A phase II trial of small-dose bortezomib, lenalidomide and dexamethasone (sVRD) as consolidation/maintenance therapy in patients with multiple myeloma

The aim of this multicenter, open-label, single-arm, phase II study was to determine the efficacy and safety of sVRD in Japanese patients with MM in the consolidation/maintenance setting. The primary end point of this study was the best ORR during 6 courses of sVRD. Secondary end points included progression-free survival (PFS), OS and safety. This study was conducted according to the Declaration of Helsinki and was approved by the institutional review board of each participating center. The institutional review board-approved consent form was signed by all patients before participating in this study. This trial is registered at www.​umin.​ac.​jp (#UMIN8236).

Eligible patients were age ≥20 and ≤80 years, with measurable symptomatic MM. Patients must have received at least 1 prior regimen and achieved at least a partial response (PR) by the International Myeloma Working Group (IMWG) Uniform Response Criteria. Other eligibility criteria included Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2, and an expected survival of more than 3 months. Adequate pulmonary, cardiac, renal and hepatic functions were required.

Patients received subcutaneous bortezomib (1.3 mg/m² on days 1 and 15), oral lenalidomide (10 mg on days 1–21) and oral dexamethasone (40 mg on days 1, 8, 15 and 22). The course was repeated every 4 weeks for 6 cycles. Patients with at least a PR at the end of cycle 6 could continue sVRD treatment. Patients discontinued therapy if they experienced progressive disease (PD) or unacceptable toxicity, if no more additional benefits could be expected or if the patient/investigator decided to discontinue therapy for any reason. Dose adjustments were permitted based on grade 3 or 4 AEs or based on an investigator’s decision; bortezomib could be reduced from 1.3 to 1.0 mg/m², lenalidomide from 10 to 5 mg/day and dexamethasone from 40 to 20 mg/day. If a similar severity of toxicity occurred at the reduced dose, study treatment was discontinued. Antiviral prophylaxis, bisphosphonates, aspirin thromboprophylaxis and erythropoietic agents were permitted during the study. Granulocyte colony-stimulating factor was also allowed.

Response assessments were conducted before enrollment and after each course of sVRD treatment. The ORR was defined as the proportion of patients whose best overall response was either a stringent complete response (sCR), complete response (CR), very good PR (VGPR) or PR based on responses as assessed using IMWG Uniform Response Criteria. sCR, CR, VGPR and PR required two consecutive assessments made at any time before progression or initiation of any new therapy. Patients were followed for disease progression and OS for up to 3 years after discontinuation or completion of therapy.

AEs were assessed at each visit and were graded according to National Cancer Institute Common Terminology Criteria (NCI-CTC) for AEs (Version 4.0). Data were collected until 30 days after the last dose of study drug, except for secondary primary malignancies (SPM) (which were assessed all along during follow-up). SPM was defined as any malignancy observed after introduction of sVRD treatment.

The median follow-up time was estimated using the reverse Kaplan–Meier method. PFS was calculated as the time from the start of treatment to the first documentation of PD or death if the patient died as a result of any cause before progression. OS was calculated as the time from the start of treatment to death. The Kaplan–Meier method was used to estimate the survival distribution. Univariate survival analysis was performed using the Kaplan–Meier method. The significance of differences in survival curves was assessed with the log-rank test. Multivariable analysis (Cox proportional hazards regression model) of OS was carried out on all covariates that showed a significant association with OS in univariate analysis. All analyses were conducted using GraphPad Prism version 5.0 (GraphPad Software, La Jolla, CA) and EZE (Saitama Medical Center, Jichi Medical University; http://​www.​jichi.​ac.​jp/​saitama-sct/​SaitamaHP.​files/​statmedEN.​html) [26].

From June 2012 until November 2013, 16 MM patients were enrolled at 4 sites in Japan. The data cutoff date for this analysis was March 10, 2015. Patient demographics and baseline characteristics are summarized in Table 1. The median age was 67 years (range 53–78 years); 12 patients (75.0 %) were >65 years. Eleven patients (68.8 %) were male. The median time from diagnosis to enrollment was 17 months (range 4–95 months). ECOG PS was 0 in 50.0 %, 1 in 37.5 % and 2 in 12.5 % of the patients. They had either IgG (62.5 %) or IgA (37.5 %) myeloma and had either Kappa (81.3 %) or Lambda (18.7 %) light chain. After restaging at the time of enrollment, 81.3 % of patients had stage I and 18.7 % stage II according to the classification system of the International Staging System (ISS), and 87.5 % had stage I and 12.5 % stage III according to the system of Durie and Salmon (D-S). Fluorescence in situ hybridization (FISH) performed at the time of diagnosis showed that 1 (9.1 %) out of 11 patients had del 17, 4 (44.4 %) out of 9 del 13 and 3 (42.9 %) out of 7 t(4;14). The induction therapies before enrollment in this study were as follows: 87.5 % of patients were treated with dexamethasone, 81.3 % bortezomib, 43.8 % lenalidomide, 25.0 % doxorubicin, 18.8 % melphalan and 12.5 % cyclophosphamide. 43.8 % of patients had undergone radiation therapy. 25.0 % of patients had undergone at least one HSCT.

