Revlimid Maintenance Extends Survival Without Disease Worsening in Myeloma Patients, Phase 3 Trial Shows

Long-term maintenance treatment with Revlimid (lenalidomide) significantly improves the length of time multiple myeloma patients live without disease worsening after their first-line therapy and, in some patients, also extends overall survival, a Phase 3 trial shows.

Findings from the trial were published in the study, “Lenalidomide maintenance versus observation for patients with newly diagnosed multiple myeloma (Myeloma XI): a multicentre, open-label, randomised, phase 3 trial,”  in The Lancet Oncology.

Celgene‘s Revlimid is an immunomodulatory medicine that directly kills myeloma cells and activates the immune system to help eliminate these cancer cells. Revlimid maintenance has been shown to delay disease progression, when given after an autologous stem cell transplant — one that uses a patient’s own cells — but some studies suggest it poses no survival benefit to patients.

For patients who are not eligible for a stem cell transplant, the treatment also seems to be of benefit, when given continuously in combination with dexamethasone. However, studies have not yet examined if Revlimid maintenance has any effect on patients with high-risk genetic abnormalities, mostly because no study yet has included a sufficient number of patients for this analysis.

Thus, researchers aimed to assess the benefit of Revlimid maintenance treatment in patients with newly diagnosed multiple myeloma who achieved at least a minimal response to their first line-treatment.

The Phase 3 trial — called Myeloma XI (NCT01554852) — included 4,420 patients allocated to intensive or non-intensive induction treatment, depending on their fitness: fit patients, who were mostly younger, received chemotherapy plus an autologous stem cell transplant, while less fit, mostly older patients were given a non-intensive chemotherapy treatment.

Patients who responded were then randomized to either Revlimid maintenance (1,137 patients) or observation only (834 patients).

The primary goal of the maintenance part was to determine if Revlimid delayed disease progression or death and extended overall survival. Secondary measures included the time to disease progression or death after a third myeloma treatment, time to improved response, and toxicity.

The study included patients between the ages of 59 and 72 years, most of whom were men (61%) and white (93%). Patients had between stage I and III disease, and their genetic risk ranged from standard (51% of patients) to ultra-high (12%).

Results showed that patients receiving Revlimid lived 39 months without their disease worsening, compared with 20 months for the observation arm. This translated into a 54% reduction in the risk of disease progression or death.

The benefits in progression-free survival were seen across all subgroups, including transplant-eligible and transplant-ineligible patients, and in all risk subgroups — standard risk, high-risk, and ultra-high risk. Interestingly, while patients with complete or very good partial responses also benefited from the maintenance treatment, those with a partial or minimal response to their induction treatment appeared to benefit the most.

Revlimid did not improve the survival rates in the overall population, with 78.6% of patients living past the three-year mark, compared with 75.8% of those in the observation group. However, patients who received a stem cell transplant lived significantly longer on Revlimid than with observation only, with 87.%, versus 80.2%, of patients still alive at three years.

This survival benefit was not observed in transplant-ineligible patients, nor in any risk group, but was also seen in younger patients — an effect that researchers attribute to their eligibility for a stem cell transplant.

“This is a major breakthrough as it shows that the long-term use of lenalidomide significantly improves the time myeloma patients stay in remission after initial therapy,” Graham Jackson, MD, from the Northern Institute for Cancer Research at Newcastle University, said in a press release.

“It is a huge step and, importantly, identifies that for younger patients lenalidomide improves their overall survival for this difficult-to-treat bone marrow cancer,” added Jackson, a consultant hematologist at Newcastle’s Freeman Hospital who led the U.K.-wide study.

Despite its efficacy, more patients in the Revlimid group experienced severe adverse events (45%) than those on observation (17%). The most common serious or life-threatening adverse events among those receiving the active treatment were blood-related and included low levels of immune cells called neutrophils, low platelet counts, and anemia.

In an editorial comment in the same journal, María-Victoria Mateos MD, PhD, and Verónica González de la Calle, MD, PhD, from the University Hospital of Salamanca, attribute the lack of a survival benefit to subsequent treatments taken by the patients — some patients in the observation group received Revlimid in later treatment approaches.

“Lenalidomide maintenance seems to be effective, well tolerated, and convenient, despite the lack of overall survival benefit, because of the influence of rescue therapies in the overall survival,” they wrote.

“Maintenance with lenalidomide is the standard of care, but the future has to move towards a personalised medicine approach that aims to improve overall survival and quality of life, which means giving the right drug to the right patient at the right time for the optimal duration,” Mateo and de la Calle concluded.