Melphalan, Prednisone And Thalidomide Research Articles

Cost-Effectiveness of Newly Emerging Regimens for Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Autologous Stem Cell Transplantation (ASCT) Compared with the Current Standards of Care in EU5

▪Background: Lenalidomide and low-dose dexamethasone (Rd)-based therapies are widely used in the USA, while both Rd and bortezomib, melphalan, and prednisone (VMP) are used in Europe as first-line treatments (Txs) for patients (pts) ineligible to receive ASCT (Moreau P, et al. Ann Oncol. 2017;28:52-61). Of these, only Rd has the advantage of being an oral therapy which stimulates the immune system, is non-stem cell toxic, and has demonstrated both progression-free survival (PFS) and overall survival (OS) advantages compared with melphalan, prednisone and thalidomide (MPT). Rd is generally well tolerated, enabling pts to benefit from continuous therapy in contrast to the fixed duration employed for VMP. Newer regimens, such as the quadruplet daratumumab (Dara) in combination with VMP, have shown improved PFS vs VMP in the ALCYONE study, however, are yet to demonstrate an OS benefit (Mateos MV, et al. N Engl J Med. 2018;378:518-28). No study has compared VMP + Dara with Rd. Although clinical considerations are important in Tx decisions, combination regimens involving newer agents tend to add costs and require demonstration of significant added value to be considered cost-effective, especially given their potential impact on health system budgets. This analysis assessed the cost-effectiveness of Rd vs VMP, and compared these regimens with VMP + Dara, as first-line therapy for NDMM pts ineligible for ASCT from the perspective of the national health services (NHSs) of EU5 countries.Methods: A partitioned survival model was developed to model PFS and OS over a lifetime horizon. PFS and OS parametric functions for Rd were derived using published real-world Kaplan-Meier curves. A network meta-analysis was conducted to derive hazard ratios (HRs) for Rd vs VMP + Dara and vs VMP. In the absence of OS data for VMP + Dara, any advantages in survival are unknown. For the purposes of this analysis, a conservative estimate of OS equivalency compared with Rd was used, yet a range of values are possible. Drug acquisition costs were sourced from national drug price databases. Resource utilization costs were sourced from UK NHS reference costs and converted to EU5 country costs using producer price indices published by OECD; an average of all EU5 country costs was used. EQ-5D utilities for pre- and post-progression disease states were taken from Ramsenthaler C, et al. BMC Cancer. 2016;16:427. Disutilities for regimens requiring subcutaneous injections and intravenous infusions were applied (Stopeck A, et al. J Med Econ. 2012;15:712-23).Results: The base case analysis produced a total number of 3.17, 2.23, and 3.12 quality-adjusted life years (QALYs) for Rd, VMP, and VMP + Dara, respectively. The incremental cost-effectiveness ratio (ICER) for Rd vs VMP was EUR 43,030/QALY, indicating that Rd is cost-effective vs VMP at a willingness-to-pay threshold of EUR 50,000/QALY. Rd dominates VMP + Dara, having a greater gain in QALYs at lower cost. The ICER for VMP + Dara vs VMP was EUR 202,903, well above any acceptable cost-effectiveness threshold in Europe.Discussion: Achieving durable remission while minimizing toxicities in first-line Tx is an important Tx goal, as it has a bearing on the subsequent Tx journey both from an outcome and cost perspective. Individual country pharmacoeconomic assessments have shown Rd is cost-effective vs VMP (SMC No 1096/15, 2015; AWMSG advice 2116, July 2016; Usmani SZ, et al. J Med Econ. 2016;19:243-58), and a recent cost impact analysis suggested substantial cost savings with Rd use relative to VMP + Dara at first-line Tx (Jackson G, et al. HemaSphere 2018;2:PS1429). Limited clinical data and experience with VMP + Dara mean that estimates of long-term clinical outcomes (e.g. OS) associated with this regimen and costs of managing adverse events are not fully known and may not accurately reflect outcomes in clinical practice. In contrast, PFS and OS benefits for Rd vs MPT have been demonstrated (Facon T, et. al Blood. 2018;131:301-10), and an indirect Tx comparison reported statistically significant PFS and OS benefits for Rd vs VMP (Weisel K, et al. Leuk Lymphoma. 2017;58:153-61). As additional regimens are evaluated to assess clinical benefits over current standards of care, cost-effectiveness analyses are warranted to help define their place in the management of NDMM. For example, it may be interesting to compare Rd and Rd-based triplet regimens with VMP + Dara once relevant clinical data become available. DisclosuresAshcroft:Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria; Amaris Medical: Consultancy, Honoraria. Shephard:Celgene: Consultancy; Amaris Consulting: Employment. Elnoursi:Celgene: Consultancy; Amaris Consulting: Employment. Pelligra:Evidera: Employment. Dhanasiri:Celgene International: Employment, Equity Ownership.

