Paola Tacchetti

Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study

BACKGROUND Thalidomide plus dexamethasone (TD) is a standard induction therapy for myeloma. We aimed to assess the efficacy and safety of addition of bortezomib to TD (VTD) versus TD alone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma. METHODS Patients (aged 18-65 years) with previously untreated symptomatic myeloma were enrolled from 73 sites in Italy between May, 2006, and April, 2008, and data collection continued until June 30, 2010. Patients were randomly allocated (1:1 ratio) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily for the first 14 days and 200 mg daily thereafter) plus dexamethasone (40 mg daily on 8 of the first 12 days, but not consecutively; total of 320 mg per cycle), either alone or with bortezomib (1·3 mg/m(2) on days 1, 4, 8, and 11). The randomisation sequence was computer generated by the study coordinating team and was stratified by disease stage. After double autologous stem-cell transplantation, patients received two 35-day cycles of their assigned drug regimen, VTD or TD, as consolidation therapy. The primary endpoint was the rate of complete or near complete response to induction therapy. Analysis was by intention to treat. Patients and treating physicians were not masked to treatment allocation. This study is still underway but is not recruiting participants, and is registered with ClinicalTrials.gov, number NCT01134484, and with EudraCT, number 2005-003723-39. FINDINGS 480 patients were enrolled and randomly assigned to receive VTD (n=241 patients) or TD (n=239). Six patients withdrew consent before start of treatment, and 236 on VTD and 238 on TD were included in the intention-to-treat analysis. After induction therapy, complete or near complete response was achieved in 73 patients (31%, 95% CI 25·0-36·8) receiving VTD, and 27 (11%, 7·3-15·4) on TD (p<0·0001). Grade 3 or 4 adverse events were recorded in a significantly higher number of patients on VTD (n=132, 56%) than in those on TD (n=79, 33%; p<0·0001), with a higher occurrence of peripheral neuropathy in patients on VTD (n=23, 10%) than in those on TD (n=5, 2%; p=0·0004). Resolution or improvement of severe peripheral neuropathy was recorded in 18 of 23 patients on VTD, and in three of five patients on TD. INTERPRETATION VTD induction therapy before double autologous stem-cell transplantation significantly improves rate of complete or near complete response, and represents a new standard of care for patients with multiple myeloma who are eligible for transplant. FUNDING Seràgnoli Institute of Haematology at the University of Bologna, Bologna, Italy.

Prospective, Randomized Study of Single Compared With Double Autologous Stem-Cell Transplantation for Multiple Myeloma: Bologna 96 Clinical Study

PURPOSE We performed a prospective, randomized study of single (arm A) versus double (arm B) autologous stem-cell transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma (MM). PATIENTS AND METHODS A total of 321 patients were enrolled onto the study and were randomly assigned to receive either a single course of high-dose melphalan at 200 mg/m2 (arm A) or melphalan at 200 mg/m2 followed, after 3 to 6 months, by melphalan at 120 mg/m2 and busulfan at 12 mg/kilogram (arm B). RESULTS As compared with assignment to the single-transplantation group (n = 163 patients), random assignment to receive double ASCT (n = 158 patients) significantly increased the probability to attain at least a near complete response (nCR; 33% v 47%, respectively; P = .008), prolonged relapse-free survival (RFS) duration of 18 months (median, 24 v 42 months, respectively; P < .001), and significantly extended event-free survival (EFS; median, 23 v 35 months, respectively; P = .001). Administration of a second transplantation and of novel agents for treating sequential relapses in up to 50% of patients randomly assigned to receive a single ASCT likely contributed to prolong the survival duration of the whole group, whose 7-year rate (46%) was similar to that of the double-transplantation group (43%; P = .90). Transplantation-related mortality was 3% in arm A and 4% in arm B (P = .70). CONCLUSION In comparison with a single ASCT as up-front therapy for newly diagnosed MM, double ASCT effected superior CR or nCR rate, RFS, and EFS, but failed to significantly prolong overall survival. Benefits offered by double ASCT were particularly evident among patients who failed at least nCR after one autotransplantation.

Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation

We prospectively analyzed the prognostic relevance of positron emission tomography-computed tomography (PET/CT) at diagnosis, after thalidomide-dexamethasone (TD) induction therapy and double autotransplantation (ASCT) in 192 newly diagnosed multiple myeloma (MM) patients. Presence at baseline of at least 3 focal lesions (FLs; 44% of cases), a standardized uptake value (SUV) > 4.2 (46%), and extramedullary disease (EMD; 6%) adversely affected 4-year estimates of progression-free survival (PFS; ≥ 3 FLs: 50%; SUV > 4.2: 43%; presence of EMD: 28%). SUV > 4.2 and EMD were also correlated with shorter overall survival (OS; 4-year rates: 77% and 66%, respectively). Persistence of SUV > 4.2 after TD induction was an early predictor for shorter PFS. Three months after ASCT, PET/CT was negative in 65% of patients whose 4-year rates of PFS and OS were superior to those of PET-positive patients (PFS: 66% and OS: 89%). In a multivariate analysis, both EMD and SUV > 4.2 at baseline and persistence of fluorodeoxyglucose (FDG) uptake after ASCT were independent variables adversely affecting PFS. PET/CT involvement at diagnosis, after novel agent-based induction and subsequent ASCT is a reliable predictor of prognosis in MM patients. This study is registered at www.clinicaltrials.gov as NTC01341262.

Aspirin, Warfarin, or Enoxaparin Thromboprophylaxis in Patients With Multiple Myeloma Treated With Thalidomide: A Phase III, Open-Label, Randomized Trial

PURPOSE In patients with myeloma, thalidomide significantly improves outcomes but increases the risk of thromboembolic events. In this randomized, open-label, multicenter trial, we compared aspirin (ASA) or fixed low-dose warfarin (WAR) versus low molecular weight heparin (LMWH) for preventing thromboembolism in patients with myeloma treated with thalidomide-based regimens. PATIENTS AND METHODS A total of 667 patients with previously untreated myeloma who received thalidomide-containing regimens and had no clinical indication or contraindication for a specific antiplatelet or anticoagulant therapy were randomly assigned to receive ASA (100 mg/d), WAR (1.25 mg/d), or LMWH (enoxaparin 40 mg/d). A composite primary end point included serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment. RESULTS Of 659 analyzed patients, 43 (6.5%) had serious thromboembolic events, acute cardiovascular events, or sudden death during the first 6 months (6.4% in the ASA group, 8.2% in the WAR group, and 5.0% in the LMWH group). Compared with LMWH, the absolute differences were +1.3% (95% CI, -3.0% to 5.7%; P = .544) in the ASA group and +3.2% (95% CI, -1.5% to 7.8%; P = .183) in the WAR group. The risk of thromboembolism was 1.38 times higher in patients treated with thalidomide without bortezomib. Three major (0.5%) and 10 minor (1.5%) bleeding episodes were recorded. CONCLUSION In patients with myeloma treated with thalidomide-based regimens, ASA and WAR showed similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths compared with LMWH, except in elderly patients where WAR showed less efficacy than LMWH.

Bortezomib-Based Versus Nonbortezomib-Based Induction Treatment Before Autologous Stem-Cell Transplantation in Patients With Previously Untreated Multiple Myeloma: A Meta-Analysis of Phase III Randomized, Controlled Trials

PURPOSE To characterize efficacy and safety of bortezomib-based versus nonbortezomib-based induction regimens through an integrated analysis of data from phase III studies in transplantation-eligible patients with previously untreated myeloma. PATIENTS AND METHODS Patient-level data from the IFM 2005-01 (bortezomib-dexamethasone v vincristine-doxorubicin-dexamethasone [VAD] induction), HOVON-65/GMMG-HD4 (bortezomib-doxorubicin-dexamethasone v VAD), and PETHEMA GEM05MENOS65 (bortezomib-thalidomide-dexamethasone v thalidomide-dexamethasone) studies were pooled in an integrated analysis of efficacy and safety. Study-level data from the GIMEMA MM-BO2005 study (bortezomib-thalidomide-dexamethasone v thalidomide-dexamethasone) supplemented the integrated patient-level analysis. Key efficacy end points were post-transplantation complete plus near-complete response (CR+nCR) rate and progression-free survival (PFS). RESULTS Patient-level data for 1,572 patients (bortezomib-based induction, n = 787; nonbortezomib-based induction, n = 785) were included. Post-transplantation CR+nCR rate was significantly higher following bortezomib-based versus nonbortezomib-based induction (38% v 24%; odds ratio, 2.05; P < .001); the benefit remained similar (pooled odds ratio, 1.96) when GIMEMA MM-BO2005 data were included. Median PFS was 35.9 months versus 28.6 months with bortezomib-based versus nonbortezomib-based induction, respectively (hazard ratio, 0.75; P < .001); 3-year overall survival (OS) rates were 79.7% and 74.7%, respectively (hazard ratio for OS, 0.81; P = .0402). Median duration of induction treatment was 11 weeks in both treatment groups. Rates of peripheral neuropathy during induction were 34% versus 17% (grade ≥ 3, 6% v 1%). Overall, 3% and 4% of patients died during bortezomib-based and nonbortezomib-based induction, respectively. CONCLUSION Bortezomib-based induction results in significant improvements in response and PFS/OS compared with nonbortezomib-based induction and is generally well tolerated, with a higher rate of peripheral neuropathy but no apparent increase in risk of death during induction.

Thalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure

Abstract:  Salvage therapy of patients with advanced, relapsed and refractory multiple myeloma (MM) is often limited by poor marrow reserve and multi‐organ impairment. In particular, renal failure occurs in up to 50% of such patients, and this further limits the use of conventional chemotherapy. Thalidomide, both alone and in combination with dexamethasone, has been demonstrated to be useful in patients with advanced MM, as responses could be achieved in 30–60% of the cases. From May 2000 to November 2003, 20 consecutive MM patients (15 males, five females, median age 66.5 yr) with stage III relapsed/refractory MM and renal failure, defined as serum creatinine >130 mmol/L, gave their informed consent to be enrolled in a clinical trial aimed at evaluating the efficacy and the toxic effects of thalidomide. Three patients were undergoing chronic haemodialysis during the time of entry in the study. Eight patients have been treated with thalidomide as a single agent, at a starting dose of 100 mg/d, that was to be increased to 400 mg/d in case of good tolerance. Twelve patients have been treated with thalidomide at the maimum dose of 200 mg/d plus dexamethasone 40 mg/d for four consecutive days every 4 wk. A >50% decrease in serum or urine M component was observed in nine patients (45%), seven of whom have been treated with thalidomide + dexamethasone and three with thalidomide alone. Six additional patients achieved a minor response (>25% paraprotein decrease); the total response rate was thus 75%. Median response duration was 7 months (range 2–24 months). Four patients were refractory to treatment. Recovery of a normal renal function was observed in 12 of 15 responsive patients, two additional patients, in chronic haemodialysis, showed a reduction of serum creatinine. Toxicity profile of thalidomide with or without dexamethasone was comparable with that observed in patients with a normal renal function. In conclusion, our data show that thalidomide can be safely administered in patients with advanced MM and renal failure.

Neuropathy in multiple myeloma treated with thalidomide A prospective study

Background: Thalidomide is effective as a first-line therapy for the treatment of multiple myeloma (MM), but its use is limited by peripheral neurotoxicity. Objective: To study the occurrence of both myeloma-related neuropathy and thalidomide-induced neuropathy in 31 patients with newly diagnosed MM. Methods: Clinical and electrophysiologic examinations were performed in 31 patients with newly diagnosed MM before and after 4 months of therapy with thalidomide (200 mg/day, total dose: 21 g) aimed at debulking MM, before autologous transplantation. After transplantation, the patients took thalidomide, 200 mg/day for another 3 months (total dose over three months: 18 g) and then underwent a final clinical and electrophysiologic checkup. Results: At baseline, four patients presented a mild sensorimotor peripheral neuropathy related to MM, which tended to worsen slightly during treatment with thalidomide. At the end of treatment, 83% of the patients had clinical and electrophysiologic evidence of a mild sensory rather than motor, axonal, length-dependent polyneuropathy, whereas 100% of the patients showed improvement to the basic pathology (≥partial response). Conclusions: Peripheral neuropathy, sometimes subclinical, and mild in our patients, is a common, early side effect of thalidomide therapy. The high doses (21 g) used in all patients for a relatively short time (4 months) rule out any correlations between neuropathy, total dose, and duration of treatment.

Neurological toxicity of long-term (>1 yr) thalidomide therapy in patients with multiple myeloma.

