SEARCH

SEARCH BY CITATION

Keywords:

  • pegylated liposomal doxorubicin;
  • bortezomib;
  • multiple myeloma;
  • recurrent;
  • refractory;
  • thalidomide;
  • lenalidomide

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

BACKGROUND

Recently, the authors reported improved time to disease progression (TTP) with a combination of pegylated liposomal doxorubicin (PLD) and bortezomib compared with bortezomib alone in a phase 3 randomized trial in patients with recurrent/refractory multiple myeloma (MM). In the current analysis, they determined 1) the efficacy of PLD plus bortezomib versus bortezomib alone in patients with MM who had failed on prior thalidomide/lenalidomide (immunomodulatory drug [IMiD]) treatment and 2) the efficacy and safety profile of PLD plus bortezomib in IMiD-exposed and IMiD-naive patients.

METHODS

This prespecified analysis included 646 patients who were randomized to receive either PLD with bortezomib (n = 324; 194 IMiD-naive patients and 130 IMiD-exposed patients) or bortezomib alone (n = 322; 184 IMiD-naive patients and 138 IMiD-exposed patients). The primary efficacy endpoint was TTP, and secondary endpoints included overall survival, response rate, and safety.

RESULTS

The median TTP was significantly longer with PLD plus bortezomib compared with bortezomib alone in IMiD-exposed patients (270 days vs 205 days). No statistical difference was noted with respect to TTP between IMiD-naive (295 days) versus IMiD-exposed (270 days) subgroups who received PLD plus bortezomib. A sustained trend favoring combination therapy was observed in analyses of overall survival. In patients who achieved a response, the response duration was comparable for IMiD-naive patients and IMiD-exposed patients in the combination treatment group and lasted a median of 310 days and 319 days, respectively. The incidence of grade 3/4 adverse events was similar with PLD plus bortezomib regardless of prior IMiD exposure.

CONCLUSIONS

A significantly prolonged TTP was observed with combined PLD plus bortezomib combination therapy compared with bortezomib alone despite prior IMiD exposure. For the combination treatment arm in the IMiD-naive and IMiD-exposed subgroups, TTP was comparable. Similarly, the safety profile of the PLD plus bortezomib combination was unaltered by prior IMiD exposure. Cancer 2008. © 2008 American Cancer Society.

An estimated 19,900 new cases of multiple myeloma are expected to be diagnosed in the U.S. in 2007, and an estimated 10,790 patients will die from the disease during this same period.1 In Europe, there are >77,000 patients receiving treatment for multiple myeloma at any time.2 With the advent of new therapies, 5-year survival rates have increased substantially over the past several decades, and the median survival also appears to be increasing from approximately 2 to 3 years in 1998 to approximately 5 to 7 years in 2005.1, 3, 4 Although myeloma remains incurable, the availability of new agents with greater efficacy provides an opportunity to improve outcomes further through the development of new combination regimens. Examples of newer agents include immunomodulatory drugs5–7 (IMiDs), such as thalidomide and lenalidomide, new formulations of doxorubicin with improved cardiac safety8 (such as pegylated liposomal doxorubicin [PLD]), and proteasome inhibitors (such as bortezomib).

Although these new treatments provide improved safety and patient convenience, there still is room for improvement in the rates of overall and complete response (CR), and regimens combining these novel agents with more traditional chemotherapeutic agents (or with each other) have been suggested as a means to improve the quality and duration of response. For example, combining IMiDs with chemotherapy-based regimens—such as combined PLD, vincristine, and dexamethasone (DVd) or combined bortezomib and PLD—has produced higher CR/near CR and overall response (OR) rates in phase 2 studies of patients with recurrent or refractory multiple myeloma.9–11 Specifically, studies9, 12 evaluating the efficacy and safety of DVd plus lenalidomide (the DVd-R regimen) reported OR rates of 60% and 67%, including CRs and near CRs in 24% and 33% of patients, respectively. Similarly, the addition of thalidomide to bortezomib/PLD treatment resulted in a 65% OR rate, including 23% of patients who had a CR. Thus, it appears that multiple agents can be combined to optimize treatment and produce a greater proportion of CRs in patients with multiple myeloma.

