Bortezomib, melphalan, and prednisone in elderly patients with relapsed/refractory multiple myeloma

A multicenter, open label phase 1/2 study

Authors


  • All authors provided the conception, design, and analysis and interpretation of the data for this article. The first and last authors critically revised the article for important intellectual content and gave the final approval of the version to be submitted.

Abstract

BACKGROUND:

In elderly patients with newly diagnosed multiple myeloma (MM), the addition of bortezomib to standard, combined oral melphalan and prednisone (MP) significantly increases the response rate and event-free survival compared with MP alone.

METHODS:

In this phase 1/2 trial, the authors assessed the dosing, efficacy, and safety of a lower dose-intensity MP schedule plus weekly bortezomib as salvage treatment for elderly patients with MM. To assess the maximum tolerated dose, 19 patients who had relapsed/refractory MM after 1 or 2 lines of treatment entered the first phase of the study. They received melphalan at a dose of 24 mg for 28 days; bortezomib 1.3 mg/m2 on days 1, 8, 15, and 22; and prednisone at a dose of 50 mg every other day of a 28-day cycle for a total of 9 cycles. At the end of the first phase, based on the good efficacy and acceptable toxicity of this combination, an additional 23 patients were enrolled.

RESULTS:

After a median follow-up of 21 months, of 42 patients who relapsed, 24 (57%) obtained at least a partial response, 4 had stable disease, and 11 had progressive disease. The median time to progression was 18 months, and the median overall survival was 30 months. Grade 3 and 4 toxicity was observed in 16 of 42 patients (38%) and was more frequent during the early cycles.

CONCLUSIONS:

A weekly infusion of bortezomib associated with lower dose-intensity MP induced a high proportion of responses and was well tolerated in elderly patients with relapsed/refractory MM. Cancer 2013. © 2012 American Cancer Society.

