- Email: [email protected]
Histone deacetylase inhibitors in multiple myeloma
Comment
With regard to chemotherapy duration, Jones and colleagues used a short course of chemotherapy on the basis of the results of a randomised trial4 by the same group, in which four cycles of docetaxel and cyclophosphamide were superior to four cycles of the standard regimen of doxorubicin and cyclophosphamide. However, the optimum duration of adjuvant chemotherapy is an old issue, first investigated by Gianni Bonadonna in 1978.7 More recent studies have reported conflicting results, with some studies of new generation anthracycline-taxane regimens showing improved results with longer chemotherapy administration, whereas others have shown much the same efficacy when four cycles of the doxorubicin and cyclophosphamide were compared with six cycles of the same regimen.8,9 A short-course of an anthracycline-free regimen, as investigated by Jones and colleagues, is a very attractive option; however, the harms of using a potentially less effective regimen, in view of its short duration, and the omission of an anthracycline, a toxic, but very active option in HER2-amplified disease, should be taken into account.3 Risk assessment deserves additional considerations: although the axillary lymph-node status is a strong prognostic factor, some biological factors, such as HER2 status, identify higher risk patients, irrespective of nodal status. As a consequence, the classification of a patient with three involved nodes and HER2amplified disease as at lower risk, as in the study by Jones and colleagues,1 might be harmful and could lead to undertreatment of a subset of patients actually at higher risk of recurrence.10 In conclusion, in view of the study design (phase 2, single group) and the short follow-up (2 years), in our
opinion, the regimen proposed by Jones and colleagues cannot yet be deemed a viable option for patients with HER2-positive breast cancer, irrespective of their risk of recurrence. *Alessandra Gennari, Lucia Del Mastro SC Oncologia Medica, EO Ospedali Galliera, Genova 16128, Italy (AG); and UO Sviluppo Terapie Innovative, Dipartimento di Oncologia, IRCCS AOU San Martino—IST—Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy (LDM) [email protected] We declare that we have no conflicts of interest. 1
2
3
4
5 6
7
8
9
10
Jones SE, Collea R, Paul D, et al. Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study. Lancet Oncol 2013; published online Sept 3. http://dx.doi.org/10.1016/S1470-2045(13)70384-X. Di Leo A, Desmedt C, Bartlett JMS, et al. HER2 and TOP2A as predictive markers for anthracycline- containing chemotherapy regimens as adjuvant treatment of breast cancer: a meta-analysis of individual patient data. Lancet Oncol 2011; 12: 1134–42. Gennari A, Sormani MP, Pronzato P, et al. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 2008; 100: 14–20. Jones SE, Savin MA, Holmes FA, et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 2006; 24: 5381–87. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365: 1273–83. Burstein HJ, Piccart-Gebhart MJ, Perez EA, et al. Choosing the best trastuzumab-based adjuvant chemotherapy regime: should we abandon anthracyclines? J Clin Oncol 2012; 30: 2179–82. Tancini G, Bonadonna G, Valagussa P, Marchini S, Veronesi U. Adjuvant CMF in breast cancer: comparative 5-year results of 12 versus 6 cycles. J Clin Oncol 1983; 1: 2–10. Swain SM, Jong-Hyeon Jeong J, Geyer CE, et al. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med 2010; 362: 2053–65. Shulman LN, Cirrincione CT, Berry DA, et al. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: cancer and leukemia group B 40101. J Clin Oncol 2012; 30: 4071–76. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer, 2013. Ann Oncol 2013; published online Aug 4. DOI:10.1093/annonc/mdt303.
