Melphalan-prednisone Research Articles

Melphalan and prednisone versus melphalan, prednisone and thalidomide for elderly and/or transplant ineligible patients with multiple myeloma: a meta-analysis

Trials comparing efficacy of melphalan prednisone (MP) with MP plus thalidomide in transplant ineligible, elderly patients with multiple myeloma have provided conflicting evidence. Although there is agreement regarding improved response rates (RRs) and higher toxicity with the addition of thalidomide to MP, the impact on progression free survival (PFS) and overall survival (OS) is less clear. We performed a meta-analysis comparing efficacy of melphalan, prednisone and thalidomide (MPT) and MP by pooling results on RR, PFS and OS reported in all the identified randomized controlled trials (RCTs) under a random effects model. Overall, six prospective RCTs, with data extractable from five published trials (n=1571) [corrected] were identified. The pooled odds ratio of responding to therapy with MPT vs MP was 3.39 (P<0.001, 95% CI: 2.24-5.12). The pooled hazard ratios for PFS and OS were and 0.68 (P<0.001; 95% CI: 0.55-0.82) and 0.80 (P=0.07; 95% CI: 0.63-1.02), respectively, in favor of MPT. The odds ratios for high grade peripheral neuropathy and deep venous thrombosis were 6.6 and 2.4, respectively, in favour of MP. There was significant heterogeneity among the RCTs. Our meta-analysis demonstrates that in previously untreated, transplant ineligible, elderly myeloma patients, the addition of T to MP results in significantly improved RR and PFS with a trend towards improvement in OS compared with MP alone, but at a cost of significantly greater toxicity.

Is the Low-Thalidomide Dose MPT Regimen Beneficial?

Is the Low-Thalidomide Dose MPT Regimen Beneficial?

Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group

The combination of melphalan-prednisone-thalidomide (MPT) has been investigated in several clinical studies that differed significantly with regard to patient characteristics and treatment schedules. This prospective trial differs from previous melphalan-prednisone (MP) vs. MPT trials by treatment dosing, duration, routine anticoagulation, and permission for a crossover. Newly diagnosed patients with multiple myeloma (MM) (n=122) aged greater than 55 yr, not eligible for transplantation were randomized to receive 8 cycles of M (9 mg/m(2) /d) and P (60 mg/m(2) /d) for 4d every 6 wk (n=62) or MP and thalidomide (100 mg/d) continuously (n=60). Primary endpoint was treatment response and toxicities following 4 and 8 cycles of therapy. Secondary endpoints were disease-free (DFS) and overall survival (OS). Overall, MPT-treated patients were younger (median 69 yr vs. 72 yr; P=0.016) and had a higher incidence of renal impairment (RI, 19% vs. 7%, respectively; P=0.057). After 4 cycles of treatment (n=115), there were more partial responses or better in the MPT arm than in the MP arm (57.9% vs. 37.5%; P=0.030). However, DFS and OS were not significantly different between the arms after a median of 23 months follow-up (median OS 26.0 vs. 28.0 months, P=0.655; DFS 21.0 vs. 14.0 months, P=0.342, respectively). Crossover to MPT was required in 11 patients, 57% of whom responded to treatment. A higher rate of grade 3-4 infections was observed in the MPT arm compared with the MP arm (22.4% vs. 7.0%; P=0.033). However, none of these infections were associated with febrile neutropenia. Death within the first 3 months was observed more frequently in the MP arm (n=8, 14.0%) than in the MPT arm (n=2, 3.4%; P=0.053). Long-term discontinuation and dose reduction rates were also analyzed (MPT: 15.5% vs. MP: 5.3%; P=0.072). Although patients treated with MPT were relatively younger and had more frequent RI, better responses and less early mortality were observed in all age groups despite more frequent discontinuation.

A Phase III Study of Enoxaparin Vs Aspirin as Thromboprophylaxis for Newly Diagnosed Myeloma Patients Treated with Lenalidomide-Based Regimen.

AbstractAbstract 1092 Background:Newly diagnosed myeloma (MM) patients who receive thalidomide-based regimens have a high risk of thromboembolic events. Preliminary studies on MM patients receiving a combination of lenalidomide (R) and dexamethasone have shown an increased incidence of thrombosis as well, with a calculated odds ratio of about 3.5 of developing thrombosis. Aims:In a prospective, multicenter phase III trial (RV-MM-PI-209) newly diagnosed patients were treated with lenalidomide and low-dose dexamethasone (Rd) induction and subsequently randomized to receive consolidation with lenalidomide + melphalan + prednisone (MPR) or high dose melphalan (MEL200). In this sub-study we evaluated the safety and the efficacy of low-molecular weight heparin (LMWH) or low-dose aspirin (ASA) as anticoagulant prophylaxis during Rd induction and MPR consolidation. End-points were incidence of venous thromboembolism (VTE), acute cardiovascular events, sudden death, major and minor bleeding. Methods:402 newly diagnosed MM patients were enrolled in the randomized trial RV-MM-PI-209. Treatment schedule included four 28 day cycles of lenalidomide (25 mg days 1–21) and low-dose dexamethasone (40 mg days 1,8,15,22) (Rd) as induction. As consolidation, patients were randomized to receive six 28-day cycles of melphalan (0.18 mg/kg days 1–4), prednisone (2 mg/kg days 1–4) and lenalidomide (10 mg days 1–21) (MPR, N=202) or tandem melphalan 200 mg/m2 with stem-cell support (MEL200, N=200). All eligible patients were randomly assigned to receive LMWH (Enoxaparin 40 mg/d, N=166) or ASA (Aspirin 100 mg/d, N=176) for the duration of the induction therapy and for consolidation therapy in the MPR group; 60 patients were excluded from this sub-study because of indication for anticoagulant/antiplatelet therapy or high-risk of bleeding. Results:Patient characteristics and distribution of major risk factors were similar in the two groups. At the time of the present analysis 381 and 130 patients are evaluable during Rd induction and consolidation respectively. During the induction phase, the overall incidence of any grade 3–4 thrombotic events was 1% in the LMWH group, 2,4% in the ASA group (p=.45). VTE, mostly of the lower limbs were equally distributed in the two groups (1%; p not significant), while pulmonary embolism was observed only in the ASA group (2%; p not significant). Median time to onset of thrombotic events for patients who received LMWH or ASA were 2.1 and 1 months, respectively. No acute cardiovascular events were observed and only minor bleeding was detected in the LMWH group (1%). During consolidation no thrombotic events were observed in the MPR group, only one central venous catheter thrombosis was observed in the MEL200 group. Conclusion:The overall incidence of thrombotic events was less than 5% in all groups and confirmed the safety of low dose dexamethasone in association with Lenalidomide. No significant benefit was seen with LMWH over ASA in this patient population. LMWH and ASA are likely to be effective thromboprophylactic regimens in lenalidomide treated patients with newly diagnosed multiple myeloma. The analysis will be updated for the meeting.Table 1Incidence of thrombotic events, acute cardiovascular events, sudden death and bleeding events.EventsLMWH (N =166)ASA (N =176)Grade 3–4 thrombotic events, (%)12Acute cardiovascular events, (%)00Sudden deaths, (%)00Major and minor bleeding, (%)10Total events, (%)22 Disclosures:Cavallo:CELGENE: Honoraria. Guglielmelli:CELGENE: Honoraria; JANSSEN-CILAG: Honoraria. Boccadoro:CELGENE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; JANSSEN-CILAG: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees; JANSSEN-CILAG: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Achievement of Complete Response Is a Strong Prognostic Factor In Elderly Newly Diagnosed Myeloma: Retrospective Analysis of 1175 Patients