INTRODUCTION

Multiple myeloma (MM) is a uniformly fatal malignancy of the plasma cells. The median age of patients at diagnosis is approximately 70 years, and approximately 33% of patients are aged ≥75 years. Recently, new advances in our understanding of the pathogenesis of MM have led to the introduction of agents that hit multiple pathways of malignant plasma cells and their cross-talk with the bone marrow microenvironment. Melphalan is 1 of the most active drugs for the treatment of MM1 and is used in association with prednisone and, more recently, with new drugs for elderly patients or for younger patients at a high dose with hematopoietic stem cell support (autologous or allogeneic). Among the new drugs, bortezomib was the first proteasome inhibitor to enter the clinic and to be approved for the treatment of MM.2 The rationale for combining bortezomib with combined melphalan and prednisone (MP) chemotherapy is based on the different mechanisms of action and the potential synergism of bortezomib with melphalan and steroids. In vitro, it has been demonstrated that bortezomib restores melphalan sensitivity to melphalan-resistant cell lines and synergizes with melphalan in killing myeloma cells, thereby allowing the use of lower concentrations of melphalan.3 Bortezomib (Velcade; Millennium Pharmaceuticals, Cambridge, Mass) plus standard MP (VMP) significantly increased response rates and remission durations compared with historic controls who received MP alone.4 The VMP combination has been approved for previously untreated patients who are ineligible for stem cell transplantation; in addition, bortezomib alone or in combination with pegylated liposomal doxorubicin has been approved for patients with relapsed MM.5, 6 The recommended dose and schedule of bortezomib is 1.3 mg/m2 administered as a bolus intravenous injection on days 1, 4, 8, and 11 of a 21 day cycle.7 The limitation of this schedule is the peripheral neuropathy, a well known and important side effect of bortezomib,8 which produces a primarily small fiber and painful, axonal, sensory distal neuropathy and often leads to dose modifications and drug discontinuation.9 To reduce toxicity and improve patient compliance, a weekly infusion of bortezomib has been used in different trials. In a study by Reeder et al,10 after the first 33 patients received twice-weekly bortezomib, an additional series of 30 patients received weekly infusions. The rate of grade 3 and 4 adverse events was lower in the group that received once-weekly bortezomib compared with the group that received twice-weekly bortezomib (grade 3, 37% vs 48%; grade 4, 3% vs 12%). In an Italian Group for Adult Hematologic Diseases (GIMEMA) study,11 nonhematologic grade 3 and 4 adverse events were reported in 35% of patients who received once-weekly treatment and in 51% of patients who received twice-weekly treatment. The incidence of grade 3 and 4 peripheral neuropathy was 8% in the once-weekly group and 28% in the twice-weekly group. In both studies, improvement in the safety profile was not associated with any reduction in the regimen's efficacy. Concerning adverse events, hematologic toxicity is the main, unfavorable, dose-limiting effect of oral melphalan and is manifested mainly by leukopenia and thrombocytopenia when used at the standard dose of 0.18 mg/kg (50 mg per month). Myelosuppression usually occurs after 2 to 3 weeks of melphalan therapy, but leukopenia may occur in a proportion of patients after 5 days. Leukocyte and platelet counts usually return to normal levels during the fifth week, but leukopenia and/or thrombocytopenia may persist for 6 weeks or longer after drug discontinuation. However, irreversible bone marrow depression has been reported in some patients who received the drug; therefore, the patient's hematologic status must be carefully monitored. Lower doses of melphalan may offer clinical utility, overcoming this adverse event. In a phase 1/2 study, Berenson et al12 defined the maximum tolerated dose (MTD) as 1.0 mg/m2 bortezomib and 0.10 mg/kg melphalan, which, in patients with relapsed or refractory MM, led to a response rate of 68%. These encouraging results led us to use low-dose melphalan; and, based on our previously experience,13 we chose the continuous administration. It is well documented that glucocorticoids have antitumor activity in MM, and several different doses and schedules of prednisone have been used. According to Southwest Oncology Group trial 9210l,14 we used a prednisone dose of 50 mg every other day. We designed the current study to determine whether a novel VMP schedule (lower melphalan dose intensity at 24 mg for 28 days and weekly bortezomib at 1.3 mg/m2) is safe and capable of inducing a significant partial response (PR) rate in elderly patients with relapse/refractory MM, including patients aged ≥75 years who are vulnerable because of their comorbid conditions, which complicate the presentation and management of the disease.

MATERIALS AND METHODS

Patient Selection

Between March 2008 and February 2010, 42 patients with MM were enrolled in the current study. We obtained informed consent from all patients, the study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the local ethics committee. To take part in this study, patients had to have relapsed or refractory disease after receiving 1 or 2 lines of treatment, including high-dose chemotherapy with stem cell support, conventional polychemotherapy, thalidomide, and bortezomib and melphalan-based regimens; and they had to exhibit any quantifiable serum monoclonal protein value (generally, but not necessarily, an immunoglobulin G M-protein level >1 g/dL and an immunoglobulin A M-protein level >0.5 g/dL) and, when applicable, a urine light-chain excretion level >200 mg/24 hours or nonsecretory myeloma, >30% plasma cells in the bone marrow, and at least 1 plasmacytoma level >2cm, as determined by clinical examination or applicable imaging studies (ie, magnetic resonance image or computed tomography scan). Patients who had pre-existing peripheral neuropathy or grade ≥2 peripheral neuropathy within 14 days before enrollment were excluded.

Study Design

The primary objective of this phase 1/2, multicenter, Italian, noncomparative, open-label study was to assess the safety and efficacy (a PR or better) of the VMP regimen as salvage treatment for elderly patients with advanced and refractory MM. The secondary objectives were to determine the durations of progression-free survival (PFS) and overall survival (OS). In the first stage of the study, prednisone was combined with different dose levels of melphalan and different schedules of bortezomib in 19 patients to define the MTD, which was evaluated after the first 3 cycles of VMP. The MTD dose was defined by 2 parameters (Table 1): the number of patients who obtained a response (at least 5 PRs) and the number of patients (<10) who presented with the following toxicities: grade 4 neutropenia for >4 weeks or grade 4 hematologic toxicity, except for neutropenia, or any grade 3 nonhematologic toxicity. The plan was to test the dose levels of melphalan and bortezomib described below.

