The American Society of Hematology 2011 Annual Meeting had a number of sessions dedicated to clinical trials in patients with multiple myeloma. Several key compounds were featured in the presentations.
Dr. Paul Richardson from the Dana Farber Cancer Institute presented results on the MM-002 Phase II randomized trial of the novel immunomodulatory drug pomalidomide with or without low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (Abstract 1881).
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The phase I portion of this study with the drug had previously established 4 mg q. day on days 1 through 21 of each 28-day cycle as the maximally tolerated dose. The phase II portion of the trial presented at the meeting randomized patients to one of two dose schedules. The first arm received 4 mg of pomalidomide together with low-dose dexamethasone 40 mg once weekly. The other arm got pomalidomide 4 mg as a single agent, with the option to add low-dose dexamethasone at the time of disease progression. Patients had to have had prior therapy that included at least two cycles of lenalidomide and two cycles of bortezomib, and had to have documented progression during or within 60 days of their last treatment.
The study included a total of 221 patients on the two arms. An intention to treat overall response rate of 34% for pomalidomide and low-dose dexamethasone and 13% for single-agent pomalidomide was noted.
The time to progression was 1.9 months for pomalidomide with low-dose dexamethasone and 2.9 months for pomalidomide. Responses were seen in both lenalidomide refractory and lenalidomide and bortezomib still refractory patients.
Grade 3/4 adverse events noted were mainly hematological, with neutropenia in 38% to 45% and thrombocytopenia in 19% to 21%. FDA filing seeking accelerated approval for the drug on the basis of this trial is expected.
Dr. Xavier Leleu, also presented high response rates to the combination of pomalidomide and dexamethasone in patients with relapsed and refractory myeloma in the final analysis of the IFM2002-02 trial (Abstract 812). In this trial, 84 patients were enrolled and randomized to one of two treatment arms looking at two different dosing schedules, a 21 out of 28 day schedule and uninterrupted 28 day treatment regimen.
The majority of patients enrolled were refractory to both lenalidomide and bor-tezomib therapy, and an overall response rate of 34.5% was noted with median time to progression of 9.1 months and overall survival of 13.4 months. Progression-free survival of 3.8 months was noted in patients refractory to both bortezomib and lenalidomide.
In addition, Dr. Martha Lacy (Abstract 3963) and Dr. Joseph Mikhael (Abstract 2942), both from the Mayo Clinic, in separate poster representations, provided updated results on cohorts of patients treated with pomalidomide and dexamethasone, showing similarly high response rates in heavily pretreated patients, both at doses of 2 mg and 4 mg daily given uninterrupted 28-day treatment cycles.
Dr. Antonio Palumbo presented data from a phase I/II study of a three-drug combination of pomalidomide, cyclophosphamide, and prednisone in patients with multiple myeloma relapsed and refractory to lenalidomide treated at a number of Italian centers (Abstract 632).
Dr. Tomer Mark from the Weill Cornell Medical College in New York presented results on a three-drug regimen of clarithromycin, pomalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma (Abstract 635). Both the trials showed very impressive results with close to two thirds of the patients having responses to therapy.
I, on behalf of my colleagues, presented final results from the bortezomib-naïve cohort of the PX-171-004 phase II study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma (Abstract 813).
Carfilzomib is a next-generation proteosome inhibitor that selectively and irreversibly binds to its target, resulting in sustained inhibition in the absence of off-target effects relative to bortezomib. The study population consisted of 165 patients who had relapsed and/or refractory multiple myeloma following one to three prior regimens.
Carfilzomib was given daily for two consecutive days on three consecutive weeks in 28-day cycles, for up to 12 cycles, with the option of patients continuing on beyond 12 cycles on a companion study. The first 59 patients were treated at a dose level of 20 mg/m2, and the next 70 patients at 20 mg/m2 in cycle 1, then escalated to 27 mg/m2 with all subsequent cycles.
The majority of patients had been exposed to an immunomodulatory drug, alkylating agents, corticosteroids, and stem cell transplantation. About two thirds of the patients were refractory to their most recent line of therapy. An overall response rate of 42% in cohort 1, and 52% in cohort 2, was seen. The responses were durable with median time to progression of 8.3 months in cohort 1, and greater than or equal to 11.3 months in cohort 2.
The most common adverse events were fatigue, nausea, dyspnea, cough, and anemia. The majority were grade 1/2 in severity. Carfilzomib was associated with minimal peripheral neuropathy, with only one patient experiencing grade 3/4 neuropathy requiring a dose reduction. Twenty two patients continued treatment beyond year 1 on an extension protocol.
Dr. Andrzej Jakubowiak from the University of Chicago presented final results from a phase I/II study of carfilzomib, lenalidomide, and low-dose dexamethasone in front-line treatment of patients with multiple myeloma (Abstract 631). A total of 53 patients were enrolled on this clinical trial. Very impressive response rates were noted with a 100% response rate and 79% CR/near CR late in the 19 patients who had completed 12 cycles of treatment at the time of reporting.
“Carfilzomib is currently before the FDA seeking accelerated approval based on the PX-171-003A1 trial, which demonstrated activity of the drug in a patient population that had been exposed to both bortezomib and an immunomodulatory drug and was relapsed and refractory to their last line of therapy.”
