Efficacy and safety profile of long-term exposure to lenalidomide in patients with recurrent multiple myeloma

Authors


  • Guillemette Fouquet and Stéphanie Tardy are co-first authors. Cyrille Hulin and Xavier Leleu are co-last authors.

Abstract

BACKGROUND

Lenalidomide in combination with dexamethasone (Len/Dex) is indicated for patients with recurrent/refractory multiple myeloma (RRMM) who were treated with 1 prior therapy until evidence of disease progression. The objective of the current study was to determine the efficacy and safety profile of long-term exposure to Len/Dex.

METHODS

A total of 50 patients with RRMM who were treated with long-term Len for ≥ 2 years from 2 Intergroupe Francophone du Myélome (IFM) centers (Lille and Nancy) were included in the current study.

RESULTS

The median age of the patients was 58 years, with 30% of the patients aged > 65 years, 49% having an International Staging System stage of 2 and 3, 12% having severe renal insufficiency, and 8% demonstrating an adverse result on fluorescence in situ hybridization. Approximately 56% of the patients received treatment with Len/Dex for ≥ 3 years. The median duration of treatment with Len/Dex was 3 years (range, 2 years-7 years). The response rates for partial response or better and very good partial response or better for the overall cohort were 96% and 74%, respectively, which is similar to patients exposed to Len for ≥ 3 years. With a median follow-up of 4 years, 19 (38%) patients had stopped treatment with Len/Dex. The time to disease progression rate at 37 months was 78% and 91%, respectively, in patients exposed to Len for 2 years to < 3 years and for ≥ 3 years (P = 025). The safety profile was manageable, similar to that of Len when administered for a shorter period of time; 16% of patients had grade 3 to 4 neutropenia, 6% had thrombopenia, 6% had anemia, and 20% experienced thromboembolic events, all of venous type. The annual incidence rate of second primary malignancy was 1.96% in the current series.

CONCLUSIONS

The results of the current study confirmed that the Len/Dex combination is feasible for long-term use in patients with RRMM, with a significant benefit noted in terms of time to disease progression for prolonged treatment with Len/Dex. Cancer 2013;119:3680–3686. © 2013 American Cancer Society.

INTRODUCTION

Lenalidomide belongs to the class of oral immunomodulatory drugs, demonstrating both tumoricidal and immunomodulatory effects in patients with multiple myeloma (MM) and thereby allowing immediate tumor cell death along with sustained disease control when used continuously. Lenalidomide is currently approved in Europe in combination with dexamethasone (Len/Dex) for the treatment of patients with recurrent and/or refractory MM (RRMM) who have received at least 1 prior therapy. The Len/Dex combination is approved at the best-tolerated dose of both Len and Dex until evidence of disease progression.

MM is an incurable plasma cell neoplasm characterized by a high rate of disease recurrence. Despite important improvements in therapies that have provided significant benefits in survival outcome,[1] to the best of our knowledge MM remains incurable. Nevertheless, long-term disease control is now achievable due to novel therapies such as bortezomib and Len, provided that not only are the best drugs available to patients, but also that the use of these drugs is optimized so that patients receive treatment for a long time. Although the short-term profile of response and toxicity of Len is well known, to the best of our knowledge neither the tolerability profile of long-term exposure to the combination of Len/Dex nor its effect on response rate and survival have been well described to date.

In the current study, we sought to determine the efficacy and safety profile of long-term exposure to Len/Dex in patients with RRMM.

MATERIALS AND METHODS

Patients

A total of 50 patients from 2 centers (Lille and Nancy, France) were recruited for the current retrospective study. Patients were required to be aged > 18 years, to be diagnosed with RRMM, and to have received Len for at least 2 consecutive years. The patients also had to have been treated with Len for ≥ 2 years, with a special focus on those patients receiving Len for ≥ 3 years. All patients initiated treatment with a Len/Dex regimen. A thromboprophylaxis was recommended up to 2010, and was then mandatory afterward, the choice of which was at the discretion of the treating physician. The study was approved by the ethics committee of regional university hospitals of Lille, France and was conducted in accordance with the principles of the Declaration of Helsinki.

Assessment

All patients who were recruited had complete follow-up records. All response rates were determined according to International Myeloma Working Group criteria.[2]

Statistical Analysis

Descriptive data were collected for the cohort. All survival endpoints were evaluated using the Kaplan-Meier estimates and compared with the log-rank test. The estimate of the relative risk of event and its 95% confidence interval were estimated using the proportional hazards model. All analyses were performed using SPSS statistical software (version 15.0; SPSS Inc, Chicago, Ill).

