KRd vs VRd for initial therapy of newly diagnosed multiple myeloma

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Published: 1 Jun 2020
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Dr Shaji Kumar - Mayo Clinic, Rochester, USA

Dr Shaji Kumar speaks to ecancer about the results of the ENDURANCE trial that were presented at the ASCO 2020 Virtual Meeting.

The trial looks at carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) for initial therapy of newly diagnosed multiple myeloma (NDMM).

Dr Kumar reports that while KRd was found to be effective for initial therapy there was no advantage to using it over VRd, which remains the current standard of care for these patients.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

The ENDURANCE trial is a phase III trial that was designed to ask the question if carfilzomib lenalidomide dexamethasone combination is better than the current standard of care that is bortezomib lenalidomide and dexamethasone for newly diagnosed myeloma. The trial was designed just to ask that question in patients who either are not eligible to go to a stem cell transplant or were planning on deferring their stem cell transplant to the time of their first disease progression. We specifically looked at patients who did not have high risk features to complement an ongoing phase III trial that was specifically looking at high risk patients in the same setting. 

The study was designed to ask two different questions, it was a randomised trial. The first question to be addressed was the comparison between the two different induction therapies in terms of their progression free survival. The study also had a second co-primary endpoint that is to look at the impact of duration of lenalidomide maintenance given after induction therapy. So patients who completed the induction therapy were randomised a second time to receive lenalidomide maintenance, either for two years or until disease progression, continuously. The focus of the current presentation at ASCO which represents the first analysis or the analysis for the first endpoint which is the progression free survival following the two different induction therapies.

The trial included only patients with newly diagnosed multiple myeloma who had received no more than one cycle of therapy but did not have any proteasome inhibitors or immunomodulatory drugs as part of that one cycle. Also patients who did not have any high risk features like translocation 14;16 or 14;20 or deletion 17p or an LDH that was significantly elevated, more than two times the upper limit of normal, or patients with plasma cell leukaemia.

So essentially we are looking at a group of patients with standard or intermediate risk multiple myeloma. The study randomised patients to either getting bortezomib lenalidomide dexamethasone as twelve three-week cycles or carfilzomib lenalidomide dexamethasone as nine four-week cycles. The dose of lenalidomide was the same in both arms. In the three-week cycle in VRd it was given for 14 days out of 21 days, in the KRd it was given for 21 days out of 28 days. The bortezomib was given at 1.3mg/m2 twice weekly for two weeks on, one week off each cycle whereas carfilzomib was given at 36mg/m2 twice a week for three weeks on, one week off after the initial two doses of 20mg/m2. Dexamethasone was standard dose as well.

The second interim analysis when we met 75% of the anticipated progression events demonstrated that there was no difference in the progression free survival between carfilzomib lenalidomide dexamethasone and bortezomib lenalidomide dexamethasone, two important proteasome inhibitor IMiD triplets that we use for initial therapy of multiple myeloma. With both the regimens the median progression free survival was approximately 34 months from the time of induction therapy.

We did notice that there was a higher rate of deeper responses, like very good partial response, in the carfilzomib lenalidomide dexamethasone even though the overall response rate was identical for both the arms. However, this improved depth of response did not translate to an improvement in the progression free survival in this phase III trial which we think is likely related to the more severe toxicities that we observed in the carfilzomib lenalidomide dexamethasone arm. Overall, about 43% of the patients in the bortezomib arm and about 61% of patients in the carfilzomib arm completed the intended number of cycles of induction therapy. The majority of patients who went off study before completing the induction therapy did so because of adverse events or patient refusal to continue with the induction therapy.

When you look at the overall toxicity rates, while the overall rates of all toxicities seemed similar between the two arms when you look at grade 3-5 non-haematological toxicity this was significantly more in the carfilzomib arm. More importantly, when we look at the cardiac pulmonary and renal toxicity this appeared to be significantly more in the carfilzomib arm. In contrast, we saw significantly more peripheral neuropathy in the bortezomib lenalidomide dexamethasone arm.

At the time of the most recent follow-up, as of January 2020, the overall survival appears to be identical and the three year estimate of overall survival is approximately 85% in both arms in the clinical trial. The clinical trial is continuing to follow patients to look at the second co-primary endpoint which is the overall survival based on the two different maintenance strategies for these patients.

All patients have already been randomised who completed the induction therapy. Approximately 530 patients have been randomised to either indefinite lenalidomide or two years of lenalidomide maintenance. They will continue on therapy and will continue to be followed for overall survival events. We hope that we will have the results of that second randomisation in the next couple of years.

This phase III trial clearly shows that the combination of a proteasome inhibitor, an immunomodulatory drug and dexamethasone is effective for initial therapy. The results that we saw in the bortezomib lenalidomide dexamethasone arm is consistent with what has been observed in other phase III trials. The trial does not show an advantage of using carfilzomib lenalidomide dexamethasone in these patients for initial therapy so bortezomib lenalidomide dexamethasone still continues to be the standard of care for initial treatment of multiple myeloma who don’t have high risk features and in whom an autologous stem cell transplantation is not anticipated.