Quick Poll results from the November Issue of OncoFacts 2010

In the past several years, a number of novel agents have been approved for use in the management of multiple myeloma. These, of course, include bortezomib, thalidomide, lenalidomide, and pegylated liposomal doxorubicin. However, there are many new agents under investigation for multiple myeloma, and hopefully a number of these novel agents will become clinically available within the next few years. Below is a list of agents currently in phase II or phase III trials for multiple myeloma: Carfilzomib Tanespimycin Perifosine Elotuzumab Pomalidomide Vorinostat How familiar are you with these agents?

I am very familiar with all of these agents
5.42%  5.42%
I am somewhat familiar with all of these agents
5.83%  5.83%
I am familiar with some, but not all of these agents
24.58%  24.58%
I have heard of most of these agents but am not particularly knowledgeable of them
16.25%  16.25%
I have heard of only a couple of these agents
34.17%  34.17%
I am unaware of all of these agents
13.75%  13.75%

Discussion

Carfilzomib is a novel proteasome inhibitor, which unlike bortezomib, causes prolonged irreversible inhibition of the proteasome. In phase II trials, in heavily pre-treated relapsed and refractory myeloma, carfilzomib has yielded combined partial response (PR) and minimal response (MR) rates of 26%.1 In myeloma patients with 3 or fewer previous lines of therapy, the overall response rate (ORR) was 35.5%.2 In bortezomib naïve patients, ORR = 57% and in patients with prior bortezomib therapy, ORR was 18%. These studies are ongoing with further results to be presented in the future.

Tanespimycin is a heat shock protein (HSP) 90 inhibitor. Heat shock protein 90 is a chaperone protein that helps maintain the stability and functional shape of many oncogenic signaling proteins. Inhibition of HSP90 promotes proteasomal degradation of these proteins. Heat shock protein 90 is over-expressed in myeloma and is further upregulated in myeloma cells on exposure to bortezomib. Tanespimycin and bortezomib in combination induce synergistic killing of myeloma cells in vitro. A phase II trial led by Paul Richardson from the Dana-Farber Cancer Institute using the combination of tanespimycin and bortezomib demonstrated durable anti-myeloma activity in both bortezomib refractory and bortezomib naïve myeloma patients.3 A phase III trial of bortezomib plus tanespimycin versus bortezomib alone in relapsed myeloma is ongoing.

Perifosine is a novel oral anti-cancer agent that modulates Akt, and a number of other key signal transduction pathways, including the JNK and MAPK pathways, all of which are pathways associated with programmed cell death, cell growth, cell differentiation and cell survival. Bortezomib has been shown in pre-clinical studies to activate Akt. In combination with dexamethasone, perifosine has demonstrated activity in advanced relapsed/refractory myeloma.4 At the ASH 2008 meeting, Paul Richardson reported the results of a phase I/II trial of perifosine plus bortezoimib in 76 heavily pre-treated patients who were either refractory to bortezomib or relapsed following treatment with bortezomib.5 The ORR was 37% to 40% in this heavily pre-treated group of myeloma patients. A phase III trial comparing bortezomib-dexamethasone-placebo versus bortezomib-dexamethasone-perifosine is planned.

Elotuzumab (HuLuc 63) is a humanized monoclonal antibody that binds to CS1, a cell surface glycoprotein that is highly expressed on myeloma cells but minimally expressed on normal human cells. Elotuzumab may also induce anti-tumor effects through antibody-dependent cellular cytotoxicity activity on myeloma cells. Elotuzumab has shown activity in phase I trials in refractory myeloma and is currently in phase II trials in combination with bortezomib.6

Pomalidomide (CC4047) is a third generation oral IMiD in clinical trials for multiple myeloma. A phase II trial of the combination of pomalidomide and dexamethasone in relapsed and refractory MM was recently reported by the Mayo Clinic group in the Journal of Clinical Oncology.7 Sixty-three percent of patients achieved a complete response (CR). Responses were seen in 40% of the lenalidomide-refractory patients, 37% of the thalidomide-refractory patients and 60% of the bortezomib-refractory patients. Forty percent of patients experience peripheral neuropathy but almost all cases were grade 1 or 2. All patients received prophylactic aspirin 325 mg daily.

Vorinostat (SAHA) is an histone deacetylase inhibitor already approved by the US Food and Drug Administration (FDA) for T-cell lymphoma. Vorinostat has been shown to have activity in relapsed/refractory myeloma with ORR = 38% to 43% in phase II studies. Responses rates in myeloma patients with prior bortezomib exposure were 29% to 38%.8 Trials are ongoing combining vorinostat with bortezomib and with lenalidomide.

  
References:
1. Jagannath S, Vij R, Stewart AK, et al. Initial results of PX-171-003, an open-label, single-arm, phase II study of carfilzomib (CFZ) in patients with relapsed and refractory multiple myeloma (MM). Blood. 2008;112(11). Abstract 864.
2. Vij R, Wang M, Orlowski R, et al. Initial results of PX-171-004, an open-label, single-arm, phase II study of carfilzomib (CFZ) in patients with relapsed myeloma (MM). Blood. 2008;112(11). Abstract 865.
3. Richardson PG, Chanan-Khan A, Lonial S, et al. Tanespimycin (T) + bortezomib (BZ) in multiple myeloma (MM): Confirmation of the recommended dose using a novel formulation. Blood. 2007;110(11). Abstract 1165.
4. Richardson P, Lonial S, Jakubowiak A, et al. Multi-center phase II study of perifosine (KRX-0401) alone and in combination with dexamethasone (dex) for patients with relapsed or relapsed/refractory multiple myeloma (MM): promising activity as combination therapy with manageable toxicity. Blood. 2007;110(11). Abstract 1164.
5. Richardson P, Wolf J, Jakubowiak A, et al. Phase I/II results of a multicenter trial of perifosine (KRX-0401) + bortezomib in patients with relapsed or relapsed/refractory multiple myeloma who were previously relapsed from or refractory to bortezomib. Blood. 2008;112(11). Abstract 870.
6. ClinicalTrials.gov. A phase 1/2 , multi-center, open-label, dose escalation study of elotuzumab (humanized anti-S1 monocolonal IgG1 antibody) and bortezomib in subjects with multiple myeloma following one to three prior therapys. (HuLuc63-1702). Available from: http://www.clinicaltrials.gov/ct2/show/NCT00726869?term=elotuzumab+bortezomib&rank=1. Accessed November 2, 2009.
7. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009;27(30):5008-5014.
8. 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(11). Abstract 871.

* The aggregate results from this question were compiled from the responses submitted by oncologists who participated in the OncoFacts Quick Poll monthly question.