RESULTS

Patient Characteristics

The median age was of the patients 58 years (range, 39 years-79 years), with 15 patients (30%) aged > 65 years (elderly MM). The male:female ratio was 1.2, 48% of the patients were International Staging System stage of 2 and 3, 12% had severe renal insufficiency (creatinine clearance < 30 mL/min), and 8% demonstrated an adverse result on fluorescence in situ hybridization (del17p and/or t(4;14)). Twenty-eight patients (56%) received Len/Dex for ≥ 3 years. The characteristics of the patients are summarized in Table 1. The median time from diagnosis to the start of treatment with Len/Dex was 4.5 years (range, 1 years-16 years) for the overall cohort and 3 years (range, 1 year-8 years) for the elderly patients (those aged > 65years) (P = .05).

Table 1. Patient Characteristics at Start of Therapy With the Combination of Lenalidomide Plus Dexamethasone (n = 50) and in Patients Treated with Lenalidomide for ≥3 Years (n = 28)a
Characteristic, no.(%)Overall Cohort N = 50Cohort With ≥3 Years of Lenalidomide N = 28
  1. Abbreviations: CrCl, creatinine clearance; FISH, fluorescence in situ hybridization; ISS, International Staging System; Len/Dex, lenalidomide plus dexamethasone.

  2. a

    The P value was not found to be statistically significant across the study cohorts.

Age >65 y15 (30)10 (36)
ISS 2 and 324 (48)13 (46)
Severe renal insufficiency (CrCl <30 mL/min)6 (12)0
Adverse FISH (del17p and/or t(4;14))4 (8)2 (7)
Len/Dex at first recurrence25 (50)13 (46)
Len/Dex at second recurrence19 (38)8 (29)

Thirty-six patients were eligible and received an autologous transplantation upfront with high-dose melphalan at a dose of 200 mg/m2 as a conditioning regimen, and received 4 cycles of either vincristine, doxorubicin, and Dex (33 patients) or bortezomib and Dex (3 patients) as induction therapy before transplantation. The remaining 14 patients who were deemed ineligible for transplantation upfront received either 12 cycles of melphalan, prednisone, and thalidomide (9 patients) or 9 cycles of melphalan, prednisone, and bortezomib (5 patients).

Len/Dex Regimen

The majority of patients were treated with Len-based regimens early in their disease history and up to the fifth line of treatment. Overall, 25 patients (50%) received Len/Dex at the time of first recurrence, 19 patients (38%) received it at the time of second recurrence, and 6 patients (12%) received it at the time of subsequent recurrences. Among elderly patients (those aged > 65 years), Len/Dex was given at the time of first recurrence in 10 patients (66%). For all patients, Len was administered orally, at a starting dose of 10 mg to 25 mg daily (42 patients [84%] at a dose of 25 mg, 7 patients [14%] at a dose of 15 mg, and 1 patient [2%] at a dose of 10 mg), from day 1 to day 21 every 28 days. The reasons for dose adaptations were creatinine clearance in approximately 50% of patients, and initial altered health status for the remaining patients. The majority of patients received Dex at a dose of 40 mg weekly; the remaining patients received Dex at a dose of 10 mg or 20 mg weekly; 40 mg daily from day 1 to day 4 every 28 days; or 40 mg at days 1, 4, 8, and 11 every 28 days.

Len Dose Reduction

We first examined whether patients who initiated treatment at a reduced dose of Len (7 patients [14%] at 15 mg and 1 patient [2%] at 10 mg) had a different treatment profile for the past 2 and 3 years of treatment with Len/Dex. We found that this set of patients had a similar response rate (very good partial response or better [≥ VGPR], 79% and 67%, respectively), duration of treatment (median of 3 years in the 2 groups), and median time to disease progression (TTP); had a similar discontinuation and dose reduction rate; and demonstrated no difference in terms of toxicity profile compared with patients with no initial dose reduction at the start of treatment with Len/Dex (P value was not significant [NS] across cohorts).

We also studied patients who had a dose reduction for Len during treatment with Len/Dex. Seventeen patients (34%) had a dose reduction during the treatment course of Len/Dex; 13 of 42 patients had their dose reduced from 25 mg to 15 mg and 10 mg and 4 of 7 patients had their dose reduced from 15 mg to 10 mg. None of the patients who had a dose reduction experienced any nonhematological toxicity; all had dose reductions related to grade 3 neutropenia and thrombopenia. We found that this group of patients also had a similar response rate including ≥ VGPR (71% and 70%, respectively), duration of treatment (median, 3 years in the 2 groups), and median TTP, and no difference in terms of toxicity profile compared with patients with no dose reduction during the course of Len/Dex (P value NS across cohorts).