These improvements have been accompanied by studies suggesting that the order in which different therapies are used in patients with recurrent or refractory disease may impact their efficacy and safety. For example, combination thalidomide and dexamethasone therapy is approved for the treatment of newly diagnosed multiple myeloma.7, 13 However, results from a pooled analysis of 2 phase 3 trials indicated that prior thalidomide exposure may result in partial cross-resistance to subsequent treatment with lenalidomide, resulting in reduced response rates (53% vs 63% in thalidomide-naive patients) and shorter time to progression (TTP) (8.5 months vs 14.2 months in thalidomide-naive patients).14, 15 In addition, patients with prior thalidomide exposure appear to be at greater risk for venous thromboembolic events with subsequent lenalidomide therapy.15

In light of these data suggesting an element of cross-resistance between thalidomide and lenalidomide, we were interested in determining the impact of prior IMiD use on the efficacy of the PLD plus bortezomib regimen. Therefore, we performed a prespecified analysis of the results from a previously reported phase 3 study that compared PLD plus bortezomib with bortezomib alone16 to determine how prior exposure to thalidomide/lenalidomide impacted the therapeutic advantage of prolonged TTP with the PLD plus bortezomib combination compared with bortezomib alone. The effect of prior thalidomide/lenalidomide exposure on the safety profile of both treatment arms also was assessed.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Study Population and Design

This prespecified analysis involved patients from a previously reported randomized, parallel-group, open-label, multicenter, phase 3 study that compared PLD plus bortezomib with bortezomib alone in 646patients with multiple myeloma who had disease progression after an initial response to at least 1 line of prior therapy or who were refractory to initial treatment. Patients who had received prior doxorubicin, PLD, or the equivalent amount of another anthracycline had to have received a cumulative dose of ≤240 mg/m2 (calculated by using the following equivalent doses: 1 mg doxorubicin = 1 mg PLD = 1.8 mg epirubicin = 0.3 mg mitoxan- trone = 0.25 mg idarubicin). Patients were excluded from the study if they had previously been treated with bortezomib, experienced disease progression as the initial response to an anthracycline-containing regimen, or had a left ventricular ejection fraction below normal institutional limits. Review boards at participating institutions approved the study, which was conducted according to the Declaration of Helsinki, the International Conference on Harmonization, and the Guidelines for Good Clinical Practice; and all patients provided written, informed consent.

Patients were randomized to receive either PLD at a dose of 30 mg/m2 as a 1-hour intravenous infusion on Day 4 and bortezomib at a dose of 1.3 mg/m2 as a 5-second intravenous bolus dose on Days 1, 4, 8, and 11 of every 21-day cycle or bortezomib alone at a dose of 1.3 mg/m2 on the same dose and schedule. Treatment continued for at least 2 cycles beyond a CR or until disease progression or unacceptable toxicity occurred, for a maximum of 8 cycles. However, patients with levels of paraprotein that continued to decrease by >25% from course to course after 8 cycles were allowed to continue treatment for as long as treatment was tolerated and there was a response. In the current analysis, the results were stratified on the basis of whether patients had received prior IMiD therapy or were IMiD naive.

The primary efficacy endpoint was TTP, and secondary endpoints included overall survival, response rate, and safety. Methods of response and progression assessment were described previously.16 Safety assessments included adverse event (AE) reports, changes in clinical laboratory findings, and cardiac function tests (multiple-gated acquisition scan, echocardiogram, electrocardiogram).