AbstractAbstract 1949 Introduction:There is extensive evidence from numerous studies in the transplant setting that achievement of complete response (CR) or at least very good partial response (VGPR) is significantly associated with prolonged progression-free survival (PFS) and overall survival (OS). In elderly myeloma patients CR was a rare event since new drugs has been added to standard melphalan-prednisone (MP). After the introduction of novel agents, CR represents an achievable goal, also outside of the transplant setting. Aims:to assess the impact of response to treatment on time-to-event parameters (PFS and OS) in elderly myeloma patients. Methods:We retrospectively analysed newly diagnosed myeloma patients, older than 65 years old, or younger but not eligible for high-dose chemotherapy and transplant. Patients were enrolled in 3 multicentre randomized European trials of the GIMEMA and Hovon groups, and were treated with MP (n=332), MP plus thalidomide (MPT, n=332), MP plus bortezomib (VMP, n=257) or MP plus bortezomib-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT, n=254). PFS, OS and duration of CR were analysed by the Cox proportional hazards model, comparing the two arms by the Wald test and calculating 95% confidence interval (CI). Univariate and multivariate analyses were performed for the following variables: age at diagnosis (>75 vs. ≤75 yrs), International Staging System (ISS) stages, type of chemotherapy and best response achieved. Best response was treated as a time-dependent variable. Results:A total of 1,175 patients, enrolled from November, 2001 to January, 2009, were retrospectively analysed. The best response to treatment was available in 1,136 patients: CR was reported in 195, VGPR in 212, PR in 397. Baseline characteristics according to best response achieved in patients who obtained CR, VGPR or PR were similar. Since response rates vary according to treatment regimens the proportion of patients who received MP, MPT, VMP, and VMPT-VT was different in the different response categories. After a median follow-up of 29 months, PFS was significantly higher in patients who achieved CR compared to those who obtained VGPR (HR 0.16; 95% CI 0.10–0.24; p<0.001) or PR (HR 0.07; 95% CI 0.04–0.13; p<0.001). The advantage in PFS translated into an advantage in OS: patients obtaining CR have a significantly prolonged OS than patients who achieved VGPR (HR 0.15; 95% CI 0.08–0.28; p<0.001) or PR (HR 0.08; 95% CI 0.04–0.16, p<0.001), (table). In multivariate analysis CR achievement was as an independent predictor of longer PFS and OS, regardless of age, ISS stage, and treatment administered. In patients > 75 years, both PFS and OS were shorter as compared to younger patients. Despite these differences, the impact of CR on outcome was identical. In the subgroup of patients > 75 years, PFS was significantly prolonged in patients who achieved CR, compared with those who obtained VGPR (HR 0.26; 95% CI 0.12–0.58, p = 0.001) or PR (HR 0.20; 95% CI 0.10–0.41, p < 0.001). Accordingly, OS was significantly higher in patients who achieved CR, compared with those who obtained VGPR (HR 0.13; 95% IC 0.03–0.58; p = 0.007), or PR (HR 0.12; 95% IC 0.03–0.51, p = 0.004), (table). No significant PFS differences between patients obtaining CR during the first 6 months of treatment or later were seen (HR 1.06; 95% IC 0.49–2.27; p=0.878). Similarly, no OS differences between these two groups were detected (p = 0.676). Duration of CR was comparable in patients who obtained CR during or after the first 6 months of treatment (HR 0.66; 95% CI 0.30–1.45; p = 0.305). Patients whose CR lasted more than 18 months have a significant OS benefit compared to patients who did not (p=0.006). Conclusions:These finding highlight the importance of CR, also outside of the transplant setting, regardless of age, ISS and treatment administered, and support the use of new drugs, also in patients older than 75 years, to achieve and maintain maximal response.Table:PFS an OS according to best response in all patients and in patients >75 years old.CRVGPRPRAll patients3-year PFS67%27%27%3-year OS91%70%67%Patients >75 years old3-year PFS79%24%23%3-year OS88%65%57% Disclosures:Gay:Celgene: Honoraria. Bringhen:Calgene: Honoraria; Janssen-Cilag: Honoraria. Guglielmelli:Celgene: Honoraria; Janssen Cilag: Honoraria. Boccadoro:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson : Membership on an entity's Board of Directors or advisory committees. Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Use of bortezomib to overcome the poor prognosis of t(4;14), but not del(17p), in young patients with newly diagnosed multiple myeloma.

8113 Background: Translocation t(4;14)(p16;q32) has been associated with a poor outcome in multiple myeloma. This poor prognosis has been identified both in patients treated with melphalan-prednisone (MP) and in those treated with high-dose melphalan after a VAD induction. For instance, in 100 patients with t(4;14) treated with VAD and MEL200, the median PFS and OS were 21 months and 41 months, respectively, as compared to 37 months and 65 months for patients lacking the t(4;14) (Moreau et al., Leukemia 2007). Some preliminary studies have suggested that bortezomib was able to overcome the poor prognosis of the translocation in elderly patients treated with MP-bortezomib (San Miguel et al., NEJM 2008). Methods: In order to address this important question, we analyzed 507 patients treated in the IFM, according to the IFM-2005-01 trial, arm B: induction with 4 cycles of bortezomib (Velcade)/dexamethasone (VD), followed by one or two courses of high-dose melphalan (MEL200). Results: A translocation t(4;14) was observed in 106 of these 507 patients treated with VD, whereas del(17p) was found in 60 patients. Of note, 10 patients presented both the t(4;14) and the del(17p). The median PFS was 28 and 35 months, in patients with or without the t(4;14), respectively (p<0.02). At 3 years, 73% of the patients with t(4;14) were still alive, as compared to 89% of the patients lacking the translocation (p=0.002). For comparison, the OS results were respectively 48% (patients with t(4;14)) and 73% (patients lacking the translocation) in patients treated with a VAD induction within the same period. Thus, it seems that VD is able to significantly overcome the poor prognosis of t(4;14). We also looked at the prognostic value of del(17p) in this series of patients treated with VD. In contrast to the t(4;14) situation, VD was enable to rescue patients with del(17p) (same PFS and OS for patients treated with VD than for those treated with a VAD induction). Conclusions: Thus, this study (by far the largest so far reported) shows that VD as induction before intensification is able to improve the prognosis of patients with t(4;14), but not of those with del(17p). Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Janssen-Ortho

Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

The Newly Diagnosed Myeloma Patient – Therapeutic Approaches

The outcome for myeloma patients has significantly improved over the last decade, mainly due to the introduction of new drugs with a singular mechanism of action such as thalidomide and lenalidomide (revlimid), both immunomodulatory drugs (IMIDs), and the proteasome inhibitor bortezomib (velcade). In newly diagnosed young patients, induction regimens such as bortezomib–thalidomide or lenalidomide plus dexamethasone will replace vincristine, doxorubicin and dexamethasone (VAD), followed by high-dose melphalan. Maintenance with IMIDs may represent the new standard of care for young multiple myeloma (MM) patients. This approach is being challenged by continuous treatment with novel agents and the postponement of a transplant until relapse. Allogeneic transplant should be conducted within the context of clinical trials. In elderly patients or non-transplant candidates, new regimens based on melphalan–prednisone plus thalidomide, velcade or lenalidomide have become new standards. The reduction of side effects while maintaining efficacy of treatment is most important in the elderly population.

Bortezomib Does Not Increase Thromboembolic Risk in Multiple Myeloma and May Offer a Protective Effect with Thalidomide/Lenalidomide-Based Therapy: Review of Data From Phase 3 Trials and Studies of Novel Combination Regimens.

Abstract 1873Poster Board I-898Patients with multiple myeloma (MM) are at elevated risk of venous thromboembolism (VTE), specifically deep-vein thrombosis (DVT) and pulmonary embolism (PE). The VTE risk in MM is increased by various patient- and disease-related factors; however, type of anti-MM therapy represents a key factor, with a substantially elevated risk in patients treated with the immunomodulatory drugs (IMiDs) thalidomide (thal) or lenalidomide (len) in combination with dexamethasone (dex) and/or chemotherapy (Palumbo et al, Leukemia 2008); VTE risk with len-dex (RD) is further increased with concomitant erythropoietin (EPO). By contrast, treatment with the proteasome inhibitor bortezomib (btz), either alone or in combination, does not increase VTE risk. In the VISTA phase 3 trial of melphalan-prednisone (MP) vs btz plus MP (VMP) in previously untreated MM patients ineligible for high-dose therapy (San Miguel et al, N Engl J Med 2008), data from an updated safety analysis showed similar rates of DVT (VMP: 5/340 [1%], four grade 3; MP: 6/337 [2%], two grade 3) and PE (VMP: 4/340 [1%], two grade 4; MP: 3/337 [1%], one grade 3, two grade 4) between arms; as reported by Richardson et al (IMW 2009), rates of DVT/PE were not affected by use of erythropoiesis-stimulating agents, including EPO. These findings reflect those from the APEX phase 3 trial of single-agent btz vs high-dose dex in relapsed MM (Lonial et al, Br J Haematol 2008); rates of DVT/PE were low (0.6% vs 2.7%) and unaffected by concomitant EPO use, and VTE risk appeared lower with btz vs dex, controlling for EPO use (odds ratio 0.207, p=0.046). As previously reported, btz shows anti-hemostatic effects in patients with relapsed or refractory MM, resulting in a decrease in platelet count and significant reductions in agonist-induced platelet aggregation (Zangari et al, Haematologica 2008); these findings support btz exerting anti-thrombotic actions and thus potentially providing a protective effect in combination with regimens with elevated VTE risk. A review of data from phase 3 trials of btz- and/or IMiD-based therapy in frontline MM and other studies of novel combination regimens supports this hypothesis. Despite the confounding effect of variable VTE prophylaxis, btz-based regimens are associated with DVT/PE rates of 0–4% (Figure), similar to those seen with MP and dex alone (Palumbo et al, Leukemia 2008), whereas IMiD-based btz-free regimens are generally associated with substantially higher rates. Direct comparisons of regimens of thrombogenic potential with/without btz demonstrate lower VTE risk with btz; as previously reported, DVT rates of 0% vs 10% (p=0.0006) were seen with DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide) with vs without btz in an analysis of patients enrolled on two University of Arkansas trials (Zangari et al, ASH 2004). Palumbo et al (EHA 2009) also reported lower rates of VTE events with btz, thal, dex (VTD, ∼4.5%) and VMP—thal (VMPT, ∼2.7%) vs TD (7%) in a phase 3 randomized trial of aspirin, low molecular weight heparin, and warfarin as VTE prophylaxis, while in another phase 3 study Rosiñol et al (ASH 2008) showed a lower rate of thrombotic events with VTD vs TD (1.7% vs 13%, p=0.02, no prophylaxis). Indirect, between-study comparisons of VTE risk support these findings; in six phase 3 studies, TD was associated with 5.5–23% DVT/PE, while in two phase 3 studies, the rate with VTD was 1.7–4%. Similarly, rates were 6–12% in five phase 3 studies of MP-thal (MPT) vs 4% with VMPT (Palumbo et al, EHA 2009). Finally, len-low-dose dex (Rd) and RD resulted in DVT/PE rates of 12–27% in two phase 3 studies, whereas a rate of only 4% was reported in a phase 1/2 study of btz-RD (RVD) by Richardson et al (IMW 2009). Taken together, these findings confirm the low VTE risk associated with btz and support a potential protective effect of btz in combination with IMiD-based regimens associated with elevated VTE risk. [Display omitted] Disclosures:Zangari:Milllennium: Honoraria, Research Funding; Novartis: Research Funding; Celgene: Honoraria; OrthoBiotech: Honoraria; Optum Health: Honoraria; Educational Concepts Group, LLC: Membership on an entity's Board of Directors or advisory committees. Fink:DOD Radioprotectants: Research Funding.