Response of oral Melphalan, Prednisone and Thalidomide (MPT) on symptomatic multiple myeloma patients who are non-transplant candidates

Background: Oral melphalan, prednisone and Thalidomide (MPT) has been tested and proved efficacy in multiple myeloma (MM). But, no data are available on the response rate and adverse effect of oral MPT in diagnosed symptomatic MM patients who are non-transplant candidates in our population and ethnic diversity. Here, we evaluated response rate and adverse effects of MPT.Methods: 16 diagnosed symptomatic MM patients (age range 45-75 years) received MPT (Melphalan 4 mg/m2 divided dose and Prednisone 40 mg/m2 once daily for 7 days every month plus Thalidomide 100 mg/day at night continuously) from January 2010 to December 2011 at department of Hematology, Dhaka medical college and hospital, Dhaka. After 3 courses of MPT, 2 patients had no improvement, so changed to another protocol. Rest 14 patients had completed 6 cycles of MPT and evaluated for both response rate and toxicity.Results: The overall response rate (ORR) was 87.5% (n=14); complete response (CR) rate 50% (n=8), partial response (PR) rate 31.25% (n=5), minimal response (MR) rate 6.25% (n=1) and no response (NR) was 12.50% (n=2) of patients. During MPT therapy, MM patients noticed abdominal discomfort in 31.11% (n=14), insomnia in 17.78% (n=8), constipation in 13.33% (n=6), numbness/ peripheral neuropathy in 13.33% (n=6) and developed infection in 6.67% (n=3) and hyperglycaemia in 4.44% (n=2) of patients. Life threatening complications like DVT were absent. Almost all adverse effects were mild, reversible grade 1/2 toxicity and mostly developed within first cycle of MPT. Treatment related mortality was absent.Conclusions: It clearly reveals MPT induces increase response rate with low cost and minimal side effects which might bring hope to the poor patients of our country.J Dhaka Medical College, Vol. 25, No.1, April, 2016, Page 61-66

Final Survival Analysis From the FIRST Trial: Lenalidomide Plus Low-Dose Dexamethasone Until Progression (Rd Cont) v Melphalan, Prednisone and Thalidomide (MPT), and Rd for 18 Cycles (Rd18) for Transplant-Ineligible (TNE) Patients (Pts) With Newly Diagnosed Multiple Myeloma

Final Survival Analysis From the FIRST Trial: Lenalidomide Plus Low-Dose Dexamethasone Until Progression (Rd Cont) v Melphalan, Prednisone and Thalidomide (MPT), and Rd for 18 Cycles (Rd18) for Transplant-Ineligible (TNE) Patients (Pts) With Newly Diagnosed Multiple Myeloma

E1A06: A phase III trial comparing melphalan, prednisone, and thalidomide (MPT) versus melphalan, prednisone, and lenalidomide (MPR) in newly diagnosed multiple myeloma (MM).

8511 Background: Melphalan, prednisone and thalidomide (MPT) is an accepted regimen in newly diagnosed MM. Early studies suggested that lenalidomide (R) might be substituted for thalidomide (T) wit...

Efficacy of Lenalidomide in Patients with Multiple Myeloma Previously Treated by Melphalan-Prednisone and Thalidomide