All patients could complete 6 courses of sVRD treatment (Table 2). The median duration of sVRD treatment was 8.0 courses (range 6–28 courses), with 56.3 % (n = 9) and 25.0 % (n = 4) undergoing >6 and >12 cycles, respectively. At the data cutoff date, all 16 patients had discontinued treatment. The reasons for treatment discontinuation were completion of 6 courses (n = 7, 43.8 %), disease progression (n = 3, 18.8 %), SPM of acute lymphoblastic leukemia (ALL) (n = 1, 6.3 %), AE of grade 2 pneumonia (n = 1, 6.3 %) or other (patient refusal or physician preference) (n = 4, 25.0 %).

All 16 patients were response-evaluable. The ORR during 6 courses of sVRD treatment is shown in Table 3. 43.8 % had an sCR, 0 % CR, 6.3 % VGPR, 50.0 % PR and 0 % PD. The ORR and CR rate (i.e., at least CR) were 100 and 43.8 %, respectively. In detail, at enrollment, 4 patients were determined to be in sCR, 1 in CR, 2 in VGPR and 9 in PR. During 6 courses of sVRD, 4 patients with sCR at enrollment remained in sCR. One patient with CR and 2 with VGPR achieved sCR. In 9 patients with PR, 1 achieved VGPR, but 8 remained in PR. Nevertheless, 2 out of 8 patients with PR after 6 courses of sVRD finally achieved VGPR or sCR after a total of 18 or 24 courses of sVRD, respectively. Status at enrollment of a patient with del(17p) was PR, and his best overall response was the same PR. Table 4 demonstrates that all four patients (No. 5–8) who obtained deeper response during 6 courses of sVRD were treated without lenalidomide in induction therapies.

With a median follow-up time of 29.4 months (range 16.1–33.1 months), 13 out of 16 patients are still alive, 11 of whom are progression-free for a maximum of 33.1 months. Three patients died and their cause of death was disease progression in all cases. One of these three patients who died had SPM of myelodysplastic syndrome (MDS). One had chromosomal abnormality of del(17p). It is noteworthy that the three patients who discontinued sVRD treatment due to PD were the same three patients who died in spite of various post-study therapies. Figure 1 shows the Kaplan–Meier estimates of PFS and OS. The median PFS was not reached, and the 2.5-year PFS was 66.6 % (95 % confidence interval [CI] 36.9–84.8 %). The median survival time (MST) was also not reached, and the 2.5-year survival rate was 77.3 % (95 % CI 44.3–92.2 %).

When analyzing prognostic factors for OS, univariate analysis using the log-rank test confirmed well-known prognostic parameters such as PS (P = 0.00569), albumin (P = 0.0000323), ISS (P = 0.0123) and del 17 (P = 0.00157) to be of prognostic relevance in our patient cohort (Table 5). Regarding best overall response during 6 courses of sVRD, OS was negatively influenced by PR compared with sCR, CR or VGPR (P = 0.0334). Furthermore, disease progression as a reason for discontinuation of sVRD had a negative impact on OS in comparison with other reasons (P = 0.0000374). These results indicated that refractoriness to the sVRD regimen could not be easily rescued by any post-study therapies. Nevertheless, none of the variables selected on univariate analysis was an independent prognostic marker for OS in the Cox proportional hazards regression model since the number of patients for multivariate analysis was small.

One dose modification of dexamethasone from 40 to 20 mg/day was required because of grade 2 hypertension after the 3rd course of sVRD. One patient had discontinued all study drugs because of grade 2 pneumonia after 6 courses of sVRD. AEs are summarized in Table 6. Grade 2 sensory neuropathy was reported in two patients; however, neuropathy occurred in each patient during their induction therapies and lasted thereafter with no worsening. Grade 2 neutropenia occurred in 2 patients, pneumonia in 2, thrombocytopenia in 1, hypertension in 1, constipation in 1 and anemia in 1. There were no grade 3 or 4 hematologic or nonhematologic AEs.

After enrollment, 2 new hematologic malignancies, i.e., ALL in one patient and MDS in another patient, were diagnosed (Table 7). The time from diagnosis to enrollment was 38 or 60 months in the patient with ALL or MDS, respectively. The former patient was pretreated with vincristine, adriamycin and dexamethasone (VAD) and autologous HSCT (ASCT) and then underwent 18 courses of sVRD treatment. He discontinued sVRD due to the occurrence of ALL. He has been alive after the standard induction/consolidation chemotherapy for ALL and allogeneic HSCT. The latter patient was pretreated with VAD and bortezomib plus dexamethasone (Bd) and then underwent sVRD treatment. After the 7th course, the sVRD regimen was stopped due to disease progression. The combination regimen of melphalan, prednisone and lenalidomide (MPR) was introduced as a post-study therapy, and a gradual dose reduction of melphalan was needed because of progressive pancytopenia. The diagnosis of MDS was made based on the findings of bone marrow aspiration. He finally died of PD.