Sustained Health-Related Quality of Life (HRQoL) Improvement in Newly Diagnosed Multiple Myeloma Patients Treated with Bortezomib/Melphalan/Prednisone Versus Melphalan/Prednisone: Results From the VISTA Trial.

Abstract 1881Poster Board I-904 Introduction:The impact of multiple myeloma treatment on patient-reported health-related quality of life (HRQoL) merits careful evaluation since treatment effect and toxicity may impact HRQoL. Previously, the positive impact of achieving CR in the VISTA study on HRQoL had been reported at the fourth cycle after CR onset. The aim of this study was to describe the rate of patients who experienced a sustained HRQoL improvement after best response and the overall HRQoL impact of best response. Patients and Methods:The VISTA trial was a randomized, open-label, multicenter study designed to compare the efficacy and safety of VMP to melphalan/prednisone (MP) in subjects with previously untreated multiple myeloma who were ineligible for transplantation. Patients were followed over a 9-cycle period (54 weeks) and for a post-treatment follow-up phase. Response to therapy was defined according to the European Group for Blood and Marrow Transplantation criteria. The European Organization for Research on Treatment of Cancer (EORTC) QLQ-C30, a HRQoL questionnaire commonly used in multiple myeloma, was administered at screening, day 1 of each cycle during the treatment phase, and every 8 weeks until progression during follow-up. A sustained HRQoL improvement was defined as a change in score of at least 5 points (Dubois et al, JCO 2006; 24:976–82) for at least 2 consecutive cycles after best response (Complete Response [CR], Partial Response [PR] or Minimal Response [MR]). The rate of sustained improvement and the time to sustained improvement were calculated in the population of patients who were followed for at least 2 cycles after best response (n=363). Treatment groups were compared using a log-rank test. Cox proportional hazard models were applied to explore the effect of covariates (type of best response, score at baseline, score at best response) on the chance of sustained improvement in each EORTC QLQ-C30 score. Results:Mean and median age of study patients was 72 and 71 years, respectively; 51% were female, mean and median KPS was 80. All EORTC domain scores were similar at baseline across the study arms. Worse health was reported in all domains with VMP arm at best tumor response onset. However, after best response onset, patients in the VMP arm had a higher sustained HRQoL improvement rate than those in the MP arm in 14 of the 15 EORTC QLQ-C30 scores. VMP patients had a slightly lower sustained response rate only in Cognitive Functioning: 27% vs 28%, respectively. VMP patients were more likely than MP patients to experience a statistically significant sustained response in three QLQ-C30 domains according to the log-rank test: Nausea/Vomiting (p=0.0095), Appetite Loss (p=0.0170), and Diarrhea (p=0.0082). The differences for Nausea and Diarrhea remained significant in the Cox models when adjusted for baseline score, score at best response, and type of response (CR, PR or MR). VMP patients also had a higher rate of sustained response over MP patients for Global Health (49% vs 40%), Pain (40% vs 32%), and Insomnia (32% vs 24%). However, these differences were not statistically significant. Conclusions:Patients treated with VMP more frequently experienced a sustained HRQoL improvement in most of the EORTC QLQ-C30 domains than patients in the MP arm after best tumor response. In particular, the likelihood of a sustained improvement in Nausea and Diarrhea was significantly higher in VMP patients, independent of the type of response and the respective symptom score at baseline and at time of best response. Although the incidences of nausea and diarrhea were higher in the VMP arm at best response onset, these data suggest that HRQoL decrements reported by patients begin to improve with best response onset. Further analysis is planned. Disclosures:Dhawan:Janssen Cilag: Employment, Equity Ownership. Robinson:Johnson & Johnson: Employment, Equity Ownership, Research Funding. Meunier:Mapi Values: Employment. Regnault:Mapi Values: Employment. Rosa:Mapi Values: Employment. Cakana:Janssen Cilag: Employment, Equity Ownership. van de Velde:Johnson & Johnson: Employment, Equity Ownership. Richardson:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. San Miguel:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; OrthoBiotech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Bortezomib Plus Melphalan–Prednisone Continues to Demonstrate a Survival Benefit Vs Melphalan–Prednisone in the Phase III VISTA Trial in Previously Untreated Multiple Myeloma After 3 Years' Follow-up and Extensive Subsequent Therapy Use.