AbstractAbstract 4075 Introduction.The association of Melphalan-Prednisone and Thalidomide (MPT) is approved as first-line treatment in elderly patients with Multiple Myeloma (MM). This treatment demonstrated significant benefit in terms of overall survival (OS) and Progression Free Survival (PFS) as opposed to MP alone. Lenalidomide (Len), used in combination with Dexamethasone (Len/Dex), is recommended to treat patients with relapsed MM who received a prior therapy. Len is an oral immunomodulator similar to Thalidomide (T). Both these drugs have identical activity but their safety profiles are different. So, in case of successive use of MPT and Len/Dex, it is legitimate to think that the efficacy of Len is affected by the previous use of T, probably because of the resistance to Len developed by relapsed or refractory patients. Therefore, we carried out a retrospective, multicentric study in order to assess the efficacy and safety of Len in patients with relapsed MM previously treated by MPT. Method.Our survey included 64 elderly patients with symptomatic MM from three French hematology centers. All the patients showed a relapsed MM treated with first-line treatment of MPT. Len was administered at first or second relapse. The main objective was to assess the efficacy of Len in terms of response rate, OS and PFS. Another objective was to evaluate the tolerance to Len and MPT treatments and to identify the predictive factors of efficacy of Len like the response rate, the duration of remission after MPT treatment and the line number of treatment before using Len. Results.The median age of patients at diagnosis was 73.5 years old and the sex ratio was 1. The M-protein was IgG for 64% of patients, IgA for 20%, light chains for 14% and IgD for 2%. Concerning the International Staging System, 35% of patients were stage I, 28% were stage II and 37% were stage III. MPT was administered with a 100mg/d thalidomide dose to 83% of patients. The median duration of T treatment was 13 months [range: 0.1 – 29.5]. The overall response rate (ORR) was 90% with 53% of partial response (PR), 27.5% of very good partial response (VGPR) and 9.5% of complete response (CR). Five patients stopped T because of progression on therapy, 36 because of toxicity out of which 26 because of peripheral neuropathy and 2 thromboembolic events. The median response duration after MPT was 25.5 months. Len was administered at first relapse to 47 patients (73.5%) and at second relapse for the others (n=17). The second-line treatment for these 17 patients was bortezomib-based regimen treatment. The daily dose of Len was 15 to 25 mg, always associated with low dose of Dex, for 83% of patients. Ten cycles of Len/Dex were administered on average. For 23/64 patients, the Len/Dex treatment is going on, 21/41 patients stopped because of progression and 17/41 because of toxicity (hematologic toxicity: 8/17, thromboembolic events: 2/17, general and gastrointestinal disorder: 7/17). The Len ORR was 78% (CR: 3.5%, VGPR: 27.5%, PR: 47%). The median SSP after initiation of Len is 12.8 months. The median OS after initiation of Len is 43 months and the OS rate is 58% at 3 years. Since the diagnosis, No predictive factor has a significant impact on the efficacy of Len. No second primary malignancies were reported. Conclusion.Our study shows that the efficacy and safety of Len is satisfactory, even after a Thalidomide treatment. The ORR and median PFS are similar to published data. There is no increase of toxicity for patients on Len, especially concerning thromboembolic events.With the development of new drugs like Carfilzomib, Pomalidomide and Eculizumab, the perspective of treatment increased as well as the number of lines. The choice of therapeutic sequences must be taken into account. In this study, we show that the MPT – Len/Dex sequence is effective and safe for elderly MM patients. Disclosures:Roussel:celgene: Honoraria; janssen: Honoraria. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees. Leleu:celgene: Honoraria; janssen: Honoraria. Facon:onyx: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Hulin:celgene: Honoraria; janssen: Honoraria.

Phase II study of melphalan, thalidomide and prednisone combined with oral panobinostat in patients with relapsed/refractory multiple myeloma

The combination of melphalan, prednisone and thalidomide (MPT) has demonstrated efficacy and acceptable toxicity in newly diagnosed and relapsed/refractory patients with multiple myeloma (MM). Panobinostat is a potent oral pan-deacetylase inhibitor (pan-DACi). In preclinical and clinical studies, panobinostat showed good anti-myeloma activity in combination with several agents. This phase II study evaluated the combination of a fixed dose of MPT with escalating doses of panobinostat (three times weekly for 3 weeks, followed by a 9-day rest period) in relapsed/refractory MM. We used a two-stage design to determine whether the combination was safe and effective. At least a partial response was observed in 38.5% of patients. The maximum tolerated dose of panobinostat in combination with MPT could not be determined due to the high rate of dose-limiting toxicities experienced with panobinostat at doses of 10 and 15 mg. The most common grade 3/4 adverse events were neutropenia (71%) and thrombocytopenia (35.5%). In conclusion, MPT in combination with panobinostat three times weekly for 3 weeks followed by a 9-day rest period is not well tolerated in patients with relapsed/refractory MM. Future studies should evaluate alternative dose schedules of panobinostat.

