Although treatment for multiple myeloma (MM) has considerably improved in the past decade, MM continues to be an incurable hematological malignancy that causes most patients to eventually relapse and die from their illness. Thus, the identification of effective salvage strategies remains a priority.
In this trial, the authors evaluated the safety and efficacy of bortezomib and dexamethasone [V: on days 1 and 15 (1.3 mg/mq); D: on days 1-2 and 15-16, every 28-day cycle until progression (20 mg/d)] as maintenance therapy (MT) in patients with advanced MM who responded to salvage therapy that used a bortezomib-containing regimen.
Forty-nine MM patients were enrolled in this study between October of 2004 and April of 2008. All patients who were included in this study were responsive to a prior salvage therapy with bortezomib and had a measurable disease. The bortezomib and dexamethasone MT improved the quality of responses to complete remission in 4 patients and very good partial response in 3 patients. In addition, 10 patients experienced at least a 50% improvement in their symptoms. The median time to progression (TTP) was 16 months with a progression-free survival of 61% after 1 year. The overall response after 1 year was 76%, and the cumulative incidence of death due to disease progression, which was adjusted for competitive risk events, was 14%. Non-dose-limiting toxicities included neuropathy (predominantly grade 1), herpes zoster reactivation, pneumonia, and gastrointestinal affections (constipation and diarrhea). Three patients developed grade 2 neuropathy, which required a bortezomib dose reduction to 1.0 mg/mq. No grade 3 or 4 toxicities were recorded.
Multiple >myeloma (MM) is a malignant plasma cell proliferation disorder that causes approximately 17,000 deaths each year in Europe.1 The survival of MM patients has improved considerably in the past decade because of melphalan-based high-dose therapy2, 3 and the emerging role of novel therapies, including thalidomide, bortezomib, and lenalidomide.4-7 Unfortunately, MM remains an incurable disease, and almost all patients will eventually relapse and die from their illness. Indeed, the median survival time of MM is approximately 4 to 5 years (2 years after relapse).8 Thus, the identification of effective salvage strategies to control or delay disease progression remains a priority.
Corticosteroid maintenance has been shown to prolong the duration of response, although the effect on survival has been controversial.9, 10 Interferon-alpha has been demonstrated to cause frequent side effects and has only demonstrated a modest increase in progression-free survival (PFS) and overall survival (OS).11
Thalidomide has also been considered for MM maintenance. Compared with no treatment or pamidronate treatment alone, OS for patients who were randomized to receive thalidomide maintenance therapy improved as demonstrated in a French trial.12 In addition, Barlogie et al13 studied post–autologous stem cell transplantation (ASCT) patients and reported a trend toward an increase in OS using thalidomide treatment at 72-month follow-up. In a similar experimental setup, Spencer et al14 demonstrated an OS rate of 86% for a thalidomide-treatment group compared with 75% for a control group. Despite the findings from 3 separate phase III studies that thalidomide maintenance improves OS, thalidomide has not been widely used because of concerns about its toxicity, which appears to be both dose dependent and cumulative.15
Lenalidomide may offer the same advantages as thalidomide but without the same degree of toxicity, and large randomized trials are now addressing its role after melphalan in the post-transplantation setting16 and in the management of elderly patients.17
Bortezomib was the first proteasome inhibitor to enter the clinic and be approved for the treatment of MM.7, 18 Several studies have demonstrated the efficacy of bortezomib as a front-line therapy in advanced MM.7, 19 A trial involving patients with newly diagnosed MM, the HOVON-65/GMMG-HD4 phase III clinical trial, has compared a bortezomib-containing regimen (PAD-B) given during induction before ASCT and in the subsequent maintenance phase with an anthracyclin-containing regimen given during induction and followed by maintenance with thalidomide (VAD-T).20 Preliminary data demonstrated bortezomib to be superior, which had an overall complete response rate, including maintenance, of 27% versus 5% for the VAD-T arm. Chromosome abnormalities, such as the deletion of chromosome 13, did not affect the efficacy of bortezomib. Peripheral neuropathy and constitutional symptoms were the major adverse effects of this treatment.