Abstract 3859Poster Board III-795The initial results of the pivotal, international, phase III VISTA trial demonstrated the superiority of bortezomib (Velcade®) plus melphalan–prednisone (VMP) versus MP alone across all efficacy end points, including overall survival (OS), in previously untreated multiple myeloma (MM) patients ineligible for high-dose therapy (San Miguel et al, N Engl J Med 2008). We conducted a planned updated survival analysis of VISTA after a median >3 years of follow-up and with the majority of patients having received subsequent therapy. We confirmed the previously demonstrated OS benefit of VMP versus MP, examined the use of subsequent therapy and its efficacy following VMP and MP, and evaluated the survival of patients who had received subsequent therapy. Patients were randomized to receive nine 6-week cycles of VMP (N=344; bortezomib 1.3 mg/m2, d 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, d 1, 8, 22, 29, cycles 5–9; melphalan 9 mg/m2 d 1–4, prednisone 60 mg/m2, d 1–4, all cycles) or MP (N=338) alone. Response was assessed using EBMT criteria with central laboratory M-protein analysis. After disease progression, patients were followed for survival and subsequent therapy, including investigator-assessed best response to subsequent therapies. The median age of patients was 71 years, 30% were aged ≥75 years, 34% had ISS stage III MM, and 33% had β2-microglobulin >5.5 mg/L. After median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP vs MP (hazard ratio [HR] 0.653, p=0.0008); median OS was not estimable vs 43.1 months, and 3-year OS rates were 68.5% vs 54.0% with VMP vs MP, respectively. This OS benefit was seen consistently across patient subgroups predefined by baseline characteristics. Within the VMP arm, OS was longer among patients aged <75 vs ≥75 years (HR 1.664, p=0.011; 3-year OS: 74.1% vs 55.5%); by contrast, there were no significant differences, although there were trends to longer OS among patients with creatinine clearance ≥60 versus <60 mL/min (HR 1.291, p=0.238; 3-year OS: 74.5% vs 63.1%) and patients with standard- vs high-risk cytogenetics (HR 1.346, p=0.399; 3-year OS 71.6% vs 56.1%). At data cut-off (16 March 2009), 178 (52%) VMP and 233 (69%) MP patients had received subsequent therapy; median time to subsequent therapy (28.1 vs 19.2 months, HR 0.527, p<0.0001) and median treatment-free interval (17.6 vs 8.4 months, HR 0.543, p<0.0001) were superior with VMP vs MP. Receipt of and response to subsequent bortezomib-, thalidomide-, and lenalidomide-based therapy are summarized in the Table. Median survival from start of subsequent therapy following VMP and MP was 30.2 vs 21.9 months (HR 0.815, p=0.21) among all patients receiving subsequent therapy. This updated analysis of VISTA confirms that VMP results in significantly longer OS compared with MP, despite 50% of MP patients being rescued with bortezomib-based therapy in the relapsed setting. VMP treatment used upfront appears more beneficial than treating with conventional agents and saving bortezomib- and other novel-agent-based treatment until relapse. Subsequent therapies appeared similarly effective in the VMP and MP arms, with our analysis also demonstrating the benefit of retreatment with bortezomib-based therapies following VMP. In addition, post-relapse survival among all patients receiving subsequent therapy appeared longer following VMP, indicating that frontline bortezomib use does not induce more resistant relapses.TableResponse among patients who received subsequent therapyVMP (N=178)MP (N=233)Received subsequent therapy containing:*Bortezomib, n (%)43 (24)116 (50)Thalidomide, n (%)81 (46)110 (47)Lenalidomide, n (%)57 (32)30 (13)Overall response rate (%) to subsequent therapy:Bortezomib-based4759Thalidomide-based4153Lenalidomide-based5952*Patients could have received >1 agent, either in combination or separately in different subsequent lines of therapy Disclosures:Mateos:Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Richardson:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dimopoulos:Millennium Pharmaceuticals, Inc.: Honoraria; Ortho-Biotech: Consultancy, Honoraria. Shpilberg:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees. Kropff:Ortho Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees. Petrucci:Janssen Cilag: Honoraria; Celgene: Honoraria. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria. Dmoszynska:Millennium: Research Funding. Schots:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Esseltine:Millennium: Employment, Equity Ownership. Liu:Johnson & Johnson: Employment, Equity Ownership. Cakana:Johnson & Johnson: Employment, Equity Ownership. van de Velde:Johnson & Johnson: Employment, Equity Ownership. San Miguel:Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Pharmacogenomic (PGx) Analysis of Bortezomib-Associated Peripheral Neuropathy in the Phase 3 VISTA Trial of Bortezomib Plus Melphalan–Prednisone Versus Melphalan–Prednisone in Multiple Myeloma.

Pharmacogenomic (PGx) Analysis of Bortezomib-Associated Peripheral Neuropathy in the Phase 3 VISTA Trial of Bortezomib Plus Melphalan–Prednisone Versus Melphalan–Prednisone in Multiple Myeloma.

Induction with Velcade®/Dexamethasone Partially Overcomes the Poor Prognosis of t(4;14), but Not That of Del(17p), in Young Patients with Multiple Myeloma.

Abstract 957Translocation t(4;14)(p16;q32) has been associated with a poor outcome in multiple myeloma. This poor prognosis has been identified both in patients treated with melphalan-prednisone (MP) and in those treated with high-dose melphalan after a VAD induction. For instance, in 100 patients with t(4;14) treated with VAD and MEL200, the median PFS and OS were 21 months and 41 months, respectively, as compared to 37 months and 65 months for patients lacking the t(4;14) (Moreau et al., Leukemia 2007). Some preliminary studies have suggested that bortezomib (Velcade®) was able to overcome the poor prognosis of the translocation in elderly patients treated with MP-Velcade® (San Miguel et al., NEJM 2008). In order to address this important question, we analyzed 436 patients treated in the IFM, according to the IFM-2005-01 trial, arm B: induction with 4 cycles of Velcade®/Dexamethasone (VD), followed by one or two courses of high-dose melphalan (MEL200). A translocation t(4;14) was observed in 67 of these 436 patients treated with VD (15%), whereas del(17p) was found in 51 patients (11%). Of note, 10 patients presented both the t(4;14) and the del(17p). The median PFS was 25 and 36 months, in patients with or without the t(4;14), respectively (p=0.006). At 3 years, 76% of the patients with t(4;14) were still alive, as compared to 88% of the patients lacking the translocation (p=.003). For comparison, the OS results were respectively 62% (patients with t(4;14)) and 73% (patients lacking the translocation) in patients treated with a VAD induction. Thus, it seems that VD is able to partially overcome the poor prognosis of t(4;14). We also looked at the prognostic value of del(17p) in this series of patients treated with VD. In contrast to the t(4;14) situation, VD was enable to rescue patients with del(17p) (same PFS and OS for patients treated with VD than for those treated with a VAD induction). Thus, this study (by far the largest so far reported) shows that VD as induction before intensification is able to improve the prognosis of patients with t(4;14), but not of those with del(17p). Disclosures:Avet Loiseau:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Moreau:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Facon:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Attal:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Harousseau:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees.

Phase 3b UPFRONT Study: Interim Results From a Community Practice-Based Prospective Randomized Trial Evaluating Three Bortezomib-Based Regimens in Elderly, Newly Diagnosed Multiple Myeloma Patients.

