Bortezomib Initiation Research Articles

High Response Rate and Improved Graft-Versus-Host Disease (GVHD) Following Bortezomib as Salvage Therapy after Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation (RIC allo-SCT) for Multiple Myeloma (MM).

Bortezomib has been shown to be an efficient treatment for MM. Similarly, a potent allogeneic graft-versus-myeloma effect can be induced against MM. However, despite progress in terms of transplant-related mortality, a significant proportion of patients may still relapse or progress after RIC-allo-SCT. This retrospective report describes the results of 37 MM patients who received bortezomib (1.3 or 1.0 mg/m2 intravenously, days 1, 4, 8, and 11) as a salvage therapy after progression following RIC-allo-SCT. Median age was 49 years. All patients (100%) received and failed at least one autologous stem cell transplantation prior to RIC allo-SCT. Median time between the initial diagnosis of MM and allo-SCT was 11 (range, 6–96) months. Patients were not treated in a combined autologous/allo-SCT strategy. Before bortezomib initiation, 14 patients (38%) received and failed DLI. Also, 20 patients (54%) received and failed thalidomide (because of disease progression or toxicity). Overall, 32 patients (86%) received bortezomib salvage in progressive disease, while 5 patients (14%) were in PR. Median time between allo-SCT and bortezomib initiation was 20 (range, 1–65) months. At time of bortezomib initiation, the majority of patients (n=26; 70%) did not have any symptoms of chronic GVHD, while 8 patients (22%) had some form of limited chronic GVHD, and 3 patients (8%) had extensive signs. The median number of bortezomib cycles administered was 6 (range, 1–15). Peripheral neuropathy was frequently observeded after bortezomib (n=13; 35%; 4 grade 2 and 9 grade 1). Mild thrombocytopenia not requiring platelets transfusions was observed in 9 cases (24%). Fatigue was also observed in 7 patients (19%). None of the patient had to discontinue the treatment because of a life-threatening adverse event, and no treatment-related toxic deaths were observed. In terms of GVHD, patients did not experience reactivation or worsening of GVHD symptoms. Interestingly, two patients among the three patients with extensive GVHD signs at the beginning of bortezomib experienced a significant improvement and were staged as limited chronic GVHD at last follow-up. In all, 27 patients (73%; 95%CI, 59%–87%) achieved an objective disease response after starting of bortezomib (7 CR, 7 VGPR, and 13 PR). Prior use of thalidomide and/or DLI did not influence disease response to bortezomib. There was also no difference in disease response when using bortezomib in combination or without dexamethasone. With a median follow-up of 9 (range, 3–42) months from bortezomib initiation, 25 patients (68%; 95%CI, 53%–83%) still had a sustained objective disease response (5 CR, 5 VGPR, and 15 PR). Ten patients (27%) died and 27 are still alive with a median overall follow-up after allo-SCT of 80 (range, 18–153) months. The majority of deaths were directly attributed to disease progression (n=8; 80% of all deaths). Most importantly, patients achieving an objective disease response (CR, VGPR or PR) after introduction of bortezomib enjoyed a significantly higher overall survival as compared to non-responding patients (P=0.002). Collectively, these data demonstrate that bortezomib is a safe and potentially efficient option for MM patients failing RIC allo-SCT.

Good Safety and Tolerance Profiles of Long Term Treatment of Advanced Multiple Myeloma (MM) with Bortezomib.