Objective: Thalidomide is remarkably active in advanced relapsed and refractory multiple myeloma (MM), so that its use has been recently proposed either in newly diagnosed patients or as maintenance treatment after conventional or high‐dose therapy. This latter therapeutic approach has risen the concern of side‐effects of long‐term therapy with this drug. Methods: We analysed long‐term toxicity of 40 patients (27 M, 13 F, median age = 61.5 yr) who received salvage therapy with thalidomide ± dexamethasone for longer than 12 months (median 15, range 12–44) at our centre. All the patients had achieved at least a stable disease upon treatment with thalidomide alone (200–400 mg/d, n = 20) or thalidomide (200 mg/d) and dexamethasone (40 mg/d for 4 d every 4 wk) (n = 20). Results and conclusions: Neurotoxicity was the most troublesome and frequent toxic effect that was observed after long‐term treatment, the incidence averaging 75%. Among these 30 patients symptoms included paraesthesias, tremor and dizziness. Neurotoxicity was grade 1 in six patients (15%); grade 2 in 13 patients (32.5%), thus determining thalidomide dose reduction to 100 mg/d; and grade 3 in 11 patients (27.5%) who had subsequently to interrupt therapy despite their response. Electromyographic study, performed in patients with grade ≥2 neurotoxicity, revealed a symmetrical, mainly sensory peripheral neuropathy, with minor motor involvement. The severity of neurotoxicity was not related to cumulative or daily thalidomide dose, but only to the duration of the disease prior to thalidomide treatment, although no patients presented neurological symptoms at study entry. These results suggest that long‐term thalidomide therapy in MM may be hampered by the remarkable neurotoxicity of the drug, and that a neurological evaluation should be mandatory prior to thalidomide treatment, in order to identify patients at risk of developing a peripheral neuropathy.

Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study

This multicenter, open-label phase 2 trial determined the safety and efficacy of carfilzomib, a novel and irreversible proteasome inhibitor, in combination with cyclophosphamide and dexamethasone (CCyd) in patients with newly diagnosed multiple myeloma (NDMM) ≥65 years of age or who were ineligible for autologous stem cell transplantation. Patients (N = 58) received CCyd for up to 9 28-day cycles, followed by maintenance with carfilzomib until progression or intolerance. After a median of 9 CCyd induction cycles (range 1-9), 95% of patients achieved at least a partial response, 71% achieved at least a very good partial response, 49% achieved at least a near complete response, and 20% achieved stringent complete response. After a median follow-up of 18 months, the 2-year progression-free survival and overall survival rates were 76% and 87%, respectively. The most frequent grade 3 to 5 toxicities were neutropenia (20%), anemia (11%), and cardiopulmonary adverse events (7%). Peripheral neuropathy was limited to grades 1 and 2 (9%). Fourteen percent of patients discontinued treatment because of adverse events, and 21% of patients required carfilzomib dose reductions. In summary, results showed high complete response rates and a good safety profile. This trial was registered at clinicaltrials.gov as #NCT01346787.

Short-Term Thalidomide Incorporated Into Double Autologous Stem-Cell Transplantation Improves Outcomes in Comparison With Double Autotransplantation for Multiple Myeloma

PURPOSE To assess potential benefits with thalidomide incorporated into double autologous stem-cell transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma (MM). PATIENTS AND METHODS One hundred thirty-five patients who received thalidomide from induction until the second ASCT were retrospectively analyzed in comparison with an equal number of pair mates treated with double ASCT not including thalidomide. RESULTS On an intention-to-treat basis, the addition of thalidomide to double ASCT effected a significant improvement in the rate (68% v 49%; P = .001) and duration (62% v 33% at 4 years; P < .001) of at least very good partial response (VGPR), time to progression (TTP; 61% v 41% at 4 years; P < .001) and progression-free survival (PFS; 51% v 31% at 4 years; P = .001). A trend was also noted for extended overall survival (OS) among thalidomide-treated patients (69% at 5 years v 53% for the control group), although the difference between the two groups was not statistically significant (P = .07). Benefits with thalidomide in increasing the rate of VGPR or better response, TTP, and PFS were confirmed in a multivariate analysis. Median OS after relapse was 24 months for patients receiving thalidomide added to double ASCT and 25 months for the control group. Overall, 17% of patients discontinued thalidomide, including 8% because of drug-related adverse events. CONCLUSION In comparison with double ASCT, the addition of first-line thalidomide to double ASCT improved clinical outcomes. Short-term thalidomide was generally well tolerated and had no adverse impact on postrelapse survival.