Abstract 129In this US community-based, randomized, open-label, multicenter phase 3b study, we compare the safety and efficacy of three highly active bortezomib (Velcade®, Vc)-based regimens for multiple myeloma (MM), Vc–thalidomide–dexamethasone (VcTD), Vc–dexamethasone (VcD), and Vc–melphalan–prednisone (VcMP), in previously untreated MM patients (pts) ineligible for high-dose therapy and autologous stem cell transplantation. Use of these regimens is supported by data from phase 3 studies; only VcMP has been investigated specifically in elderly pts. Here we present data from a pre-specified interim analysis (IA) of 210 pts performed after the first 70 pts in each arm had the opportunity to complete four cycles of therapy. Pts with symptomatic, measurable MM were randomized (1:1:1) to receive 49 weeks of therapy: 24 weeks (eight 21-day cycles) of induction with VcD (Vc 1.3 mg/m2, days 1, 4, 8, 11; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [Cycles 1–4)], days 1, 2, 4, 5 [Cycles 5–8]), VcTD (Vc 1.3 mg/m2, days 1, 4, 8, 11; T 100 mg/d, d1-21; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [Cycles 1–4), days 1, 2, 4, 5 [Cycles 5–8]) or VcMP (Vc 1.3 mg/m2, days 1, 4, 8, 11; M 9 mg/m2 and P 60 mg/m2, day 1–4, every other cycle), followed by 25 weeks (five 35-day cycles) of maintenance with Vc alone (1.6 mg/m2, days 1, 8, 15, 22). Prophylactic aspirin, full dose warfarin, or low molecular weight heparin was administered to the VcTD arm unless medically contraindicated.The primary endpoint is progression-free survival; secondary endpoints include overall survival, duration of response, time to next therapy, quality of life (QoL) using the EORTC QLQ-C30 questionnaire, safety and tolerability, and efficacy (CR/nCR, VGPR, PR, and ORR). Responses were assessed by investigators using central laboratory data, applying the International Myeloma Working Group uniform criteria. An Independent Data Monitoring Committee (IDMC) assessed safety, tolerability, response rates and QoL data to determine which two of the three arms should continue enrolling pts. Pts in the VcD, VcTD, and VcMP arms had median ages of 74, 73, and 72 years, respectively; 83%, 58%, and 73% had ISS stage ll/lll and 21%, 22% and 32%, respectively, were non-Caucasian. In the VcD, VcTD, and VcMP arms, mean number of treatment cycles (for the first four cycles) and total Vc doses (16 doses for the first four cycles) were similar: 3.8, 3.6, and 3.7 cycles and 14.5, 13 and 13.8 Vc doses, respectively. The VcD arm had the lowest rate of adverse events (AEs) grade ≥3 (58% vs 71% each in the VcTD and VcMP arms, respectively), as well as the lowest rate of discontinuations due to AEs (10% vs 18% and 16% in the VcTD and VcMP arms, respectively). The VcTD arm had the highest rate of serious AEs (50% vs 39% and 36% in the VcD and VcMP arms, respectively), as well as peripheral neuropathy (PN) of any grade (48% vs 29% and 30% in the VcD and VcMP arms, respectively). PN grade ≥3 was 6%, 12% and 13% in the VcD, VcTD, and VcMP arms, respectively. The VcTD arm had higher rates of serious embolism/thrombosis (8% vs 6% and 3%) than in the VcD and VcMP arms, respectively. All three regimens demonstrated substantial activity. The overall response rate was 60%, 70%, and 52% in the VcD, VcTD, and VcMP arms, respectively (complete response (CR)/near CR: 13%, 18% and 15%; ≥very good partial response 15%, 23% and 24%, respectively). QoL functional scores improved in all arms, except for physical, role function and global health status, which worsened in the VcTD arm only. At a preplanned IA, the three Vc-based regimens were evaluated as having similar risk/benefit considerations after four cycles. The regimens were active with well-characterized and predictable toxicities. The study continues to enroll in all three arms as recommended by the IDMC. The UPFRONT trial demonstrates the feasibility of conducting a large, randomized, outpatient, phase 3b trial in community-based oncology centers in the United States. Disclosures:Niesvizky:Celgene: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Research Funding, Speakers Bureau; Proteolix: Consultancy, Research Funding. Flinn:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Rifkin:Millennium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Cephalon: Speakers Bureau. Gabrail:Millennium Pharmaceuticals, Inc: Research Funding. Phooshkooru:Millennium Pharmaceuticals, Inc: Consultancy, Honoraria. Charu:Millennium Pharmaceuticals, Inc: Consultancy, Honoraria, Research Funding. Corzo:Millennium Pharmaceuticals, Inc.: Employment. Neuwirth:Millennium Pharmaceuticals, Inc: Employment.

Towards a new standard of care for patients with myeloma?

New agents such as immunomodulatory drugs and proteasome inhibitors have substantially changed the treatment paradigm of multiple myeloma, with the combinations melphalan–prednisone–thalidomide and melphalan–prednisone–bortezomib now regarded as new standards of care for elderly patients.1–3 In younger patients, the introduction of bortezomib into pre-transplant induction regimens4 and lenalidomide as consolidation-maintenance5 has showed promising results.

Thalidomide in Multiple Myeloma in the Elderly

Melphalan prednisone was the mainstay of myeloma treatment in the 1960s with 50% of overall response, yet this treatment was associated with a short duration of response and a poor median overall survival (only 3 years). Thalidomide, initially used as an antiemetic and sedative agent, was demonstrated to have substantial antitumor activity in multiple myeloma and other solid cancers. The first studies established a promising response among patients with relapsed or refractory disease. Melphalan–prednisone–thalidomide is currently the treatment of choice for a large proportion of elderly myeloma patients ineligible for autologous stem cell transplantation. Melphalan prednisone is appropriate only for a minority of patients with poor performance status and/or significant comorbidities. Thalidomide has opened a complete new field of novel agents termed the IMiDs®class of immunomodulatory drugs; of which, lenalidomide (Revlimid®, Celgene Corporation, NJ, USA) and pomalidomide (Actimid™, Celgene Corporation, NJ, USA) are the next and last in line developed agents, respectively. These options could lead to more personalized treatment approaches, based on patient comorbidities, as the novel agents have somewhat different toxicity profiles. Questions regarding the relative efficacy of melphalan-based regimens versus dexamethasone-based regimens with low-dose dexamethasone will require randomized Phase III trials. Additionally, the important issue of maintenance treatment needs to be further investigated. These new and emerging therapies offer multiple effective treatment options for multiple myeloma patients and greatly enhance the treatment strategies for clinicians.

Thalidomide Versus Bortezomib-Based Regimens for Relapsed Myeloma: Meta-Analysis and Indirect Meta-Analysis

