis,” he says.

Jones estimates that she has had at least 20 bone marrow biopsies since being diagnosed with multiple myeloma — four of which have been since she became a non-secretor. “It’s been pretty much every four months,” she says, noting that she also has regular PET scans.

Doctors don’t treat patients with non-secretory myeloma any differ­ently than they treat those who have myeloma that secretes proteins.

“Everything is exactly the same,” says Dr. Shaji Kumar, a hematolo­gist and internist at Mayo Clinic in Rochester, Minnesota. “Other than the difference in biology in terms of the secretion of the protein itself, we don’t really think the disease behaves differently when comparing the non-secretory type versus the secretory type.”

Most patients with multiple myeloma receive a combination of chemotherapy or targeted therapy drugs, along with a steroid. Some patients also have a bone marrow or stem cell transplant. However, multiple myeloma isn’t curable. That’s why monitoring the disease and its response to treatment is so critical. Patients with myeloma often relapse after some time in remission.

“Once the disease comes back, we try to use different combinations of drugs and mix and match them to make sure we have drugs that patients haven’t seen before,” Kumar notes. “We also look at side effects they have had with previous therapy, the logistics of administration and whether somebody can come to the clinic once or twice a week to get infusions or (whether) they prefer oral therapies. All those considerations go into making that decision.”

Monitoring patients for relapse is systematic for most individuals with myeloma, as they have intermittent blood and urine tests — but that’s not possible for non-secretors.

“We cannot monitor their blood tests month after month,” Joseph says. “There (are) no set guidelines on frequency, but we rely on serial bone marrow biopsies and PET scans, MRIs or some kind of definitive imaging.

Limited Data and Bouts of Frustration

Some patients with myeloma participate in clinical trials of multiple myeloma drugs, giving them access to new therapies. But that’s not typically an option for those with non-secretory myeloma, as the condition is so uncommon.

“There’s just not a lot of data on this, because non-secretory myeloma is a relatively rare phenomenon,” Tuchman says. “Most studies exclude non-secretory myeloma.”

That’s because, according to Tuchman, the standard systems for assessments of response on clinical studies, such as published response criteria by groups such as the International Myeloma Working Group (IMWG), are based on tracking the immuno­globulin protein patterns. Patients start a new treatment, myeloma cells die and make less protein, blood and urine immunoglobulin levels hopefully drop, and that tells clinical researchers, physicians and patients that the treatment is working.

In people with non-secretory myeloma, “it’s impossible to measure response by the standard, protein-based systems, and use those patients’ experience to learn what you’re trying to learn from the study,” he says.

Tuchman notes that large multi-institutional registry studies include databases that can be analyzed to provide some insight into the experiences of individuals with non-secretory myeloma. There’s also much to be learned from the patients themselves.

The HealthTree Foundation, which works to help patients with blood cancers learn about their disease, has started a support community specifically for individuals with non-secretory myeloma. Jones, who serves as a coach for HealthTree and co-leader of its non-secretory myeloma group, has been involved with the group since it began.

“It lets us compare notes and talk to one another and see [whether] things are consistent,” she notes. “Once I found other [patients] who were also non-secretors, it was just so comforting.

“We’ve had doctors come and talk to our group, and we’ve been encouraging them to use us. We’re telling them, ‘Hey, we are something you’ve never seen before; we are a very large group of non-secretors. I think that should be pretty useful to researchers. Here's your study right here — just ask us.”

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