High-dose chemotherapy followed by autologous stem cell transplantation can prolong survival for patients with multiple myeloma. However, patients remain at a high risk of relapse even after transplantation. Maintenance therapy can extend remission in these patients, and clinical trials at The University of Texas MD Anderson Cancer Center are exploring new maintenance regimens to further improve patients’ outcomes.
Myeloma patients and their physicians must weigh the possible benefit of prolonged remission against the risk of adverse effects from maintenance therapy. “The challenge,” said Jatin Shah, M.D., an associate professor in the Department of Lymphoma and Myeloma, “is finding therapies that are effective at maintaining remission and at the same time are easy for patients to take over a period of years, with a simple regimen and few and mild side effects. The goal is to help patients continue therapy with minimal disruption of their everyday lives.”
Low-dose lenalidomide is the most common maintenance regimen for myeloma patients. Two recent clinical trials showed that low-dose (10 mg) daily oral lenalidomide prolonged remission by 18–24 months after stem cell transplantation compared with watchful waiting. Early data from one of the studies suggested that this therapy also prolongs survival.
To minimize adverse effects and increase the tolerability of maintenance therapy, lenalidomide has usually been given alone. Nevertheless, minor effects such as diarrhea, rash, and fatigue do occur. By far the greatest concern is a second primary cancer, which occurs in 8%–9% of myeloma patients who receive lenalidomide maintenance therapy but in only 3%–4% of those who do not receive it. “While this doubling of risk still means second cancers occur in only a minority of patients,” Dr. Shah said, “it is an important risk that patients have to be aware of.”
Bortezomib and ixazomib
Although low-dose lenalidomide maintenance therapy has been shown to be effective and well tolerated, researchers are looking for ways to further prolong remission and survival after transplantation while minimizing the risk of a second cancer. The combination of lenalidomide with the proteasome inhibitor bortezomib was shown to be effective in patients with newly diagnosed and relapsed myeloma. However, bortezomib can be given only as an injection or infusion, so patients would have to visit the clinic every week or two for an indefinite period if they were to receive the drug as maintenance therapy.
In an effort to improve patient convenience and quality of life, researchers at MD Anderson are currently testing the second-generation proteasome inhibitor ixazomib (also called MLN9708)—which is given orally—in combination with lenalidomide for myeloma maintenance therapy in a clinical trial. “We think that this will be an effective strategy in prolonging remission,” said Dr. Shah, the trial’s principal investigator. “But we don’t know how much improvement we’ll see or what the side effects will be. That’s the reason for the trial.”
Because the focus is on long-term outcomes such as relapse and survival, the investigators are still waiting for results. “What we can say right now,” Dr. Shah said, “is that we have not seen any unusual or unexpected toxic effects in the patients who have begun the therapy. We’re reassured by how well the therapy is tolerated by most patients.”
Dr. Shah said that the all-oral regimen allows patients to work full time, travel, and take part in the activities they enjoy. “They come to the cancer center once a month, they get their pills, and they continue to maintain a good quality of life,” Dr. Shah said. “We’ve seen no limitations for the majority of these patients. It’s very encouraging to see that patients are able to do everything they want to do despite the therapy—and we hope that we’re providing not only increased time in remission but also better quality time.”
Maintenance therapy research continues
Dr. Shah hopes that eventually there will be a marker to identify which patients need maintenance therapy and which do not. “The question is not how to identify patients who will respond to maintenance therapy, since most do, but rather how to identify patients who will do well without the therapy and thus can be spared the potential side effects,” he said. “One of the things we’re looking at is minimal residual disease. Patients who could be shown by special tests to have no minimal residual disease at a deep molecular level, signifying deep remission, might not need maintenance therapy. I think incorporating such a test is the next major step.”
Another question that is yet to be answered is the optimal duration of maintenance therapy. Although some oncologists think that shortening the duration of maintenance therapy would reduce the incidence of second primary neoplasms, Dr. Shah and his colleagues at MD Anderson believe more data are needed. While the use of limited-duration maintenance therapy in some centers may one day provide such data, Dr. Shah said, “Right now, we think that indefinite therapy—continuing the therapy for as long as the patient is still benefiting from and tolerating therapy—is the best way to go.”
Looking toward the future, Dr. Shah and his colleagues at MD Anderson have plans for additional trials to refine myeloma maintenance therapy further. “We expect to use the data from the current ixazomib trial to support a potential phase III trial in which we’ll compare lenalidomide alone with a lenalidomide-ixazomib combination.”
And other trials are in the works at MD Anderson. One planned trial, which will begin later this year, will look at the new monoclonal antibody elotuzumab. Elotuzumab targets a protein called SLAM family member 7, which is expressed on the surface of all myeloma cells in the majority of patients. “Elotuzumab goes after only the myeloma cells,” Dr. Shah said. “In a phase II trial, elotuzumab with lenalidomide delayed relapse by 24–33 months, much longer than the 11 months seen in patients treated with lenalidomide in previous trials who were used as historical controls. This potential doubling or tripling of remission time in a phase II trial is significant.”
Elotuzumab is currently an intravenous formulation, requiring patients to come to the center for treatment weekly at first and then over time transition to monthly treatment. However, Dr. Shah said, “The upside is that elotuzumab is not like standard chemotherapy, so we expect minimal additional side effects besides those from the lenalidomide—a nice benefit. And, considering the earlier results showing a doubling or tripling of survival, we are optimistic about the potential for prolonged remissions we’ll see with the combination in the maintenance setting.”
At this time, no other centers in the United States are offering maintenance regimens with ixazomib or elotuzumab, to Dr. Shah’s knowledge. Dr. Shah said, “We’re very excited that we are able to offer our myeloma patients unique, innovative trials of therapies that may give them a longer, healthier life.”
For more information, contact Dr. Jatin Shah at 713-745-6130, firstname.lastname@example.org, or email@example.com. To learn more about the ongoing clinical trial of ixazomib for myeloma maintenance therapy, visit www.clinicaltrials.org and select study No. 2012-0277.
OncoLog, March 2015, Volume 60, Issue 3