Advances put the familiar “incurable” label for multiple myeloma in question

I had a good view of Geraldine Ferraro as she joined her running mate at the podium in San Francisco’s Moscone Center in July 1984.  Ferraro made history that night, the first woman to appear on a major party ticket in a U.S. presidential election.  I was sent to cover the Democratic National Convention by a Twin Cities business magazine because Minnesota’s Walter F. Mondale was to be his party’s nominee.

In 1998, at age 63, Ferraro became the public face of multiple myeloma, an incurable but treatable blood cancer.  She had no symptoms but lab tests over time showed a gradual increase in antibodies made by her white blood cells. More tests confirmed the diagnosis.  She had entered a world in which a mortal threat can be pushed back for years but never permanently defeated.

Until her death in 2011 at age 75, Ferraro was a relentless champion of advances in treatment and research in the hope that the “incurable” label of multiple myeloma might one day slip away.  She would be encouraged by recent study results and headlines like “From no hope to a potential cure for a deadly blood cancer” and “Can we truly cure multiple myeloma? Experts say yes.”

The five-year relative survival for multiple myeloma patients today is 64 percent, nearly twice what it was when Ferraro was diagnosed in 1998.  Nearly 200,000 Americans are living with multiple myeloma, and some 36,000 Americans are projected to be diagnosed with the disease this year.

Professor Michael Linden, who heads LMP’s Division of Hematopathology, is as encouraged as Ferraro would have been by what is happening in hospitals, clinics, research centers, and innovative companies with respect to multiple myeloma and other diseases of plasma cells, key cells of the adaptive immune system.  That’s in part because of how CAR-T cell therapies are changing the treatment landscape after decades of standard chemotherapy and stem cell transplantation.

As defined by the National Cancer Institute, CAR-T cell therapy is “a type of treatment in which a patient's T cells (a type of immune system cell) are changed in the laboratory so they will attack cancer cells.”  The gene for a special receptor (a chimeric antigen receptor (CAR) that binds to a certain protein on the patient’s cancer cells) is added to the patient’s T cells in the laboratory. Large numbers of the engineered CAR-T cells are grown in the laboratory and then infused into the patient.  LMP professor Sophia Yohe and colleagues published “A primer on chimeric antigen receptor T-cell therapy: What does it mean for pathologists?” in 2021.

“Right now, the only multiple myeloma patients that qualify for CAR-T cell therapy are patients with relapsed, refractory disease,” Linden said in an interview, noting that most of these patients have received both standard chemotherapy and an autologous stem cell transplant.  “CAR-T is a last choice treatment.”

The standard approach for treating multiple myeloma patients, Linden said, is induction, consolidation, and maintenance. Induction is a four-drug regimen followed by an autologous stem cell transplant (consolidation) and then maintenance with either an oral medication or a monoclonal antibody, a biological drug that needs to be infused or injected.  Patients who relapse following maintenance therapy or are refractory to at least one prior line of treatment may be eligible for CAR-T cell therapy.

Linden said he is involved in a clinical trial in which investigators are using an immunomodulatory drug (iberdobmide) as maintenance after CAR-T cell therapy with ide-cel (ABECMA® - idecabtagene vicleucel) to prevent patients from relapsing.  The CAR-T targets a cell-surface receptor molecule called B-cell maturation antigen or BCMA, which is over-expressed in malignant plasma cells.  Another CAR-T cell therapy, called cilta-cel (CARVYKTI® - ciltacabtagene autoleucel), also targets BCMA but has been a more effective therapy, Linden said.  “The puzzle is, now that you’ve given a patient CAR-T, how do you prevent relapse?” 

Authors of a recent study reported that one third (32/97) of patients remain alive and progression-free for five years or more after a single cilta-cel infusion, with nearly half of that group showing no sign of minimal residual disease (MRD), a warning sign for eventual relapse. Does that constitute a cure?

Though CAR-T cell therapy for refractory myeloma is in the spotlight, the drug armamentarium for fighting the disease continues to expand.  Categories include antibody-drug conjugates (ADCs), “biological missiles” that combine the targeting ability of monoclonal antibodies with the cell-killing power of cytotoxic drugs, and bispecific antibodies that bind two targets together, in this case a killer T-cell with a malignant plasma cell.

“What’s going to start happening, now, is our ability to alter the standard approach to treating multiple myeloma,” Linden said. “My colleagues are introducing a new trial in which we’re going to try to get rid of the auto-transplant [autologous stem cell transplantation].  Instead of consolidating with an auto-transplant, you consolidate with a bispecific antibody.  Those are ‘off the shelf’ medications.  You don’t have to take blood cells out of the patient for the treatment as you do with auto-transplants and CAR-T cell therapy.”

That possibility reflects the growing sophistication of multiple myeloma therapy – using the precise interventions in the precise sequence at the optimal time.  In perhaps few other fields of oncology is such sophistication so readily apparent.  Genetic testing is used to aid decisions around the best treatment for patients.

“What’s supposed to happen if this works – and I think it will – it’s going to change care for myeloma patients because they may not need to be transferred to a tertiary care center for a stem cell transplant,” Linden said.  “Patients can get the bispecific drugs by a myeloma specialist who works in a community oncology practice.”

While stem cell transplantation is effective in removing the remaining myeloma cells after induction therapy and paving the way for reconstituting the marrow with the patient’s blood-forming stem cells, it has its downsides.  It can put the patient at risk for infection in the post-transplant setting, and long-term consequences of transplantation include secondary myeloid malignancies such as acute myeloid leukemia and myelodysplastic syndrome, Linden said. 

Linden is part of the Alliance for Clinical Trials in Oncology, one of six national clinical trials network groups launched in the 1970 with National Cancer Institute (NCI) funding.  “Alliance has different disease cadres including a leukemia group, a lymphoma group, and a multiple myeloma group,” Linden said.   He’s currently the chair of the Alliance Pathology and Laboratory Medicine Committee, which has responsibility for developing educational programs, providing quality control services, and serving as a scientific resource for other Alliance committees.

“I became the pathologist for the myeloma cadre in 2017,” he said.  “It took a while to get started, but now whenever the myeloma physicians in the group propose a new clinical trial, they turn to me to ask ‘what samples should we bank for future research?  And what correlative studies can we conduct based on patient samples?’”

“The world of therapy for multiple myeloma is changing quickly.”