RELAPSED/REFRACTORY DISEASE

A phase 2 study of bortezomib in relapsed, refractory myeloma.
N Engl J Med. 2003 Jun 26;348(26):2609-17.
Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Srkalovic G, Alsina M, Alexanian R, Siegel D, Orlowski RZ, Kuter D, Limentani SA, Lee S, Hideshima T, Esseltine DL, Kauffman M, Adams J, Schenkein DP, Anderson KC.
In this phase II trial, 202 patients with refractory myeloma received bortezomib for up to 8 cycles (6 months). Patients received dexamethasone 20 mg PO on the day of bortezomib and the day after, in case of no disease response. Results:
  - Response rate: 35%
  - Median duration of response: 12 months
  - Median overall survival: 16 months
Significant toxicities (grade III) included:
  - Thrombocytopenia (28%), neutropenia (11%)
  - Peripheral neuropathy (12%)
  - Fatigue (12%)

A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma.
Br J Haematol. 2004 Oct;127(2):165-72.
Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Adams J, Kauffman M, Esseltine DL, Schenkein DP, Anderson KC.
In this phase II trail, 54 patients with relapsed/refractory myeloma were randomized to receive bortezomib 1.0 or 1.3 mg/m2 IV, for a maximum of 8 cycles. Patient received dexamethasone in case of no disease response. Results:
  - Response rate: 37% with 1.0 mg/m2 and 50% with 1.3 mg/m2
Most common grade III toxicities:
  - Thrombocytopenia (24%), neutropenia (17%)
  - Peripheral neuropathy (9%)

Bortezomib in recurrent and/or refractory multiple myeloma. Initial clinical experience in patients with impaired renal function.
Cancer. 2005 Mar 15;103(6):1195-200.
Jagannath S, Barlogie B, Berenson JR, Singhal S, Alexanian R, Srkalovic G, Orlowski RZ, Richardson PG, Anderson J, Nix D, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators.

Bortezomib or high-dose dexamethasone for relapsed multiple myeloma.
N Engl J Med. 2005 Jun 16;352(24):2487-98.
Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Bladé J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC; Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators.
In this study, 669 patients with relapsed myeloma were randomized to bortezomib (1.3 mg/m2 IV on days 1, 8, 15, 22 every 5 weeks for 3 cycles) vs high-dose dexamethasone (40 mg PO on days 1-4, 9-12, 17-20 every 5 weeks for 4 cycles, then on days 1-4 every 4 weeks for 5 cycles). Patients assigned to the dexamethasone arm were allowed to cross over to the bortezomib arm in case of disease progression. Patients had received 1-3 previous therapies. Results:
  - Response rate was higher in the bortezomib arm (38% vs 18%)
  - Rate of CR was 6% in the bortezomib arm and <1% in the dexamethasone arm
  - Time to progression was longer in the bortezomib arm (6.2 months vs 3.5 months)
  - Overall survival was longer in the bortezomib arm. 1-year OS was 80% in the bortezomib arm and 66% in the dexamethasone arm.
  - Grade 3-4 toxicities were seen in 75% of patients in the bortezomib arm vs 60% of patients in the dexamethasone arm.

Clinical factors predictive of outcome with bortezomib in patients with relapsed, refractory multiple myeloma.
Blood. 2005 Nov 1;106(9):2977-81.
Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D, Rajkumar SV, Hideshima T, Xiao H, Esseltine D, Schenkein D, Anderson KC; SUMMIT Investigators.
Data review fro 202 myeloma patients enrolled in a phase II trial showed that response to bortezomib was not associated with sex, race, performance status, myeloma isotype, number of previous therapies, and type of previous therapies. Even beta2-microglobulin level and monosomy 13, two poor prognostic factors, were not predictive of poor response to bortezomib. After multivariate analysis, age >65 and degree of plasma cell infiltration in the bone marrow >50% were associated with lower response to bortezomib. Response to bortezomib was 19% in patients older than 65 vs 32% in patients younger than 65, and it was 20% in patients with >50% plasma cells in the bone marrow vs 35% in patients with >50% plasma cells in the bone marrow.

