Lambrolizumab (MK-3475) is a humanized anti–PD-1 monoclonal antibody that has demonstrated significant benefit for those patients with advanced Malignant Melanoma regardless of their prior therapy with anti-CTLA 4 antibody, YERVOY® (Ipilimumab). The programmed death 1 (PD-1) receptor is an inhibitory receptor expressed on activated T-cells in the tumor micro environment. The anti–PD-1 antibody by blocking the PD-1 receptor essentially unleashes the immune system to fight off cancer cells. This information published in the NEJM in June 2013 and presented at the 2013 ASCO annual meeting gives an additional option for patients with advanced Malignant Melanoma.
Tag: Multiple Myeloma
MYELOMA – mSMART is the way to go
Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) developed by the Mayo Clinic, unlike the present staging systems takes cytogenetic features into consideration and stratifies patients into High risk, Intermediate risk and Low risk groups. The clinician, based on the risk, then decides on the most appropriate therapy. This Risk-Adapted Therapy should result in better outcomes without compromising care. The 2013 mSMART Consensus Guidelines were published in the April issue of the Mayo Clinic Proceedings.
POMALYST® (Pomalidomide)
The FDA on February 8, 2013 granted accelerated approval to POMALYST® for the treatment of patients with multiple myeloma who have received at least two prior therapies, including REVLIMID® (Lenalidomide) and VELCADE® (Bortezomib), and have demonstrated disease progression on or within 60 days of completion of the last therapy. POMALYST® capsules are a product of Celgene Corporation.
Pomalidomide in Combination with Low-Dose Dexamethasone Demonstrates a Significant Progression Free Survival and Overall Survival Advantage, in Relapsed/Refractory MM A Phase 3, Multicenter, Randomized, Open-Label Study
SUMMARY: Pomalidomide (POM) is a novel, oral, immunomodulatory drug which is far more potent than Thalidomide (THALOMID® and Lenalidomide (REVLIMID®) and has been shown to be active in REVLIMID® and Bortezomib (VELCADE®) refractory patients. In this phase III trial, the efficacy and safety of POM given along with low-dose dexamethasone (LoDEX) (n=302) was compared with high-dose dexamethasone (HiDEX) (n=153) in patients who were refractory to both REVLIMID® and VELCADE®. The primary endpoint was Progression Free Survival (PFS). The Overall Survival (OS) was only evaluated if PFS was statistically significant. With a median follow up of 18 weeks, the PFS was significantly longer in the POM + LoDEX group compared to the HiDEX group (15.7 vs 8.0 weeks; hazard ratio [HR], 0.45; P < .001). Following interim analysis, the OS was significantly longer in the POM + LoDEX group compared to HiDEX group (median not reached vs 34 weeks; HR, 0.53; P< .001). The authors concluded that this oral treatment regimen should be the new standard of care for patients who have disease refractory to REVLIMID® and VELCADE®. Carfilzomib (KYPROLIS®), a new parenteral proteasome inhibitor is another option for patients with resistant and refractory multiple myeloma. Dimopoulos MA, Lacy MQ, Moreau P, et al. 54th ASH Annual Meeting and Exposition 2012, LBA-6
A Phase 1/2 Study of Weekly MLN9708, an Investigational Oral Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients with Previously Untreated Multiple Myeloma (MM)
SUMMARY: Bortezomib (VELCADE®) is a parenteral proteosome inhibitor with remarkable activity in multiple myeloma. This agent however, can be associated with neuropathy in about 30- 40% of the patients, when given intravenously twice a week, and in about 10-15% of patients when given subcutaneously. MLN9708 is an oral, reversible proteasome inhibitor with favorable toxicity profile and lower incidence of peripheral neuropathy (PN). In the phase I component of this trial, 15 patients were enrolled and a maximum tolerated dose of 4 mg of MLN9708, taken orally once a week, was established. For the phase II component of this study, 50 treatment naïve patients with multiple myeloma were enrolled and MLN9708 was given at a dose of 4 mg orally on days 1, 8, and 15, in combination with lenalidomide (REVLIMID®) (25 mg once daily on days 1 to 21) and dexamethasone (40 mg on days 1, 8, 15, and 22) every 28 days for up to 12 cycles. Patients subsequently went on to receive maintenance therapy with MLN9708 once a week until progression. In this regimen, MLN9708 was essentially substituted for VELCADE®. The overall response rate was 96%, with Very Good Partial Response seen in more than 44% of patients and 26% Complete Response rate. More importantly grade 1 neuropathy was only seen in 8% and grade 3 neuropathy developed in 3% of the patients. The authors concluded that the responses with this new combination is similar to the VRD (VELCADE®, REVLIMID®, and Dexamethasone) regimen but with significantly less neuropathy and more importantly, all three drugs can be given orally. Kumar SK, Berdeja JG, Niesvizky R, et al. 54th ASH Annual Meeting and Exposition 2012, Abstract 332
KYPROLIS® (Carfilzomib injection)
The FDA on July 20, 2012 granted accelerated approval to KYPROLIS® for the treatment of patients with multiple myeloma who have received at least two prior therapies, including VELCADE® (Bortezomib) and an immunomodulatory agent, and have demonstrated disease progression on or within 60 days of the completion of the last therapy. KYPROLIS® is a product of Onyx Pharmaceuticals.
