This month we will be focusing on data from the recent 12th International Myeloma Workshop (IMW) 2009. This meeting was held on February 26 - March 1, 2009 in Washington, DC. A large amount of information from that meeting was covered for you during our Best of the Day program from the IMW. I would encourage you to view those interviews to gain the perspective of a number of the national thought leaders in multiple myeloma.

“Best of the Day^SM from the 12th International Myeloma Workshop”

Novel Agents and Combinations

We will now focus on novel agents and novel combinations discussed at the IMW meeting. Tremendous advances have been made in the management of multiple myeloma over the past 2 decades with autologous-SCT and the development of immunomodulatory compounds and proteasome inhibitors, but myeloma remains incurable for the vast majority of patients. Continued research into novel agents and combinations that could perhaps lead to very durable CRs in the future remains important.

During this year’s IMW meeting there were updates on the phase II trials being performed with the novel proteasome inhibitor, carfilzomib. These trials are evaluating the benefit of carfilzomib in patients with relapsed myeloma and also in the relapsed/refractory patients. Carfilzomib is strongly synergistic with dexamethasone, activates caspase 8, 9 and 3 and is capable of overcoming bortezomib resistance. Peripheral neuropathy, fatigue and nausea are said to be less with carfilzomib than with bortezomib.

In patients with relapsed myeloma (Abstract 493) and a median of 2 prior treatment regimens the ORR rate as reported by Dr Ravi Vij in bortezomib naïve patients was 54%, including 1 CR, 2 VGPRs and 4 PRs. In those patients previously treated with bortezomib, the partial response (PR) rate was 19%, with 6% major responses (MRs).

Dr Sundar Jagannath reported the results of another phase II study (Abstract 377) of patients with relapsed/refractory myeloma and a median of 5 prior treatment regimens. The clinical cenefit rate (CBR) was 26% of the 39 evaluable patients, which included 5 PRs and 5 MRs. Forty-one percent of those patients achieved stable disease. For the PR/MR patients, the TTP was 219 days compared to 72 days for non-responders.

Drs David Siegel and Donna Weber reported the results of phase I/II studies combining the HDAC inhibitor, vorinostat, with bortezomib (Abstracts 241, 242 & 248). Pre-clinical studies suggested that vorinostat was capable of enhancing the pro-apoptotic effects of other anti-MM drugs. In heavily pre-treated myeloma populations 26% of patients achieved PR, 21% minor response (MR) and 53% stable disease (SD). Adverse events included nausea, diarrhea, vomiting and thrombocytopenia. The recommended phase II dose was vorinostat 400mg daily with bortezomib 1.3 mg/m² twice a week. A nearly 800 patient phase III study was recently initiated randomizing patients with myeloma with 1-3 previous treatments to bortezomib with or without vorinostat.

Another HDAC inhibitor, LBH589 or panobinostat, is also being evaluated in relapsed myeloma. Two abstracts report the results of 2 phase I trials combining panobinostat with lenalidomide (#329) or bortezomib (#337). The trial combining of lenalidomide, dexamethasone and panobinostat is ongoing and the combination appears to be well tolerated at dose level 2. The combination of bortezomib and panobinostat is also proving to be safe and well tolerated. Dr Paul Richardson reported at the IMW meeting that overall response rates to this combination are in the 50% range with some CRs and VGPRs being seen.

Another interesting combination currently being evaluated is that of bortezomib plus heat shock protein 90 (HSP90) inhibitors. HSP90 is upregulated by bortezomib. When a HSP90 inhibitor, such as tanespimycin, is combined with bortezomib a synergistic effect is seen. A phase III trial is ongoing in previously treated patients with myeloma randomizing them to bortezomib with or without tanespimycin. Studies combining lenalidomide with HSP90 inhibitors are also underway.

A phase I/II trial of the Akt inhibitor perifosine plus bortezomib was presented by Dr Paul Richardson for a multi-center group of investigators (Abstract 347). Perifosine is an oral signal transduction modulator that inhibits Akt. Akt has been shown to be upregulated by bortezomib. Patients with myeloma with at least 1 prior therapy were eligible. Eighty-four patients including 18 in the phase I portion of the study were treated. Eighty-six percent of the patients had relapsed/refractory disease with a median of 5 prior treatments. All patients had previous exposure to bortezomib. Seventy-three patients completed at least 2 cycles of therapy and were evaluable for response. The ORR in patients who were bortezomib relapsed was 55%, in patients who were bortezomib refractory 32% and for all evaluable patients 38%. Median TTP for all evaluable patients was 6.4 months.

Data was also presented regarding a novel monoclonal antibody which targets CS1, a cell surface glycoprotein highly expressed on all myeloma cells. A phase I trial of elotuzumab in combination with bortezomib was presented by Dr Andrej Jakubowiak from the University of Michigan (Abstract 264). All patients had relapsed myeloma with 1-3 prior regimens. Treatment was well tolerated with a number of responses seen in the first 3 cohorts.

Dr Sagar Lonial from Emory University also presented the results of a phase Ib trial combining elotuzumab with lenalidomide and dexamethasone in relapsed myeloma. This study is ongoing, but early results have shown no unexpected adverse events and objective responses in 4 of the first 6 patients treated.

OncoFacts™ Editor:

James Epstein, MD

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