Extended follow-up of a phase II trial in relapsed, refractory multiple myeloma: final time-to-event results from the SUMMIT trial.
Cancer. 2006 Mar 15;106(6):1316-9.
Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin DH, Rajkumar SV, Srkalovic G, Alsina M, Anderson KC.
202 patients with relapsed/refractory myeloma were treated with bortezomib 1.3 mg/m2 IV on days 1, 4, 8, and 11 every 21 days, for up to 8 cycles (in case of suboptimal response, they also received dexamethasone 20 mg PO on the day of and the day after bortezomib). Results:
  - Response rate was 28%: PR 18%, nCR 6%, CR 4%. Minimal response 7%
  - Median time to progression: 7 months (14 months in responding patients vs 1.3 months in non-responding patients)
  - Median overall survival: 17 months (not reached at 23 months of follow-up in responding patients vs 8 months in non-responding patients)

Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone.
Haematologica. 2006 Jul;91(7):929-34.
Jagannath S, Richardson PG, Barlogie B, Berenson JR, Singhal S, Irwin D, Srkalovic G, Schenkein DP, Esseltine DL, Anderson KC; SUMMIT/CREST Investigators.
This study reviews data from 202 patients enrolled in the SUMMIT trial and 54 patients enrolled in the CREST trial. In those two trials, patients with refractory myeloma received bortezomib, and dexamethasone (20 mg PO on the day of and the day after bortezomib) was added in case of no response, i.e., presence of progressive disease after 2 cycles or stable disease after 4 cycles. The addition of dexamethasone produced an improvement of disease response in 13/74 (18%) patients in the SUMMIT trial, and 9/27 (33%) in the CREST trial. Combining the data, 22 of  101 (22%) patients with no response to bortezomib single agent had a therapeutic response when dexamethasone was added to bortezomib.

Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial.
Blood. 2007 Nov 15;110(10):3557-60.
Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, Miguel JS, Bladé J, Boccadoro M, Cavenagh J, Alsina M, Rajkumar SV, Lacy M, Jakubowiak A, Dalton W, Boral A, Esseltine DL, Schenkein D, Anderson KC.
This is an updated analysis of the APEX (Assessment of Proteasome Inhibition for Extending Remissions) trial, a study that demonstrated an increased response rate and improved overall survival of bortezomib vs high-dose dexamethasone in patients with relapsed multiple myeloma. Response rate was 43% with bortezomib and 9% with dexamethasone. After a median follow-up of 22 months, the median survival was 30 months with  bortezomib and 24 months with dexamethasone. The survival advantage of 6 months was reached despite a significant crossover from the dexamethasone arm to tthe bortezomib arm.

An observational, retrospective analysis of retreatment with bortezomib for multiple myeloma.
Clin Lymphoma Myeloma. 2008 Jun;8(3):140-5.
Conner TM, Doan QD, Walters IB, LeBlanc AL, Beveridge RA.
This is a retrospective review of data from patients with multiple myeloma treated with bortezomib and subsequently retreated with the same agent, with therapy given at least 2 months apart. Median time between bortezomib treatments was 10 months. Response among 82 evaluable patients:
  - Less than PR: 63%
  - PR: 15%
  - VGPR: 6%
  - Progressive disease: 6%
  - Death: 10%

Weekly treatment with bortezomib for patients with recurrent or refractory multiple myeloma: a phase 2 trial of the Minnie Pearl Cancer Research Network.
Cancer. 2008 Aug 15;113(4):765-71.
Hainsworth JD, Spigel DR, Barton J, Farley C, Schreeder M, Hon J, Greco FA.
40 patients with myeloma in relapse/progression after 1-2 lines of therapy received bortezomib 1.6 mg/m2 IV weekly for 4 weeks, followed by 1 week without therapy. Results:
  - Response rate: 55%
  - Median progression-free survival: 9.6 months
  - 1-year progression-free survival: 39%
  - 1-year overall survival: 75%
  - 2-year overall survival: 51%
  - Grade 3-4 neuropathy: 10%
Response rate and duration of disease remission seemed similar to those observed with twice-weekly bortezomib.

Bortezomib plus dexamethasone is highly effective in relapsed and refractory myeloma patients but responses are short-lived.
Eur J Haematol. 2009 Nov;83(5):449-54.
Corso A, Varettoni M, Mangiacavalli S, Zappasodi P, Pica GM, Algarotti A, Pascutto C, Lazzarino M.
70 MM patients were treated with bortezomib, with or without dexamethasone. Bortezomib was found to be highly effective in inducing a therapeutic response (RR: 59%, including 7% CR), but the duration of response was short: the median time to progression was 5.6 months (7.3 months in patients achieving CR/VGPR, and 3.8 months in patients achieving PR).

 

 


Giampaolo Talamo, M.D.