Bortezomib is a first-in-class proteasome inhibitor approved for the treatment of MM patients who have received at least one prior therapy. Classically, patients receive bortezomib 1.3 or 1.0 mg/m2 by IV bolus on days 1, 4, 8, and 11 of a 21-day cycle, associated or not to dexamethasone, for a total number of 8 cycles. Such administration schema is associated with a remarkable anti-tumor activity and response. However, a significant number of patients who are initially responders to bortezomib, will progress after drug discontinuation, raising the question of long term or maintenance treatment with bortezomib. The objective of this analysis was to evaluate the tolerance and safety profiles of long term treatment with bortezomib in a cohort of 16 patients with relapsed and/or refractory MM treated in a single institution. Eligible patients for this analysis are those who had relapsed MM, and who continued to receive bortezomib (1.3 or 1.0 mg/m2) as a long term therapy beyond the classical 8 cycles. All medical charts were uniformly reviewed in detail for assessment of toxicity, safety and response. The median age was 53 (range, 27–74) years. The majority of patients had already received at least one prior autologous or allogeneic stem cell transplantation (n=12; 75%). Also, 12 patients (75%) had received prior treatment with thalidomide at a median dose of 200 mg/day, for a median duration of 7 months. Before treatment with bortezomib, 7 patients (44%) already had some form of peripheral neuropathy (PN). With a median follow-up of 16 months from bortezomib initiation, patients from this series received a median of 10 (range, 9–16) cycles of bortezomib administered over a median period of 11 (range, 7–35) months. Overall, 6 patients had evidence of bortezomib-associated PN (38%; 4 grade 1, 1 grade 2 and 1 grade 3; sensory symptoms in all cases). Other bortezomib-related toxicities included thromobopenia (n=8; 50%; 1 grade 1, 5 grade 2, and 2 grade 3–4). General fatigue was also common and was encountered in 5 (31%) patients. Overall, bortezomib-associated toxicities led to dose reduction or increase of treatment cycle duration in 9 patients (56%), but none of the patients had to definitively discontinue treatment because of unacceptable toxicity. At last follow-up, 6 patients are still receiving bortezomib, 4 patients died from disease progression, no patient died from treatment-related causes, and the remaining 12 patients are still alive. Long term treatment with bortezomib was associated with an objective disease response rate in 87% (95%CI, 60–98%) of patients (n=14; 3 CR, 8 VGPR, 3 PR). The Kaplan-Meier estimate for overall survival is shown in the figure below. Though relatively small, results from this series suggest that long term treatment with bortezomib is feasible. Toxicity, tolerance and safety profiles of long term treatment are comparable to those observed with the standard schedule and manageable after dose reduction. Therefore, prospective studies aiming to optimize bortezomib administration schedule and duration (beyond the classical 8 cycles) are warranted, since such long term treatment can yield major objective disease response. [Display omitted]

Neuropathy in Multiple Myeloma Patients Treated with Bortezomib: A Multicenter Experience.

INTRODUCTION: Bortezomib (B) is the first proteasome inhibitor to be used in clinical practice and has been recently approved for second line treatment of multiple myeloma (MM) patients(pts). Several trials demonstrated that Bortezomib is relatively well tolerated; however, manageable non-hematologic and hematologic toxicity has been reported. The dose limiting toxicity is peripheral neuropathy (PN), reported up to 35% of the patient population.AIM: We evaluated the incidence and severity of PN in 179 MM patients that received B as single agent or in combination.MATERIAL AND METHODS: Patients characteristics were as follows: median age was 66.7 years (range: 32–82) with 52% male; 55 patients were at the onset of the disease, 124 were pre-treated. Median time from diagnosis to treatment with B was 25.4 months (range 0–111), median value of β2-microglobulin was 3.02 (0.2–20). Risk factors for PN included prior use of thalidomide in 68 patients (38%), vincristine in 75 patients (41.8%) and 15 patients (8.8%) had diabetes mellitus.RESULTS: Patients received bortezomib alone (?) or in combination with either dexamethasone (n=52), or chemotherapy (n=114) or thalidomide (n=38). Overall, the response rate (≥PR) was 86%. PN of grade ≥2 was observed in 73 pts (41%); grade 3–4 occurred in 32 (18%). Median time to the onset of bortezomib-related PN was 84 days (range, 10–449) after bortezomib initiation. In most cases (93%), patients had sensory symptoms, while 5 patients (7%) experienced both sensory and motor symptoms. Bortezomib-related PN led to therapy discontinuation in 31 pts (17%). For PN treatment, pts received mostly supportive therapy (analgesics, gabapentin, pregabalin, amitriptyline and vitamin supplements). Of the 31 patients with bortezomib-related PN that required discontinuation, resolution or improvement occurred in 16 (51.6%), at a median time of 140 days (range, 27–346) from B discontinuation. Data analysis of the PN risk factors (age, diabetes, sex, β2M, neurotoxic pre-treatment) showed a significant association with age >75 years (p<0.013) and a trend with thalidomde pre-treatment (p=0.07); noteworthy, PN risk was not increased in pts treated with bortezomib and thalidomide in combination. Furthermore, responses were independent to PN.CONCLUSIONS: In our experience, PN is a relatively frequent side effect of bortezomib treatment, generally manegeable by dose reduction or discontinuation and reversible in the majority of pts. Patients with advanced age can be considered at higher risk, while the combination of thalidomide and bortezomib did not increase the risk of PN. Further studies are needed to better define the PN pathogenesis and develop optimal strategies to improve the B related PN management.