Background: Thalidomide (T) and bortezomib (B) in combination with melphalan-prednisone (MP) were both shown to be superior to treatment with MP. However, head-to-head comparison of these regimens is lacking. When direct comparison is not available, indirect meta-analysis of randomized controlled trials (RCTs) can be performed. Such an analysis preserves the original randomization and therefore is considered to be more reliable than comparison based on non-RCT data.Methods: Previously described methods for adjusted indirect comparisons developed by Bucher et al and Glenny et al were used. We created the following chain of inference: we first pooled RCTs that compared MPT with MP, and BMP vs. MP. We then compared the pooled estimate to obtain the unbiased estimate in treatment differences between BMP vs. MPT.Results: 4 RCTs compared MPT vs. MP and 1 BMP vs. MP. Data from RCT by Waage et.al. were not available. The results for all comparisons are summarized in the table. Meta-analysis of 3 RCTs comparing MPT vs. MP showed no difference in overall survival (OS), and treatment-related mortality (TRM). However, event-free survival (EFS), partial response (PR), complete response (CR) and very good partial response (VGPR) were significantly better with MPT, but at the risk of significant grade III-IV adverse events (AE), and deep-vein thrombosis (DVT). OS, EFS, CR and VGPR was significantly better with BMP vs MP in 1 RCT, but at significant risk for grade III-IV AE. There was no difference between BMP and MP in terms of TRM, DVT, and PR. Comparison of BMP versus MPT showed no difference in OS, EFS, TRM, DVT, and PR. However BMP is associated with significantly less grade III-IV AE and better CR.Conclusion: There was no difference in OS, EFS, or TRM between BMP and MPT. However, treatment with BMP results in improved complete response, while grade III-IV AE were more common in MPT arm. The lack of statistical difference is likely due to insufficient power (absence of evidence) rather than true differences of no effect (evidence of absence). Since the power of this indirect meta-analysis was low, direct head-to-head comparison between these competing regimens is warranted.Table.OutcomeComparisonsMPT versus MP (3 RCT; N= 852)ConclusionBMP versus MP (1 RCT; N=682)ConclusionBMP versus MPTConclusionOSHR=0.747 (95%CI 0.534, 0.046); p=0.089No differenceHR=0.607 (95%CI 0.425, 0.866); p=0.006BMP betterHR=0.812 (95%CI 0.498, 1.325); p=0.405No differenceEFSHR=0.569 (95%CI 0.484, 0.668); p=0MPT betterHR=0.483 (95%CI 0.37, 0.63); p=0BMP betterHR=0.85 (95%CI 0.623, 1.159); p=0.304No differenceTRMRisk ratio (RR)=0.976 (95%CI 0.469, 2.031); p=0.949No differenceRR=0.566 (95%CI 0.167, 1.917); p=0.361No differenceRR=0.58 (95%CI 0.14, 2.405); p=0.453No differenceDVTRR=3.586 (95%CI 2.021, 6.632); p=0.00MP betterRR=0.991 (95%CI 0.243, 4.041); p=0.99No differenceRR=0.276 (95%CI 0.61, 1.261); p=0.0971No differenceGrade III-IV AERR=4.257 (95%CI 3.402, 5.327); p=0.0MP betterRR=1.512 (95%CI 1.255, 1.814); p=0.0MP betterRR=0.355 95%CI 0.265, 0.474; p=0.00BMP betterCRRR=0.911 (95%CI 0.875, 0.948); p=0.00MPT betterRR=0.728 (95%CI 0.676, 0.783); p=0BMP betterRR=0.799 (95%CI 0.735, 0.869); p=0.00BMP betterVGPRRR=0.778 (95%CI 0.720, 0.840); p=0.005MPT betterRR=0.947 (95%CI 0.907, .990); p=0.016BMP betterRR=1.219 (95%CI 1.115, 1.331); p=0.00MPT betterPRRR=0.885 (95%CI 0.794, 0.986); p=0.027MPT betterRR=0.914 (95%CI 0.821, 1.018); p=0.101No differenceRR=1.033 (95%CI 0.887, 1.203); p=0.675No difference

Indirect Comparison of the Efficacy of Melphalan-Prednisone-Bortezomib Relative to Melphalan-Prednisone-Thalidomide and Melphalan-Prednisone for the First Line Treatment of Multiple Myeloma

Melphalan-prednisone (MP) combination has been considered a standard of care for front line treatment of multiple myeloma in patients non eligible for transplant. Melphalan-prednisone-bortezomib (MPV) combination has been approved in the United States in patients non eligible for high-dose chemotherapy (HD-C) and has recently received a positive opinion from the CHMP in Europe. Melphalan-prednisone-thalidomide (MPT) was approved in Europe in patients >65 or not eligible for HD-C. There is no head-to-head trial directly comparing MPV to MPT. The objective of the current study was to compare the efficacy of MPV to MP and MPT as first line treatment of multiple myeloma in patients non eligible for transplant. Six randomized placebo controlled trials investigating the efficacy of MPT (5) and MPV (1) relative to MP were identified with a systematic literature review. The endpoints of interest were overall survival (OS), progression free survival (PFS) and overall and complete response. Relative efficacy estimates of MPT versus MP as obtained from the MPT-MP trials were combined with meta-analysis techniques and simultaneously indirectly compared with the relative efficacy of MPV versus MP from the MPV-MP trial (VISTA). This adjusted indirect comparison was performed with Bayesian fixed and random effects models. As compared to frequentist approach, Bayesian meta-analysis offers a more informative summary of the likely value of efficacy after observing the data and allows for direct probabilistic inferences. Of the three interventions compared, there was an 81% probability that MPV was the most efficacious intervention in terms of overall response and a >99% probability in terms of complete response. With MPV a patient was two times more likely to show a complete response than with MPT (Relative Risk=2.15; 95%Credible Interval (CrI): 0.99–4.45). Both MPV and MPT showed greater OS than MP (HR=0.61; 95%CrI: 0.42–0.88 and HR=0.61; 95%CrI: 0.47–0.78 respectively); the indirect comparison showed similar efficacy in terms of OS between MPV and MPT (MPV vs MPT: Hazard Ratio=1.00; 95%CrI 0.64–1.57). Both MPV and MPT also displayed greater PFS than MP (MPV versus MP: HR=0.61; 95%CrI 0.49–0.76 and MPT versus MP HR=0.51; 95%CrI 0.41–0.63 respectively) and showed similar efficacy (MPV vs MPT: HR=1.19; 95%CrI: 0.87–1.63). In this study, both MPV and MPT are more efficacious than MP in terms of response, PFS and OS. MPV is expected to result in a greater complete and overall response than MPT. No difference in OS or PFS was displayed. Further analyses will need to be undertaken once evidence base data is more mature.

Updated Follow-up and Results of Subsequent Therapy in the Phase III VISTA Trial: Bortezomib Plus Melphalan–Prednisone Versus Melphalan–Prednisone in Newly Diagnosed Multiple Myeloma