Safety Profile

Overall, 23 patients (46%) experienced adverse events of clinical significance (defined as ≥ grade 3 or that required dose interruption or reduction) with Len: 10 patients with hematological toxicities (neutropenia in 8 patients, thrombopenia in 3 patients, and anemia in 3 patients) and 13 patients with nonhematological toxicities (septic syndrome in 2 patients, diarrhea in 1 patient, cutaneous reaction in 2 patients, asthenia in 1 patient, and venous thromboembolism [VTE] in 7 patients) (Table 2). The median time to the first occurrence of these adverse events was 8 months (range, 8 months-27 months) for hematological toxicities and 4 months (range, 1 month-37 months) for nonhematological toxicities. We did not observe any excess of clinically significant adverse events in patients who were treated with Len/Dex for ≥ 3 years versus those treated for 2 years to < 3 years. The toxicity profile was similar across age categories and the number of previous lines of therapy. The patients who experienced adverse events with clinical significance had a similar discontinuation rate, similar duration of treatment, similar response rate including ≥ VGPR (78% for patients who had hematological toxicities and 61.5% for patients with nonhematological toxicities), and similar TTP versus patients who did not experience an adverse event (P value NS across cohorts).

Table 2. Adverse Events Profile Observed in the Studied Population as a Whole, and Across Cohortsa
Adverse Event, No. (%)Overall Cohort2 to <3 Years≥3 Years
  1. a

    P values were not found to be statistically significant across the study cohorts.

Neutropenia, grade 3–48 (16)2 (9)6 (21)
Thrombopenia, grade 3–43 (6)2 (9)1 (4)
Anemia, grade 3–43 (6)1 (4)2 (7)
Thromboembolic events10 (20)4 (18)6 (21)

We also observed 25 patients who experienced clinically significant adverse events with Dex, 9 of whom had to permanently stop dexamethasone. We did not observe any excess of Dex-related adverse events with clinical significance in patients treated with the combination of Len/Dex ≥ 3 years versus those treated for 2 years to < 3 years. This toxicity profile of Dex was similar across age categories and number of previous lines of therapy, and the patients had a similar discontinuation rate with Len, a similar duration of treatment with Len, a similar response rate including and ≥ VGPR, and a similar TTP (P value NS across cohorts).

Overall, 10 patients (20%) experienced a thromboembolic event (VTE), all of which were of venous type. The median time to the first occurrence of VTE was 5 months (range, 1 month-28 months), including 4 of 10 in patients with ≥ 3 years of treatment with Len/Dex. With the exception of 1 patient, all cases of VTE occurred while the patient was receiving VTE prophylaxis: 5 patients were receiving aspirin, 2 patients were receiving prophylactic doses of low-molecular-weight heparin, and 2 patients were being treated with vitamin K antagonist (target International Normalized Ratio, 2-3). It is interesting to note that 2 patients in the current series had a previous history of VTE but none experienced VTE while receiving Len/Dex, which is most likely related to adequate VTE prophylaxis.

We recorded a second primary malignancy (SPM) in 3 patients (larynx, lung, and myelodysplastic syndrome), corresponding to an annual incidence rate of 1.96%. The SPMs occurred at a median time of 4 years from the time of the initiation of Len, and after Len therapy was already withdrawn in 2 of 3 patients; the latter patient stopped Len at the time of the diagnosis of a SPM, after 27 months of treatment. It is interesting to note that none of the patients treated with Len/Dex for > 3 years experienced any SPM.

Response and Survival

The response rate (overall response rate [ORR] and partial response or better [≥ PR]) in the entire cohort was 96% (n = 48), including 37 patients (74%) with ≥ VGPR. The response rate was similar across age categories and numbers of lines of therapy. The median time to first and best response was 2 months (range, 1 month-5 months) and 4.5 months (range, 2 months-9 months), respectively. With a median follow-up of 4 years, 9 patients (18%) had developed disease progression. The median TTP was not reached in the current series, and the estimated 4-year TTP was 51.5%.

We then focused especially on the patients who had received Len/Dex for at least 3 years compared with those who received Len/Dex for at least 2 years but ≤ 3 years (Table 3). The ORR and ≥ VGPR rates were 96% and 67%, respectively, in patients exposed to Len for ≥ 3 years, similar to the entire cohort. The observed TTP rate at 37 months was 78% in patients exposed to Len for 2 years to < 3 years and 91% in patients exposed to Len for ≥ 3 years (odds ratio, 11,052 [95% confidence interval, 1-130]; P = .025) (Fig. 1).

