BREAKING NEWS: Dr. Berenson’s Kyprolis results live up to the hype!

Two weeks ago, Dr. Berenson hinted on our Myeloma Cure Panel broadcast that there were surprisingly hopeful numbers in a study he was conducting on relapsed/refractory patients.  This trial is one of the under the radar, good news stories from ASH.

I couldn’t release these results until 6 PM Eastern time today.  I have highlighted important points in BOLD:

4063 A Phase 1/2 Study of Carfilzomib As a Replacement for Bortezomib for Multiple Myeloma (MM) Patients (pts) Refractory to a Bortezomib-Containing Combination Regimen

James R. Berenson, MD1,2,3, James D. Hilger, Ph.D.1*, Robert Dichmann, MD4*, Dipti Patel-Donnelly, MD5, Ralph V. Boccia, MD6, Alberto Bessudo, MD7, Laura V. Stampleman, MD8*, Donald S. Gravenor, MD9*, Shahrooz Eshaghian, MD10, Youram Nassir, MD11*, Regina A. Swift, RN2* and Robert Vescio, MD10

1Oncotherapeutics, West Hollywood, CA
2James R. Berenson, MD, Inc., West Hollywood, CA
3Institute for Myeloma & Bone Cancer Research, West Hollywood, CA
4Central Coast Medical Oncology, Santa Maria, CA
5Virginia Cancer Specialists, PC, Fairfax, VA
6Center for Cancer and Blood Disorders, Bethesda, MD
7San Diego Pacific Oncology Hematology Associates, Inc., Encinitas, CA
8Monterey Bay Oncology, Monterey, CA
9Oncology, Family Cancer Center, Memphis, TN
10Cedars-Sinai Medical Center, Los Angeles, CA
11Cancer Care Institute, Los Angeles, CA
Background: Carfilzomib has shown promise in treating both newly diagnosed and relapsed/refractory MM patients. Recent data has suggested that single agent carfilzomib can produce a response for MM pts refractory to previous treatment regimens, including prior bortezomib-containing regimens. We conducted an intrapatient Phase 1/2 trial investigating the safety and efficacy of carfilzomib as a replacement for bortezomib in bortezomib-containing regimens to which pts have progressed.

Methods: Eligible pts had to have progressed while receiving their most recent bortezomib-containing regimen after at least 4 doses of bortezomib at ≥ 1.0 mg/m² in ≤ 4 weeks per cycle. Patients treated with bortezomib-containing combination regimens, including alkylating agents, anthracyclines, glucocorticosteroids, and/or immunomodulatory agents were eligible. Carfilzomib replaced bortezomib in each regimen via intravenous administration over 30 min on days 1, 2, 8, 9, 15, and 16 of each 28 day cycle. For each pt, carfilzomib doses were escalated on each of the first 4 cycles from 20 to 27, 36, and 45 mg/m² or until maximum tolerated dose (MTD) was reached for that regimen. Aside from carfilzomib replacing bortezomib, regimens utilized the same dose(s) and schedule(s) of each drug administered in the most recent bortezomib-containing regimen to which the patient was refractory.

Results: The trial has currently enrolled 32 of 45 planned patients. Pts received a median of 6 prior treatments (range, 1-18) and 2 different bortezomib-containing regimens (range, 1-13). Pts were treated with carfilzomib and 13 different combination regimens at varying doses and schedules. Agents in these combination regimens varied per patient, potentially including any of the following: ascorbic acid, bendamustine, clarithromycin, cyclophosphamide, dexamethasone, lenalidomide, melphalan, methylprednisolone, pegylated liposomal doxorubicin, and/or thalidomide. Six patients received a regimen containing IMiDs (thalidomide or lenalidomide). Pts have completed a median of 3 cycles (range: 0-12) with a median of 5.9 months of follow up (range: 0.4-14.1). To date, 1 regimen, carfilzomib + ascorbic acid + cyclophosphamide, has reached MTD with the maximum dose of carfilzomib (45 mg/m2) without any DLTs.

Efficacy data stems from 24 of 32 enrolled pts who have completed at least 1 cycle of treatment. Clinical benefit was seen in 18 (75%) pts (complete response = 8.3%; very good partial response = 16.7%; partial response = 29.2%; minor response = 20.8%) with another 16.7% showing stable disease. Notably, response was achieved for each type of agent included in the trial across a variety of specific treatment combinations. Only 3 pts have progressed while on study, one with progressive disease after an initial response. Kaplan-Meier analysis reveals the median progression-free survival (PFS) at this point in the study to be 10 months (95% confidence interval: 8.6-11.2). The median time to progression (TTP) and duration of response (DOR) have not yet been reached.

Safety data stems from all 32 enrolled pts. The most common grade 3/4 hematologic adverse events include: thrombocytopenia, occurring in 16 pts (G3: 5; G4: 2); lymphopenia occurring in 12 pts (G3: 6; G4: 1) and fever occurring in 2 pts (G3). The most common grade 3/4 non-hematologic adverse events include: fever, occurring in 8 pts (G3: 2); urinary tract infection, occurring in 3 pts (G3: 1); sepsis occurring in 1 pt (G4); pneumonia occurring in 2 pts (G3: 1); tumor lysis syndrome occurring in 1 pt (G3). Ten pts experienced a serious adverse event on study.

Conclusions: These early results suggest that carfilzomib is an effective and tolerable replacement for bortezomib among pts who are refractory to bortezomib-containing combination regimens. These results appear to be applicable to a variety of combination regimens consisting of a wide array of therapeutic agents.

Disclosures: Berenson: Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau.

I believe this study would have gotten a lot more attention if it had been a few months farther along.  Stage 1/2 studies rarely get much play.  But a 75% response rate (26% CR/VGPR) are superior to most combo studies here at ASH this year.

There is no question that the study should be broken down to include patients of the same Velcade included/Kyprolis substituted therapies.

Very encouraging.  If docs can achieve the same type of results substituting pomalidomide for Revlimid, the way myeloma specialists treat relapsed/refractory patients may never be the same.

Feel good and keep smiling!  Pat

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