Histone deacetylase inhibitors in multiple myeloma Published Online September 19, 2013 http://dx.doi.org/10.1016// S1470-2045(13)70425-X See Articles page 1129
1038
A hallmark of many tumours is increased deacetylation of histone and non-histone proteins due to an increase in activity of histone deacetylase (HDAC). Various cellular processes are adversely affected by increased histone deacetylation promoting transcriptional suppression and also by deacetylation changing the functions of numerous non-histone proteins. The cellular processes affected include pathways central to cancer pathogenesis such as apoptosis, cell-cycle regulation and differentiation, and several HDAC inhibitors
are being developed for clinical use to reverse these defects. Multiple myeloma is a malignancy of plasma cells within the bone marrow, and has an incurable relapsing and remitting course, despite advances made with new therapies. Preclinical data and early phase trials of the broad HDAC inhibitors vorinostat and panobinostat in multiple myeloma suggested promising antitumour activity with in-vitro synergy with the proteasome inhibitor, bortezomib, and also activity with immunomodulatory drugs such as lenalidomide.1–3 www.thelancet.com/oncology Vol 14 October 2013
Comment
www.thelancet.com/oncology Vol 14 October 2013
Examples of this strategy include ACY-1215, which is a selective HDAC6 inhibitor, that inhibits VEGF pathways and heat-shock protein 90 function, and a prototype novel HDAC3 inhibitor BG45, that triggers myeloma apoptosis; these drugs have promising preclinical activity and improve survival in xenograft mouse models of myeloma.5,6 HDAC inhibitors might be more effective as a continuous therapy in combination with a new drug. The Myeloma XI trial (NCT01554852) is investigating a combination of vorinostat and lenalidomide as a maintenance strategy with patients randomly allocated placebo, lenalidomide, or lenalidomide plus vorinostat and should hopefully address this issue. Dimopoulos and colleagues’ study is important in that it affirms the synergy of the combination of vorinostat and bortezomib in the first phase 3 trial of HDAC inhibitors in multiple myeloma and supports further exploration of HDAC inhibition. Future developments in the specialty include continued exploration of HDAC inhibitors, especially for a more targeted approach using selective HDAC inhibitors, finding optimal partners for HDAC inhibitors in combination therapies, and optimising dose and scheduling. Dimopoulos and colleagues’ study also supports further exploration of HDAC inhibition in other cancers in which early phase trials are showing promise.
Ramon Andrade 3dciencia/Science Photo Library
However as single agents in relapsed-refractory disease, the HDAC inhibitors vorinostat and panobinostat have only shown modest activity at best, with some reports of stabilisation of disease but few objective responses.2 In The Lancet Oncology, Meletios Dimopoulos and colleagues4 report the results of a randomised phase 3, placebo-controlled trial with more than 600 patients that supports the beneficial effect of the addition of a broad spectrum HDAC inhibitor, vorinostat, to bortezomib with significantly improved response compared with bortezomib alone. Bortezomib alone was used as the control arm whereas in clinical practice bortezomib is invariably given in combination with dexamethasone and other drugs—although at the time the study was started the benefit of this combination was less well established. The study raises a number of issues around the efficacy and tolerability of present HDAC inhibitors. Despite the significant improvement in the proportion of patients who had an objective response, the median improvement in progression-free survival (PFS) was only 0·8 months, suggesting that responses are usually not durable. The combination of vorinostat and bortezomib seemed well tolerated with patients receiving a median of seven cycles of treatment but more grade 3–4 thrombocytopenia, fatigue, nausea, and diarrhoea were noted with the combination regimen than with bortezomib alone. Dose reductions were common and might partly explain the lower than expected improvement in PFS. The median age of patients in the trial was 62 years, which is young for a myeloma population and because dose reductions were frequent, revised dosing schedules will be needed for clinical application (especially in a more representative elderly population). Four classes of HDAC enzymes exist, and are classified on the basis of cellular location and function. Different HDAC inhibitors show different patterns of inhibitory activity for these enzymes.2 Improved understanding of HDAC biology in multiple myeloma is key to making improvements in effective targeting of HDAC enzymes relevant to myeloma pathogenesis and to reduce toxicity. Whether broad spectrum inhibition of a wide range of HDACs is necessary for efficacy is not known. Potentially, targeted HDAC inhibition of pathways relevant to myeloma such as aggresome function, VEGF pathways, or heat-shock protein function might offer well tolerated and effective targeted therapy.
Guy Pratt School of Cancer Sciences University of Birmingham, Edgbaston, Birmingham B15 2TT, UK, and Department of Haematology, Birmingham Heartlands Hospital, Birmingham, UK [email protected] I declare that I have no conflicts of interest. 1
2
3
4
5
6
Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA 2004; 101: 540–45. Richardson PG, Mitsiades CS, Laubach JP, et al. Preclinical data and early clinical experience supporting the use of histone deacetylase inhibitors in multiple myeloma. Leuk Res 2013; 37: 829–37. Richardson PG, Schlossman RL, Alsina M, et al. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood 2013; published online Aug 15. DOI:10.1182/blood-2013-01-481325. Dimopoulos M, Siegel DS, Lonial S, et al. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol 2013; published online Sept 19. http://dx.doi.org/10.1016/ S1470-2045(13)70398-X. Santo L, Hideshima T, Kung AL, et al. Preclinical activity, pharmacodynamic and pharmacokinetic properties of a selectiveHDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood 2012; 119: 2579–89. Minami J, Suzuki R, Mazitschek R, et al. Histone deacetylase 3 (HDAC3) as a novel therapeutic target in multiple myeloma. Leukemia 2013; published online Aug 5. DOI:10.1038/leu.2013.231.
