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Bortezomib in combination with dexamethasone for relapsed multiple myeloma
Leukemia Research 29 (2005) 587–590
Bortezomib in combination with dexamethasone for relapsed multiple myeloma Martin H. Kropffa,1 , Guido Bispinga,1 , Doris Wenninga , Sarah Volpertb , Jo¨elle Tchindab , Wolfgang E. Berdela , Joachim Kienasta,∗ a
Department of Medicine/Hematology and Oncology, University of M¨unster, Albert-Schweitzer-Str. 33, 48149 M¨unster, Germany b Department of Human Genetics, University of M¨ unster, Vesaliusweg 12-14, 48149 Muenster, Germany Received 4 August 2004; accepted 2 November 2004 Available online 15 January 2005
Abstract Fifteen patients with advanced multiple myeloma were scheduled to receive bortezomib 1.3 mg/m2 IV days 1, 4, 8, and 11 every 3 weeks for eight cycles in combination with dexamethasone. One patient (7%) achieved a complete response, 10 (67%) a partial response, and one (7%) a minor response (MR) resulting in an overall response rate (≥MR) of 80% (9/9 with ≥ 2nd untreated and 3/6 with refractory relapse). Responses occurred after a median of 3 weeks and were independent of conventional prognostic parameters including deletion of chromosome 13. Adverse events, mainly myelosuppression, neuropathy and fatigue, were manageable. © 2004 Elsevier Ltd. All rights reserved. Keywords: Multiple myeloma; Bortezomib; Dexamethasone
1. Introduction Single agent bortezomib treatment at the dosage and schedule published by Richardson et al. [1] stabilizes disease in nearly 60% of patients with relapsed, refractory multiple myeloma (MM). However, only 35% of patients achieve an objective (≥minor) response. In a subsequent randomized comparison with pulsed dexamethasone, bortezomib therapy was associated with a highly significant prolongation of the time to myeloma progression and a longer overall survival [2]. Dexamethasone adds to clinical anti-myeloma activity of bortezomib by inducing 18% responses in patients with either stable or progressive disease on bortezomib alone [1]. Moreover, preclinical evidence suggests additive effects when dexamethasone is combined with bortezomib in multiple myeloma and acute lymphoblastic leukemia [3,4]. ∗ 1
Corresponding author. Tel.: +49 251 83 52801; fax: +49 251 83 52804. E-mail address: [email protected] (J. Kienast). These two authors contributed equally to the manuscript.
0145-2126/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2004.11.004
In an attempt to improve disease response, we evaluated a primary bortezomib/dexamethasone combination in patients with multiple myeloma in ≥ 2nd untreated or refractory relapse.
2. Material and methods 2.1. Study group In an exploratory pilot trial, 15 consecutive patients with multiple myeloma in ≥ 2nd untreated (n = 9) or refractory (n = 6) relapse were treated with bortezomib in combination with dexamethasone. Eligible patients had not been pretreated with bortezomib, were 18–80 years old, had an ECOG performance status of 0–2, and adequate renal, hepatic, pulmonary, and cardiac function. Pre-existing peripheral neuropathy ≥ grade 2 or neuropathic pain of any grade were exclusion criteria. Bone marrow specimens for cytogenetic analyses (karyotyping and FISH) were drawn from all patients prior to enrolment. The study was conducted in
588
M.H. Kropff et al. / Leukemia Research 29 (2005) 587–590
accordance with the Declaration of Helsinki including all current amendments, and the study protocol was approved by the local ethics committee. Written informed consent was obtained from all patients. 2.2. Therapy Patients were scheduled to receive up to eight 3-week treatment cycles of bortezomib (1.3 mg/m2 as a single bolus IV on days 1, 4, 8, 11) followed by a 10-day rest period (days 12 through 21). In addition, the patients received dexamethasone 20 mg PO once daily on the day of bortezomib injection and the day thereafter (days 1, 2, 4, 5, 8, 9, 11, and 12). 2.3. Dose modifications Adverse events were graded according to the National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE), Version 3.0 (cancer therapy evaluation programme, Department of Health and Human Services, December 2003. http://ctep.cancer.gov). Treatment was withheld for ≥ grade 3 non-hematologic adverse events (apart from neuropathy). Once toxicity had resolved, treatment with bortezomib was resumed at a 25% reduced dose. For neuropathy of grade 1 with pain or grade 2, bortezomib was immediately reduced by 25%. For neuropathy of grade 2 with pain or grade 3, bortezomib was withheld until resolution and reinitiated with a reduced dose of bortezomib at 0.7 mg/m2 and a once weekly schedule. Treatment was not stopped for myelosuppression of any grade if interim response evaluations precluded myeloma progression as the cause of cytopenia. 2.4. Definition of response The EBMT/IBMTR/ABMTR criteria were used for definition of response [5].