Table 1. Maximum Tolerated Dose
 No. of Patients With Grade 3/4 Toxicity
No. of Partial Responses≤34-10≥10
≤4Restart a cycle with an increased dose: Melphalan 48 mg/28 d, bortezomib 1.3 mg/m2 weeklySTOP the studySTOP the study
≥5Continue to a second phaseContinue to a second phaseRestart a new phase with a reduced dose: Melphalan 24 mg/28 d, bortezomib 1.3 mg/m2 every other month

Level 0: Starting dose

The starting dose consisted of melphalan 24 mg for 28 days for a total of 9 cycles (2 mg on Monday, Wednesday, and Friday every week for a total of 9 cycles) and bortezomib 1.3 mg/m2 as a bolus intravenous injection on days 1, 8, 15, and 22. Each cycle was repeated every 28 days for a total of 9 cycles.

Level −1

The next dose level was melphalan 24 mg for 28 days for a total of 9 cycles (2 mg on Monday, Wednesday, and Friday every week for a total of 9 cycles) and bortezomib 1.3 mg/m2 as a bolus intravenous injection on days 1, 8, 15, and 22. Each cycle was repeated every 56 days for a total of 5 cycles.

Level +1

The +1 dose level was melphalan 48 mg for 28 days for a total of 9 cycles (4 mg on Monday, Wednesday, and Friday every week for a total of 9 cycles) and bortezomib 1.3 mg/m2 as a bolus intravenous injection on days 1, 8, 15, and 22. Each cycle was repeated every 28 days for a total of 9 cycles.

Patients were observed through the first 3 cycles of therapy to evaluate side effects and response rates. At the end of this first phase, an additional series of 23 patients was enrolled.

Drug Administration

In this trial, we started with a reduced dose of melphalan (24 mg for 28 days: 2 mg on Monday, Wednesday, and Friday every week), bortezomib (1.3 mg/m2 as a bolus intravenous injection on days 1, 8, 15, and 22), and prednisone (50 mg every other day) for a total of 9 cycles, as soon as the screening visits of the pretreatment period had been completed. The plan was to modify the dose of bortezomib and/or melphalan in accordance with the toxicity registered during the first phase of the study. A new cycle was allowed if the neutrophil count was >1 × 109/L, the platelet count was >50 × 109/L, and nonhematologic adverse events were grade <2. A delay of 2 weeks was allowed without any dose modification. A new cycle delay beyond a maximum of 2 weeks required dose reduction.

Efficacy and Safety Assessments

Blood samples were collected at screening, during the treatment period at each scheduled bortezomib administration, and during long-term follow-up until the development of confirmed disease progression. Treatment response was monitored by measuring serum and urine protein levels using uniform response criteria of the International Myeloma Working Group to define responses.15 All adverse events were assessed at each visit and graded according to the National Cancer Institute Common Terminology Criteria (version 3).16 Treatment outcome was evaluated in terms of PFS and OS. PFS was calculated from the time of initial diagnosis to the time of progression, relapse after response, or death from any cause. Follow-up for patients who did not experience 1 of these events was censored at the date of last contact. OS was calculated from the time of initial diagnosis to the time of death from any cause, and the follow-up of surviving patients was censored at the last contact date.