Features and Risk Factors of Peripheral Neuropathy during Treatment of Advanced Multiple Myeloma with Bortezomib.

Bortezomib has demonstrated activity and safety in heavily pretreated patients with relapsed and/or refractory multiple myeloma (MM). Peripheral neuropathy (PN) is among the most frequent adverse events reported with bortezomib, requiring dose-adjustment and careful patient-clinical monitoring. The aim of this retrospective single centre study was to determine the frequency, characteristics, and reversibility of PN from bortezomib treatment of 100 consecutive advanced MM patients treated with bortezomib 1.0 or 1.3 mg/m2 IV bolus on days 1, 4, 8, and 11, every 21 days. PN was evaluated by investigator neurological examination at baseline, during the study, and at last follow-up. Patients characteristics at baseline prior to bortezomib initiation were as follow: median age: 60 (range, 27–77), prior history of diabetes: n=8 (8%), prior autologous transplantation: n=76 (76%), prior treatment with thalidomide: n=75 (75%) with a median dose of 200 (range, 50–600) mg for a median duration of 8 (range, 1–61) months. Median duration between thalidomide discontinuation and bortezomib initiation was 5 (range, 0–43) months. Before treatment with bortezomib, 48 patients (48%) already had some form of PN [grade 1, n=27 (56%); grade 2, n=16 (33%); grade 3, n=5 (11%)]. With a median follow-up of 8 (range, 0.1–32) months from bortezomib initiation, patients from this series received a median of 4 (range, 1–12) cycles of bortezomib. Bortezomib-related emergent PN was observed in 38 patients (38%; 95%CI, 28–47%), with grade 1, 2, 3, and 4 PN occurring in 17 (45%), 15 (39%), 5 (13%) and 1 (3%) patients respectively. Median time to onset of bortezomib-related PN was 53 (range, 11–182) days after bortezomib initiation. In most cases (n=30; 79%), patients had sensory symptoms, while 8 patients (21%) experienced both sensory and motor symptoms. Bortezomib-related PN led to dose reduction or discontinuation in 18 patients. Of the 38 patients with bortezomib-related PN, resolution to baseline or improvement occurred in 20 (53%) patients, at a median time of 3 (range, 1–8) months. In univariate analysis, comparing patients with and without bortezomib-related PN, prior history of treatment with thalidomide (P=0.009), patient baseline grade of PN at bortezomib initiation (P=0.04), number of bortezomib cycles administered (P=0.0005), and cumulative dose (mg) of bortezomib received by patients (P=0.001), were found to be significantly associated with the risk of emergence of bortezomib-related PN. In multivariate analysis, the total number of cycles of bortezomib (less or more than 4 cycles), and a prior history of treatment with thalidomide were the strongest parameters significantly associated with an increased incidence of bortezomib-related PN (P=0.03; OR=2.6; 95%CI, 1.1–6.1 and P=0.02; OR=3.9; 95%CI, 1.2–12.6 respectively). In all, we conclude that, though relatively frequent, bortezomib-associated PN seemed reversible in a majority of patients and manageable after dose reduction or discontinuation. However, the finding that the development of bortezomib-related PN seems to be dependent of the patient history of prior neurotoxic therapy (mainly thalidomide), raises the question of the optimal sequence and schedule of administration of these anti-MM effective drugs as single agents, but also in combination.

A prospective study of the effects of once weekly bortezomib on markers of bone metabolism in patients with multiple myeloma (MM)