3. Results A total of 15 patients with multiple myeloma in ≥ 2nd untreated (n = 9) or refractory (n = 6) relapse received a median number of four cycles of bortezomib/dexamethasone (range 2–8). Patient demographics and baseline disease characteristics are shown in Table 1. One patient with refractory relapse achieved a complete response (7%). Ten patients (67%) had a partial response and one (7%) a minor response resulting in an overall response rate of 80% (52–96%, 95% CI) (Table 2). Responders included three of six patients with refractory and all nine patients with untreated relapse. The median time to best response was 3 weeks. No single disease characteristic at baseline was predictive for response to treatment (not shown). Importantly, out of 10 patients with a chromosome 13 deletion, 8 achieved a ≥ partial response.
Table 1 Patient characteristics at baseline Variable
Proportion of patients n
%
Sex (male) 10 Age >60 years 10 >70 years 2 Myeloma type IgG 9 IgA 3 IgD 0 Light chain only 3 Non-secretory 0 Light chain 13 2 Non-secretory 0 Performance status 0 4 1 6 2 4 Serum 2-microglobulin, >3.0 mg/l 3 Bone marrow plasma cells, >50% 12 Abnormal karyotype (n = 14) 6 13 (FISH, n = 14) 9 Duration of prior remission PD under prior regimen 4 ≤3 months 2 4–12 months 7 >12 months 2 Prior myeloma therapy >12 months 14 >60 months 4 No. of prior regimens 1 0 2 5 3 5 4 2 ≥5 3 Prior thalidomide treatment 10 No. of prior high-dose therapies with autologous transplant 0 5 1 5 2 5 3 0 Prior allogeneic transplant 0
67 67 13 60 20 0 20 0 87 13 0 27 40 27 20 80 43 71 27 13 47 13 93 27 0 33 33 13 20 67 33 33 33 0 0
PD: progressive disease. Because of rounding, some percentages do not add to 100.
Table 2 Response to treatment
Complete response Partial response Minor response Stable disease Progressive disease
Number of patients
Proportion of patients (%)
1 10 1 1 2
7 67 7 7 13
Because of rounding, the percentages do not add to 100.
M.H. Kropff et al. / Leukemia Research 29 (2005) 587–590 Table 3 Adverse events Variable (maximum toxicity per patient)
Proportion of patients n
%
Anemia 3 4
2 1
13 7
Neutropenia 3 4
4 1
27 7
Infection 3 4
1 0
7 0
Herpes zoster 2 3
1 1
7 7
Thrombocytopenia 3 4
0 7
0 47
Bleeding
0
0
Neuropathy 2 3 4
3 1 0
20 7 0
Fatigue 1 2 3
3 2 3
20 13 20
Median event free and overall survival were not reached. After a median follow-up of 5 months, 5/15 patients were non-responders (n = 1) or had experienced disease progression (n = 4). Notably, two patients with sustained paraprotein and bone marrow remission had extramedullary myeloma progression. Adverse events are listed in Table 3. Myelosuppression was frequent and profound during the first treatment cycle. However, in responders myelosuppression gradually diminished with subsequent courses. In addition, there was no evidence of cumulative hematologic toxicity even in nonresponders. Forty-four percent of patients required blood cell transfusions during the first cycle; during the second and third cycles the percentages of transfusion dependent patients decreased to 23 and 11%, respectively. There was no case of neutropenic infection or thrombocytopenic bleeding. Only one patient required hospital admission for adverse events. Grade 2–4 cardiac, pulmonary, hepatic, gastrointestinal or renal toxicities were not observed. Neuropathy and fatigue were the most frequent toxicities necessitating dose modifications or cessation of study therapy.