Statistical Analysis

The study design, according to the Bryant and Day method,17 was a 2-stage phase 1/2 trial. Nineteen patients were required for the first phase; and, based on the first-phase results, the study was allowed to continue to a second stage, which included an additional group of 23 patients (for a total of 42 patients). Estimates of PFS and OS distribution were calculated using the Kaplan-Meier method,18 and time-to-event distributions were compared using the log-rank test.19

RESULTS

Patients

Between March 2008 and February 2010, 42 elderly patients with relapsed/refractory MM were included in this study and received VMP therapy. The patients included 17 men and 25 women, as reported in Table 2. The median patient age was 73 years (interquartile range [IQR], 70-79 years), and 18 patients were aged >75 years. The median hemoglobin value was 10.5 g/dL (IQR, 9.75-11.8 g/dL), and 7 patients (16.7%) had renal insufficiency (creatinine >1.5 mg/dL). Eleven of 42 patients (26%) had received 2 lines of therapy, including a bortezomib-based regimen in 26% of patients. Prior therapies included steroids, alkylating agents, anthracyclines, thalidomide, lenalidomide, or a combination of these agents. Thirty-three percent of patients had received prior high-dose chemotherapy and stem cell transplantation. The median time from diagnosis to the first dose of VMP therapy was 40 months (IQR, 24-64 months). All patients were analyzed for response on the date of follow-up.

Table 2. Patient Characteristics, N = 42
CharacteristicNo. of Patients (%)
  1. Abbreviations: IQR, interquartile range; VMP, bortezomib with standard melphalan and prednisone.

Sex 
 Men17 (40.4)
 Women25 (59.6)
Age 
 Median age [IQR], y73 [70-79]
 Patients aged ≥75 y18 (42)
Median hemoglobin level [IQR], g/dL10.5 [9.75-11.8]
Creatinine, mg/dL 
 ≤1.535 (83.3)
 ≥1.57 (16.7)
Median time from diagnosis to the first dose of VMP [IQR], months40 [24-64]
Median previous lines therapy 
 131 (74)
 211 (26)
Previous first-line therapy 
 Autologous transplantation14
 Conventional chemotherapy10
 Lenalidomide-containing regimen8
 Bortezomib-containing regimen7
 Thalidomide-containing regimen3
Previous second-line therapy 
 Conventional chemotherapy3
 Lenalidomide-containing regimen2
 Bortezomib-containing regimen4
 Thalidomide-containing regimen2

Dose Findings

After 3 cycles of dose level 0 (melphalan 24 mg for 28 days and bortezomib 1.3 mg/m2 on days 1, 8, 15, and 22 repeated every 28 days), the first 19 patients were evaluated for side effects and response rate. The 12 PRs obtained and the 7 episodes of grade 3 and 4 toxicities observed allowed us to continue the same dose for the subsequent 23 patients.

Efficacy

After a median follow-up of 21 months (IQR, 17-26 months), 24 patients achieved at least a PR. The overall response rate (ORR) was 57%, and it rose to 66.5% when patients who had stable disease were considered (Table 3). The median time to progression was 18 months (95% confidence interval [CI], 12.8-20.2 months), and the PFS rate at 37 months was 21% (95% CI, 10%-45%) (Fig. 1). Sixteen patients died of from disease progression, 1 patient died from acute heart failure, 1 patient died from pulmonary edema, and 2 patients died from infections. The median OS was 30 months (95% CI, 17.2-37 months), and the OS rate at 37 months was 44% (95% CI, 28%-69%) (Fig. 2).

Table 3. Efficacy
VariableValue
  1. Abbreviations: CI, confidence interval; CR, complete response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; SD, stable disease.

Median follow-up (95% CI), months21.1 (17.2-24.8)
ORR: CR plus PR, %57
ORR plus SD, %66.5
Median time to progression (95% CI), months18 (12.8-20.2)
PFS at 37 mo (95% CI), %21 (10-45)
OS at 37 mo (95% CI), %44 (28-69)
Figure 1.

Progression-free survival is illustrated.

Figure 2.

Overall survival is illustrated.

