Bortezomib is a treatment option for patients (pts) with newly diagnosed and relapsed multiple myeloma (MM). However, many patients ultimately relapse or become refractory to bortezomib and there is a need for more effective and well-tolerated treatment strategies after failure of prior bortezomib-based regimens. Vorinostat, a novel inhibitor of Class I and II histone deacetylase (HDAC), was the first FDA-approved HDAC inhibitor for the treatment of cutaneous manifestations of advanced T-cell lymphoma in pts with progressive, persistent or recurrent disease on, or following, two prior systemic therapies. In preclinical models of MM, vorinostat has demonstrated antiproliferative and proapoptotic activity alone and in combination with bortezomib. Preliminary results from an ongoing Phase I trial have shown that oral vorinostat in combination with bortezomib is effective in pretreated pts with MM, including some pts previously treated with bortezomib (

Weber et al. Haematologica 2008;93(S1):0640
). This case series reports on our clinical experience with six pts with MM who failed previous bortezomib therapy and were subsequently treated with vorinostat in combination with bortezomib. Six pts received vorinostat 300 mg once daily (Days 1–14) combined with bortezomib 1.3 mg/m2 on Days 1, 4, 8, and 11 in a 21-day cycle. Pt 1, (male; aged 53 yrs) had Stage IV IgAl MM, and had failed an autologous and allogeneic bone marrow transplant (BMT) and was refractory to prior therapy with dexamethasone, cyclophosphamide, etoposide, cisplatin and bortezomib. This patient achieved a minor response (MR) for 12 mths with vorinostat and bortezomib combination therapy. Pt 2 (male; aged 56 yrs) had relapsed Stage III IgAk MM, and had experienced disease progression on previous bortezomib and liposomal doxorubicin therapy and failed a subsequent autologous BMT. Treatment with vorinostat and bortezomib resulted in a very good partial remission for 8 mths. Pt 3 (female; aged 62 yrs) had relapsed Stage III IgAl relapsed MM, and had previously failed bortezomib/lenalidomide and bortezomib/liposomal doxorubicin therapy. Initiation of vorinostat and bortezomib combination therapy resulted in an MR of 3 mths. The remaining three pts in this case series had all relapsed after prior thalidomide or a combination of bortezomib/lenalidomide and an autologous BMT. Two of these pts had Stage II MM (Pt 4: female, aged 60 yrs, IgAk; Pt 5: male, aged 54 yrs, IgAl) and one female pt (aged 45 yrs) had Stage III IgAk disease. All three pts responded to vorinostat plus bortezomib combination therapy; Pt 4 experienced stable disease for 3 mths, whilst Pts 4 and 5 have shown MR for 2 and 4 mths, respectively. For each, the number of treatment cycles received matched the duration of response. In these six pts, vorinostat and bortezomib was generally well tolerated, with Grade 2 nausea and diarrhea as the only adverse events reported. This case series documents the clinical application of vorinostat in combination with bortezomib and suggests this combination of vorinostat is effective in pts with relapsed and/or refractory MM after failure of prior bortezomib-based regimens. Randomized clinical trials are warranted to evaluate the efficacy of this combination in this population.

PatientAgeStage/IgRelapsed/refractoryPrior treatmentResponseDuration of response (months)
1 53 IV/IgAl Refractory Auto/allo BMT DCEP/bortezomib MR 12 
2 56 III/IgAk Relapsed Bortezomib/liposomal doxorubicin Auto BMT VGPR 8 
3 62 II/IgGl Relapsed Bortezomib/lenalidomide bortezomib/liposomal doxorubicin therapy MR 3 
4 60 II/IgGk Relapsed Thalidomide or lenalidomide/bortezomib auto BMT SD 3 
5 54 II/IgGl Relapsed Thalidomide or lenalidomide/bortezomib auto BMT MR 2 
6 45 III/IgGk Relapsed Thalidomide or lenalidomide/bortezomib auto BMT MR 4 
PatientAgeStage/IgRelapsed/refractoryPrior treatmentResponseDuration of response (months)
1 53 IV/IgAl Refractory Auto/allo BMT DCEP/bortezomib MR 12 
2 56 III/IgAk Relapsed Bortezomib/liposomal doxorubicin Auto BMT VGPR 8 
3 62 II/IgGl Relapsed Bortezomib/lenalidomide bortezomib/liposomal doxorubicin therapy MR 3 
4 60 II/IgGk Relapsed Thalidomide or lenalidomide/bortezomib auto BMT SD 3 
5 54 II/IgGl Relapsed Thalidomide or lenalidomide/bortezomib auto BMT MR 2 
6 45 III/IgGk Relapsed Thalidomide or lenalidomide/bortezomib auto BMT MR 4 
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Topics:
bortezomib, multiple myeloma, vorinostat, brachial plexus neuritis, liposomes, lenalidomide, doxorubicin, thalidomide, combined modality therapy, bone marrow transplantation, allogeneic

Disclosures: Mazumder:Millennium: Honoraria; Celgene: Honoraria. Off Label Use: Vorinostat is a histone deacetylase (HDAC) inhibitor that was approved in the FDA in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease on or following two systemic therapies. Vesole:Millennium: Speakers Bureau; Merck: Stock ownership.

2008, The American Society of Hematology
2008
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