SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, close to 27,000 new cases will be diagnosed in 2015 and 11,240 will die of the disease. The U.S. Food and Drug Administration (FDA) granted accelerated approval on February 23, 2015 to Panobinostat (FARYDAK®), in combination with VELCADE® (Bortezomib) and Dexamethasone, for the treatment of patients with Multiple Myeloma. The authors in the PANORAMA I trial evaluated the outcomes in previously treated advanced Multiple Myeloma patients, by taking advantage of the synergy between VELCADE®, a proteosome inhibitor and FARYDAK® (Panobinostat), a histone deacetylase (HDAC) inhibitor and treating these patients with a combination of these two agents. HDACs are a family of enzymes that play an important role in the regulation of gene expression.
To briefly summarize the structure of a chromosome, individual loops of coiled double-helix DNA wrap around a histone protein to form a nucleosome. Nucleosomes are then coiled together to form chromatin fibers, which looks like beads on a string. The chromatin fibers are coiled even more tightly to form chromosomes. HDAC enzymes catalyze the removal of acetyl groups and regulate the level of acetylation of the histones and non-histone proteins and transcription of several genes. Hypoacetylation of histones has been associated with a condensed chromatin structure that results in the repression of gene transcription, whereas acetylated histones are associated with a more open chromatin structure and activation of gene transcription. HDACs are grouped into four major classes (Class I, II, III and IV) and regulate cell-cycle progression, cell survival, angiogenesis and immunity. The HDAC Class I enzymes are HDAC1, 2, 3 & 8 and are typically found in the nucleus where they are able to repress transcription. The HDAC Class II enzymes include HDAC4, 5, 6, 7, 9 and 10 and are able to move between the cytoplasm and nucleus and function in signal transduction. In Multiple Myeloma, the important enzyme to target is HDAC6.
FARYDAK® is an oral, pan-histone deacetylase inhibitor which inhibits cell cycle progression and ultimately results in apoptosis. FARYDAK® inhibits the aggresome pathway of protein degradation which is upregulated when proteosome pathway is inhibited by VELCADE®. Based on preclinical data demonstrating synergy between VELCADE® and FARYDAK® in Myeloma, the PANORAMA 1 trial, enrolled patients with relapsed or refractory Multiple Myeloma who had received one to three prior lines of therapy and were not VELCADE® refractory. In this phase III trial, patients were randomly assigned to receive either FARYDAK® (N=387) or placebo (N=381), each along with IV VELCADE® and oral Dexamethasone. In this study, treatment was given in two 24 week phases. The first 24 week treatment phase was cycles 1 thru 8, where patients received placebo or FARYDAK® 20 mg orally QD 3 times a week for 2 weeks of a 3 week cycle; VELCADE® 1.3 mg/m2 IV twice weekly for 2 weeks of a 3 week cycle and Dexamethasone 20 mg PO on the day of and day after VELCADE®. Patients with clinical benefit (defined as complete response, partial response or stable disease, without significant toxicities) after the first eight cycles could proceed to the second phase of treatment in which FARYDAK® and Dexamethasone administration schedule remained the same but VELCADE® was administered once weekly for 2 weeks of the 3 week cycle. The median age was 63 years, 48% of patients had received at least two lines of therapy and 57% of patients had prior autologous stem cell transplantation and 43% had prior therapy with VELCADE®. The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), near Complete/Complete Response (nCR/CR) rate, Duration of Response (DOR), and safety. Among the patients enrolled in the FARYDAK® group (N = 387), 44% completed first phase of treatment and 26% completed the second phase of treatment. After a median follow up of 28 months, the primary end point of the study was met with a 37% decrease in the risk of disease progression in all the FARYDAK® group of patients compared to the placebo group (12 months vs 8.1 months, HR=0.63, P<0.0001). The median PFS was 14.65 months for those in the FARYDAK® group who completed the first phase of treatment and 17.64 months for those who completed the second