Statistical Methods

The duration of TTP and the response duration for each group was estimated by using the Kaplan-Meier method. Statistical comparisons were made by using the log-rank test and Cox proportional hazards models to calculate hazards ratios (HRs) and 95% confidence intervals (95% CIs) between treatment groups.16 A heterogeneity test for the TTP between subgroups was conducted by using a Cox model with the addition of a treatment by subgroup interaction term. Response rates were summarized by using descriptive statistics. Summary statistics were provided for key baseline demographics and clinical characteristics and AEs of interest.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

Demographic and Baseline Clinical Characteristics

In total, 646 patients with recurrent or refractory multiple myeloma were assigned randomly to receive either PLD and bortezomib (n = 324; 194 IMiD-naive patients and 130 IMiD-exposed patients) or bortezomib alone (n = 322; 184 IMiD-naive patients and 138 IMiD-exposed patients) and were included in this analysis. Of all 268 IMiD-exposed patients, 252 patients (94%) had received prior thalidomide, and 16 patients (6%) had received prior lenalidomide. The groups were comparable with respect to age, sex, and baseline Eastern Cooperative Oncology Group performance scores (Table 1). In both treatment groups, a substantially greater percentage of IMiD-exposed versus IMiD-naive patients had received ≥2 prior treatment regimens (92% vs 49%, respectively, for the combination treatment arm and 88% vs 49%, respectively, for the bortezomib alone arm).

Table 1. Baseline Demographic and Clinical Characteristics
CharacteristicNo. of patients (%)
IMiD naiveIMiD exposed
PLD plus bortezomib, n = 194Bortezomib, n = 184PLD plus bortezomib, n = 130Bortezomib, n = 138
  1. IMiD indicates immunomodulatory drugs; PLD, pegylated liposomal doxorubicin; SD, standard deviation; ECOG, Eastern Cooperative Oncology Group.

Mean ± SD age, y61.9 ± 10.0161 ± 9.9960.7 ± 8.9962.1 ± 8.94
Sex
 Men113 (58)96 (52)76 (58)78 (57)
 Women81 (42)88 (48)54 (42)60 (43)
Time since initial diagnosis
 Total no.192181129137
 Median [range], mo32.3 [2–185]29.8 [3–151]46.3 [6–181]46.7 [5–244]
Cytogenetic abnormality
 Not done121 (62)114 (62)67 (52)72 (52)
 Yes31 (16)35 (19)25 (19)26 (19)
 No39 (20)28 (15)36 (28)38 (28)
 Not evaluable3 (2)7 (4)2 (2)2 (1)
Extramedullary plasmacytomas
 0182 (94)170 (92)123 (95)129 (93)
 17 (4)12 (7)4 (3)3 (2)
 21 (1)1 (1)2 (2)2 (1)
 31 (1)1 (1)1 (1)2 (1)
 ≥43 (2)0 (0)0 (0)2 (1)
ECOG score
 083 (43)83 (45)56 (43)62 (45)
 1110 (57)101 (55)74 (57)75 (55)
No. of prior therapies
 198 (51)94 (51)11 (8)16 (12)
 ≥296 (49)90 (49)119 (92)122 (88)
Type of prior therapy
 Corticosteroid192 (99)183 (99)130 (100)138 (100)
 Alkylating agent182 (94)172 (93)117 (90)119 (86)
 Anthracycline117 (60)120 (65)103 (79)96 (70)
 Stem cell transplantation92 (47)93 (51)94 (72)80 (58)
β2-microglobulin, mg/L
 ≤2.523 (12)22 (12)22 (17)23 (17)
 >2.5 and ≤5.5118 (61)106 (58)63 (48)72 (52)
 >5.553 (27)56 (30)45 (35)43 (31)
Mean±SD albumin, g/dL3.81 ± 0.603.82 ± 0.703.75 ± 0.613.66 ± 0.62