Another clinical trial is currently ongoing in newly diagnosed MM patients who are not candidates for ASCT. This trial is comparing induction treatment with bortezomib plus melphalan, thalidomide, and prednisone (VMPT) with bortezomib plus MP (VMP). After induction, only the VMPT arm has been scheduled to receive a maintenance treatment of bortezomib at a reduced dose (1.3 mg/mq every other week) until disease recurrence or intolerable toxicity. The results of this trial will help to clarify the role of bortezomib in induction treatment, as well as the benefit derived from a prolonged but reduced dose of bortezomib in the maintenance phase of newly diagnosed MM patients.21
The present study was the first trial to evaluate the safety and the efficacy of bortezomib/dexamethasone maintenance therapy in patients with relapsed and relapsed/refractory MM who responded to salvage therapy with bortezomib-containing regimens.
PATIENTS AND METHODS
Between October 2004 and April 2008, a total of 49 patients were enrolled in the study. All the patients had relapsed after a previous chemotherapy or the disease was refractory, which was defined by progression during treatment or within 60 days after the completion of treatment. All patients received salvage therapy, which was at the discretion of the referring hematologist. Salvage therapy included bortezomib as a single agent, bortezomib in combination with steroids and/or thalidomide, and bortezomib in association with anthracyclines. Patients who were responsive to salvage therapy that utilized a bortezomib-containing regimen were eligible for inclusion in the study. Patients in complete remission (CR) after salvage therapy were not eligible for inclusion in this study because of the lack of measurable disease. In addition, patients with disease progression were excluded for their apparent resistance to bortezomib therapy.
To be included in this study, patients had to be at least 18 years old, had relapsed or were refractory after more than 1 line of treatment, had exhibited a previous response to bortezomib therapy, had exhibited measurable disease (defined as a monoclonal immunoglobulin concentration on serum electrophoresis of at least 5 g/L [0.5 g/dL] IgG and IgA, 2 g/L [0.2 g/dL] IgD, or urinary excretion of at least 200 mg monoclonal light chain per 24 hours), and had a platelet count of 75 × 109/L or higher.
Patients with a preexisting peripheral neuropathy or grade ≥2 or patients who were refractory to bortezomib were excluded.
This was a multicenter, noncomparative, open-label study investigating the combination of bortezomib and dexamethasone as maintenance therapy in patients with advanced MM. The primary objectives of this study were to demonstrate the efficacy of bortezomib and dexamethasone by demonstrating at least 30% of patients were in partial remission (PR) and to determine an acceptable rate of toxicity for grade 3 nonhematological effects and grade 4 hematological effects. The secondary objectives of this study were to determine the durations of PFS and OS. We received informed consent from all the patients, and the study was conducted in accordance with the Declaration of Helsinki. In addition, the local ethics committee approved this protocol.
When used as a maintenance therapy, bortezomib (Janssen & Cilag; Johnson & Johnson Pharmaceutical Research and Development, LLC, Raritan, NJ) was administered by intravenous bolus on days 1 and 15 (1.3 mg/mq), and dexamethasone was given orally (20 mg/day) on days 1-2 and 15-16 of every 28-day cycle until relapse. The therapy started within 60 days of the end of salvage therapy. Responsive patients continued treatment until relapse.
Efficacy and Safety Assessments
Blood samples were collected at screening, before each intravenous treatment, and at the end of the study. A complete neurological evaluation was performed during the initial screening, during treatment as needed, and at the end of treatment.
Treatment response was monitored by measuring serum and urine protein levels using the uniformed response criteria of the International Myeloma Working Group to define responses.22 Briefly, a CR required the disappearance of myeloma protein in serum and urine and negative immunofixation. A very good partial response (VGPR) required at least a 90% reduction in myeloma protein level in serum or urine (myeloma protein level <100 mg/24 hours). A PR required at least a 50% reduction in myeloma protein level in serum and a 90% decrease in urine. Stable disease (SD) was defined as all responses that did not meet the criteria for CR, VGPR, PR, or progressive disease. Progressive disease (PD) was defined as an increase of at least 25% in myeloma protein level from baseline. Bone marrow plasmacytosis, skeletal disease, and serum calcium level were included in the response evaluation. All adverse events were assessed at each visit and graded according to the National Cancer Institute Common Terminology Criteria (version 3).23 Causes of death were recorded as disease related, drug toxicity, other causes, or a combination of these factors.
Progression-free survival was defined as the time from the start of maintenance to disease progression or patient death from any cause. A univariate analysis of factors that affected PFS was performed via the log-rank test. The cumulative incidence of death from disease progression was calculated from the start of maintenance therapy to death from either disease progression or another cause. According to the method of Gooley et al,24 death from other causes has been considered to be a competing event in the calculation of the cumulative incidence of death from disease progression.