Carfilzomib is currently before the FDA seeking accelerated approval based on the PX-171-003A1 trial, which demonstrated activity of the drug in a patient population that had been exposed to both bortezomib and an immunomodulatory drug and was relapsed and refractory to their last line of therapy.
Dr. Sagar Lonial presented the results of a phase II study of elotuzumab in combination with lenalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (Abstract 303).
Elotuzumab is a humanized IgG-1 monoclonal antibody targeting human CS1, a cell surface glycoprotein. CS1 is highly expressed in over 95% of multiple myeloma cells, with lower expression on NK cells, and little to no expression on normal tissue. Patients were randomized to two dose levels of elotuzumab, 10 mg/kg or 20 mg/kg IV, in combination with lenalidomide 25 mg days 1 through 21, and low-dose dexamethasone 40 mg once weekly, with the elotuzumab being administered once weekly during the first two cycles, and every other week beyond cycle 2.
A total of 73 patients were enrolled who had relapsed and refractory disease after one to three prior therapies. Responses were seen in 92% and 73% of patients at the 10 mg/kg and 20 mg/kg doses, respectively, for an overall response rate of 82%. With a median follow-up of 14.1 months, the median progression-free survival has not been reached.
The most common grade 3/4 treatment emergent adverse events were hematological, with a low incidence of infusion reactions.
Histone Deacetylase (HDAC) Inhibitors
Dr. Meletios Dimopoulos presented results of the Vantage 088 trial of vorinostat, an oral inhibitor of the histone deacetylase class 1 and class 2 proteins, in combination with bortezomib in patients with relapsed and refractory multiple myeloma (Abstract 811). In this trial, 637 patients who had received one to three prior antimyeloma regimens, excluding patients with prior resistance to bortezomib, were enrolled from 174 centers in 33 countries.
Patients received a 21-day cycle of bor-tezomib at 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, plus oral vorinostat 400 mg daily or placebo on days 1 through 14. An overall response rate of 56% in the vorinostat vs 41% in the placebo arm was noted (p < 0.0001). Though the trial met its primary endpoint of improvement of progression-free survival when vorinostat was added to bortezomib, the benefit was relatively modest — 7.83 months vs 7.63 months HR (95% CI) 0.774 ( 0.64- 0.94). The two-year overall survival was similar in both arms of the study.
Dr. David Siegel from Hackensack University Medical Center presented results of Vantage 095, a global phase IIB trial combining vorinostat with bortezomib in bortezomib-refractory patients (Abstract 480); 143 patients were enrolled from 41 centers in 12 countries. Patients received a 21-day cycle of bortezomib at 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, plus oral vorinostat 400 mg daily on days 1 through 14.
If the patient had no change in disease burden after four cycles or progressive disease after two cycles of treatment, oral dexamethasone at 20 mg the day of and day after each dose of bortezomib could be added to the treatment regimen. A response rate of 17% was observed.
Dr. Paul Richardson presented data on a phase II study of the pan-deacetylase inhibitor panobinostat in combination with bortezomib and dexamethasone in relapsed and bortezomib-refractory multiple myeloma (Panorama 2 trial) (Abstract 814). The combination of panobinostat and bortezomib was shown to have responses in patients with bortezomib-refractory disease.
Other Abstracts of Note
Dr. Ruben Niesvizky from Weill Cornell Medical College presented data on a community-based phase IIIB (UPFRONT) study comparing the efficacy and safety of three bortezomib-based regimens: bortezomib and dexamethasone (VD); bortezomib, thalidomide, and dexamethasone (VTD); and bortezomib, melphalan, and prednisone (VMP); followed by weekly bortezomib maintenance in elderly, newly diagnosed, transplant-ineligible patients with multiple myeloma (Abstract 478).
Preliminary outcomes data suggest that triplet therapy with VTD or VMP may offer little advantage over doublet therapy with VD for improving response rates and survival outcomes in this patient population. However, outcomes data are still immature, and patients continue to be followed for progression and survival status. Rates of grade ≥3 adverse effects, serious adverse events, discontinuations due to AEs, and peripheral neuropathy were highest in the VTD arm. VTD was also associated with poorer overall quality of life vs VD and VMP. Maintenance with single-agent V was well tolerated, with limited additional toxicity compared with induction.
Dr. Jesus San Miguel from Salamanca, Spain, reported on the final results of the phase III VISTA trial (Abstract 476), which showed continued overall survival benefit after five years of follow-up with bortezomib, melphalan, and prednisone, versus melphalan and prednisone, in patients with previously untreated multiple myeloma with patients on the combination of three drugs, achieving a median overall survival of 56.4 months, compared with an overall survival of 45.4 months for patients treated with melphalan and prednisone (p = 0.0029).
In addition, data were presented on a number of phase I/II trials studying a variety of compounds, including an oral proteosome inhibitor (MLN9708), a pan-proteosome inhibitor, marizomib (NPI-0052), an antibody drug conjugate directed against CD138 (BT062), MEK1/2 inhibitor (EZD6244). All of these trials showed single-agent activity with these novel compounds.