Data: Revlimid Triple Combo Is Better as Myeloma Maintenance Therapy

Analysis shows combination therapy more effective than Revlimid alone

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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In people with newly diagnosed multiple myeloma following a stem cell transplant, a triple-combination maintenance therapy — of Revlimid (lenalidomide), Kyprolis (carfilzomib) and dexamethasone — significantly extended the time to disease progression or death, by 49%, compared with Revlimid alone.

That’s according to an interim analysis of data from the ongoing ATLAS Phase 3 trial (NCT02659293), which is testing the combination therapy in 180 patients. The analysis also found that the triple combo — commonly known as KRd — resulted in higher rates of minimal residual disease (MRD)-negativity, or the absence of small traces of cancer cells in circulation after treatment.

While the combination was associated with higher rates of side effects than Revlimid alone, it was still within acceptable safety and tolerability limits.

“To our knowledge, this study is the first randomised phase 3 trial suggesting superiority of an alternative maintenance therapy to [Revlimid] alone,” researchers wrote. “The treatment regimen and outcomes require further confirmation with a longer follow-up of this ongoing trial.”

The study, “Carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone as maintenance therapy after autologous stem-cell transplantation in patients with multiple myeloma (ATLAS): interim analysis of a randomised, open-label, phase 3 trial,” was published in The Lancet Oncology. It was funded by Amgen, which markets Kyprolis, and Celgene, which developed Revlimid.

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An autologous hematopoietic stem cell transplant is a treatment option for multiple myeloma patients that uses the person’s own stem cells. After a round of chemotherapy to kill off cancer cells, the individual’s own cells are used to re-populate the blood with healthy cells.

Such transplants are typically followed by a course of maintenance therapy, usually with Revlimid, to help prevent myeloma progression. This treatment course has been shown to significantly prolong progression-free survival, or the time to disease progression or death.

Data in recent years have suggested that using Revlimid alongside other maintenance therapies, after a stem cell transplant, may offer increased clinical benefit for patients. However, clinical trials have yielded mixed results, or are still ongoing.

“With these trials still in progress, there is a scarcity of definitive findings from Phase 3 trials to show that any alternative maintenance therapy is superior to [Revlimid] alone,” the researchers wrote.

Now, a team from Poland reported interim results from the ongoing ATLAS trial, which is testing a combination of Revlimid plus Kyprolis and dexamethasone in newly-diagnosed patients who received a stem cell transplant.

In a previous Phase 2 trial (NCT01816971), 14 treatment cycles of this combination, given after a stem cell transplant, led to a median progression free survival of more than five years since diagnosis. That “suggests that this regimen has potential to surpass the current standard of care,” the researchers wrote.

The ATLAS trial, being conducted at 12 sites in the U.S. and Poland, involves adults with newly diagnosed myeloma who completed up to two induction regimens followed by a single stem cell transplant.

Participants were randomly assigned to receive KRd or Revlimid alone for up to 36 treatment cycles of 28 days each. Treatment was initiated 80–130 days after transplant.

The study employed a risk-adapted design to reduce the risk of toxic side effects and lower treatment costs. If participants in the KRd arm achieved MRD-negativity after cycle six and were considered to be at low risk of disease progression, they completed only eight cycles of KRd and were then switched to Revlimid-only to minimize the risk of toxicity.

Those who failed to fulfill those parameters received the full 36 cycles of KRd, and all participants were then switched to Revlimid alone until they experienced disease progression, unacceptable side effects, or withdrew from the study.

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The study’s primary goal is to assess progression-free survival rates. Secondary measures include the proportion of patients achieving MRD-negativity, duration of MRD negativity and its correlation with progression-free survival, overall survival, and death.

As of the data cut-off, on Dec. 31, 2021, patients had been followed in the trial for a median of 33.8 months, or nearly three years.

Of the included participants, 47% were female. The median age was 59. Among the 93 patients assigned to receive KRd, 41 received only eight cycles of the triple-combo and the switched to Revlimid. The remaining were given the 36 cycles before switching.

Interim data showed that the combination maintenance therapy significantly delayed the time to disease progression or death compared with Revlimid alone. Specifically, the median progression-free survival was 59.1 months in the triple combo group, compared with 41.4 months in the Revlimid group, reflecting a 49% reduction in the risk of disease progression or death.

This reduction in the risk of disease progression or death also was observed in the group of patients who met the criteria to switch from KRd to Revlimid after eight cycles compared with those who started on Revlimid alone from the start.

Overall survival was not significantly different between the two groups, but data showed that more patients in the KRd arm achieved MRD negativity after six cycles (53%) compared with the Revlimid arm (31%).

Patients in the KRd arm experienced a slightly higher rate of mild to moderate side effects, including cardiac and vascular events, but similar rates of serious or life-threatening adverse events.

A treatment-related adverse event in the KRd group — respiratory failure due to severe pneumonia — led to death for one patient. Still, side effects leading to treatment discontinuation were more frequent in the Revlimid group (12% vs. 4%).

Results overall suggest that KRd combination therapy “might offer a progression-free survival benefit compared with [Revlimid] alone,” the researchers wrote, noting that their risk-adapted design could “prevent overtreatment.”

Still, “these findings need to be [interpreted] with caution while awaiting the final analysis planned at 4 years of follow-up from the time of enrolment of the last patient,” they noted.