Abstract
Background: Patients with relapsed/refractory multiple myeloma (RRMM) often have a large tumor burden with significant bone marrow involvement, conferring a poor prognostic feature. Those patients with significant bone marrow involvement may benefit from combination regimens with increased activity. Orlowski et al. reported a phase III randomized trial with pegylated liposomal doxorubicin (PLD) + bortezomib (B) vs. B alone in RRMM, which demonstrated improved time to progression (TTP) with the combination of PLD+B. (Orlowski, JCO 2007) We investigated the effect of bone marrow involvement on overall response rates and time to progression (TTP) of PLD+ B versus B alone in patients with RRMM.
Methods: Eligible patients were randomized to bolus IV B 1.3 mg/m2 on days 1, 4, 8, and 11 of each 3-week cycle (n=322) or to the same B regimen plus IV PLD 30 mg/m2 on day 4 (n=324) of each cycle. The subsets of patients with bone marrow involvement and those with >30% involvement were analyzed retrospectively.
Results: A total of 379 patients had bone marrow involvement and 349 patients had >30% bone marrow involvement compared with 259 with no bone marrow involvement. Time to disease progression (TTP) and complete response (CR) + partial response (PR) rates for PLD+B vs B alone in patients with or without any bone marrow involvement or >30% bone marrow involvement are listed in the table.
. | PLD+B . | B . | P valueb . | Hazard Ratioc . |
---|---|---|---|---|
a. Based on Kaplan-Meier product-limit estimates. | ||||
b. Based on stratified Log-rank test. | ||||
c. A hazard ratio >1 indicates an advantage for PLD+B. | ||||
d. Cochran-Mantel-Haenszel test controlling for Beta2 microglobulin and response to initial treatment. | ||||
No bone marrow involvement, N | 132 | 127 | ||
TTP, Median days (95% CI)a | 251 (212, 282) | 198 (162, 227) | 0.0134 | 1.69 (1.11, 2.57) |
Total CR+PR, n/evaluable (%) | 49/118 (42) | 43/124 (35) | 0.2887d | |
Any bone marrow involvement, N | 188 | 191 | ||
TTP | 311 (264, 354) | 197 (169, 222) | .0001 | 1.91 (1.37, 2.67) |
Total CR+PR | 94/183 (51) | 88/182 (48) | .5187d | |
>30% bone marrow involvement, N | 172 | 177 | ||
TTP | 276 (221, 415) | 183 (158, 211) | .0005 | 1.83 (1.30, 2.58) |
Total CR+PR | 82/168 (49) | 69/170 (41) | .1446d |
. | PLD+B . | B . | P valueb . | Hazard Ratioc . |
---|---|---|---|---|
a. Based on Kaplan-Meier product-limit estimates. | ||||
b. Based on stratified Log-rank test. | ||||
c. A hazard ratio >1 indicates an advantage for PLD+B. | ||||
d. Cochran-Mantel-Haenszel test controlling for Beta2 microglobulin and response to initial treatment. | ||||
No bone marrow involvement, N | 132 | 127 | ||
TTP, Median days (95% CI)a | 251 (212, 282) | 198 (162, 227) | 0.0134 | 1.69 (1.11, 2.57) |
Total CR+PR, n/evaluable (%) | 49/118 (42) | 43/124 (35) | 0.2887d | |
Any bone marrow involvement, N | 188 | 191 | ||
TTP | 311 (264, 354) | 197 (169, 222) | .0001 | 1.91 (1.37, 2.67) |
Total CR+PR | 94/183 (51) | 88/182 (48) | .5187d | |
>30% bone marrow involvement, N | 172 | 177 | ||
TTP | 276 (221, 415) | 183 (158, 211) | .0005 | 1.83 (1.30, 2.58) |
Total CR+PR | 82/168 (49) | 69/170 (41) | .1446d |
Regardless of bone marrow involvement or extent of bone marrow involvement, there was a statistically significant benefit in TTP for PLD+B vs. B alone. Safety profiles for the 2 regimens in the subsets of patients with or without bone marrow involvement were consistent with the known toxicities of the 2 agents.
Conclusions: These data suggest that the combination of PLD+B is an active salvage therapy and superior to B alone in patients with RRMM, regardless of the presence or extent of bone marrow involvement. Patients with significant bone marrow involvement and associated poor risk due to increased tumor burden may benefit from the addition of PLD.
Disclosures: Blade:J&J-Janssen-Cilag Spain: Consultancy, Honoraria. San Miguel:J&J: Consultancy, Honoraria; Millennium: Consultancy, Honoraria. Sonneveld:Janssen-Cilag: Consultancy. Luo:Centocor Ortho Biotech Services: Employment. Lantz:Centocor Ortho Biotech Services: Employment. Lowery:Centocor Ortho Biotech Services: Employment. Harousseau:Millennium: Advisory Board; Ortho Biotech: Speakers Bureau. Orlowski:Ortho Biotech: Advisory Board; Millennium: Advisory Board.
Author notes
Corresponding author
This feature is available to Subscribers Only
Sign In or Create an Account Close Modal