Safety

During the first phase of our study, grade 3 and 4 toxicity was observed in 7 of 19 patients (36.8%), including thrombocytopenia (2 patients), neutropenia (1 patient), infections (2 patients), diarrhea (1 patient), and neuropathy (1 patient). Among the overall series of 42 patients, the most common grade 1 and 2 adverse events were infections, neuropathy, and diarrhea (Tables 4 and 5), which typically were mild to moderate and were manageable with routine support. Peripheral neuropathy was observed in 14 of 42 patients (33%). Grade 3 and 4 toxicity was observed in 16 of 42 patients (38%) and was more frequent during the early cycles. Major grade 4 hematologic toxicities consisted of thrombocytopenia (4 patients) and anemia (1 patient), all of which were manageable. Major grade 3 and 4 nonhematologic toxicities included infections (5 patients), diarrhea (3 patients), neuropathy (3 patients), hepatic toxicity (2 patients), peripheral edema (1 patient), constipation (2 patients), heart failure (1 patient), and ischemic heart syndrome (1 patient). Among the 3 patients who had neuropathy, 1 had a pre-existing grade 1 neuropathy that worsened to grade 3 with treatment. Four patients had their bortezomib dose reduced to 1 mg/m2 and were able to continue the treatment. Because of toxicity, 4 patients discontinued treatment, including 1 patient who had a near complete response, 2 patients who had a PR, and 1 patient with stable disease. Two patients received granulocyte colony-stimulating factor support; and, with the receipt of acyclovir prophylaxis, no herpes reactivation was recorded.

Table 4. Hematologic Toxicity
 No. of Patients (%)a
Hematologic ToxicityGrade 1-2Grade 3Grade 4
  • a

    Four patients (9%) dropped out because of toxicity, including 2 patients who had a partial response, 1 patient with progressive disease, and 1 patient who had a near complete response.

Anemia28 (66)3 (7)1 (2)
Neutropenia13 (30)2 (5)0 (0)
Thrombocytopenia27 (64)6 (14)4 (9)
Table 5. Nonhematologic Toxicity
 No. of Patients (%)
Nonhematologic ToxicityGrade 1-2Grade 3-4
Infections15 (36)5 (12)
Neuropathy11 (26)3 (7)
Hepatic toxicity0 (0)2 (5)
Peripheral edema4 (9)1 (2)
Constipation5 (12)2 (5)
Heart failure0 (0)1 (2)
Heart ischemic syndrome0 (0)1 (2)
Diarrhea9 (21)3 (7)
Nausea and vomiting5 (12) 