Efficacy

Tables 2 and 3 summarize efficacy results for the 2 treatment arms according to prior IMiD exposure. In the IMiD-exposed subgroup, PLD plus bortezomib maintained the higher median TTP compared with bortezomib alone (270 days vs 205 days; HR, 1.62; 95% CI, 1.08–2.41 [P = .018]) (Fig. 1, Table 2), similar to the results in the total study population reported previously.16 A similar advantage for combination therapy compared with bortezomib alone was observed among IMiD-naive patients (Table 2). Within the PLD plus bortezomib arm, the median TTP was comparable in both IMiD-naive and IMiD-exposed patients (295 days and 270 days, respectively). There was no statistically significant difference in the heterogeneity test between subgroups (IMiD-naive vs IMiD-exposed; P = .446) (Fig. 2).

thumbnail image

Figure 1. The time to disease progression in patients who were exposed to thalidomide/lenalidomide therapy and pegylated liposomal doxorubicin (PLD) plus bortezomib versus bortezomib alone.

Download figure to PowerPoint

thumbnail image

Figure 2. The time to disease progression in patients who received pegylated liposomal doxorubicin plus bortezomib, immunomodulatory drug (IMiD)-naive patients versus patients with previous exposure to IMiDs.

Download figure to PowerPoint

Table 2. Time to Disease Progression
Time to disease progression, dIMiD naiveIMiD exposed
PLD plus bortezomib, n = 194Bortezomib, n = 184PLD plus bortezomib, n = 130Bortezomib, n = 138
  • IMiD indicates immunomodulatory drugs; PLD, pegylated liposomal doxorubicin; 95% CI, 95% confidence interval; NA, not achieved; HR, hazards ratio.

  • *

    Based on Kaplan-Meier product-limit estimates.

  • Based on stratified log-rank test.

  • Bortezomib versus PLD plus bortezomib. An HR >1 indicates an advantage for PLD plus bortezomib.

Median (95% CI)*295 (224–331)189 (158–216)270 (204-NA)205 (169–238)
P.000057.0177
HR (95% CI)2.01 (1.42–2.84)1.62 (1.08–2.41) 
Table 3. Response and Overall Survival
EndpointNo. of patients (%)
IMiD naiveIMiD exposed
PLD plus bortezomibBortezomibPLD plus bortezomibBortezomib
  • IMiD, immunomodulatory drugs; PLD, pegylated liposomal doxorubicin; CR, complete response, PR, partial response; VGPR, very good partial response; 95% CI, 95% confidence interval; NA, not achieved; HR, hazards ratio.

  • *

    Based on Kaplan-Meier product-limit estimates.

  • Based on stratified log-rank test.

  • Bortezomib versus PLD plus bortezomib. An HR >1 indicates an advantage for PLD plus bortezomib.

Response rate
 Total no.180177123133
 Objective response: CR plus PR85 (47)76 (43)59 (48)57 (43)
 CR9 (5)5 (3)5 (4)3 (2)
 PR76 (42)71 (40)54 (44)54 (41)
 Near CR17 (9)13 (7)11 (9)12 (9)
 CR plus VGPR48 (27)33 (19)38 (31)27 (20)
Duration of response*
 Total no.85765957
 Median d [95% CI]310 [297–394]206 [174-NA]319 [243-NA]227 [176–274]
Time to mortality*
 Total no.194184130138
 Censored183 (94)168 (91)113 (87)115 (83)
 Deaths11 (6)16 (9)17 (13)23 (17)
 P.356.278
 HR [95% CI]1.44 [0.66–3.10]1.42 [0.75–2.66] 

Within the IMiD-exposed subgroup, there were 17 deaths (13%) in the combination treatment arm compared with 23 deaths (17%) in the bortezomib alone group (Table 3). Although this difference was not statistically significant, there was a trend toward an overall survival benefit for the combination treatment arm (P = .278; HR, 1.42; 95% CI, 0.75–2.66). A similar advantage for combination therapy compared with bortezomib alone was observed among IMiD-naive patients (Table 3). At the request of the U.S. Food and Drug Administration, an updated survival analysis was performed for the overall study population using a newer data cutoff date of November 28, 2006; this updated analysis demonstrated that there was a statistically significant difference in survival favoring the combination versus bortezomib monotherapy.16 An updated analysis using the newer cutoff date likewise was performed for the IMiD-naive and IMiD-exposed subgroups. The updated analysis demonstrated a sustained trend toward a survival benefit for the combination, both for the IMiD-naive patients (P = .117; HR, 1.49; 95% CI, 0.90–2.46) and for the IMiD-exposed patients (P = .246; HR, 1.32; 95% CI, 0.83–2.10).