Based on the results of the large, international, phase III VISTA trial in previously untreated MM patients ineligible for high-dose therapy with stem cell transplantation (HDT-SCT), bortezomib (VELCADE®) was approved by the US FDA for the initial treatment of multiple myeloma (MM). Data from VISTA showed that bortezomib plus melphalan–prednisone (VMP) was superior to melphalan–prednisone (MP) across all efficacy end points, including response rates (overall and complete response [CR] rates), time to progression (TTP), time to subsequent therapy (TTNT), and overall survival (OS). Patients (N=682) from 151 centers in 22 countries in Europe, North and South America, and Asia were randomized (1:1) to 54 weeks treatment with VMP (N=344) or MP (N=338). Patients received nine 6-week cycles of bortezomib 1.3 mg/m2 (days 1, 4, 8, 11, 22, 25, 29, 32 in cycles 1–4 and days 1, 8, 22, 29 in cycles 5–9) with melphalan 9 mg/m2 and prednisone 60 mg/m2 (days 1–4 in cycles 1–9), or melphalan plus prednisone, per the dose and schedule described above. The primary end point was TTP, with progression determined using European Group for Blood and Marrow Transplantation (EBMT) criteria. Median age was 71 years; 30% of patients were aged ≥75 years. At baseline, 34% of patients had Karnofsky Performance Status (KPS) ≤70%, 33% had β2-microglobulin >5.5 mg/L, and 34% had International Staging System (ISS) Stage III disease. An Independent Data Monitoring Committee recommended the trial be stopped based on a protocol-specified interim analysis as the statistical boundary for the primary end point had been crossed. VMP was well tolerated, with patients remaining on VMP therapy for a median of 46 weeks (8 cycles) versus 39 weeks (7 cycles) with MP; median total dose of bortezomib received was 38.5 mg/m2. Collection of tumor assessment data was stopped after presentation of the positive interim analysis. Collection of survival data, subsequent therapy data and safety/recovery data continued. Updated follow-up through April 25, 2008 confirms a statistically significant survival benefit for VMP versus MP (HR=0.64, P=0.0032) after a median follow-up of 25.9 months. Three-year survival rates were 72% versus 59%, respectively. TTNT and treatment-free interval (TFI) were also significantly longer in the VMP arm (TTNT 28.1 vs 19.2 months, HR=0.53, P<0.000001; TFI 16.6 vs 8.4 months, HR=0.54, P<0.00001). Fewer patients in the VMP versus MP arm (38% vs 57%, respectively) required subsequent therapy. Of the patients receiving subsequent therapy in the VMP and MP arms, 16% and 43% received bortezomib, 49% and 44% received thalidomide, and 19% and 6% received lenalidomide, respectively. Re-treatment with bortezomib was effective in the VMP arm (6% CR) (Table); a 10% CR rate was reported in the MP arm after bortezomib-based therapy. Peripheral neuropathy (PN) in the VMP treatment arm improved or resolved in 79% of events (median 1.9 months), with 60% of PN events resolving completely (median 5.7 months). VMP is an active and well-tolerated treatment option for previously untreated MM patients and significantly prolongs survival and time to subsequent therapy. Patients can be successfully treated with subsequent immunomodulatory-based combination therapy and can also be retreated with bortezomib, achieving high response rates with manageable toxicity.Table. Investigator-reported best responses with subsequent therapies per treatment armVMP arm (n=129)*MP arm (n=194)Subsequent therapy and number of patients who received therapy*Complete response (%)Partial response (%)Complete response (%)Partial response (%)Bortezomib or bortezomib combination (n=105)6331045Thalidomide combination (n=149)444352Lenalidomide Combination (n=37)452055* Other agents were used as subsequent therapy including dexamethasone; patients could receive multiple-agent regimens

Superior Outcomes Associated with Complete Response: Analysis of the Phase III VISTA Study of Bortezomib Plus Melphalan–Prednisone Versus Melphalan–Prednisone

Complete response (CR) has been shown to be prognostic for improved long-term outcomes, including progression-free survival and overall survival (OS), in previously untreated multiple myeloma (MM) patients receiving high-dose therapy and stem cell transplant (SCT; Harousseau et al, IMW 2007; van de Velde et al, Haematologica 2007). However, there is limited evidence of such a correlation in the non-transplant setting. In the large, international phase III VISTA study in previously untreated MM patients ineligible for SCT, bortezomib plus melphalan–prednisone (VMP) demonstrated superiority to MP across all efficacy end points, including response rates, time to progression (TTP), and OS. Here, we assess the differential prognostic impact of best response on time-to-event parameters in VISTA, and evaluate the impact of timing of CR on outcome in patients receiving VMP. A total of 682 patients (median age 71 years) were randomized to receive nine 6-week cycles of VMP (N=344; bortezomib 1.3 mg/m2, days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1–4, and days 1, 8, 22, 29, cycles 5–9, plus melphalan 9 mg/m2 and prednisone 60 mg/m2, days 1–4, cycles 1–9) or MP (N=338). The primary end point was TTP. Response and progression were determined using European Group for Blood and Marrow Transplantation (EBMT) criteria; in a post-hoc analysis, response was determined using International Myeloma Working Group (IMWG) uniform criteria. Associations between long-term outcomes and response were examined in the intent-to-treat population by multivariate Cox regression analysis with time-dependent covariates, adjusted for stratification factors (baseline β2-microglobulin and albumin; region), with age, sex, race, MM type, baseline Karnofsky Performance Status, and number of bone lesions as covariates. Among evaluable patients, response rates to VMP vs MP were 71% vs 35%, including 30% vs 4% CR, by EBMT criteria, and 74% vs 39%, including 33% vs 4% CR and 8% vs 4% VGPR, by IMWG criteria. Median TTP was 24.0 vs 16.6 months. CR by EBMT criteria was associated with significantly longer TTP (hazard ratio [HR] 0.45, p=0.004; Figure), time to next therapy (TNT; HR 0.44, p=0.014), and treatment-free interval (TFI; HR 0.37, p=0.004) vs PR, plus improved OS (medians not reached; clear separation between the curves; HR=0.59, p=0.265; statistical significance not seen likely due to a small number of deaths). Significant benefit was seen for CR and PR vs no response by EBMT criteria for all four parameters, including OS. Findings were similar for CR vs VGPR+PR vs no response by IMWG criteria. Importantly, CR was associated with significantly longer TTP (HR 0.45, p=0.019) and TFI (HR 0.39, p=0.026) vs VGPR, with a trend towards longer TNT (HR 0.54, p=0.126); no significant differences for these parameters were seen for VGPR vs PR. However, these findings should be interpreted with caution due to the small number of patients achieving VGPR. Among patients achieving CR (EBMT criteria) with VMP, there were no clear differences in clinical benefit associated with achieving CR early (cycles 1–4, within 24 weeks) vs later (cycle 5 onwards, after 24 weeks), although TTP and overall duration of response appeared slightly longer with later CRs, possibly due to the inherent slightly longer duration of therapy (mean 7.4 vs 8.5 cycles). In conclusion, this analysis demonstrates the prognostic significance of CR on long-term outcomes in the setting of non-intensive therapy. The data show that CR is associated with improved outcomes vs VGPR by IMWG criteria, and indicate that the clinical benefit of CR with VMP is similar regardless of time to achieve CR, supporting continuation of therapy to achieve maximal response. [Display omitted]