4. Discussion In this cohort of relapsed myeloma patients with a high prevalence of chromosome 13 deletions, treatment with
589
bortezomib in combination with dexamethasone resulted in a high rate of objective remissions suggesting additive antimyeloma activity. The response rate was just as high in patients with a chromosome 13 deletion. This result confirms preclinical data by Zavrski et al. reporting growth inhibition and apoptosis by proteasome inhibitors in human bone marrow myeloma cells irrespective of chromosome 13 deletion [6]. Responses occurred promptly at manageable toxicity. Major adverse events requiring interruption or modification of the schedule comprised fatigue and neuropathy with frequencies and intensities comparable to the data published [1]. Despite less stringent criteria for the inclusion of patients with poor bone marrow reserve, no patients suffered thrombocytopenic bleeding or bacterial infection attributable to neutropenia. Moreover, there was virtually no gastrointestinal toxicity or postural hypotension indicating that the combination of bortezomib with dexamethasone improved tolerability. Though the remission rate was high, remissions often were not durable. This fact underlines the need for consolidating treatment and evaluation of bortezomib combinations with other anti-myeloma agents, such as melphalan, doxorubicin, cyclophosphamide, or thalidomide [7–9]. Moreover, in line with preclinical data indicating an interference of bortezomib with plasma cell/bone marrow stroma interactions [10], the present two cases of extra-medullary disease progression in otherwise responding patients suggest that bortezomib is particularly active in the myeloma/marrow microenvironment. This clinical observation requires attention in future trials. Acknowledgement The authors thank E. Schuck and A. Kruse for excellent patient care and data collection. References [1] Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. New Engl J Med 2003;348:2609–17. [2] Richardson P, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al. Bortezomib vs. dexamethasone in relapsed multiple myeloma: a phase 3 randomized study. In: Annual Meeting Proceedings of the American Society of Clinical Oncology, vol. 23, 2004. p. 558. [3] Leblanc R, Catley LP, Hideshima T, Pien CS, Elliott PJ, Anderson KC. Proteasome inhibitor PS-341 inhibits human multiple myeloma cell growth in a murine model. Blood 2001;98:774a. [4] Horton TM, Plon SE, Blaney SM, DˇıArgenio DZ, Berg SL. Synergistic cytotoxicity of bortezomib (formerly PS-341) and dexamethasone in acute lymphoblastic leukemia. Blood 2003;102:3207a. [5] Blad´e J, Samson D, Reece D, Apperley J, Bj¨orkstrand B, Gahrton G, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and hemopoietic stem cell transplantation. Br J Haematol 1998;102:1115–23.
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M.H. Kropff et al. / Leukemia Research 29 (2005) 587–590
[6] Zavrski I, Naujokat C, Niem¨oller K, Jakob C, Heider U, Langelotz C, et al. Proteasome inhibitors induce growth inhibition and apoptosis in myeloma cell lines and in human bone marrow myeloma cells irrespective of chromosome 13 deletion. J Cancer Res Clin Oncol 2003;129:383–91. [7] Yang HH, Swift R, Sadler K, Vescio R, Adams J, Schenkein D, et al. A phase I/II trial of VELCADE and melphalan combination therapy (Vc+M) for patients with relapsed or refractory multiple myeloma (MM). Blood 2003;102:235a. [8] Orlowski RZ, Voorhees PM, Garcia RA, Hall MD, Lehman MJ, Johri A, et al. Phase I study of the proteasome inhibitor bortezomib in
combination with pegylated liposomal doxorubicin in patients with refractory hematologic malignancies. Blood 2003;102:449a. [9] Zangari M, Barlogie B, Jacobson J, Rasmussen E, Burns M, Kordsmeier B, et al. VTD regimen comprising Velcade (V) + Thalidomide (T) and added DEX (D) for non-responders to V + T effects a 57% PR rate among 56 patients with myeloma (M) relapsing after autologous transplant. Blood 2003;102:236a. [10] Hideshima T, Chauhan D, Hayashi T, Akiyama M, Mitsiades N, Mitsiades C, et al. Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma. Oncogene 2003;22:8386–93.
