Continuous-duration maintenance therapy offers no overall survival gain in patients with newly diagnosed multiple myeloma

Abstract

Continuous-duration maintenance therapy until disease progression is the current standard-of-care treatment after the completion of induction therapy for patients newly diagnosed with multiple myeloma, but results from a new phase 3 clinical trial are likely to change that approach.

In the National Cancer Institute (NCI)–sponsored ENDURANCE study, researchers compared continuous-duration maintenance therapy to fixed-duration maintenance therapy after induction therapy in patients with newly diagnosed standard-risk myeloma who did not undergo up-front autologous stem cell transplantation. Findings show that continuous-duration therapy did not lead to significantly longer overall survival than fixed-duration maintenance therapy stopped after 2 years.

“This is really a practice-changing study because, although it’s not the first study to look at fixed-duration therapy, it’s the first trial to show the impact on overall survival,” says Amrita Krishnan, MD, director of the Judy and Bernard Briskin Center for Multiple Myeloma Research at City of Hope in Irvine, California, and Nason–Hollingsworth Endowed Chair for Multiple Myeloma at City of Hope in Duarte, California. “It’s pushed us in the field to rethink how we treat patients with maintenance therapy. However, the results must be interpreted with caution as overall survival also depends on access to therapies at the time of relapse.”

The randomized, open-label, phase 3 clinical trial began recruitment in 2013 and was completed in 2019; the median follow-up was 7 years. After induction, 516 adult patients with newly diagnosed multiple myeloma were randomized to a continuous (indefinite)-duration group (n = 260) or a fixed-duration group (n = 256). Participants either were considered ineligible for or were not planning on receiving an up-front autologous stem cell transplant.

Patients with newly diagnosed multiple myeloma who had completed induction therapy and were considered to be at standard risk based on cytogenic testing were randomized 1:1 either to receive continuous therapy with the immunomodulatory drug lenalidomide until progression or to stop treatment after 2 years. The trial did not include patients with high-risk disease.

At a median follow-up of 86 months, overall survival was not significantly different between the two groups.

Eighty patients died in each arm; the overall survival rate at 7 years was 68.6% in the continuous-duration group and 69.0% in the fixed-duration group (difference, −0.4 percentage points; 95% confidence interval [CI], –9.0 to 8.3 percentage points; p = .93). The progression free-survival rate at 7 years was 36.1% in the continuous-duration group and 29.7% in the fixed-duration group (difference, 6.4 percentage points; 95% CI, –2.6 to 15.4 percentage points).

The 5-year cumulative incidence of second primary cancers (excluding nonmelanoma skin cancer) was higher with continuous-duration therapy than with fixed-duration therapy (11.2% vs. 8.3%). The rate of grade 3 or higher nonhematologic adverse events was also greater in the continuous-duration group (48.2% vs. 31.5%).

Over the past 20 years, the treatment of patients with newly diagnosed multiple myeloma has improved survival rates and, in some cases, led to potential cures. At the same time, treatment has evolved from a defined treatment duration to continuous therapy. However, the appropriate duration has not been determined, and data on fixed-duration therapy have been limited.

As a result, researchers designed the ENDURANCE trial to discover if continuous maintenance therapy improves outcomes in comparison with fixed-duration maintenance therapy.

Paul Gater, a multiple myeloma survivor and patient advocate with the SWOG Cancer Research Network, praises researchers for delving into the subject.

“It’s a big question for myeloma patients—how much maintenance do I need and for how long?” he says. “We talk to patients with other cancers, and they are not in treatment all the time.”

To Gater, who was diagnosed with multiple myeloma in 2014 and is currently off treatment after many years of therapy, the findings are highly encouraging for newly diagnosed standard-risk patients.

“If I were in this group, I’d be on the phone to my doctor’s office tomorrow asking, ‘How am I doing? Can I stop treatment?’” he says. “Their physician may have reasons for keeping them on treatment, but at least this provides solid data in a prospective, phase 3 study that they should bear in mind.”

Quality-of-life improvements with fixed-duration therapy are especially important for patients, he adds, noting, “Stopping maintenance means you can get on with your life a little more rather than having to worry about when these side effects of treatment might pop up. And these drugs are not cheap, depending on your insurance, so not having that cost burden is also a good thing in terms of overall quality of life and stress levels.”

Commenting on the study’s implications, Dr Krishnan says, “Many of us are already doing this with standard-risk patients who have had deep responses. If they have had more than 2 years of lenalidomide, we’re considering the option of discontinuing it.”

Patients will have different reactions to the findings, Dr Krishnan says, noting that some will be eager to stop treatment, whereas others will be nervous about their recurrence risk if they do so.

Both Gater and Dr Krishnan emphasize that the treatment landscape for multiple myeloma has changed since the trial was launched 12 years ago. Modern induction therapy is now a four-drug regimen that, in addition to lenalidomide, includes the anti-CD38 monoclonal antibody daratumumab, the protease inhibitor bortezomib, and the corticosteroid dexamethasone.

Future studies should evaluate both the four-drug therapy regimen and stem cell transplants in the context of fixed-duration maintenance therapy, Dr Krishnan says. She points to a large 1400-patient study called the DRAMMATIC trial as an example. She is the national chair of the study, which is evaluating maintenance therapy after stem cell transplantation in both patients with standard-risk multiple myeloma and patients with high-risk multiple myeloma.

Having completed accrual in January 2025, the DRAMMATIC trial is expected to provide more insights by randomizing patients who are minimal residual disease negative at 2 years to receive either continuous- or fixed-duration maintenance therapy.

“The field of myeloma is changing quickly, and fixed-duration therapy will continue to be the future because we have more and more effective induction therapies,” Dr Krishnan says.