New Agents for Multiple Myeloma treatment presented at ASH 2008
At the 2008 meeting of the American Society of Hematology in San Francisco in December, there were several oral presentations of new and promising agents for the treatment of patients with multiple myeloma.
Zolinza™ (vorinostat) and Velcade®
Zolinza is a histone deacetylase inhibitior that is being tested in a variety of lymphoid malignances. On October 6, 2006, the U.S. Food and Drug Administration approved Zolinza for the treatment of the cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease following two systemic therapies. At ASH 2008, U.S. researchers reported that the combination of Zolinza™ (vorinostat) and Velcade® (bortezomib) is active for the treatment of relapsed/refractory myeloma.[1] There were 34 patients with relapsed/refractory myeloma in this study. The partial response rate was 26%, with an additional 21% having a minimal response and 53% having stable disease. Dexamethasone was added to Zolinza and Velcade in 21 additional patients. Two achieved a very good partial response, seven had a partial response, and 10 had stable disease. These authors concluded that the combination of Zolinza and Velcade was active even in patients previously treated with Velcade.
Carfilzomib and Dexamethasone
Carfilzomib is a novel, irreversible, epoxomicin-related proteasome inhibitor. Carfilzomib currently has orphan drug status for the treatment of multiple myeloma. Preclinical studies have shown that carfilzomib can overcome the resistance of myeloma cells to conventional agents and acts synergistically with dexamethasone.[2] At ASH 2008 researchers involved in a U.S. multi-center trial (PX-171-004) reported that carfilzomib and dexamethasone was a promising new agent for the treatment of myeloma.[3] There were 31 patients with relapsed myeloma in this study. Eighty-seven percent had received a prior stem cell transplant. For 13 patients who had not received Velcade, the overall response rate was 54%, including one complete response, two very good partial responses, and four partial responses; four patients had stable disease. Sixteen patients had received prior treatment with Velcade, and 19% achieved a partial response. One patient had a minimal response, and nine had stable disease.
A second study (PX-171-003) evaluated carfilzomib in 39 patients, all of whom had received prior treatment with Velcade; in addition, 89% had received a prior stem cell transplant.[4] The clinical benefit rate was 26%, including five patients with a partial response.
Carfilzomib will undoubtedly be evaluated in patients with less advanced disease and probably compared with Velcade for up-front treatment of myeloma.
Pomalidomide (CC4047)
Pomalidomide is an oral analog of thalidomide with significant immunomodulatory effects. It stops the growth of blood vessels, stimulates the immune system, and may directly kill cancer cells. Pomalidomide is also an inhibitor of angiogenesis. A Phase I study showed a complete remission rate of 17% in patients with relapsed or refractory myeloma with daily pomalidomide.[5] Fifty-four percent of patients in this study had a 50% or greater decrease in paraprotein. The main side effects were deep vein thrombosis, which occurred early and late. A Phase II study used an alternate day regimen of pomalidomide in an attempt to decrease thrombotic side effects.[6] The alternate day schedule appeared to eliminate thrombotic complications. There were 20 patients in this study, and the complete response rate was 10%; a greater than 50% reduction in paraprotein was achieved in half the patients. At ASH 2008 daily pomalidomide and low-dose dexamethasone were evaluated in 37 patients with relapsed or refractory myeloma.[7] All patients receive aspirin for prophylaxis against thrombotic complications. Seventy-six percent of patients had received a prior stem cell transplant, and 62% had received Thalomid® (thalidomide) or Revlimid® (lenalidomide). The overall response rate was 62%, and 24% had a very good partial response. The response was 29% in patients who had received prior Revlimid. Pomalidomide promises to be a rival of Revlimid and Thalomid in the treatment of patients with myeloma.
CNTO 328
CNTO 328 is a chimeric monoclonal antibody that specifically binds to and neutralizes human IL-6 with high affinity. A Phase I study has been performed in patients with lymphoma and myeloma. Preclinical studies suggest synergy of CNTO with Velcade.[8] At ASH 2008 researchers involved in a U.S. multi-center trial reported that the combination of Velcade and CNTO 328 was active in patients with relapsed or refractory myeloma.[9] This study included 21 patients, of whom 11 had received a prior stem cell transplant and eight had received prior Velcade or Thalomid. Fifty-seven percent achieved a partial or complete remission, and the median time to disease progression was 280 days. These authors will be performing a trial of Velcade plus CNTO 328 versus Velcade and placebo.
Velcade® and Perifosine
Researchers from several U.S. institutions have reported a 40% overall response rate to the combination of perifosine and Velcade® (bortizomib) in patients with multiple myeloma who had been previously treated with Velcade.[10] Perifosine belongs to a new class of anti-tumor drugs that targets cell membranes, inhibits Akt activation, and induces apoptosis.