phase of treatment. With regards to the secondary endpoints in the FARYDAK® vs placebo groups, the ORR was 60.7% vs 54.6% (P=0.87), nCR/CR rate was 27.6% vs 15.7% (P=0.00006), median duration of response was13.1months vs 10.9 months and median time to progression was 12.7 months vs 8.5 months respectively. It was noted that the nCR/CR rate was 52.9% for those patients who completed the second phase of treatment. The most common grade 3/4 adverse events in the FARYDAK® vs placebo arms included thrombocytopenia (67% vs 31%), neutropenia (35% vs 11%), and diarrhea (26% vs 8%) and these toxicities were manageable with dose reduction and supportive care. The authors concluded that a combination of FARYDAK®, VELCADE® and Dexamethasone significantly improves Progression Free Survival in patients with relapsed and refractory Multiple Myeloma, with manageable toxicities. Miguel JS, Hungria VTM , Yoon S, et al. 56th ASH Annual Meeting and Exposition, 2014. Abstract#4742
Tag: Multiple Myeloma
FARYDAK® (Panobinostat)
The FDA on February 23, 2015 granted accelerated approval to FARYDAK® for use in combination with VELCADE® (Bortezomib) and Dexamethasone for the treatment of patients with Multiple Myeloma who have received at least two prior regimens, including VELCADE® and an immunomodulatory agent. FARYDAK® capsules are a product of Novartis Pharmaceuticals.
IMBRUVICA® (Ibrutinib)
The FDA on January 29, 2015 approved IMBRUVICA® for the treatment of patients with Waldenstrom’s Macroglobulinemia (WM). IMBRUVICA® was initially approved in November 2013 for the treatment of patients with Mantle Cell Lymphoma (MCL) who have received at least one prior therapy. IMBRUVICA® also received approval in February 2014 for the treatment of Chronic Lymphocytic Leukemia (CLL) in patients who received at least one prior therapy and in July 2014 for the treatment of CLL with 17p deletion. IMBRUVICA® is an oral capsule and is a product of Pharmacyclics, Inc.
Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma
SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 24,050 new cases were diagnosed in 2014 and 11,090 died of the disease. KYPROLIS® (Carfilzomib) is a second generation selective, epoxyketone proteasome inhibitor and unlike VELCADE® (Bortezomib), proteasome inhibition with KYPROLIS® is irreversible. KYPROLIS® monotherapy is presently approved in the United States for use in patients with relapsed and refractory Multiple Myeloma following a phase 2b single arm study which showed a 24% overall response rate in this patient group. REVLIMID® (Lenalidomide) given along with weekly Dexamethasone, was associated with significantly improved Progression Free Survival (PFS) when administered until disease progression, in patients with newly diagnosed Multiple Myeloma. The combination of REVLIMID® and weekly Dexamethasone is considered a reference regimen for both newly diagnosed and relapsed multiple myeloma. VELCADE® in combination with REVLIMID® and Dexamethasone showed an overall response rate of 64% and a median PFS of 9.5 months in patients with relapsed and refractory Multiple Myeloma. Based on this background the authors conducted this randomized, open label, multicenter, phase III study in which the safety and efficacy of a combination of KYPROLIS® (Carfilzomib), REVLIMID® and weekly Dexamethasone (KYPROLIS® group) was compared with a combination of REVLIMID® and weekly Dexamethasone (control group), in patients with relapsed Multiple Myeloma. Seven hundred and ninety two (N=792) patients were randomly assigned in a 1:1 ratio to KYPROLIS® group (N=396) and control group (N=396). Eligible patients included those with Multiple Myeloma who had received one to three prior treatments which included VELCADE® or REVLIMID and Dexamethasone combination, provided that they did not have disease progression during treatment with these agents. The 28 day treatment cycle consisted of KYPROLIS® IV given on days 1, 2, 8, 9, 15, and 16 (starting dose, 20 mg/m2 on days 1 and 2 of cycle 1 with a target dose of 27 mg/m2 thereafter) during cycles 1 through 12 and on days 1, 2, 15, and 16 during cycles 13 through 18, following which KYPROLIS® was discontinued. REVLIMID® 25 mg PO was given on days 1 through 21 and Dexamethasone 40 mg PO was administered on days 1, 8, 15, and 22. Patients in