Transplant-eligible patients with newly diagnosed multiple myeloma responded well to treatment with a four-drug regimen, according to results of a phase II study.
Among adult patients, the overall response rate was 90% and the estimated overall survival rate was 80% at 3 years following stem cell transplantation, reported Pamela S. Becker, MD, PhD, of the University of Washington in Seattle, and colleagues.
The regimen consisted of bortezomib (Velcade), cyclophosphamide, dexamethasone, and liposomal doxorubicin (BCDD). The induction regimen, developed with the goal of improving depth of response, complete response rates, and ease of administration, successfully prepared patients for transplant with preservation of ability to mobilize and collect peripheral blood stem cells, they wrote in an open letter to the editor in Blood Cancer Journal.
"The BCDD regimen is easily administered weekly on an outpatient basis, for 3 weeks (on days 1,8,15) of each 4 week cycle. Another advantage is that the drugs are typically available without the high co-pay that can be incurred with the oral thalidomide or lenalidomide (IMid) agents. While there are many newer agents available for multiple myeloma, such as elotuzumab, daratumumab, panobinostat, or the newer proteasome inhibitors, they have been FDA approved for relapsed or refractory disease rather than initial therapy," Becker explained in an email to MedPage Today in an email.
Tolerability of the four-drug regimen was assessed in a pilot phase that enrolled relapsed, refractory patients who had failed at least one prior regimen, not including dexamethasone alone (cohort 1, n=5); then newly diagnosed patients naïve to previous treatment other than prior dexamethasone ≤ 320 mg were enrolled (cohort 2, n=25).
The regimen consisted of bortezomib (1.6 mg/m2 IV), cyclophosphamide (300 mg/m2 IV), and dexamethasone (40 mg po or IV) on days one, eight, and 15, and liposomal doxorubicin (30 mg/m2 IV) on day eight of a 28-day cycle. Four cycles were intended to be completed before autologous stem cell transplant.
Included patients had quantifiable monoclonal protein or light chain identified by serum protein electrophoresis, urine protein electrophoresis, or serum-free light-chain assay. Eastern Cooperative Oncology Group performance status was 0-2. Adequate blood counts, as well as renal, hepatic, and cardiac function were required.
Five of the 25 treatment-naive patients died, one due to massive pulmonary embolism on day 13 of the first treatment cycle; two at 15 and 34 months due to disease progression; and two from unknown cause.
Occurrence of the embolism in a patient with no known hypercoagulable risk resulted in a protocol amendment to include prophylactic treatment with aspirin, low molecular weight heparin, or warfarin in patients on thalidomide or lenalidomide (Revlimid) at high risk according to published criteria.
Grade 3 adverse events included hand/foot syndrome, infection without neutropenia, gastrointestinal hemorrhage due to Mallory-Weiss tear, diarrhea, weight loss, anemia, mucositis, and chronic obstructive pulmonary disease exacerbation.
After treatment, 21 patients proceeded to successful mobilization and collection of peripheral blood stem cells and stem cell transplantation.
Following stem cell transplantation, 38% of those achieved complete response, 24% had very good partial response, and 29% had partial responses based on day plus-80 restaging. Two patients died from progressive disease following transplant.
Median follow-up among the 20 survivors is 49 months; median survival has not been reached, the authors noted.
The current study was informed by earlier research assessing modified regimens in previously untreated multiple myeloma patients. In that 2011 prospective phase II trial, a modified three-drug regimen used pegylated liposomal doxorubicin at a low-dose (5 mg/m2) on the same days that bortezomib was administered (days 1, 4, 8 and 11), and a longer 4-week, rather than a 3-week, dosing schedule. Patients were treated to their maximum response plus two additional cycles.
According to the results, 35 previously untreated multiple myeloma patients achieved a high overall response rate of 86%, along with a marked decrease in the incidence and severity of peripheral neuropathy, palmar-plantar erythrodysesthesia, and myelosuppression with the longer dosing schedule compared with the standard 3-week dosing cycle used with these drugs.
"Our results contribute to the mounting evidence that reducing the dose of bortezomib and increasing the cycle length significantly reduces toxicity without compromising efficacy of this proteasome inhibitor when used for the treatment of previously untreated MM patients," the authors wrote.
Becker's group concluded that given the observed "excellent rates of estimated overall survival (80%) at 3 years and response (90%) after BCDD and current consistent availability of pegylated liposomal doxorubicin support a future direct comparison of BCDD to other drug regimens."
The study was supported by Millennium The Takeda Oncology Company to the University of Washington and by the FHCRC/UW Cancer Consortium Cancer Center Support Grant of the NIH.
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