Lenalidomide vs bortezomib maintenance choice post-autologous hematopoietic cell transplantation for multiple myeloma

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Abstract

Maintenance therapy post-autologous hematopoietic cell transplantation (AHCT) with either lenalidomide or bortezomib for multiple myeloma (MM) have separately been shown to improve progression-free survival (PFS), but have never been directly compared. We performed a retrospective study to investigate progression-free and overall survival outcomes and toxicities of lenalidomide maintenance therapy compared with bortezomib maintenance in MM patients post-AHCT. This study included 156 patients who received post-AHCT lenalidomide or bortezomib maintenance therapy for MM. The primary outcome was PFS. Ninety-two patients received lenalidomide maintenance and 64 received bortezomib maintenance post-AHCT. By multivariable analysis, maintenance therapy choice and cytogenetics risk did not impact PFS or OS. Staging by International Staging System and pre-maintenance disease response were the greatest predictors for PFS. Treatment-related toxicities were as anticipated with 5.4% of patients receiving maintenance lenalidomide experiencing secondary primary malignancies (SPMs) compared with 3% for bortezomib. These findings suggest there were no differences in PFS or OS between lenalidomide and bortezomib maintenance therapy options for post-transplantation MM patients. These data should be validated in a larger, prospective cohort to determine if maintenance choice should be guided by side effect profile and patient anticipated tolerance rather than by disease biology alone.

Introduction

Multiple myeloma (MM) is a malignant hematological disorder characterized by monoclonal proliferation of plasma cells. Autologous hematopoietic stem cell transplantation (AHCT) for MM is commonly used for patients with newly diagnosed myeloma in eligible patients [1,2,3,4]. AHCT and routine use of modern therapies has improved the 5-year survival rates, from 34.8% (1998–2001) to 44.6% (2006–2009) [5,6,7,8,9,10,11]. Despite these advances, MM remains incurable and relapse occurs for most patients [12].

Post-AHCT maintenance therapy is one approach for sustaining disease control and prolonging progression-free survival (PFS) [3, 13,14,15,16]. Optimal choice for maintenance therapy has not yet been established, but various agents have been used, including corticosteroids, thalidomide, lenalidomide, and bortezomib in various combinations [15,16,17,18,19,20,21,22]. While they have collectively been shown to improve PFS, their impact on overall survival (OS) is unclear, with some studies demonstrating OS benefit and others not [1, 15, 22,23,24]. Post-AHCT maintenance guidelines commonly recommend use of lenalidomide for standard-risk disease and bortezomib for intermediate and high-risk disease based on cytogenetics [22, 25,26,27].

Lenalidomide and bortezomib are two maintenance therapy options with low toxicity profiles that may offer survival benefit [16, 21]. Limited data are available evaluating the outcomes in patients who receive lenalidomide compared with bortezomib maintenance therapy. The aim of this study was to compare the PFS of lenalidomide and bortezomib as post-AHCT maintenance therapy for newly diagnosed MM.

Methods

Patients and study design

A retrospective study of 156 patients with newly diagnosed MM was performed. Evaluable patients received AHCT at Vanderbilt University Medical Center with melphalan conditioning for newly diagnosed MM between 2004 and 2016 after induction with lenalidomide-based and/or bortezomib-based therapy. The primary outcome was PFS. Secondary outcomes were OS and treatment-related toxicities. Patients who received tandem transplantations (autologous or allogeneic) and patients with a diagnosis other than MM were excluded (n = 17). Patients receiving up to three lines of induction therapy were permitted for analysis. Maintenance therapy was defined as monotherapy with either lenalidomide or bortezomib and started 2–4 months post-AHCT. Lenalidomide maintenance was administered at a starting dose of 10 mg/day and increased to 15 mg/day as tolerated. Bortezomib maintenance was administered as 1.3 mg/m2 subcutaneous every 2 weeks. Choice of maintenance therapy between lenalidomide and bortezomib was determined by physician and patient preference based on cytogenetics, anticipated tolerance and drug cost in some cases. Institutionally, patients received maintenance for a minimum of 2 years if progression did not occur prior to that time point. Thereafter, patients and provider discussed the risks and benefits of continuing maintenance therapy. If the decision was made to stop maintenance at this time it was considered completion of maintenance therapy.

Definitions

High-risk myeloma was defined as chromosomal abnormalities detected by conventional cytogenetics or fluorescence in situ hybridization (FISH) consisting of t(14;16), t(14;20), and deletion 17p [26]. Intermediate-risk myeloma was defined as t(4;14), monosomy 13, hypodiploidy and gain of 1q [28]. Response to therapy and disease progression was defined according to response criteria determined by the International Myeloma Working Group [29].