Bortezomib in combination with dexamethasone for relapsed multiple myeloma Martin H. Kropffa,1 , Guido Bispinga,1 , Doris Wenninga , Sarah Volpertb , Jo¨elle Tchindab , Wolfgang E. Berdela , Joachim Kienasta,∗ a
Department of Medicine/Hematology and Oncology, University of M¨unster, Albert-Schweitzer-Str. 33, 48149 M¨unster, Germany b Department of Human Genetics, University of M¨ unster, Vesaliusweg 12-14, 48149 Muenster, Germany Received 4 August 2004; accepted 2 November 2004 Available online 15 January 2005
Abstract Fifteen patients with advanced multiple myeloma were scheduled to receive bortezomib 1.3 mg/m2 IV days 1, 4, 8, and 11 every 3 weeks for eight cycles in combination with dexamethasone. One patient (7%) achieved a complete response, 10 (67%) a partial response, and one (7%) a minor response (MR) resulting in an overall response rate (≥MR) of 80% (9/9 with ≥ 2nd untreated and 3/6 with refractory relapse). Responses occurred after a median of 3 weeks and were independent of conventional prognostic parameters including deletion of chromosome 13. Adverse events, mainly myelosuppression, neuropathy and fatigue, were manageable. © 2004 Elsevier Ltd. All rights reserved. Keywords: Multiple myeloma; Bortezomib; Dexamethasone
1. Introduction Single agent bortezomib treatment at the dosage and schedule published by Richardson et al. [1] stabilizes disease in nearly 60% of patients with relapsed, refractory multiple myeloma (MM). However, only 35% of patients achieve an objective (≥minor) response. In a subsequent randomized comparison with pulsed dexamethasone, bortezomib therapy was associated with a highly significant prolongation of the time to myeloma progression and a longer overall survival [2]. Dexamethasone adds to clinical anti-myeloma activity of bortezomib by inducing 18% responses in patients with either stable or progressive disease on bortezomib alone [1]. Moreover, preclinical evidence suggests additive effects when dexamethasone is combined with bortezomib in multiple myeloma and acute lymphoblastic leukemia [3,4]. ∗ 1
Corresponding author. Tel.: +49 251 83 52801; fax: +49 251 83 52804. E-mail address: [email protected] (J. Kienast). These two authors contributed equally to the manuscript.
0145-2126/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2004.11.004
In an attempt to improve disease response, we evaluated a primary bortezomib/dexamethasone combination in patients with multiple myeloma in ≥ 2nd untreated or refractory relapse.
2. Material and methods 2.1. Study group In an exploratory pilot trial, 15 consecutive patients with multiple myeloma in ≥ 2nd untreated (n = 9) or refractory (n = 6) relapse were treated with bortezomib in combination with dexamethasone. Eligible patients had not been pretreated with bortezomib, were 18–80 years old, had an ECOG performance status of 0–2, and adequate renal, hepatic, pulmonary, and cardiac function. Pre-existing peripheral neuropathy ≥ grade 2 or neuropathic pain of any grade were exclusion criteria. Bone marrow specimens for cytogenetic analyses (karyotyping and FISH) were drawn from all patients prior to enrolment. The study was conducted in
588
M.H. Kropff et al. / Leukemia Research 29 (2005) 587–590
accordance with the Declaration of Helsinki including all current amendments, and the study protocol was approved by the local ethics committee. Written informed consent was obtained from all patients. 2.2. Therapy Patients were scheduled to receive up to eight 3-week treatment cycles of bortezomib (1.3 mg/m2 as a single bolus IV on days 1, 4, 8, 11) followed by a 10-day rest period (days 12 through 21). In addition, the patients received dexamethasone 20 mg PO once daily on the day of bortezomib injection and the day thereafter (days 1, 2, 4, 5, 8, 9, 11, and 12). 2.3. Dose modifications Adverse events were graded according to the National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE), Version 3.0 (cancer therapy evaluation programme, Department of Health and Human Services, December 2003. http://ctep.cancer.gov). Treatment was withheld for ≥ grade 3 non-hematologic adverse events (apart from neuropathy). Once toxicity had resolved, treatment with bortezomib was resumed at a 25% reduced dose. For neuropathy of grade 1 with pain or grade 2, bortezomib was immediately reduced by 25%. For neuropathy of grade 2 with pain or grade 3, bortezomib was withheld until resolution and reinitiated with a reduced dose of bortezomib at 0.7 mg/m2 and a once weekly schedule. Treatment was not stopped for myelosuppression of any grade if interim response evaluations precluded myeloma progression as the cause of cytopenia. 2.4. Definition of response The EBMT/IBMTR/ABMTR criteria were used for definition of response [5].