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.

Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma

AbstractIn this double-blind, placebo-controlled study, 363 patients with untreated multiple myeloma were randomized to receive either melphalan-prednisone and thalidomide (MPT) or melphalan-prednisone and placebo (MP). The dose of melphalan was 0.25 mg/kg and prednisone was 100 mg given daily for 4 days every 6 weeks until plateau phase. The dose of thalidomide/placebo was escalated to 400 mg daily until plateau phase and thereafter reduced to 200 mg daily until progression. A total of 357 patients were analyzed. Partial response was 34% and 33%, and very good partial response or better was 23% and 7% in the MPT and MP arms, respectively (P < .001). There was no significant difference in progression-free or overall survival, with median survival being 29 months in the MPT arm and 32 months in the MP arm. Most quality of life outcomes improved equally in both arms, apart from constipation, which was markedly increased in the MPT arm. Constipation, neuropathy, nonneuropathy neurologic toxicity, and skin reactions were significantly more frequent in the MPT arm. The number of thromboembolic events was equal in the 2 treatment arms. In conclusion, MPT had a significant antimyeloma effect, but this did not translate into improved survival. This trial was registered at www.clinicaltrials.gov as #NCT00218855.

ASH 2009 meeting report—Top 10 clinically oriented abstracts in multiple myeloma

ASH 2009 meeting report—Top 10 clinically oriented abstracts in multiple myeloma

A combination of bortezomib plus melphalan, prednisone and thalidomide (MPT) is effective for the treatment of relapsed or refractory, advanced multiple myeloma

A combination of bortezomib plus melphalan, prednisone and thalidomide (MPT) is effective for the treatment of relapsed or refractory, advanced multiple myeloma

Oral Melphalan, Prednisone and Thalidomide for Multiple Myeloma.

In newly diagnosed multiple myeloma (MM) patients, the combination melphalan, prednisone and thalidomide (MPT) induces a fast tumor response with a high response rate, but evidence that this translate into improved outcome is limited. This multicenter trial compared the efficacy and the toxicity of oral MPT with oral melphalan and prednisone (MP) in previously untreated patients. From January 2002 to December 2004, we randomised 255 patients, who were older than 65 years of age (median age 72). Data analysis was performed on July 2005. The MPT regimen included oral melphalan (4 mg/m2 for 7 days) and prednisone (40 mg/m2 7 days) for six four week cycles plus thalidomide (100 mg per day continuously until any sign of relapse or progressive disease) The MP regimen was as MPT without thalidomide. Patients who were not assigned to receive thalidomide were permitted to cross over to receive thalidomide after relapse or disease progression. Patients treated with MPT experienced higher response rates and a longer time to progression (primary end points) than patients who did not receive thalidomide. The overall response rate was 76% for MPT and 48% for MP alone (P<0.0001), and the near complete response rates were 28% and 7%, respectively (P<0.0001). Median progression free survival in the MPT and in the MP groups was 33 months and 14 months, respectively (hazard ratio, 0.47; P<0.001). MPT increase median progression free survival by almost 19 months. The 2-yr survival rate was 82% in MPT patients and 65% in MP patients (hazard ratio, 0.68; P=0.2). In MPT group, 33 patients did not complete the 6 courses because of progression disease (9), toxicity (16), death (2), and withdrawal of consent or lost to follow-up (6). In MP group, 32 patients did not complete the 6 courses because of progression disease (19), toxicity (3), death (3), and withdrawal of consent or lost to follow-up (7). By looking at those patients who completed the assigned 6 cycles in both arms, the 2-yr survival rate was 90% in MPT patients and 71% in MP patients, the difference was statistically significant (hazard ratio, 0.39; P<0.01). Grade 3 or 4 adverse events were reported in 49% of patients treated with MPT and in 25% of those treated with MP: they included thromboembolism (12% versus 2% of patients), infections (10% versus 1%), peripheral neuropathy (10% versus 1%), and hematologic toxicity (22% versus 25%) respectively. In the first 64 patients who received MPT, grade 3–4 adverse events were reported in 58% of patients. In the last 65 MPT patients, the incidence of grade 3–4 adverse events was 40%. By comparing the first cohort with the second one, thromboembolism dropped from 22% to 3% (P<0.01) and neurotoxicity from 13% to 8% (P=NS), respectively. The oral MPT was superior to the standard MP in patients with newly diagnosed myeloma. The adequate mangement of side effects reduced toxicity.