Furthermore, in the PLD plus bortezomib combination arm, the objective response rate (CRs plus partial responses [PRs]) was similar both for IMiD-exposed patients (48%) and for IMiD-naive patients (47%). Likewise, similar rates of CR, PR, near CR, and CR plus very good PR (VGPR) were observed for both IMiD-exposed and IMiD-naive patients who received PLD plus bortezomib (Table 3). In patients who achieved a response to PLD plus bortezomib, the duration of response was comparable for both IMiD-exposed and IMiD-naive patients (median, 319 days and 310 days, respectively) (Table 3).

TTP and response rates in the IMiD-resistant cohort—defined as a subgroup of patients who received prior IMiD therapy and had progressive disease as the best response to the therapy—also were analyzed. The median TTP in the IMiD-resistant cohort was comparable in patients who received PLD plus bortezomib (n = 25) versus bortezomib alone (n = 29; 183 days vs 169 days, respectively; HR, 1.41; 95% CI, 0.56–3.56 [P = .462]). Objective response rates (CR plus PR) were higher numerically in the PLD plus bortezomib combination arm versus the bortezomib alone arm (48% vs 38%; P = .504). One patient (4%) in the PLD plus bortezomib arm achieved a CR versus no patients in the bortezomib alone arm. Forty-four percent and 38% of patients in the PLD plus bortezomib and bortezomib alone arms, respectively, achieved PRs.

Safety

Overall, the proportion of patients experiencing drug-related, treatment-emergent AEs was the same for IMiD-naive patients and IMiD-exposed patients who received PLD plus bortezomib (94%); whereas the proportion of patients reporting drug-related, treatment-emergent AEs was 83% (IMiD-naive) and 90% (IMiD-exposed), respectively, for patients who received bortezomib alone. The proportion of IMiD-naive patients experiencing National Cancer Institute Common Terminology Criteria for Adverse Events v3.0 grade 3 or 4 drug-related AEs was 69% and 46% for PLD plus bortezomib versus bortezomib alone, respectively; whereas the proportion of IMiD-exposed patients experiencing grade 3 or 4 drug-related AEs was 67% and 60%, respectively. Among patients who received PLD plus bortezomib, AEs led to the discontinuation of bortezomib in 27% and 36% of IMiD-naive and IMiD-exposed patients, respectively; whereas 33% and 40% of IMiD-naive and IMiD-exposed patients, respectively, reportedly discontinued PLD because of AEs. However, it is important to note that these latter numbers are inflated artificially, because the study protocol required discontinuation of PLD when bortezomib was discontinued; thus, the majority of patients who discontinued PLD did so because AEs were the reasons bortezomib had been discontinued. Among patients who received bortezomib alone, 20% of IMiD-naive patients and 29% of IMiD-exposed patients discontinued treatment because of AEs. Overall, 7 patients, including 3 IMiD-naive patients (2 who received PLD plus bortezomib and 1 who received bortezomib alone) and 4 IMiD-exposed patients (2 who received PLD plus bortezomib and 2 who received bortezomib alone), had drug-related AEs that resulted in death.

The proportions of patients experiencing selected AEs of clinical interest are presented in Table 4. Itis interesting to note that the incidence of grade 3 or 4 events, such as peripheral neuropathy, neutropenia, febrile neutropenia, bleeding/hemorrhage, mucositis/stomatitis, hand-foot syndrome, and thrombo embolic events, was similar for both PLD plus bortezomib groups, regardless of prior IMiD exposure. Comparable safety results were observed with bortezomib alone.