7548 Background: Increased osteoclast activity in MM leads to bone resorption, osteoporosis and osteolytic bone lesions. Urinary excretion of N-telopeptide (NTX), a marker of bone resorption, decreases by 20–70% following treatment with bisphosphonates. Preclinical studies have shown bortezomib to decrease osteoclast function through inhibition of NF-kB. However, no clinical data exists on the effect of bortezomib on markers of bone resorption. Methods: Six cycles of consolidation bortezomib 1.3mg/m2 were given once weekly for 4 of every 5 weeks, 90–120 days post transplant. Urinary NTX excretion and serum osteocalcin were measured on day 1 of cycles 1, 2 and 3 of therapy. Bisphosphonates were prohibited from 42 days prior to stem cell collection and until cycle 3 of consolidation therapy. Results: 33 of 40 enrolled patients received bortezomib consolidation. Patient population and disease characteristics (no. of patients): male (22), female (11), median age 56 years (range 39–70), Stage II (9), Stage III (24), IgG (22), IgA (9), free light chain (2). The median duration between discontinuation of bisphosphonates and initiation of consolidation bortezomib was 158 days (Range 110–196). Only one patient had a &gt;50% reduction in myeloma paraprotein. Nevertheless, excretion of NTX declined by a mean of 32% over baseline values after 2 cycles of consolidation therapy. The only patient with an increase in NTX of &gt;30% was also the only patient with evidence of disease progression during this period of therapy. Contrary to reports of proteasome inhibition resulting in increased osteoblastic bone formation, a decline was seen in osteocalcin. Conclusions: Bortezomib has an inhibitory effect on osteoclastic bone resorption in MM similar to that with bisphosphonates even in the absence of effects on malignant plasma cells. Bisphosphonates may result in nephrotoxicity and osteonecrosis of the jaw and bortezomib represents an alternative agent that may control both the myeloma and bone disease. [Table: see text] No significant financial relationships to disclose.

Bortezomib in Patients with Relapsed-Refractory Multiple Myeloma (MM). Clinical Observations.

Bortezomib is a reversible proteasome inhibitor that was recently approved for the treatment of relapsed-refractory MM. However, dosage, schedule, management of adverse events and duration of response are still under investigation. We present our experience with bortezomib. 27 relapsed-refractory MM patients were studied. They were scheduled to receive bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11 every three weeks for eight cycles and dexamethazone was planned to be added at 20 mg every other day of bortezomib (2,5,9,12) if no signs of response were observed after the 1st cycle. There were 20 males and 7 females (median age 71y old). Immunoglobulin type was IgG in 16, IgA in 7, BJ in 3 and IgD in 1. All patients had received at least 2 previous treatment lines (median 4, thalidomide in 52%). At treatment initiation, 59% of patients were Durie-Salmon stage III and 63% ISS stage 3. B2Microglobulin was increased in 81%, CRP in 33%, LDH in 22%, creatinin in 7%, plasma cell bone marrow infiltration> 60% in 100%, hemoglobin< 10g/L in 59%, platelet count>100x109/L in 92% and no patient had peripheral neuropathy> grade 1. Free light chains ratio (FLCR, FREELITETM) was determined in 16 patients at baseline (increased in all) and during treatment. With the treatment scheme described above, 55% of patients received additional dexamethasone. Two in resistant relapse died during the 2nd course. Treatment was stopped or reduced in the majority of patients because of severe neuropathy after 4–6 cycles and discontinued in 3 patients because of no response (4 patients completed 3 courses, 17 completed 11, 1 completed 5, 3 terminated 6). Hematology toxicity, fatigue, gastrointestinal toxicity and fever were mild and manageable. Severe side effects were neuropathy in 63% (sensory, instability, burning pains- median time of onset 85 days after bortezomib initiation and median duration 2 months) hypotension in 7% and hypoglycemia in 3%. 21/25 (84%) patients responded (2 complete remission [CR], 4 near CR, 10 partial response, 5 minimal response. Median time to response was 42 days but with median follow-up of 6 months 6/21 (28%) patients have relapsed and 3/25 (12%) died. Relapse was aggressive (onset with acute renal failure in 3, spine plasmacytoma in 1, automatic bone fracture in 1). B2M, CRP and stage were not predictors of response or early relapse but of 8/16 with FLCR>200 at baseline, 4 were resistant and 4 relapsed. In 2 of the 4 resistant patients FLCR decreased after the 1st course and increased after the 2nd; in the same way in responders with an early relapse, FLCR started to increase during the last cycles of bortezomib. It is possible that some patients develop quickly resistance to the drug. In conclusion, Bortezomib, in combination with low-dose dexamethasone produce rapid responses but neuropathy represent a frequent and severe side effect and the duration of response is short. An adequate or palliative treatment for neuropathy is needed as well as a maintenance schedule overcoming resistance. FLCR seems to predict response and early relapse.