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With regard to chemotherapy duration, Jones and colleagues used a short course of chemotherapy on the basis of the results of a randomised trial4 by the same group, in which four cycles of docetaxel and cyclophosphamide were superior to four cycles of the standard regimen of doxorubicin and cyclophosphamide. However, the optimum duration of adjuvant chemotherapy is an old issue, first investigated by Gianni Bonadonna in 1978.7 More recent studies have reported conflicting results, with some studies of new generation anthracycline-taxane regimens showing improved results with longer chemotherapy administration, whereas others have shown much the same efficacy when four cycles of the doxorubicin and cyclophosphamide were compared with six cycles of the same regimen.8,9 A short-course of an anthracycline-free regimen, as investigated by Jones and colleagues, is a very attractive option; however, the harms of using a potentially less effective regimen, in view of its short duration, and the omission of an anthracycline, a toxic, but very active option in HER2-amplified disease, should be taken into account.3 Risk assessment deserves additional considerations: although the axillary lymph-node status is a strong prognostic factor, some biological factors, such as HER2 status, identify higher risk patients, irrespective of nodal status. As a consequence, the classification of a patient with three involved nodes and HER2amplified disease as at lower risk, as in the study by Jones and colleagues,1 might be harmful and could lead to undertreatment of a subset of patients actually at higher risk of recurrence.10 In conclusion, in view of the study design (phase 2, single group) and the short follow-up (2 years), in our
opinion, the regimen proposed by Jones and colleagues cannot yet be deemed a viable option for patients with HER2-positive breast cancer, irrespective of their risk of recurrence. *Alessandra Gennari, Lucia Del Mastro SC Oncologia Medica, EO Ospedali Galliera, Genova 16128, Italy (AG); and UO Sviluppo Terapie Innovative, Dipartimento di Oncologia, IRCCS AOU San Martino—IST—Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy (LDM) [email protected] We declare that we have no conflicts of interest. 1
2
3
4
5 6
7
8
9
10
Jones SE, Collea R, Paul D, et al. Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study. Lancet Oncol 2013; published online Sept 3. http://dx.doi.org/10.1016/S1470-2045(13)70384-X. Di Leo A, Desmedt C, Bartlett JMS, et al. HER2 and TOP2A as predictive markers for anthracycline- containing chemotherapy regimens as adjuvant treatment of breast cancer: a meta-analysis of individual patient data. Lancet Oncol 2011; 12: 1134–42. Gennari A, Sormani MP, Pronzato P, et al. HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 2008; 100: 14–20. Jones SE, Savin MA, Holmes FA, et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol 2006; 24: 5381–87. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011; 365: 1273–83. Burstein HJ, Piccart-Gebhart MJ, Perez EA, et al. Choosing the best trastuzumab-based adjuvant chemotherapy regime: should we abandon anthracyclines? J Clin Oncol 2012; 30: 2179–82. Tancini G, Bonadonna G, Valagussa P, Marchini S, Veronesi U. Adjuvant CMF in breast cancer: comparative 5-year results of 12 versus 6 cycles. J Clin Oncol 1983; 1: 2–10. Swain SM, Jong-Hyeon Jeong J, Geyer CE, et al. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med 2010; 362: 2053–65. Shulman LN, Cirrincione CT, Berry DA, et al. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: cancer and leukemia group B 40101. J Clin Oncol 2012; 30: 4071–76. Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer, 2013. Ann Oncol 2013; published online Aug 4. DOI:10.1093/annonc/mdt303.
Histone deacetylase inhibitors in multiple myeloma Published Online September 19, 2013 http://dx.doi.org/10.1016// S1470-2045(13)70425-X See Articles page 1129
1038
A hallmark of many tumours is increased deacetylation of histone and non-histone proteins due to an increase in activity of histone deacetylase (HDAC). Various cellular processes are adversely affected by increased histone deacetylation promoting transcriptional suppression and also by deacetylation changing the functions of numerous non-histone proteins. The cellular processes affected include pathways central to cancer pathogenesis such as apoptosis, cell-cycle regulation and differentiation, and several HDAC inhibitors
are being developed for clinical use to reverse these defects. Multiple myeloma is a malignancy of plasma cells within the bone marrow, and has an incurable relapsing and remitting course, despite advances made with new therapies. Preclinical data and early phase trials of the broad HDAC inhibitors vorinostat and panobinostat in multiple myeloma suggested promising antitumour activity with in-vitro synergy with the proteasome inhibitor, bortezomib, and also activity with immunomodulatory drugs such as lenalidomide.1–3 www.thelancet.com/oncology Vol 14 October 2013
Comment
www.thelancet.com/oncology Vol 14 October 2013
Examples of this strategy include ACY-1215, which is a selective HDAC6 inhibitor, that inhibits VEGF pathways and heat-shock protein 90 function, and a prototype novel HDAC3 inhibitor BG45, that triggers myeloma apoptosis; these drugs have promising preclinical activity and improve survival in xenograft mouse models of myeloma.5,6 HDAC inhibitors might be more effective as a continuous therapy in combination with a new drug. The Myeloma XI trial (NCT01554852) is investigating a combination of vorinostat and lenalidomide as a maintenance strategy with patients randomly allocated placebo, lenalidomide, or lenalidomide plus vorinostat and should hopefully address this issue. Dimopoulos and colleagues’ study is important in that it affirms the synergy of the combination of vorinostat and bortezomib in the first phase 3 trial of HDAC inhibitors in multiple myeloma and supports further exploration of HDAC inhibition. Future developments in the specialty include continued exploration of HDAC inhibitors, especially for a more targeted approach using selective HDAC inhibitors, finding optimal partners for HDAC inhibitors in combination therapies, and optimising dose and scheduling. Dimopoulos and colleagues’ study also supports further exploration of HDAC inhibition in other cancers in which early phase trials are showing promise.