both treatment groups received only REVLIMID® and Dexamethasone after cycle 18 until disease progression. Antiviral and antithrombotic prophylaxis was administered to patients in both treatment groups. The primary end point was Progression Free Survival and secondary end points included Overall Survival, the rate of overall response (partial response or better), response duration, health-related quality of life, and safety. The rate of clinical benefit (minimal response or better) was an exploratory end point. The study met its primary endpoint at the time of the pre-specified interim analysis with a significant improvement in the median Progression Free Survival for those patients in the KYPROLIS® group compared to the control group (26.3 months versus 17.6 months; HR=0.69; P=0.0001). This benefit in the PFS was demonstrated across all predefined subgroups. The median overall survival was not reached in either group and the 24 month overall survival rates were 73.3% and 65.0% in the KYPROLIS® and control groups, respectively (HR=0.79; P=0.04). The overall response rates (partial response or better) were 87.1% and 66.7% in the KYPROLIS® and control groups, respectively (P<0.001). Amongst the responders, 31.8% and 9.3% of patients in the respective groups had a complete response or better and 14.1% and 4.3% had a stringent complete response. Further, patients in the KYPROLIS® group reported superior health-related quality of life. Grade 3 or higher adverse events were reported in 83.7% and 80.7% of patients in the KYPROLIS® and control groups respectively. The authors concluded that the addition of KYPROLIS® to REVLIMID® and Dexamethasone resulted in significant improvement in PFS as compared with REVLIMID® and Dexamethasone alone, in patients with relapsed Multiple Myeloma. Additional benefits in the KYPROLIS® group included higher and deep response rates, improved health-related quality of life, a favorable risk–benefit profile and a trend towards improved Overall Survival. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. N Engl J Med 2015; 372:142-152
Panorama 1 A randomized, double-blind, phase 3 study of panobinostat or placebo plus bortezomib and dexamethasone in relapsed or relapsed and refractory multiple myeloma
SUMMARY:Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 24,050 new cases will be diagnosed in 2014 and 11,090 will die of the disease. The authors in the PANORAMA I trial evaluated the outcomes in previously treated advanced multiple myeloma patients, by taking advantage of the synergy between Bortezomib (VELCADE®), a proteosome inhibitor and Panobinostat, a histone deacetylase (HDAC) inhibitor and treating these patients with a combination of these two agents. HDACs are a family of enzymes that play an important role in the regulation of gene expression.
To briefly summarize the structure of a chromosome, individual loops of coiled double-helix DNA wrap around a histone protein to form a nucleosome. Nucleosomes are then coiled together to form chromatin fibers, which looks like beads on a string. The chromatin fibers are coiled even more tightly to form chromosomes. HDAC enzymes catalyze the removal of acetyl groups and regulate the level of acetylation of the histones and non-histone proteins and transcription of several genes. Hypoacetylation of histones has been associated with a condensed chromatin structure that results in the repression of gene transcription, whereas acetylated histones are associated with a more open chromatin structure and activation of gene transcription. HDACs are grouped into four major classes (Class I, II, III and IV) and regulate cell-cycle progression, cell survival, angiogenesis and immunity. The HDAC Class I enzymes are HDAC1, 2, 3 & 8 and are typically found in the nucleus where they are able to repress transcription. The HDAC Class II enzymes include HDAC4, 5, 6, 7, 9 and 10 and are able to move between the cytoplasm and nucleus and function in signal transduction. In Multiple Myeloma, the important enzyme to target is HDAC6. Panobinostat is an oral, pan-histone deacetylase inhibitor which inhibits cell cycle progression and ultimately results in apoptosis. Panobinostat inhibits the aggresome pathway of protein degradation which is upregulated when proteosome pathway is inhibited by VELCADE®.