Figure 1.

Median time to disease progression in months for patients who were treated with lenalidomide for > 2 years is shown according to whether the patients received either 2 to < 3 years or ≥ 3 years of treatment.

Table 3. Response Rates and Survival According to the Time Exposure to Lenalidomide
 2 to <3 Years N = 22≥3 Years N = 28P
  1. Abbreviations: NS, not significant; ORR, overall response rate; PR, partial response; VGPR, very good partial response.

ORR (≥PR), no. (%)22 (100)27 (96)NS
≥VGPR, no. (%)18 (81.8)19 (67)NS
Time to progression at 37 mo, %7891.025

Duration of Treatment

Overall, 19 patients had stopped treatment with Len/Dex, including 9 patients (18%) who stopped because of toxicity (pneumonia in 2 patients, zoster infection in 1 patient, thrombotic event/pulmonary embolism in 3 patients, diarrhea in 2 patients, and other toxicities in 1 patient), 9 patients (18%) who stopped because of progression of MM, and 1 patient (0.5%) who decided to stop treatment. The discontinuation rate of Len/Dex was similar regardless of whether patients were exposed to Len for ≥ 3 years or for 2 years to < 3 years (14% vs 18%, respectively; P value was NS). The median duration of treatment with Len/Dex was 3 years (range, 2 years-7 years) for the overall cohort and 4 years (range, 3 years-7 years) for patients treated with Len for ≥ 3 years (P value was NS). The duration of treatment was similar across age categories and across the number of lines of therapy.

DISCUSSION

The current study provides estimates of responses, TTP, and safety in patients with MM who received long-term treatment with the Len-based regimen in the setting of disease recurrence. Our data set confirmed the efficacy of Len in patients with recurrent MM, which was already reported and published in several previous trials and studies, and demonstrated its use as monotherapy but more importantly in combination.[3] The most frequently tested combination historically was with Dex, although other drugs have been tested successfully with Len plus Dex in recent years.

We observed an acceptable safety profile in patients who underwent long-term exposure to Len, allowing for a long median duration of treatment. In the current study, we observed mainly hematological toxicity that was not found to be greater in patients according to their time of exposure to Len (≥ 3 years vs 2 years to < 3 years), which confirmed no excess of prolonged cytopenias, especially neutropenias, in patients with long-term exposure to Len. We observed a relatively higher-than-expected incidence of VTE with Len/Dex in patients who had had received prophylaxis for VTE of normally < 10%.[4-7] The vast majority of patients who experienced VTE had Len/Dex initiated before the release of the most recent guidelines, and we were not able to optimize the VTE risk factors identified at that time. Remarkably, this incidence rate was not influenced by the length of time the patient was treated with Len/Dex. Overall, the toxicity profile was similar across age categories, number of previous recurrences, and whether patients were exposed to Len for > 3 years, which is consistent with that reported in previous studies.

With regard to the incidence of SPM in the current series, not only was the observed incidence rate no greater than expected in previously published studies, but more importantly, we did not observe any increased incidence of SPM in patients with ≥ 3 years of treatment with Len. In the pooled analysis of MM-009 and MM-010 trials[8] and other studies of patients with MM who were treated in the recurrent setting with Len, the incidence of SPM was low, no acute myeloid leukemia or B-cell malignancies were reported, and the incidence of solid-tumor SPMs was no different from that of the general population, with a comparison based on background cancer rates based on cancer registry data (Surveillance, Epidemiology, and End Results [SEER] database).[9] These data do not compromise the benefit-risk profile for Len in patients with MM treated in the recurrent setting, and do not limit long-term exposure to Len in patients with recurrent MM.

It is interesting to note that we noticed a greater-than-expected ORR in patients with long exposure to Len/Dex in the current series; the ORR reported by Dimopoulos et al with Len/Dex in the pooled MM-009 and MM-010 phase 3 trials in patients with MM was 60% as a whole and 67% in patients at the time of first recurrence.[8] This result can likely be explained by the fact that patients responding to the combination of Len/Dex were more likely to benefit longer from the combination, and thus to remain on Len/Dex and be recruited in the current study.[10] All patients who had previously developed disease recurrence or whose disease became refractory to Len/Dex before reaching 2 years of treatment were excluded as per the inclusion criteria in the current study. One might also consider that our studied population was characterized with a good prognostic because we noticed a lower incidence rate of < 10% among patients with adverse fluorescence in situ hybridization cytogenetic findings (deletion of 17p and/or translocation t(4;14)) in the current study. Other studies have reported greater ORRs in patients exposed to Len long term. Srivastava and al studied the combination of Len/Dex as initial therapy in 286 consecutive patients with newly diagnosed MM, and observed an ORR of 72% in the entire cohort, including 26% of patients with ≥ VGPR, and 86% and 46%, respectively, among patients who stayed on therapy for ≥ 12 months (93 patients; 32%), thus demonstrating an improvement in the response rate with long-term exposure to Len/Dex.[11]