Ramon Andrade 3dciencia/Science Photo Library
However as single agents in relapsed-refractory disease, the HDAC inhibitors vorinostat and panobinostat have only shown modest activity at best, with some reports of stabilisation of disease but few objective responses.2 In The Lancet Oncology, Meletios Dimopoulos and colleagues4 report the results of a randomised phase 3, placebo-controlled trial with more than 600 patients that supports the beneficial effect of the addition of a broad spectrum HDAC inhibitor, vorinostat, to bortezomib with significantly improved response compared with bortezomib alone. Bortezomib alone was used as the control arm whereas in clinical practice bortezomib is invariably given in combination with dexamethasone and other drugs—although at the time the study was started the benefit of this combination was less well established. The study raises a number of issues around the efficacy and tolerability of present HDAC inhibitors. Despite the significant improvement in the proportion of patients who had an objective response, the median improvement in progression-free survival (PFS) was only 0·8 months, suggesting that responses are usually not durable. The combination of vorinostat and bortezomib seemed well tolerated with patients receiving a median of seven cycles of treatment but more grade 3–4 thrombocytopenia, fatigue, nausea, and diarrhoea were noted with the combination regimen than with bortezomib alone. Dose reductions were common and might partly explain the lower than expected improvement in PFS. The median age of patients in the trial was 62 years, which is young for a myeloma population and because dose reductions were frequent, revised dosing schedules will be needed for clinical application (especially in a more representative elderly population). Four classes of HDAC enzymes exist, and are classified on the basis of cellular location and function. Different HDAC inhibitors show different patterns of inhibitory activity for these enzymes.2 Improved understanding of HDAC biology in multiple myeloma is key to making improvements in effective targeting of HDAC enzymes relevant to myeloma pathogenesis and to reduce toxicity. Whether broad spectrum inhibition of a wide range of HDACs is necessary for efficacy is not known. Potentially, targeted HDAC inhibition of pathways relevant to myeloma such as aggresome function, VEGF pathways, or heat-shock protein function might offer well tolerated and effective targeted therapy.
Guy Pratt School of Cancer Sciences University of Birmingham, Edgbaston, Birmingham B15 2TT, UK, and Department of Haematology, Birmingham Heartlands Hospital, Birmingham, UK [email protected] I declare that I have no conflicts of interest. 1
2
3
4
5
6
Mitsiades CS, Mitsiades NS, McMullan CJ, et al. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc Natl Acad Sci USA 2004; 101: 540–45. Richardson PG, Mitsiades CS, Laubach JP, et al. Preclinical data and early clinical experience supporting the use of histone deacetylase inhibitors in multiple myeloma. Leuk Res 2013; 37: 829–37. Richardson PG, Schlossman RL, Alsina M, et al. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood 2013; published online Aug 15. DOI:10.1182/blood-2013-01-481325. Dimopoulos M, Siegel DS, Lonial S, et al. Vorinostat or placebo in combination with bortezomib in patients with multiple myeloma (VANTAGE 088): a multicentre, randomised, double-blind study. Lancet Oncol 2013; published online Sept 19. http://dx.doi.org/10.1016/ S1470-2045(13)70398-X. Santo L, Hideshima T, Kung AL, et al. Preclinical activity, pharmacodynamic and pharmacokinetic properties of a selectiveHDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood 2012; 119: 2579–89. Minami J, Suzuki R, Mazitschek R, et al. Histone deacetylase 3 (HDAC3) as a novel therapeutic target in multiple myeloma. Leukemia 2013; published online Aug 5. DOI:10.1038/leu.2013.231.
1039