DISCUSSION

MM is an incurable malignancy, and the majority of patients relapse, regardless of their initial treatment. For relapsed patients, a combination regimen based on the receipt of a novel agent backbone is an attractive therapeutic option that has the potential to allow a longer duration of response compared with previous regimens.20 Therefore, personalized therapy using dose-adjusted regimens is urgently needed for patients aged ≥75 years who are vulnerable because of their comorbid conditions, which complicate the presentation and management of the disease. In the current phase 1/2 study of elderly patients with relapsed/refractory MM, we evaluated the efficacy and safety profile of a novel VMP schedule (melphalan 24 mg for 28 days, bortezomib 1.3 mg/m2 weekly, and prednisone 50 mg every other day). In our 2-stage, phase 1/2 trial, the response and toxicity observed among the initial 19 patients of the first phase of the study allowed us to continue with the same drug doses in an additional 23 patients. We designed this trial on the basis of the results reported in the literature. The results from the “Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment With Melphalan and Prednisone” (VISTA) trial21 identified VMP as 1 of the new standards of care for the initial treatment of patients with newly diagnosed MM who were not eligible for high-dose therapy and autologous stem cell transplantation. However, approximately half (46%) of the patients who received VMP in on VISTA protocol experienced serious adverse events, and approximately 33% discontinued VMP treatment or discontinued only bortezomib because of adverse events. Neuropathy is a key iatrogenic toxicity in patients with MM, often leading to dose modifications and drug discontinuation. In newly diagnosed patients, bortezomib-induced neuropathy occurs in 47% to 64% of patients, and rates of dose modification and drug discontinuation of 14% to 30% attributable to neuropathy have been reported.4, 8 In view of the high incidence of discontinuation using twice-weekly bortezomib, the once-weekly schedule has been used in different trials. The randomized phase 3 GIMEMA trial,22 in which VMP plus thalidomide followed by maintenance with bortezomib and thalidomide was compared with VMP, was amended; and, in both treatment arms, the schedule of bortezomib was reduced from twice weekly to once weekly. Although the overall rate of grade 3 and 4 hematologic adverse events was similar between the once-weekly and twice-weekly groups, thrombocytopenia, which is a major side effect of bortezomib, was slightly less frequent in the once-weekly group. Similarly, the rate of grade 3 and 4 nonhematologic adverse events was lower in the once-weekly group compared with the twice-weekly group. The main dose-limiting toxicity, as expected, was neuropathy, which was predominantly sensory. The rates of discontinuation (5% vs 15%) and of dose reduction (17% vs 41%) as a result of neuropathy were significantly lower in the once-weekly group versus the twice-weekly group, resulting in similar cumulative doses of bortezomib in the 2 groups. In a study by the Spanish Cooperative Group for the Treatment of Hematologic Malignancies (PETHEMA),23 in which 1 cycle of twice-weekly bortezomib was followed by once-weekly dosing, the rate of grade 3 and 4 neuropathy with VMP was 5%, confirming an improvement in the safety profile without a reduction in the efficacy of the regimen. The current results demonstrate that our VMP schedule is well tolerated, with predictable and manageable toxicities, and that it is associated with clinical activity in elderly patients with relapsed or refractory MM. The combination of melphalan 24 mg for 28 days, bortezomib 1.3 mg/m2 weekly, and prednisone 50 mg every other day provides an alternative treatment option for elderly patients, for those who have an increased risk of experiencing significant morbidities from these agents, and for patients aged ≥75 years. In our study using these 3 drugs, the ORR was 57%, consistent with the rate of 67% obtained using 4 drugs (bortezomib, melphalan, prednisone, and thalidomide24) in 30 patients with relapsed MM who were younger than our cohort. Berenson et al25 demonstrated that significant clinical activity can be achieved using lower doses of melphalan and a longer and more convenient 28-day cycle of bortezomib. In their study, responses occurred in 32 of 46 (70%) evaluable patients. The median PFS in our study was 18 months, which was longer than that obtained with bortezomib in the “Assessment of Proteasome Inhibition for Extending Remissions” (APEX) study (8 months) or with lenalidomide and dexamethasone (12 months).26 In our patients, adverse events were manageable and predictable: Thrombocytopenia was the most common adverse event, and neutropenia was less common. Severe grade 3 and 4 neuropathy was observed in only 3 patients.

Taken together, the results from the current study demonstrate that VMP can be administered safely and effectively to elderly patients with relapsed/refractory MM. The schedule is specially tailored for elderly patients who are not eligible for intensive treatment, a group for which the ability to ensure an advantage in terms of response and survival, with an associated low rate of toxicity, is a primary unmet medical need.

FUNDING SOURCES

No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

Dr. Boccadoro has received research support, acts as a consultant, and is a member of the scientific advisory board of Celgene and Janssen-Cilag. Dr. Palumbo has received honoraria from Celgene, Janssen-Cilag, Bristol-Myers Squibb, Millennium Pharmaceuticals, Merck, and Onyx. Dr. Bringhen has received honoraria from Celgene, Janssen-Cilag, and Novartis and serves on the advisory committee for Merck Sharp & Dohme. Dr. Levi and Dr. Petrucci have received honoraria from Janssen-Cilag and Celgene. Dr. Foa serves on the scientific advisory board of and is a speaker for Roche, Bristol-Myers Squibb, GlaxoSmithKline, Mundipharma, Celgene, and Janssen-Cilag.

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