3. Results A total of 15 patients with multiple myeloma in ≥ 2nd untreated (n = 9) or refractory (n = 6) relapse received a median number of four cycles of bortezomib/dexamethasone (range 2–8). Patient demographics and baseline disease characteristics are shown in Table 1. One patient with refractory relapse achieved a complete response (7%). Ten patients (67%) had a partial response and one (7%) a minor response resulting in an overall response rate of 80% (52–96%, 95% CI) (Table 2). Responders included three of six patients with refractory and all nine patients with untreated relapse. The median time to best response was 3 weeks. No single disease characteristic at baseline was predictive for response to treatment (not shown). Importantly, out of 10 patients with a chromosome 13 deletion, 8 achieved a ≥ partial response.
Table 1 Patient characteristics at baseline Variable
Proportion of patients n
%
Sex (male) 10 Age >60 years 10 >70 years 2 Myeloma type IgG 9 IgA 3 IgD 0 Light chain only 3 Non-secretory 0 Light chain 13 2 Non-secretory 0 Performance status 0 4 1 6 2 4 Serum 2-microglobulin, >3.0 mg/l 3 Bone marrow plasma cells, >50% 12 Abnormal karyotype (n = 14) 6 13 (FISH, n = 14) 9 Duration of prior remission PD under prior regimen 4 ≤3 months 2 4–12 months 7 >12 months 2 Prior myeloma therapy >12 months 14 >60 months 4 No. of prior regimens 1 0 2 5 3 5 4 2 ≥5 3 Prior thalidomide treatment 10 No. of prior high-dose therapies with autologous transplant 0 5 1 5 2 5 3 0 Prior allogeneic transplant 0
67 67 13 60 20 0 20 0 87 13 0 27 40 27 20 80 43 71 27 13 47 13 93 27 0 33 33 13 20 67 33 33 33 0 0
PD: progressive disease. Because of rounding, some percentages do not add to 100.
Table 2 Response to treatment
Complete response Partial response Minor response Stable disease Progressive disease
Number of patients
Proportion of patients (%)
1 10 1 1 2
7 67 7 7 13
Because of rounding, the percentages do not add to 100.
M.H. Kropff et al. / Leukemia Research 29 (2005) 587–590 Table 3 Adverse events Variable (maximum toxicity per patient)
Proportion of patients n
%
Anemia 3 4
2 1
13 7
Neutropenia 3 4
4 1
27 7
Infection 3 4
1 0
7 0
Herpes zoster 2 3
1 1
7 7
Thrombocytopenia 3 4
0 7
0 47
Bleeding
0
0
Neuropathy 2 3 4
3 1 0
20 7 0
Fatigue 1 2 3
3 2 3
20 13 20
Median event free and overall survival were not reached. After a median follow-up of 5 months, 5/15 patients were non-responders (n = 1) or had experienced disease progression (n = 4). Notably, two patients with sustained paraprotein and bone marrow remission had extramedullary myeloma progression. Adverse events are listed in Table 3. Myelosuppression was frequent and profound during the first treatment cycle. However, in responders myelosuppression gradually diminished with subsequent courses. In addition, there was no evidence of cumulative hematologic toxicity even in nonresponders. Forty-four percent of patients required blood cell transfusions during the first cycle; during the second and third cycles the percentages of transfusion dependent patients decreased to 23 and 11%, respectively. There was no case of neutropenic infection or thrombocytopenic bleeding. Only one patient required hospital admission for adverse events. Grade 2–4 cardiac, pulmonary, hepatic, gastrointestinal or renal toxicities were not observed. Neuropathy and fatigue were the most frequent toxicities necessitating dose modifications or cessation of study therapy.