Based on preclinical data demonstrating synergy between VELCADE® and Panobinostat in Myeloma, the PANORAMA 1 trial, enrolled patients with relapsed or refractory multiple myeloma who had received one to three prior lines of therapy and were not VELCADE® refractory. In this phase III trial, patients were randomly assigned to receive either Panobinostat (N=387) or Placebo (N=381), each along with IV VELCADE® and oral Dexamethasone. For cycles 1 thru 8, patients received Panobinostat 20 mg PO or Placebo on days 1, 3, 5, 8, 10, and 12; VELCADE® 1.3 mg/m2 IV on days 1, 4, 8, and 11; and Dexamethasone 20 mg PO on days 1-2, 4-5, 8-9, and 11-12 of a 21 day cycle. Patients with clinical benefit after the first eight cycles could proceed to the second phase of treatment in which VELCADE® was administered only on D1 and D8 and Dexamethasone administered only on days 1-2 and 8-9. The median age was 63 years, 48% of patients had received at least two lines of therapy and 57% of patients had prior autologous stem cell transplantation and 43% had prior therapy with VELCADE®. The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), Overall Response Rate (ORR), near Complete/Complete Response (nCR/CR) rate, Duration of Response (DOR), and safety. After a median follow up of 28 months, the primary end point of the study was met with a 37% decrease in the risk of disease progression in the Panobinostat group compared to the Placebo group (12 months vs 8.1 months, HR=0.63, P<0.0001). With regards to the secondary endpoints in the Panobinostat vs Placebo groups, the ORR was 60.7% vs 54.6% (P=0.87), nCR/CR rate was 27.6% vs 15.7% (P=0.00006), median duration of response was13.1months vs 10.9 months and median time to progression was 12.7 months vs 8.5 months respectively. The most common grade 3/4 adverse events in the Panobinostat vs Placebo arms included thrombocytopenia (67% vs 31%), neutropenia (35% vs 11%), and diarrhea (26% vs 8%) and these toxicities were manageable with dose reduction and supportive care. The authors concluded that a combination of Panobinostat, VELCADE® and Dexamethasone significantly improves Progression Free Survival in patients with relapsed and refractory Multiple Myeloma, with manageable toxicities. Richardson PG, Hungria VTM , Yoon S, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8510)</s
Continuous treatment (CT) versus fixed duration of therapy (FDT) in newly diagnosed myeloma patients PFS1, PFS2, OS endpoints
SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 24,050 new cases will be diagnosed in 2014 and 11,090 will die of the disease. Maintenance or Continuous Treatment in patients with newly diagnosed multiple myeloma following induction and consolidation can result in significantly longer Progression Free Survival (PFS) and Overall Survival (OS), compared to those patients who receive therapy for a fixed duration of time. Not all studies however, have shown Overall Survival benefit. It has been hypothesized that Continuous Treatment could result in resistance to therapy which in turn could reduce the duration of subsequent remission after first relapse and negatively impact overall survival.