Table 4. Adverse Events of Interest
EventNo. of patients (%)
IMiD naiveIMiD exposed
PLD plus bortezomib, n = 192Bortezomib, n = 183PLD plus bortezomib, n = 126Bortezomib, n = 135
AllGrade ≥3AllGrade ≥3AllGrade ≥3AllGrade ≥3
  1. IMiD indicates immunomodulatory drugs; PLD, pegylated liposomal doxorubicin; PE, pulmonary embolism; DVT, deep vein thrombosis.

Peripheral neuropathy61 (32)8 (4)67 (37)11 (6)50 (40)6 (5)57 (42)17 (13)
Neutropenia68 (35)59 (31)40 (22)27 (15)42 (33)35 (28)24 (18)19 (14)
Febrile neutropenia6 (3)6 (3)3 (2)3 (2)4 (3)4 (3)2 (1)2 (1)
Bleeding/hemorrhage30 (16)9 (5)9 (5)0 (0)15 (12)4 (3)19 (14)4 (3)
Mucositis/stomatitis39 (20)3 (2)5 (3)1 (1)26 (21)4 (3)10 (7)0 (0)
Hand-foot syndrome29 (15)8 (4)0 (0)0 (0)21 (17)7 (6)0 (0)0 (0)
Thromboembolic events (PE and DVT)3 (2)2 (1)3 (2)2 (1)0 (0)0 (0)0 (0)0 (0)
Alopecia2 (1)0 (0)0 (0)0 (0)3 (2)0 (0)2 (1)0 (0)

The overall incidence of treatment-related cardiac AEs was low and was similar between IMiD-naive patients (7%) and IMiD-exposed patients (8%) who received PLD plus bortezomib; the rates were slightly lower in patients who received bortezomib alone: 5% and 6% in IMiD-naive and IMiD-exposed patients, respectively. Among the patients who received PLD plus bortezomib, 1 patient (1%) in the IMiD-naive group and 4 patients (3%) in the IMiD-exposed group developed congestive heart failure related to treatment. Moreover, symptomatic arrhythmias related to treatment were observed in 3 patients (2%) and 2 patients (2%) in each of these groups, respectively. In comparison, 2 IMiD-naive patients (1%) and 1 IMiD-exposed patient (1%) in the bortezomib alone group developed congestive heart failure related to treatment. Symptomatic arrhythmias related to treatment were observed in 2 IMiD-naive patients who received bortezomib alone.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The current analysis demonstrated that the therapeutic advantage of prolonged TTP attributed to the PLD plus bortezomib combination, compared with bortezomib as a single agent, was maintained regardless of exposure to IMiD therapy in prior lines of treatment in patients with recurrent or refractory multiple myeloma. Furthermore, the median TTP remained unaffected by prior IMiD exposure, even in the comparator arm that received bortezomib alone. Although the overall survival data were not sufficiently mature to indicate a statistically significant difference between treatment arms in either subgroup, a sustained trend favoring the combination therapy was observed at both analysis time points. It is interesting to note that, although the OR rates were comparable between the 2 treatment arms, the duration of response was significantly longer with PLD plus bortezomib, regardless of prior IMiD exposure. Similar to the overall study population, CR and VGPR rates in both the IMiD-naive and IMiD-exposed subgroups were higher in the combination arm versus the bortezomib monotherapy arm, supporting the hypothesis that PLD enhances the clinical benefits of bortezomib by improving the depth of a PR or CR.16 Furthermore, the OR rate and duration of response were similar in both the IMiD-naive patients and the IMiD-exposed patients who received PLD plus bortezomib. This is significant, because IMiD-exposed patients generally are pretreated more heavily and usually would be expected to have a lower rate of response to conventional agents or regimens. Clearly, prior IMiD therapy did not seem to have any impact on the efficacy of either therapeutic arm, which would suggest a lack of cross-resistance with either treatment to prior IMiD exposure. In addition, prior IMiD treatment status did not seem to compromise the safety profile of either treatment. It is noteworthy that the incidence of neuropathy greater than grade 3 was higher in the IMiD-exposed patients who received bortezomib alone than in those who received PLD plus bortezomib, suggesting a potential benefit for use of the combination in patients with a history of IMiD treatment.