Statistical analysis

PFS was defined as survival without myeloma progression or relapse from disease response. OS was defined as death by any cause. Patients alive and without progression or relapse were censored at last follow-up. Time to relapse or progression was defined as time from day 30 after AHCT to first documentation of progressive disease.

Patient- and disease-related variables and outcomes of interest were summarized using descriptive statistics. The primary objective of this study was to evaluate PFS between patients receiving post-AHCT lenalidomide maintenance compared with bortezomib maintenance. Other variables considered included age, gender, myeloma subtype (IgG vs. IgA vs. light chain only), stage by International Staging System (ISS) (stage III vs. I/II), cytogenetic abnormality risk (high/intermediate risk vs. standard risk), disease status at time of maintenance initiation (stringent complete remission (sCR)/complete remission (CR)/very good partial response (VGPR) vs. partial response (PR)/stable disease (SD)/progressive disease (PD)) and duration of maintenance therapy (< 2 years vs. ≥ 2 years).

Continuous variables were analyzed using Wilcoxon rank sum test and categorical variables were compared using Pearson’s chi-squared test. The Kaplan–Meier method was used to analyze time to disease progression in each group with stratified log-rank test. A Cox proportional hazards regression model was used to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) for PFS and OS. Variables considered in the multivariable analysis were selected a priori and included cytogenetic abnormality risk (high/intermediate risk vs. standard risk), ISS stage (III vs. I/II), maintenance therapy option (bortezomib vs. lenalidomide), and treatment response prior to maintenance initiation (PR/SD/PD vs. sCR/CR/VGPR). This study was underpowered to analyze duration of maintenance therapy. An α level of 5% was used to determine significance. Analyses were performed with R version 3.2.3 (2015-12-10) [30].

Results

A total of 156 patients were included in the study, 92 patients received lenalidomide, whereas 64 received bortezomib maintenance post-AHCT. The median follow-up time post-AHCT for survivors was 33.7 months (range 8–119.2 months). At baseline, there were no differences in ISS stage, Durie–Salmon (DS) stage, or cytogenetic risk between maintenance cohorts (Table 1). Both cohorts received a median of one line of induction therapy (range 1–3). At the time of analysis, 47% (n = 43) of patients receiving lenalidomide maintenance and 52% (n = 33) on bortezomib maintenance experienced disease progression (Fig. 1). Of these patients, 29 (67%) experienced disease progression while on lenalidomide maintenance and 14 (42%) progressed while on bortezomib maintenance (Table 2).

Table 1 Baseline characteristics of patients receiving lenalidomide or bortezomib maintenance therapy post-AHCT
Fig. 1
figure1

CONSORT flow diagram

Table 2 Patient outcomes from time of maintenance initiation

Sixty-three patients (68.5%) stopped maintenance therapy in the lenalidomide cohort and 41 patients (64.1%) stopped maintenance in the bortezomib cohort. The reasons for stopping maintenance therapy included disease progression (lenalidomide: n = 22, 34.9%, bortezomib: n = 12, 29.2%), completed therapy and changed to observation alone (lenalidomide: n = 27, 42.8%, bortezomib: n = 16, 39.0%), maintenance intolerance (lenalidomide: n = 11, 17.5%, bortezomib: n = 8, 19.5%), switch to different maintenance therapy option (lenalidomide: n = 2, 3.2%, bortezomib: n = 1, 2.4%), and other logistical/financial reasons (lenalidomide: n = 1, 1.6%, bortezomib: n = 4, 9.8%). Fourteen percent (n = 9) of patients receiving bortezomib maintenance and 24% (n = 22) of those receiving lenalidomide maintenance required dose reductions. Patients who completed therapy and changed to observation alone completed a minimum of 2 years of therapy regardless of depth of response. Among these patients, there was no difference in maintenance duration between cohorts with a median lenalidomide duration of 25.4 months (range 12.6–44.7 months) and 22.9 months with bortezomib (range 11.1–29.5 months; p = 0.09). For patients who ended maintenance therapy for other reasons, patients remained on lenalidomide maintenance for a longer duration (median 24.8 months, range 6.0–54.3 months) than on bortezomib maintenance (median 17.7 months, range 7.7–42.8 months; p = 0.01), with the difference predominately due to earlier cessation of bortezomib from intolerance.

Median time to progression was 27.5 months (range 9.8–58.1 months) in the lenalidomide cohort and 24.3 months (range 9.8–66.6 months) in the bortezomib cohort (p = 0.52) (Table 2). Patients with standard-risk myeloma had a median time to progression of 26.9 months (range 10.8–54.3 months) with lenalidomide and 25.7 months (range 10.9–66.6 months) with bortezomib (p = 0.80). For intermediate- and high-risk disease, median time to progression was 27.5 months (range 9.8–58.1 months) with lenalidomide and 24.1 months (range 9.8–48.0 months) with bortezomib (p = 0.47) (Table 3).