The current study involved the treatment of 76 patients with relapsed/refractory multiple myeloma treated with perifosine and Velcade with or without dexamethasone. All patients had received prior therapy with Velcade and 35 were deemed refractory to Velcade. Fifty-seven patients in this study were evaluable for response. The overall response rate was 40%, with 30% having stable disease. The median time to tumor progression for all patients was 19 weeks, while the median time to tumor progression for responders had not been achieved. The overall response rate for patients deemed refractory to Velcade was 37%, and the median time to tumor progression was 23 weeks. The combination of Velcade and perifosine was described as well tolerated. These data suggest that pirifosine may be a new useful agent for the treatment of patients with myeloma.
Comments: It appears that new and novel agents for the treatment of multiple myeloma are continuing to be developed at a relatively rapid rate; many of these may have a major impact on future therapy.
References:
[1] Weber D, Badros AZ, Jagannath S, et al. Vorinostat plus bortezomib for the treatment of relapsed/refractory multiple myeloma: Early clinical experience. Blood. 2008;112:322, abstract number 871.
[2] Kuhn DJ, Chen O, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2008;110:3281-3290.
[3] Vij R, Wang M, Orlowski R, et al. Initial results of PX-171-004, an open-label, single-arm, phase II study of carfilzommib (CFZ) in patients with relapsed myeloma (MM). Blood. 2008;112:320, abstract number 865.
[4] Jagannath S, Vij R, Stewart AK, et al. Initial results of PX-171-003, an open-labele, single-arm, phase II study of carfilzomib (CFZ) in patients with relapsed and refractory multiple myeloma (MM). Blood. 2008;112:319, abstract number 864.
[5] Schey SA, Field SP, Bartlett JB, et al. Phase I study of an immunomodulator thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. Journal of Clinical Oncology. 2008;22:3269-3276.
[6] Streetly MJ, Gyertson K, Daniel Y, et al. Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation. British Journal of Haematology. 2008;141:41-51.
[7] Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone (Pom/dex) is highly effective therapy in relapsed multiple myeloma. Blood. 2008;112:320, abstract number 866.
[8] Voorhees PM, Chen O, Kuhn DJ, et al. Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma. Clinical Cancer Research. 2007;13:6469-6478.
[9] Rossi J-F, Manges RF, Sutherland HJ, et al. Preliminary results of CNTO 328, an anti-interleukin-6 monoclonal antibody, in combination with bortezomib in the treatment of relapsed or refractory multiple myeloma. Blood. 2008;112:320, abstract number 867.
[10] Richardson P, Wolf J, Jakubowiak et al. Phase I/II results of a multicenter trial of perisosine (KRX-0401) + bortezomib in patients with relapsed or relapsed/refractory multiple myeloma who were previously relapsed from or refractory to bortezomib. Blood. 2008;112:321, abstract number 870.
Zolinza™ (vorinostat) and Velcade®
Zolinza is a histone deacetylase inhibitior that is being tested in a variety of lymphoid malignances. On October 6, 2006, the U.S. Food and Drug Administration approved Zolinza for the treatment of the cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients with progressive, persistent, or recurrent disease following two systemic therapies. At ASH 2008, U.S. researchers reported that the combination of Zolinza™ (vorinostat) and Velcade® (bortezomib) is active for the treatment of relapsed/refractory myeloma.[1] There were 34 patients with relapsed/refractory myeloma in this study. The partial response rate was 26%, with an additional 21% having a minimal response and 53% having stable disease. Dexamethasone was added to Zolinza and Velcade in 21 additional patients. Two achieved a very good partial response, seven had a partial response, and 10 had stable disease. These authors concluded that the combination of Zolinza and Velcade was active even in patients previously treated with Velcade.
Carfilzomib and Dexamethasone
Carfilzomib is a novel, irreversible, epoxomicin-related proteasome inhibitor. Carfilzomib currently has orphan drug status for the treatment of multiple myeloma. Preclinical studies have shown that carfilzomib can overcome the resistance of myeloma cells to conventional agents and acts synergistically with dexamethasone.[2] At ASH 2008 researchers involved in a U.S. multi-center trial (PX-171-004) reported that carfilzomib and dexamethasone was a promising new agent for the treatment of myeloma.[3] There were 31 patients with relapsed myeloma in this study. Eighty-seven percent had received a prior stem cell transplant. For 13 patients who had not received Velcade, the overall response rate was 54%, including one complete response, two very good partial responses, and four partial responses; four patients had stable disease. Sixteen patients had received prior treatment with Velcade, and 19% achieved a partial response. One patient had a minimal response, and nine had stable disease.
A second study (PX-171-003) evaluated carfilzomib in 39 patients, all of whom had received prior treatment with Velcade; in addition, 89% had received a prior stem cell transplant.[4] The clinical benefit rate was 26%, including five patients with a partial response.
Carfilzomib will undoubtedly be evaluated in patients with less advanced disease and probably compared with Velcade for up-front treatment of myeloma.