Oral melphalan, prednisone and thalidomide for newly diagnosed myeloma patients

6549 Background: Thalidomide (T) alone or in combination has been tested and proved effective in multiple myeloma. No data are available on the association of T with oral Melphalan and Prednisone (MP) in newly diagnosed patients. Here, we evaluated the potential additive and synergistic effect of the combination Melphalan, Prednisone and Thalidomide (MPT) Methods: Between June 2002 and June 2003, 42 patients (median age 72, range 61–80) with newly diagnosed symptomatic multiple myeloma received 6 courses of MP (melphalan 4 mg/sqm and prednisone 40 mg/sqm for 7 days every month) plus T 100 mg/day continuously until any sign of disease progression or relapse. The dose of T was reduced to 50% when grade 2 WHO toxicity occurred, and suspended for any grade 3. All patients have completed the 6 assigned MP courses and were evaluated for both toxicity and response rate. Results: T increased the hematologic toxicity induced by MP: grade 3–4 WHO neutropenia was observed in 14% of patients. Constipation occurred in 28% of patients. Neurological toxicity was recorded in 38% of patients. The major acute adverse events were infections (26%) and deep-vein thrombosis (19%). One patient died for septicemia, and one for pulmonary thromboembolism. T discontinuation was required in 36% of patients (thromboembolic event, infection, costipation, hematologic toxicity). After treatment, partial responses (myeloma protein reduction >50%) were observed in 93% of patients, no responses (myeloma protein reduction <50%) in 7%. Complete remissions (disappearance of monoclonal protein and negative immunofixation) were 26%, near complete remissions (disappearance of monoclonal protein and positive immunofixation) were 19%, responses with myeloma protein reduction 90–99% were 12%. Time required to obtain the maximum response was 4 months in 88% of patients. Conclusions: The incidence of infections and deep-vein thrombosis was high, suggesting the need for antibiotic and anticoagulant prophylaxis. MPT induced a response rate significantly higher in comparison with any other conventional chemotherapy program. The CR rate was similar to those observed after transplant. No significant financial relationships to disclose.

Oral melphalan, prednisone and thalidomide for newly diagnosed myeloma patients

6549 Background: Thalidomide (T) alone or in combination has been tested and proved effective in multiple myeloma. No data are available on the association of T with oral Melphalan and Prednisone (MP) in newly diagnosed patients. Here, we evaluated the potential additive and synergistic effect of the combination Melphalan, Prednisone and Thalidomide (MPT) Methods: Between June 2002 and June 2003, 42 patients (median age 72, range 61–80) with newly diagnosed symptomatic multiple myeloma received 6 courses of MP (melphalan 4 mg/sqm and prednisone 40 mg/sqm for 7 days every month) plus T 100 mg/day continuously until any sign of disease progression or relapse. The dose of T was reduced to 50% when grade 2 WHO toxicity occurred, and suspended for any grade 3. All patients have completed the 6 assigned MP courses and were evaluated for both toxicity and response rate. Results: T increased the hematologic toxicity induced by MP: grade 3–4 WHO neutropenia was observed in 14% of patients. Constipation occurred in 28% of patients. Neurological toxicity was recorded in 38% of patients. The major acute adverse events were infections (26%) and deep-vein thrombosis (19%). One patient died for septicemia, and one for pulmonary thromboembolism. T discontinuation was required in 36% of patients (thromboembolic event, infection, costipation, hematologic toxicity). After treatment, partial responses (myeloma protein reduction >50%) were observed in 93% of patients, no responses (myeloma protein reduction <50%) in 7%. Complete remissions (disappearance of monoclonal protein and negative immunofixation) were 26%, near complete remissions (disappearance of monoclonal protein and positive immunofixation) were 19%, responses with myeloma protein reduction 90–99% were 12%. Time required to obtain the maximum response was 4 months in 88% of patients. Conclusions: The incidence of infections and deep-vein thrombosis was high, suggesting the need for antibiotic and anticoagulant prophylaxis. MPT induced a response rate significantly higher in comparison with any other conventional chemotherapy program. The CR rate was similar to those observed after transplant. No significant financial relationships to disclose.