Table 3 Median time to progression by cytogenetic risk

Disease response improved while on maintenance in 34% (n = 32) with lenalidomide and 38% (n = 23) with bortezomib (Table 2). Median time to best response after maintenance initiation was 11.3 months (range 5.7–34.8 months) for the lenalidomide cohort and 9.7 months (range 6.4–19.0 months) for the bortezomib cohort (p = 0.79) (Table 2).

Mortality occurred in 19 patients (21%) in the lenalidomide cohort and 6 patients (9%) in the bortezomib cohort (p = 0.06) (Table 2). Median time to death from any cause was 62.7 months (range 31.8–91.0 months) for the lenalidomide maintenance group and 69.2 months (range 34.4–119.2 months) for the bortezomib maintenance group (p = 0.47) (Table 2).

By multivariable analysis, there was no difference in PFS or OS based on choice of maintenance therapy (Table 4). Patients with ISS stage III had significantly reduced PFS and OS compared with those with ISS stage I/II (HR 2.22; 95% CI 1.28–3.84; p < 0.01) and (HR 4.59; 95% CI 1.75–12.06; p < 0.01), respectively. Patients without deep disease response prior to maintenance initiation (PR/SD/PD) were more likely to experience disease progression compared with those with deeper response (sCR/CR/VGPR) (HR 2.19; 95% CI 1.19–4.00; p = 0.01). Cytogenetic risk did not impact PFS or OS between cohorts.

Table 4 Multivariable analysis of post-AHCT outcomes in patients with MM receiving maintenance therapy

Toxicities attributable to maintenance therapy are listed in Table 5. Nine patients in the lenalidomide group (9.8%) and 8 patients in the bortezomib group (12.5%) had adverse events severe enough to necessitate early discontinuation of maintenance therapy. New or worsening peripheral neuropathy was the most common toxicity for the bortezomib cohort (10.9%; n = 7). Cytopenias were the most common adverse events in the lenalidomide cohort (30%; n = 28). Five patients (5.4%) receiving lenalidomide maintenance experienced secondary primary malignancies (SPMs), including anaplastic astrocytoma, intracranial meningioma, endometrial carcinoma, breast adenocarcinoma and one case of Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia (ALL). Two patients (3%) receiving bortezomib maintenance developed prostate adenocarcinoma. No hematological malignancies occurred in the bortezomib cohort (Table 5). The median time from initiation of maintenance therapy to development of SPM in the lenalidomide cohort was 29.2 months (range 5.0–67.4 months) compared with 30.6 months (range 25.5–35.7 months) in the bortezomib cohort. The incidence rate of SPM for patients on maintenance therapy was 3.2 new cancers per 100 person-years of observation (95% CI 1.6–11.7) in the lenalidomide cohort compared with 2.8 new cancers per 100 person-years of observation (95% CI 0.2–7.2) in the bortezomib cohort.

Table 5 Toxicities attributable to maintenance

Discussion

We conducted a single center retrospective study of 156 MM patients who received maintenance lenalidomide or bortezomib post-AHCT. By multivariable analysis, choice of maintenance therapy between bortezomib or lenalidomide did not impact the PFS or OS in this population. Comparatively, pre-maintenance disease response and ISS stage had greatest impact on PFS. Many studies have demonstrated an improvement in PFS with use of maintenance therapy with some studies indicating an improvement in OS compared with placebo [15, 16, 21, 22]. To our knowledge, there are no published reports directly comparing lenalidomide and bortezomib maintenance. In addition, in our study, no differences in outcomes were detected based on cytogenetic profile. This may be because despite high-risk cytogenetics, choice of maintenance therapy was often driven by physician and patient preference, based on other factors, including anticipated tolerance, secondary malignancy risk, and drug cost in some cases. The relatively short follow-up time of 33.7 months for the study may further explain the reason that no difference in PFS was observed based on cytogenetics. With longer follow-up, a difference may have been seen between the two groups that is not yet identifiable. Standard of care guidelines for MM commonly recommend the use of post-AHCT lenalidomide maintenance for standard-risk patients and bortezomib maintenance for intermediate and high-risk patients [25,26,27]. These data underscore the need for a larger, prospective study in order to validate these findings and determine if maintenance choice should be guided by side effect profile and patient anticipated tolerance rather than by disease biology alone.

