Treatment of newly diagnosed multiple myeloma patients with a combination of Kyprolis (carfilzomib), Alkeran (melphalan), and prednisone does not yield superior outcomes, compared to the triple combination of Velcade (bortezomib), Alkeran, and prednisone, according to recent results of a Phase 3 trial.
During the last decade, proteasome inhibition has emerged as an effective therapeutic strategy for treating multiple myeloma and some lymphomas. Proteasomes are organelles within our cells that degrade proteins no longer needed by our bodies. They maintain the fine balance between protein synthesis and degradation. Misregulation of protein degradation, a common feature in cancer cells, promotes cell growth, development, and survival of malignant cells.
Although both Velcade and Kyprolis are proteasome inhibitors, Kyprolis showed superiority to Velcade in patients with relapsed or refractory multiple myeloma because it doubles progression free survival rates.
Based on those and other results, Kyprolis is now approved in the U.S. to treat relapsed or refractory multiple myeloma patients as a monotherapy, in combination with Decadron (dexametasone), or with Decadron plus Revlimid (lenalidomid).
To answer whether Kyprolis also improved the outcomes of newly diagnosed multiple myeloma patients, Amgen conducted the CLARION study, a multicenter, open-label, randomized Phase 3 trial (NCT01818752). The study evaluated the effectiveness and safety of Kyprolis, Alkeran, and prednisone, versus Velcade, Alkeran, and prednisone in newly diagnosed myeloma patients who were not eligible for hematopoietic stem cell transplants.
The study enrolled 955 patients (median age 72 years) who were randomized to receive the Kyprolis- or Velcade- containing regimens for 54 weeks. The study’s primary endpoint was progression free survival. Secondary endpoints included overall survival, overall response rates, and complete response rates.
Results revealed that the study did not meet its primary endpoint of superior progression free survival (PFS) in the Kyprolis group – median PFS was 22.3 and 22.1 months in the Kyprolis and Velcade groups, respectively.
In addition, Kyprolis also failed to improve patient overall survival even though the researchers say that data are not yet mature. Although not statistically significant, results suggest an increase in overall survival in the Kyprolis group.
Kyprolis seems to reduce the incidence of Grade 2 or higher peripheral neuropathy compared to Velcade (2.5% versus 35.1%), but the rates of Grade 3 or higher adverse events were similar in both groups (74.7% versus 76.2%), as were the rates of deaths derived from treatment-emergent side effects (6.5% versus 4.3%).
Dr. Sean E. Harper, executive vice president of research and development at Amgen, said in a press release: “The CLARION results, generated in the context of a melphalan-containing regimen, are disappointing, especially given the robust data we’ve seen in the second-line setting. However, the myeloma landscape has changed dramatically since the design of the CLARION study with very few newly diagnosed patients treated with melphalan-based regimens, particularly in the U.S. We remain committed to exploring Kyprolis in combination with other agents to advance the treatment of multiple myeloma.”
Currently, Amgen is supporting a randomized, open-label, multicenter Phase 3 study evaluating Kyprolis in combination with Revlimid and Decadron versus Velcade in combination with Revlimid and Decadron in newly diagnosed multiple myeloma patients. The trial, called ENDURANCE (NCT01863550), will be conducted in more than 750 U.S. institutions and is currently enrolling participants.
For information about the study’s detailed eligibility criteria and locations, click here.