PX-171-003-A1, an open-label, single-arm, phase (Ph) II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (R/R MM) Long-term follow-up and subgroup analysis
SUMMARY: KYPROLIS® (Carfilzomib) is a second generation proteasome inhibitor. Unlike VELCADE® (Bortezomib), proteasome inhibition with KYPROLIS® is irreversible. The approval of KYPROLIS® was based on a phase 2b, single-arm, multicenter clinical study in which 266 patients with advanced refractory Multiple Myeloma who had progressed on 2 or more prior therapies were evaluated. Prior therapies included treatment with VELCADE® (Bortezomib), REVLIMID® (Lenalidomide) or THALOMID® (Thalidomide). The primary end point was Overall Response Rate (ORR). The ORR with single agent KYPROLIS® was 24%, with a median duration of response of 7.4 months. This benefit was seen regardless of unfavorable cytogenetics. Peripheral neuropathy was infrequent and the most common adverse events were primarily hematologic. Patients with resistant and refractory Multiple Myeloma now have a new treatment option after a six year hiatus. Siegel DSD, Martin T, Wang M, et al. J Clin Oncol 29: 2011 (suppl; abstr 8027)
Continuous Lenalidomide Treatment for Newly Diagnosed Multiple Myeloma
SUMMARY: REVLIMID® (Lenalidomide) is an immunomodulatory agent with significant activity in patients with Multiple Myeloma, by virtue of its multiple mechanism of action. In this randomized, double blind, multicenter study, patients 65 years or older with newly diagnosed multiple myeloma, ineligible for transplantation, were randomized and the comparison was MPR followed by R (melphalan, prednisone and REVLIMID® followed by REVLIMID® maintenance) vs MPR or MP followed by placebo. There was a statistically significant prolongation in the progression free survival with a 51% reduction in the risk of progression for those who received REVLIMID® maintenance (MPR followed by R) compared to those who received MPR followed by placebo. This benefit was predominantly observed in patients who were 65-75 years of age. The response rates were also higher in the MPR-R and MPR groups compared to the MP group. There was a slightly higher incidence of second primary malignancies in those exposed to REVLIMID® (MPR-R and MPR) compared to the MP group (7% vs 3%). This study has demonstrated the benefit of adding REVLIMID® for induction therapy as well as maintenance, in patients 65-75 years of age, ineligible for transplant. Palumbo A, Hajek R, Delforge M, et al. N Engl J Med 2012;366:1759-1769
Lenalidomide after Stem-Cell Transplantation for Multiple Myeloma
SUMMARY: REVLIMID® (Lenalidomide) is an immunomodulatory agent with significant activity in patients with Multiple Myeloma, by virtue of its multiple mechanisms of action. In two, double blind, randomized, phase III trials, patients with stable disease following stem cell transplantation, were randomized to receive either REVLIMID® (Lenalidomide) or placebo maintenance, until progression. In both these studies there was a statistically significant improvement in the progression free survival or time to progression in the patient group receiving REVLIMID® maintenance. This benefit was independent of response to initial induction therapy at the time of randomization and other patient characteristics such as B2 microglobulin, cytogenetics or exposure to lenalidomide or thalidomide during induction. There was however a slightly higher incidence of second primary malignancies in the REVLIMID® group compared to the placebo group (8% vs 4%). We have come a long way, controlling this disease and maintenance REVLIMID® has paved the way, changing Multiple Myeloma into a chronic disease. McCarthy PL, Owzar K, Hofmeister CC, et al. N Engl J Med 2012;366:1770-1781 and Attal M, Lauwers-Cances V, Marit G, et al. N Engl J Med 2012;366:1782-1791