4. Discussion In this cohort of relapsed myeloma patients with a high prevalence of chromosome 13 deletions, treatment with
589
bortezomib in combination with dexamethasone resulted in a high rate of objective remissions suggesting additive antimyeloma activity. The response rate was just as high in patients with a chromosome 13 deletion. This result confirms preclinical data by Zavrski et al. reporting growth inhibition and apoptosis by proteasome inhibitors in human bone marrow myeloma cells irrespective of chromosome 13 deletion [6]. Responses occurred promptly at manageable toxicity. Major adverse events requiring interruption or modification of the schedule comprised fatigue and neuropathy with frequencies and intensities comparable to the data published [1]. Despite less stringent criteria for the inclusion of patients with poor bone marrow reserve, no patients suffered thrombocytopenic bleeding or bacterial infection attributable to neutropenia. Moreover, there was virtually no gastrointestinal toxicity or postural hypotension indicating that the combination of bortezomib with dexamethasone improved tolerability. Though the remission rate was high, remissions often were not durable. This fact underlines the need for consolidating treatment and evaluation of bortezomib combinations with other anti-myeloma agents, such as melphalan, doxorubicin, cyclophosphamide, or thalidomide [7–9]. Moreover, in line with preclinical data indicating an interference of bortezomib with plasma cell/bone marrow stroma interactions [10], the present two cases of extra-medullary disease progression in otherwise responding patients suggest that bortezomib is particularly active in the myeloma/marrow microenvironment. This clinical observation requires attention in future trials. Acknowledgement The authors thank E. Schuck and A. Kruse for excellent patient care and data collection. References [1] Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. New Engl J Med 2003;348:2609–17. [2] Richardson P, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al. Bortezomib vs. dexamethasone in relapsed multiple myeloma: a phase 3 randomized study. In: Annual Meeting Proceedings of the American Society of Clinical Oncology, vol. 23, 2004. p. 558. [3] Leblanc R, Catley LP, Hideshima T, Pien CS, Elliott PJ, Anderson KC. Proteasome inhibitor PS-341 inhibits human multiple myeloma cell growth in a murine model. Blood 2001;98:774a. [4] Horton TM, Plon SE, Blaney SM, DˇıArgenio DZ, Berg SL. Synergistic cytotoxicity of bortezomib (formerly PS-341) and dexamethasone in acute lymphoblastic leukemia. Blood 2003;102:3207a. [5] Blad´e J, Samson D, Reece D, Apperley J, Bj¨orkstrand B, Gahrton G, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and hemopoietic stem cell transplantation. Br J Haematol 1998;102:1115–23.
590
M.H. Kropff et al. / Leukemia Research 29 (2005) 587–590
[6] Zavrski I, Naujokat C, Niem¨oller K, Jakob C, Heider U, Langelotz C, et al. Proteasome inhibitors induce growth inhibition and apoptosis in myeloma cell lines and in human bone marrow myeloma cells irrespective of chromosome 13 deletion. J Cancer Res Clin Oncol 2003;129:383–91. [7] Yang HH, Swift R, Sadler K, Vescio R, Adams J, Schenkein D, et al. A phase I/II trial of VELCADE and melphalan combination therapy (Vc+M) for patients with relapsed or refractory multiple myeloma (MM). Blood 2003;102:235a. [8] Orlowski RZ, Voorhees PM, Garcia RA, Hall MD, Lehman MJ, Johri A, et al. Phase I study of the proteasome inhibitor bortezomib in
combination with pegylated liposomal doxorubicin in patients with refractory hematologic malignancies. Blood 2003;102:449a. [9] Zangari M, Barlogie B, Jacobson J, Rasmussen E, Burns M, Kordsmeier B, et al. VTD regimen comprising Velcade (V) + Thalidomide (T) and added DEX (D) for non-responders to V + T effects a 57% PR rate among 56 patients with myeloma (M) relapsing after autologous transplant. Blood 2003;102:236a. [10] Hideshima T, Chauhan D, Hayashi T, Akiyama M, Mitsiades N, Mitsiades C, et al. Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma. Oncogene 2003;22:8386–93.