The data regarding therapeutic outcomes in IMiD-exposed patients are limited. Recently, a small retrospective study (N = 21) investigated the efficacy and safety of bortezomib as salvage therapy for patients with recurrent or refractory myeloma who had received prior treatment with thalidomide.17 It is interesting to note that the objective response rates according to European Group for Blood and Marrow Transplant criteria18 were comparable to those observed for the same study population in our study (42.8% vs 43%, respectively). Furthermore, in IMiD-exposed patients, the median TTP observed with PLD plus bortezomib in the current study (270 days) appears comparable to that reported earlier with lenalidomide plus dexamethasone (258 days) in the same patient population.14, 15 In addition, the overall objective response rates appear to be comparable between these 2 combinations (48% vs 54%, respectively).

In contrast to our observations of virtually no difference in TTP and OR rates between IMiD-exposed and IMiD-naive patients who received PLD plus bortezomib, the lenalidomide plus dexamethasone combination demonstrated a notable difference in these populations. A lower TTP and lower OR rates were observed with this combination in patients who had prior IMiD exposure compared with patients who had no prior IMiD exposure.15, 19 The authors of that report concluded by suggesting the possibility of cross-resistance to lenalidomide in thalidomide-exposed patients who did not respond to lenalidomide.15 Clearly, as revealed by the current study, the response to PLD plus bortezomib or bortezomib alone appears to be unaffected by prior exposure to IMiD therapy. Even in the IMiD-resistant cohort, PLD plus bortezomib combination therapy demonstrated a similar response rate compared with the rates achieved in IMiD-naive or IMiD-exposed patients. It remains to be determined whether the cross-resistance subsequent to IMiD exposure is limited only to drugs in the same class.

The incidence of grade 3 or 4 AEs generally was similar for both PLD plus bortezomib subgroups regardless of prior IMiD exposure. More specifically, it should be noted that the rate of thromboembolic AEs observed with the combined therapy of PLD plus bortezomib was low in the absence of any required prophylaxis, regardless of whether patients received prior IMiD therapy (0% in IMiD-exposed patients, 2% for IMiD-naive patients). This is in sharp contrast to the markedly higher published rate of thromboembolic AEs (ie, pulmonary embolism and deep vein thrombosis) in patients who received lenalidomide plus dexamethasone, whether or not they had received prior thalidomide therapy (14% in thalidomide-exposed patients, 8% in thalidomide-naive patients). This suggests that the combined regimen of PLD plus bortezomib may offer improved safety over lenalidomide plus dexamethasone in patients with recurrent or refractory multiple myeloma, especially in those who have previously received thalidomide.

In conclusion, the results of the current subgroup analysis demonstrate that neither the efficacy nor the safety of the PLD plus bortezomib combination or bortezomib alone in patients with recurrent or refractory multiple myeloma is affected by prior exposure to IMiD therapy. In addition, the therapeutic advantage of a higher TTP observed with PLD plus bortezomib compared with bortezomib alone was maintained in this patient population regardless of prior IMiD exposure.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES

The authors acknowledge the sacrifices of the patients who volunteered to participate in this study and the efforts of the study site staff that cared for them; Denise Kimball, MSN, who managed the study; and Lee Schacter, MD, and Steven Sun, PhD, for assistance in developing the protocol. In addition, Linda Nash made valuable contributions to the development of the article.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. REFERENCES
  • 1
    American Cancer Society. Cancer Facts and Figures, 2006. Atlanta, Ga: American Cancer Society, Inc.; 2006.
  • 2
    Ferlay J,Bray P,Pisani P,Parkin DM. GLOBOCAN 2002: Cancer incidence, Mortality and Prevalence Worldwide. IARC CancerBase No. 5. Version 2.0. Lyon, France: IARC Press; 2004.
  • 3
    Durie BG. New approaches to treatment for multiple myeloma: durable remission and quality of life as primary goals. Clin Lymphoma Myeloma. 2005; 6: 181190.
  • 4
    Kyle RA,Gertz MA,Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003; 78: 2133.
  • 5
    Rajkumar SV,Gertz MA,Lacy MQ, et al. Thalidomide as initial therapy for early-stage myeloma. Leukemia. 2003; 17: 775779.
  • 6
    Rajkumar SV,Dingli D,Nowakowski G, et al. Thalidomide and dexamethasone in newly diagnosed multiple myeloma: long-term results in patients not undergoing upfront autologous stem cell transplantation. Proc Am Soc Clin Oncol. 2005; 23: 593s. Abstract 6632.
  • 7
    Rajkumar SV,Blood E,Vesole D,Fonseca R,Greipp PR. Phase III clinical trial of thalidomide plus dexamethasone compared with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2006; 24: 431436.
  • 8
    Safra T. Cardiac safety of liposomal anthracyclines. Oncologist. 2003; 8( suppl 2): 1724.
  • 9
    Baz R,Choueiri TK,Jawde RA, et al. Doxil (D), vincristine (V), reduced frequency dexamethasone (d) and Revlimid® (DVd-R) results in a high response rate in patients with refractory multiple myeloma (RMM). Blood. 2005; 106: 719a. Abstract 2559.
  • 10
    Padmanabhan S,Miller K,Musiel L, et al. Bortezomib (Velcade) in combination with liposomal doxorubicin (Doxil) and thalidomide is an active salvage regimen in patients with relapsed or refractory multiple myeloma: final results of a phase II study. Haematologica. 2006; 91( suppl 1): 277. Abstract 0752.
  • 11
    Hussein MA,Baz R,Srkalovic G, et al. Phase 2 study of pegylated liposomal doxorubicin, vincristine, decreased-frequency dexamethasone, and thalidomide in newly diagnosed and relapsed-refractory multiple myeloma. Mayo Clin Proc. 2006; 81: 889895.
  • 12
    Hussein MA. Lenalidomide: patient management strategies. Semin Hematol. 2005; 42: S22S25.
  • 13
    THALOMID (thalidomide) Capsules [prescribing information]. Summit, NJ: Celgene Corporation; 2007.
  • 14
    Wang M,Knight R,Dimopoulos M, et al. Lenalidomide in combination with dexamethasone was more effective than dexamethasone in patients who have received prior thalidomide for relapsed or refractory multiple myeloma. Blood (ASH Annual Meeting Abstracts). 2006; 108. Abstract 3553.
  • 15
    Wang M,Knight R,Dimopoulos M, et al. Comparison of lenalidomide in combination with dexamethasone to dexamethasone alone in patients who have received prior thalidomide in relapsed or refractory multiple myeloma. Proc Am Soc Clin Oncol. 2006; 24: 427s. Abstract 7522.
  • 16
    Orlowski RZ,Nagler A,Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007; 25: 38923901.
  • 17
    Musto P. Thalidomide therapy for myelodysplastic syndromes: current status and future perspectives. Leuk Res. 2004; 28: 325332.
  • 18
    Blade J,Samson D,Reece D, et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol. 1998; 102: 11151123.
  • 19
    Richardson PG,Schlossman RL,Weller E, et al. Immunomodulatory drug CC-5013 overcomes drug resistance and is well tolerated in patients with relapsed multiple myeloma. Blood. 2002; 100: 30633067.