To address this controversy, the authors conducted a pooled analysis of the outcomes of two randomized phase III trials, designed to compare Continuous Treatment to Fixed Duration Therapy. In trail RVMM209, patients were randomized to either induction with Lenolidomide (REVLIMID®), followed by consolidation and subsequent maintenance with REVLIMID® (Continuous Treatment) or Fixed Duration Therapy which entailed REVLIMID® based induction followed by consolidation but no maintenance therapy. In Trial GIMEMA0305, the randomization was between Bortezomib (VELCADE®) based induction followed by maintenance treatment (Continuous Treatment) and VELCADE® induction, with no maintenance treatment (Fixed Duration Therapy). The trial investigators assessed PFS1 as the time from diagnosis to the occurrence of 1st relapse, PFS2 as time from diagnosis to the occurrence of 2nd relapse and Overall Survival as time from diagnosis to death , incorporating the duration of both 1st and 2nd remission. They then evaluated, both PFS1, PFS2 and OS in newly diagnosed multiple myeloma patients who received Continuous Therapy or Fixed Duration Therapy. In this pooled analysis 452 patients received Continuous Treatment and 461 patients received Fixed Duration Therapy .The median follow up was 52 months. Patients receiving Continuous Treatment had significantly prolonged PFS1 (median 35 months vs 24 months, HR 0.58; P<0.0001), PFS2 (median 63 months vs 47 months, HR 0.69, P=0.0001) and OS (median not reached [NR] vs 70 months, HR 0.70, P=0.0019), when compared with Fixed Dose Therapy. The authors evaluated the PFS and OS from first relapse to second relapse and from first relapse to death respectively, and they noted that the outcomes were similar among patients who received Continuous Treatment or Fixed Dose Therapy following initial diagnosis. The authors concluded that Continuous Treatment significantly improved PFS1, PFS2, and OS and findings from this pooled analysis suggested that the clinical benefit observed during first remission was not negated by a shorter second remission and Continuous Treatment did not induce tumor resistance. Continuous Treatment may be essential, as patients with multiple myeloma will always have some residual disease. It should be noted that certain institutions including the Mayo Clinic cap Continuous/Maintenance treatment at approximately 2 years, due to the lack of randomized comparative data, on the value of prolonged maintenance beyond 2 years. Palumbo A, Gay F, Musto P, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8515)
Multiple Myeloma International Staging System “Staging” or Simply “Aging” System?
SUMMARY: In this provocative perspective, the authors suggest revising the present Multiple Myeloma (MM) International Staging System, to incorporate more relevant information related to the biology of the disease. The MM International Staging System (MM-ISS) takes into account Beta-2 Microglobulin (B2M) along with Serum Albumin (SA) levels to determine the prognosis in MM patients. 
Although B2M and SA may act as surrogates for the extent of the disease, the evidence is insufficient to rely on these two entities to prognosticate MM. Even though B2M can correlate with MM tumor bulk as well as act as a biomarker of renal failure related to MM, the authors cite multiple studies suggesting that elevated serum B2M can be seen independent of MM history, in healthy elderly patients, infections, autoimmune disorders and chronic renal insufficiency. Further elevated B2M can be a marker of frailty in elderly patients and can predict disability and mortality in this patient group. With regards to Serum Albumin (SA) in MM, SA is inhibited by IL6, a MM cell growth factor and thus is able to indirectly reflect MM tumor bulk. However, low SA levels can also be seen in frail and elderly patients independent of MM history. The authors point out that the stage of the disease in the MM-ISS increases with age, independent of MM tumor bulk, due to the these nonspecific factors and does not necessarily correlate with other more specific prognostic markers such as cytogenetics, particularly in elderly patients. The authors conclude that combining the MM-ISS with tumor cytogenetics will more accurately predict prognosis in MM patients. Bataille R, Annweiler C, Beauchet O. Clinical Lymphoma Myeloma and Leukemia 2013;13:635-637
Multiple Myeloma International Staging System – An Aging System
The authors in this provocative report recommend combining the Multiple Myeloma International Staging System (MM-ISS) with tumor cytogenetics, to more accurately predict prognosis in MM patients. The MM International Staging System (MM-ISS) takes into account a combination of Beta-2 Microglobulin (B2M) along with serum albumin (SA) levels to determine the prognosis in MM patients. Unfortunately both B2M and SA can be abnormal in elderly patients independent of Myeloma history and may predict disability and mortality in this patient group. The MM-ISS may therefore not accurately reflect the intrinsic malignancy of the myeloma cell clone. This information was published in Clinical Lymphoma Myeloma and Leukemia 2013. Read more at www.oncoprescribe.com
Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003) a randomised, open-label, phase 3 trial
SUMMARY: Pomalidomide (POMALYST®) is a novel, oral, immunomodulatory agent which is far more potent than Thalidomide (THALOMID®) and Lenalidomide (REVLIMID®). Only 2% of POMALYST® is excreted unchanged through the kidney whereas 80% of REVLIMID® is excreted unchanged via the kidneys. Therefore, POMALYST® may be a consideration for patients with renal insufficiency. Previously conducted phase II trials have shown POMALYST® to be active in Myeloma patients, refractory to REVLIMID® and Bortezomib (VELCADE®). In a multicenter, randomized, phase III trial, the efficacy and safety of POMALYST® given along with low-dose Dexamethasone (LoDEX) (n=302) was compared with high-dose Dexamethasone (HiDEX) (n=153) in Myeloma 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 10 months, the PFS was significantly longer in the POMALYST® + LoDEX group compared to the HiDEX group (4 month vs 1.9 months; hazard ratio [HR]= 0.48; P <0 .0001). The median OS was significantly longer in the POMALYST® + LoDEX group compared to HiDEX group (12.7 months vs 8.1 months; HR=0.74; P=0.028). The authors concluded that POMALYST® along with low- dose Dexamethasone should be the new standard of care for patients who have Multiple Myeloma refractory to REVLIMID® and VELCADE®. Carfilzomib (KYPROLIS®), a new parenteral proteasome inhibitor is another option for patients with resistant and refractory Multiple Myeloma. San Miguel J, Weisel K, Moreau P, et al. Lancet Oncol 2013;14:1055-1066
Lenalidomide plus Dexamethasone for High-Risk Smoldering Multiple Myeloma
SUMMARY: Multiple Myeloma (MM) is a clonal disorder of plasma cells in the bone marrow. It evolves from a precursor stage called Monoclonal Gammopathy of Unknown Significance (MGUS) to MM. Smoldering Multiple Myeloma (SMM) is an intermediate stage in this process of disease evolution. The risk of MGUS transforming into MM is approximately 1% per year. SMM or asymptomatic MM is a precursor to MM and is characterized by at least 10% plasma cells in the bone marrow or a M-spike of at least 3 g/dl, or both, but these patients have no evidence of active symptomatic Myeloma with associated end-organ damage such as hypercalcemia, renal insufficiency, anemia or bone lesions. Even though only 10% of patients with SMM progress to MM annually, over 50% of the SMM patients with high risk features will progress to MM in the first 2 years. The current recommendations for those with SMM are periodic monitoring and treatment intervention only when disease progresses to MM. SMM patients with high risk features include those with at least 10% plasma cells in the bone marrow, a Monoclonal component (IgG monoclonal spike of at least 3g/dL, IgA M-spike of at least 2g/dL or a urinary Bence Jones protein level of more than 1g per 24 hours) or only one of the above two criteria plus at least 95% abnormal plasma cells in the bone marrow, with a reciprocal decrease in one or two uninvolved immunoglobulins of more than 25%, compared to normal values. Identifying those who are at a high risk for progression in the SMM group, is becoming more relevant with the availability of new promising therapies. In a phase III study, 119 patients with high risk SMM were randomly assigned to receive treatment (n=57) or to be observed until progression (n=62).Treatment consisted of Lenalidomide (REVLIMID®) 25 mg given on D1-D21 and Dexamethasone (DECADRON®) 20 mg given on D1-D4 and D12-D15 of a 4 week cycle. Patients received 9 cycles of therapy followed by maintenance therapy with REVLIMID® 10 mg given on D1-D21 every four weeks for 2 years. The median follow-up time was 40 months. The primary end point was time to progression to symptomatic disease. Secondary end points included response rate, overall survival, and safety. The median time to progression was significantly longer in the treatment group compared to the observation group (hazard ratio [HR] = 0.18; P< .001). At 3 years, the survival rate was better in the treatment group than in the observation group (94% vs 80% with a 69% reduction in the risk of death. P =0.03). Treatment related toxicities were grade 2 or lower. The authors concluded that treatment intervention for patients with high risk SMM may be of value, by delaying progression to symptomatic MM and extending overall survival. It remains to be seen if treatment intervention for patients with SMM will become the standard of care. It may also be relevant to include cytogenetics in the SMM definition criteria, as treatment intervention for SMM becomes an acceptable practice. Mateos M-V, Hernandez M-T, Giraldo P, et al. N Engl J Med 2013;369:438-447