The median PFS for patients receiving lenalidomide maintenance was 27.5 and 24.3 months with bortezomib maintenance. The Intergroupe Francophone du Myelome (IFM) [15] and Cancer and Leukemia Group B (CALGB) [16] trials report median PFS of 41 and 46 months with lenalidomide maintenance, respectively. HOVON-65/GMMG-HD4 trial [21] found high-risk patients with creatinine > 2 mg/dL experienced a median PFS of 30 months with bortezomib. This discrepancy in PFS between our analysis and these clinical trials is possibly explained by clinical trial patient selection and pre-maintenance therapeutic choice. Patients in our analysis were permitted to receive up to three lines of induction therapy and prior progression with induction was permitted. These patients would have been excluded from the clinical trials listed above. In addition, in our study all patients received induction therapy with either lenalidomide or bortezomib, whereas many patients in the aforementioned studies received thalidomide induction therapy. The precise impact of this is unclear but may have impacted differences observed in PFS and highlights the point that different populations are being evaluated. Overall, this study represents a more “real-world” population compared with a clinical trial population in which patients would have been excluded per eligibility criteria.

There was no difference in median time to progression for patients with intermediate- or high-risk myeloma by cytogenetics receiving lenalidomide compared with those receiving bortezomib. Sonneveld et al. [21] evaluated use of thalidomide and bortezomib maintenance and demonstrated a significant improvement in PFS and OS for high-risk myeloma with bortezomib-based therapy. One reason for this difference may be that in the HOVON-65/GMMG-HD4 trial, patients were randomized into two cohorts. Cohort A received induction therapy with vincristine, doxorubicin, and dexamethasone followed by AHCT and then post-AHCT thalidomide maintenance. Cohort B received bortezomib, doxorubicin, and dexamethasone followed by AHCT and then bortezomib maintenance. Thus, the observed improvement in outcomes may stem from the effect of differential induction therapy rather than that of maintenance choice alone. In addition, lenalidomide was not used in this study.

SPM occurred in 5.4% with lenalidomide and 3% with bortezomib. These are consistent with other published reports, which indicate a SPM incidence of about 7–8% with lenalidomide maintenance [15, 16, 31]. In these reports, patients had a higher propensity for myeloid malignancies. Interestingly, no patients in our study developed a myeloid malignancy, although one patient receiving lenalidomide maintenance developed Philadelphia chromosome-negative B-cell ALL. There are many potential factors that may impact the risk of SPM, including effects from previous cancer treatment, host factors, and genetic predisposition [32, 33]. An individual risk–benefit analysis for continued therapy should be conducted for each myeloma patient [34,35,36], and physicians and patients should make an informed decision together.

Other possible considerations for choice of maintenance therapy that may affect physician and/or patient preference include ease of administration and cost efficacy. Lenalidomide has the advantage of daily oral administration but comes at higher expense. There are limited data evaluating the impact of maintenance therapy on quality of life. However, Teitelbaum et al. [37] demonstrated similar rates of ambulatory visits for myeloma patients treated with lenalidomide or thalidomide compared with those treated with bortezomib or other therapies. Regarding expense, a study in the Canadian healthcare system found the total annual per patient cost for lenalidomide maintenance therapy was $131,765 compared with $33,967 for bortezomib maintenance, with the differences between the two maintenance therapies mainly due to acquisition costs of the drugs rather than management of adverse effects and SPM [38]. Studies evaluating maintenance choice quality of life and pharmacoeconomics may provide guidance on other reasons for choosing one maintenance therapy over another.

Limitations of this research include being a single institutional study and retrospective analysis with relatively small sample size. The median follow-up time of 33.7 months is also relatively short. Mian et al. [39] demonstrated improved PFS and OS for patients on lenalidomide maintenance for > 2 years vs. those on maintenance for ≤ 2 years. After adjusting for patients with disease progression prior to 2 years from the analysis, our study was underpowered to analyze duration of maintenance therapy. The 2-year time point was selected based on our institutional practice for minimum planned maintenance duration. In addition, although all patients received induction therapy with either bortezomib and/or lenalidomide-based therapies, there was variability in the frequency and dosing of these agents during induction.

Conclusion

Our study further supports the use of lenalidomide and bortezomib as maintenance therapy options for MM patients post-transplantation to improve PFS. Choice of maintenance therapy does not significantly impact PFS or OS after controlling for other disease-modifying factors, including ISS stage and disease response to induction therapy. These findings should be validated to determine if maintenance therapy choice should be guided by side effect profile and patient-specific anticipated tolerance rather than disease biology alone. Further, the decision to remain on maintenance therapy should be discussed with patients while considering the risks and benefits of continued maintenance therapy.

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Correspondence to R. Frank Cornell.

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Huang, J., Phillips, S., Byrne, M. et al. Lenalidomide vs bortezomib maintenance choice post-autologous hematopoietic cell transplantation for multiple myeloma. Bone Marrow Transplant 53, 701–707 (2018) doi:10.1038/s41409-018-0177-6

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