Between October of 2004 and April of 2008, 49 advanced MM patients who were responsive to salvage therapy with bortezomib were included in the study and received maintenance therapy with bortezomib and dexamethasone (VD). The patient group included 28 men and 21 women. The median age of the patients was 71 years (IQR, 66-75 years), the median hemoglobin value was 11.3 g/dL (IQR, 10.4-18.8 g/dL), and 8 patients (16.3%) had renal failure (creatinine >2 mg/dL; Table 1). The median number of prior therapies was 2 (2-3). Thirty-nine patients (80%) received bortezomib as a single agent or in combination with steroids and/or thalidomide, and 10 patients (20%) received bortezomib in association with anthracyclines. The median time from diagnosis to the first dose of maintenance therapy was 49 months (IQR, 26-56 months), and the median number of bortezomib infusions was 8 (7-12). All patients were able to be analyzed for response at the date of the last follow-up.
Table 1. Patient Demographics and Clinical Characteristics
Demographics or Clinical Characteristics
No. of Patients (N=49)
Age, y, median (range)
Hemoglobin (g/dL), median (range)
Serum creatinine >2, n
Skeletal disease, n
Time to diagnosis, mo, median (range)
Salvage therapy regimens
Prior ASCT (not as salvage therapy)
The most common non-dose-limiting grades 1 and 2 adverse events included fatigue (8 patients), gastrointestinal symptoms (3 patients), herpes zoster reactivation (2 patients), and pneumonia (2 patients). Gastrointestinal symptoms (constipation and diarrhea) were typically mild to moderate and were manageable with routine support. The 2 patients who developed herpes zoster reactivation were not on acyclovir prophylaxis. After the introduction of acyclovir, herpes zoster reactivation was not observed. Fifteen patients developed grade 1 sensory neuropathy, which resolved with gabapentin and vitamins. Three patients developed grade 2 neuropathy, which required the dose of bortezomib to be reduced to 1.0 mg/mq. None of the patients exhibited grade 3 or 4 neuropathies or hematological toxicities, and no patient needed granulocyte colony-stimulating factor support. In addition, no deaths were reported as a consequence of adverse events.
After a median follow-up of 25 months (IQR, 20-28 months), 16 patients died from disease progression, 1 patient died from acute heart failure, and 6 patients died from infections. The maintenance therapy improved the quality of response after salvage therapy to CR in 4 patients and to VGPR in 3 patients. In addition, 10 patients achieved at least a 50% response improvement (Table 2). The overall response rate (ORR) was 34.6%, and the ORR “positive” (including SD, which counted as a positive response) was 73.4%. The median time to progression was 17 months (95% CI, 7-38 months), with a PFS at 1 year of 61% (95% CI, 48%-75%; Fig. 1). The OS at 1 year was 79% (95% CI, 75%-88%), and the cumulative incidence of death due to disease progression (adjusted for competitive risk events) was 12% (95% CI, 2%-19%; Fig. 2). In the univariate analysis, the PFS after maintenance therapy was not significantly affected by age, sex, number or type of previous therapy, hemoglobin concentration, or serum creatinine level.
Table 2. Treatment Results
No. of patients (N=49)
PD, progressive disease; SD, stable disease; PR, partial remission; VGPR, very good partial remission; CR, complete remission.
In this study, we evaluated the efficacy and safety profile of the combination of VD as maintenance therapy in patients with advanced multiple myeloma who had previously responded to salvage bortezomib-containing regimens.
Several studies have suggested that the achievement of a CR in MM patients positively affects survival,25 and new drugs have considerably improved the OS; however, almost all patients relapse, which has suggested the presence of residual disease. Ideally, maintenance therapy should be effective in residual disease control by increasing the duration of remission and ultimately in a better survival.
The use of bortezomib-containing regimens in advanced myeloma has induced a variable response rate of about 25% (the combination of bortezomib plus melphalan induced a CR or VGPR rate of 15%,26 the combination of bortezomib with thalidomide and dexamethasone induced a near-CR rate of 16%,27 and a CR or VGPR rate of at least 43% was achieved in patients who were treated with bortezomib plus melphalan, thalidomide, and prednisone28).
