KRd vs KTd followed by carfilzomib maintenance in newly diagnosed MM

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Published: 12 Dec 2019
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Prof Heinz Ludwig - Wilhelmeninen Cancer Research Institute, Vienna, Austria

Professor Ludwig talks to ecancer at ASH 2019 about an interim efficacy analysis of carfilzomib-revlimid-dexamethasone vs. carfilzomib-thalidomide-dexamethasone weekly (after two twice weekly cycles) followed by carfilzomib maintenance versus control in transplant non-eligible patients with newly diagnosed multiple myeloma (NDMM).

Recent data from the ARROW and CHAMPION-1 studies had shown significant activity of once weekly carfilzomib administration. Furthermore, the recent MUK5 and CARF studies show significantly increased PFS with carfilzomib maintenance therapy. The team compared 9 cycles of weekly carfilzomib-revlimid-dexamethasone (KRd) with weekly carfilzomib-thalidomide-dexamethasone (KTd), after 2 cycles of biweekly therapy, followed by a second randomisation to 12 cycles of carfilzomib maintenance or observation only in elderly NDMM.

It was found that once weekly carfilzomib 56mg/m² in combination with either lenalidomide or thalidomide resulted in high response rate and deep responses including MRD negative status in 47.1% of tested elderly patients with NDMM.

Treatment was associated with an acceptable tolerance profile. In a safety evaluation with 66 patients, the most frequent grade 3/4 hematologic adverse events were anemia (4.5%), leukopenia (1.5%), and thrombocytopenia (6.0%). The non-hematologic grade 3/4 AEs were infections (21.2%), cardiac failure, gastrointestinal disorders, and renal impairment (6.0% each), neurologic disorders, hypertension, and rash (3.0% each), and hepatic failure, SPM, VTE, and psychiatric disorders (1.5% each).

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.

KRd vs KTd followed by carfilzomib maintenance in newly diagnosed MM

Prof Heinz Ludwig - Wilhelmeninen Cancer Research Institute, Vienna, Austria

We present an oral presentation, give an oral presentation, on a study. It’s a randomised phase II study comparing KRd with KTd, Carfilzomib is given weekly in elderly transplant ineligible patients for induction therapy and then patients are randomised to carfilzomib maintenance for one year or observation. This is an interim analysis and presentation of interim data.

What we see at this point of time, we see a high overall response rate of 95%. The median age of the patients is 75 years so we have a high overall response rate in the elderly patient population. We have a CR rate of 30%, a very good partial response rate of 47%, so better than VGPR is 78%. We did MRD assessment in patients who were deemed to be in CR and we have 30 available tests. So the MRD positivity rate in these patients was 43% but in relation to the entire per protocol population the MRD negativity rate is 22%.

So what about progression free survival? Progression free survival at two years is 68% and overall survival at two years is 85%. There is no difference in patients with high risk cytogenetics or standard risk so we looked at patients with translocation (4;14) and/or deletion 17p. We looked at patients with amplification of 1q21 and looked at patients who have neither one of these aberrations. There is no difference in terms of progression free survival and overall survival. So the regimen is very effective in high risk patients as well.

What came to our surprise, there was no difference in PFS and OS in the elderly, meaning 75 years and older, or younger, meaning less than 75 years. So there is no difference. We looked also at immunophenotyping and immunoprofiling and this was done by Bruno Paiva. We can only show preliminary results but what we can show is a very nice correlation between NK subsets, cytolytic NK cells. When you have plenty of these NK cells you have a high probability of achieving a very deep response. So there’s a correlation, of course, between certain cell types at baseline and outcome.

We looked also at quality of life which is significantly improved during the induction therapy. Global health related quality of life, physical functioning is improved, pain is improved and fatigue is improved during the nine induction cycles. Patients were then randomised to carfilzomib maintenance or control and both groups at this point of time are analysed together. Maintenance, patients in this period enjoy a very good quality of life in all assessed parameters.

So overall it is an effective treatment yielding significant MRD negative rates; showing equal efficacy in high risk and standard risk patients; showing equal efficacy in younger elderly patients and older elderly patients and showing improvement in quality of life. There is one caveat, the elderly older patients have a little bit more grade 3 and 4 adverse events, hematologic adverse events and more infections than the younger elderly patients.

In the elderly patients, did they have many comorbidities? Were there any comorbidities with the elderly patients?

That’s an important point. We excluded patients with frail patients but patients with fit and intermediate fit patients could be enrolled. Patients with ECOG status 1 could be enrolled but patients with significant comorbidities like cardiac arrhythmias and so on were excluded from the enrolment.

What are the next steps for this study?

The next step is, looking forward, trying to complete the planned enrolment number. Then to analyse the study in greater detail and to present the data regarding cytogenetics, age, quality of life and so on in greater detail.