Another key finding of the current study was the longer median TTP on Len/Dex noted in patients treated for ≥ 3 years versus those treated for 2 to < 3 years, regardless of the ORR of either cohort. These results could be explained by the cellular effect of Len on tumor cells, which suggests that its chronic use may be beneficial to patients with myeloma.[12] Len exerts both a direct tumoricidal and an immunomodulatory effect in patients with myeloma, and it has been suggested that although the tumoricidal effects allow for an initial response by immediate tumor cell death, the immunomodulatory effects may be responsible for sustained disease control.[12] Both mechanisms, direct inhibition of tumoral cell growth and induction of apoptosis, were highlighted in previous studies, along with immunomodulation, including inhibition of myeloid cells and costimulation of lymphoid cells. An antiangiogenic effect also has been reported. Harousseau et al[10] demonstrated that approximately one-half of those patients who initially demonstrated a PR eventually obtained a complete response or near-complete response after additional cycles of treatment, suggesting deepening responses with continued treatment, making their study the first to our knowledge to highlight the importance of prolonged therapy. San Miguel et al[13] also reported that continuous Len/Dex treatment after the achievement of best response significantly prolonged survival compared with earlier discontinuation. Together, these data highlight the importance of continuing therapy with Len/Dex provided that patients are able to tolerate a Len-based regimen.

The analysis of data from the MM-009 and MM-010 trials also demonstrated that the patients who received full-dose therapy with Len/Dex for at least 12 months had a significantly higher complete response rate, along with higher progression-free survival and overall survival compared with those who had an earlier dose reduction.[14] These data were confirmed by Oehrlein and al in a retrospective analysis of 67 patients from a single center who were treated with the Len/Dex combination for RRMM.[15] In their study, patients treated with Len/Dex for at least 12 months had a higher overall survival compared with those who discontinued treatment before 12 months (42.9 months vs 14.4 months, respectively; P < .0001). We have performed similar analysis, although our data did not reach significance, which is most likely related to the limited number of patients in the current study. Based on these results, long-term treatment at the best-tolerated doses of both Len and Dex may be recommended until evidence of disease progression.[16]

Although long-term exposure to Len appears to be more and more beneficial, several questions remain regarding the addition of Dex in the long term and lowering doses of Len for the prolonged control of myeloma tumor cells. Although Len acts synergistically with Dex to inhibit myeloma cell proliferation in vitro, it has been suggested that the immunomodulatory effects could be antagonized by Dex,[16] suggesting that maintaining long-term treatment with Len could be more important than Dex once the disease is controlled.[17] Furthermore, it appears that even low doses of Len could be sufficient to preserve its immunomodulatory properties and provide adequate disease control.

However, Williams and al found a significantly positive association between a higher starting dose of Len and a longer duration of treatment duration in a series of 1286 patients with RRMM who were treated with Len/Dex at 185 treatment centers throughout the United Kingdom.[18] Their findings remind us that even if individual dose adjustments of Len can help to maintain a long-term treatment, a high starting dose is essential for initial tumor control.

The results of the current study confirmed that Len/Dex is safe in patients undergoing long-term treatment in the setting of RRMM, and we have observed a significant benefit in terms of TTP for prolonged treatment with Len/Dex in patients with RRMM. In the current study, there was a benefit noted in pursuing treatment with Len for > 3 years, highlighting that Len/Dex was approved until disease progression for all patients with myeloma in the setting of recurrent disease.

FUNDING SUPPORT

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

Drs. Herbaux, Avet Loiseau, Facon, and Leleu have received research support and lecture fees as well as acted as members of the Speakers' Bureau for Celgene. Drs. Facon and Leleu have acted as a member of the board and Speakers' Bureau as well as a consultant for and received travel expenses from Celgene, Janssen, Novartis, Amgen, LeoPharma, Onyx, Sanofi. Dr. Facon has acted as a member of the board and Speakers' Bureau as well as a consultant for and received travel expenses from Celgene, Onyx, Novartis, and Amgen. Dr. Miljkovic is employed by Celgene. Dr. Hulin has acted as a consultant for and received travel expenses from Celgene and Janssen. He has also received payment from those 2 companies for review activities.

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