With the addition of maintenance therapy after salvage therapy, we demonstrated an ORR of 34.6%. A CR and VGPR were observed in 14% of patients, whereas an overall “positive” response rate (including SD) was achieved in 73.4% of patients. Interestingly, the response rate that was induced by VD maintenance therapy was quite similar to the response rate that was achieved by adding bortezomib to other agents, such as melphalan and thalidomide. Because CR and VGPR have been shown to be predictive of remission duration and survival, we were encouraged by the increased quality of response that we observed after salvage therapy was coupled with VD maintenance therapy.
In fact, we observed a median time to progression of 16 months, which was significantly higher in a subset of advanced patients.
In agreement with the results of several studies,29, 30 in our study the responsiveness to bortezomib did not correlate with most of the standard prognostic factors. Even when bortezomib was used as maintenance therapy, it is possible that the unique mechanism of action of bortezomib overcame the influence of these adverse prognostic factors.
Moreover, a comparison of the efficacy of bortezomib plus dexamethasone in cases of MM relapse17, 31 (ORR, 67%; including 11% CR, 22% VGPR, and 18% PR, with a median time to progression [TTP] of 6.22 months) with the efficacy of lenalidomide plus dexamethasone (ORR 60%, including 15% of patients achieving CR, a median OS of 35 months, and a median TTP of 11 months), which was investigated in 2 pivotal phase III studies (MM-009 and MM-010),32, 33 demonstrates that bortezomib results in a higher incidence of ORR, including CR and VGPR, but a lower TTP. These data suggest a decisive effect on TTP of the role of using lenalidomide as maintenance therapy until relapse.
Interestingly, when a sequential approach including bortezomib as an induction and lenalidomide as a post-ASCT consolidation-maintenance strategy was explored in a phase II study,15 the authors observed a CR and VGPR response rate of 58% after induction, which became 86% during the maintenance phase. In addition, they observed a 2-year TTP of 75% and an OS of 86%. Moreover, the median time to response with bortezomib was about 1 month, and PR was more rapidly achieved than VGPR and CR. Thus, we might be able to optimize the efficacy of bortezomib when it is used as a maintenance therapy.
These data demonstrate the significant role of maintenance therapy in MM patients and suggest the possibility of using bortezomib instead of lenalidomide or indeed as part of a combination approach in maintenance therapy.
In the present study, most adverse events could be managed with the use of standard approaches. No patients developed grade 3 or 4 hematological toxicities or grade 4 peripheral neuropathy, which was likely a result of the twice-monthly bortezomib infusion. Grade 2 neuropathic pain was observed in 3 patients, and they were all treated with a high cumulative dose of bortezomib. These observations agree with the results of previous bortezomib studies,34-36 wherein the incidence of bortezomib-induced peripheral neuropathy plateaued at a cumulative dose of 42-45 mg/mq in relapsed and newly diagnosed MM patients. Importantly, our findings suggest that bortezomib can subsequently be used for maintenance therapy without any further substantial increase in the risk of peripheral neuropathy. This finding appears to contrast with thalidomide-associated peripheral neuropathy, wherein the risk continues to increase as treatment time increases.37
Despite the absence of any anticoagulant prophylaxis, no deep vein thrombosis (DVT) or pulmonary embolism (PE) was reported. These data are consistent with previous studies, which have shown that bortezomib in combination with dexamethasone and/or concomitant EPO did not appear to be associated with an elevated risk of DVT or PE.38
By administering bortezomib on a bimonthly basis, we avoided the most common adverse effects of prolonged therapy, and we were able to achieve a low rate of discontinuation.
In conclusion, the combination of dexamethasone and the novel proteasome inhibitor bortezomib as a maintenance therapy after salvage therapy induced clinically significant responses in patients with advanced MM. In addition, the toxic effects were tolerable.
Further evaluation, including randomized studies, are warranted to assess the role of bortezomib-containing regimens as maintenance therapies in the treatment of patients with advanced MM.
We thank the patients, nurses, physicians, clinical trial office staff (Francesca Pirillo, Antonella Bono, Giorgio Priolo, and Giorgio Schirripa), and Evangelista Andrea from CPO Piemonte.
CONFLICT OF INTEREST DISCLOSURES
Dr. Palumbo has received honoraria from Celgene, Janssen-Cilag, Merck, and Amgen, and is on the advisory committees of Celgene and Janssen-Cilag. Dr. Boccadoro has received research support and consultancy from and is on the scientific advisory boards of Celgene and Janssen-Cilag. Dr. Gay has received honoraria from Celgene.