Pomalidomide (CC4047)
Pomalidomide is an oral analog of thalidomide with significant immunomodulatory effects. It stops the growth of blood vessels, stimulates the immune system, and may directly kill cancer cells. Pomalidomide is also an inhibitor of angiogenesis. A Phase I study showed a complete remission rate of 17% in patients with relapsed or refractory myeloma with daily pomalidomide.[5] Fifty-four percent of patients in this study had a 50% or greater decrease in paraprotein. The main side effects were deep vein thrombosis, which occurred early and late. A Phase II study used an alternate day regimen of pomalidomide in an attempt to decrease thrombotic side effects.[6] The alternate day schedule appeared to eliminate thrombotic complications. There were 20 patients in this study, and the complete response rate was 10%; a greater than 50% reduction in paraprotein was achieved in half the patients. At ASH 2008 daily pomalidomide and low-dose dexamethasone were evaluated in 37 patients with relapsed or refractory myeloma.[7] All patients receive aspirin for prophylaxis against thrombotic complications. Seventy-six percent of patients had received a prior stem cell transplant, and 62% had received Thalomid® (thalidomide) or Revlimid® (lenalidomide). The overall response rate was 62%, and 24% had a very good partial response. The response was 29% in patients who had received prior Revlimid. Pomalidomide promises to be a rival of Revlimid and Thalomid in the treatment of patients with myeloma.
CNTO 328
CNTO 328 is a chimeric monoclonal antibody that specifically binds to and neutralizes human IL-6 with high affinity. A Phase I study has been performed in patients with lymphoma and myeloma. Preclinical studies suggest synergy of CNTO with Velcade.[8] At ASH 2008 researchers involved in a U.S. multi-center trial reported that the combination of Velcade and CNTO 328 was active in patients with relapsed or refractory myeloma.[9] This study included 21 patients, of whom 11 had received a prior stem cell transplant and eight had received prior Velcade or Thalomid. Fifty-seven percent achieved a partial or complete remission, and the median time to disease progression was 280 days. These authors will be performing a trial of Velcade plus CNTO 328 versus Velcade and placebo.
Velcade® and Perifosine
Researchers from several U.S. institutions have reported a 40% overall response rate to the combination of perifosine and Velcade® (bortizomib) in patients with multiple myeloma who had been previously treated with Velcade.[10] Perifosine belongs to a new class of anti-tumor drugs that targets cell membranes, inhibits Akt activation, and induces apoptosis.
The current study involved the treatment of 76 patients with relapsed/refractory multiple myeloma treated with perifosine and Velcade with or without dexamethasone. All patients had received prior therapy with Velcade and 35 were deemed refractory to Velcade. Fifty-seven patients in this study were evaluable for response. The overall response rate was 40%, with 30% having stable disease. The median time to tumor progression for all patients was 19 weeks, while the median time to tumor progression for responders had not been achieved. The overall response rate for patients deemed refractory to Velcade was 37%, and the median time to tumor progression was 23 weeks. The combination of Velcade and perifosine was described as well tolerated. These data suggest that pirifosine may be a new useful agent for the treatment of patients with myeloma.
Comments: It appears that new and novel agents for the treatment of multiple myeloma are continuing to be developed at a relatively rapid rate; many of these may have a major impact on future therapy.
References:
[1] Weber D, Badros AZ, Jagannath S, et al. Vorinostat plus bortezomib for the treatment of relapsed/refractory multiple myeloma: Early clinical experience. Blood. 2008;112:322, abstract number 871.
[2] Kuhn DJ, Chen O, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2008;110:3281-3290.
[3] Vij R, Wang M, Orlowski R, et al. Initial results of PX-171-004, an open-label, single-arm, phase II study of carfilzommib (CFZ) in patients with relapsed myeloma (MM). Blood. 2008;112:320, abstract number 865.
[4] Jagannath S, Vij R, Stewart AK, et al. Initial results of PX-171-003, an open-labele, single-arm, phase II study of carfilzomib (CFZ) in patients with relapsed and refractory multiple myeloma (MM). Blood. 2008;112:319, abstract number 864.
[5] Schey SA, Field SP, Bartlett JB, et al. Phase I study of an immunomodulator thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. Journal of Clinical Oncology. 2008;22:3269-3276.
[6] Streetly MJ, Gyertson K, Daniel Y, et al. Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation. British Journal of Haematology. 2008;141:41-51.
[7] Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone (Pom/dex) is highly effective therapy in relapsed multiple myeloma. Blood. 2008;112:320, abstract number 866.
[8] Voorhees PM, Chen O, Kuhn DJ, et al. Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma. Clinical Cancer Research. 2007;13:6469-6478.
[9] Rossi J-F, Manges RF, Sutherland HJ, et al. Preliminary results of CNTO 328, an anti-interleukin-6 monoclonal antibody, in combination with bortezomib in the treatment of relapsed or refractory multiple myeloma. Blood. 2008;112:320, abstract number 867.
[10] Richardson P, Wolf J, Jakubowiak et al. Phase I/II results of a multicenter trial of perisosine (KRX-0401) + bortezomib in patients with relapsed or relapsed/refractory multiple myeloma who were previously relapsed from or refractory to bortezomib. Blood. 2008;112:321, abstract number 870.
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