Melphalan-prednisone-lenalidomide Research Articles

Morbid Progression Is Common Among Patients with Multiple Myeloma and Is Associated with Shortened Overall Survival: Validation of the Progression-Free Survival Endpoint

INTRODUCTIONThe validity of progression-free survival (PFS) as a clinical endpoint in multiple myeloma (MM) has been debated, largely based on the potential association between PFS and overall survival (OS). However, MM progression can cause morbid end-organ damage. Bone lesions (B) and renal dysfunction (R) may be irreversible, while progressive anemia (A) and hypercalcemia (C), though reversible, can cause severe symptoms, and all are sources of both morbidity and mortality. There is limited research on the rates of progression or on the OS implications associated with morbid progression events compared with asymptomatic biochemical progression. We therefore aimed to characterize the presence of CRAB symptoms at the time of progression and to examine the associations between morbid relapses and OS in 2 large, randomized clinical trials in transplant-ineligible elderly patients (pts) with MM that relapsed after initial therapy.METHODSThis analysis used pooled data from the phase 3, randomized MM-020 and MM-015 trials of pts with newly diagnosed MM (NDMM) aged ≥ 65 years and included pts who progressed on study. Treatment arms in MM-020 were lenalidomide-dexamethasone (Rd) until progressive disease (PD), Rd for 18 cycles, and melphalan-prednisone-thalidomide, and in MM-015 were melphalan-prednisone, melphalan-prednisone-lenalidomide (MPR), and MPR followed by lenalidomide maintenance. CRAB (Calcium > 11.5 mg/dL, Renal insufficiency: creatinine > 2 mg/dL or creatinine clearance [CrCl] decrease by 10 mL/min, Anemia: hemoglobin < 10 g/dL, and Bone lesions) criteria were analyzed within 1 month before or after PD, defined as an increase of 25% from the lowest response value in ≥ 1 of the following: serum M protein, urine M protein, free light chain levels, or bone marrow plasma cell percentage. Pts with PD and meeting ≥ 1 CRAB criterion were considered to have morbid PD; all other pts with PD were categorized as asymptomatic. Demographic and baseline characteristics are reported by relapse group (morbid PD vs asymptomatic PD). The association between morbid PD and PFS from the time of progression (PFS2) as well as OS was examined using an adjusted Cox regression analysis adjusted for baseline pt characteristics, including age, gender, International Staging System (ISS) stage, creatinine, randomized treatment, and anemia. Other covariates were assessed in the window of 1 cycle before or after PD. PFS2 and OS were measured from time of PD. Multivariable Cox regression models estimated the association between morbid PD and PFS and OS. Direct adjusted survival curves based on these models were used to estimate median OS and PFS.RESULTSOf the 2082 pts in the pooled intent-to-treat population of MM-020 (N = 1623) and MM-015 (N = 459), 1243 pts (60%) had PD in first-line treatment for NDMM. At the time of first progression 543 pts (44%) were considered to have morbid (≥ 1 CRAB criterion) PD and 700 pts (56%) had asymptomatic PD. Of the pts with morbid PD, 12 (2%) had hypercalcemia, 271 (50%) had elevated creatinine, 370 (68%) developed anemia, and 79 (15%) developed new bone lesions. Baseline pt characteristics were generally similar between the morbid and asymptomatic PD groups, with a median age of 74.0 yrs for both groups; 51% vs 53% were male and 41% vs 37% had ISS stage III disease, respectively. Hemoglobin < 10 g/dL was less common in the morbid PD group (50% vs 80%), whereas CrCl < 60 mL/min and lactic dehydrogenase > 200 U/L were more frequent in the pts with morbid vs asymptomatic PD (40% vs 26% and 20% vs 13%, respectively).After adjustment for baseline characteristics, median PFS2 was 11.5 vs 20.0 mos in pts with morbid vs asymptomatic PD (HR = 1.56 [95% CI, 1.37-1.79]; P < .0001). Median OS was 23.2 mos in pts with morbid PD and 39.3 mos in pts with asymptomatic PD (HR = 1.51 [95% CI, 1.30-1.76]; P < .0001; Figure).CONCLUSIONSIn this retrospective analysis of 2 large, randomized controlled trials, morbid PD was common, accounting for over 40% of progression events. Moreover, potentially irreversible events, worsening renal function and new bone lesions, occurred in 22% and 15% of pts, respectively. Finally, morbid progression was associated with shortened PFS2 and OS. Additional multivariate analyses examining the relationship between other prognostic factors (including cytogenetics and FISH) and morbid PD are ongoing. [Display omitted] DisclosuresRosenberg:Amgen: Speakers Bureau. Facon:Amgen, Celgene: Speakers Bureau. Abouzaid:Celgene Corporation: Employment, Equity Ownership, Research Funding. Srinivasan:Celgene: Employment. Chung:Celgene Corporation: Employment, Equity Ownership. Parikh:Celgene Corporation: Employment. Tuscano:Takeda: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis Pharmaceuticals: Honoraria, Research Funding.

Impact of Bortezomib- or Lenalidomide-Based Induction Treatment on High Risk Cytogenetic Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Enrolled in the Gimema-MM-03-05 and EMN01 Trials

▪Introduction : Cytogenetic abnormalities by fluorescence in situ hybridization (FISH) are clinically relevant prognostic factors in MM. Data in transplant ineligible patients treated with bortezomib or lenalidomide in first-line therapy for high-risk (HiR) patients is limited. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. This sub-analysis evaluates the impact of cytogenetics on outcomes in transplant-ineligible patients with newly diagnosed MM (NDMM) treated with bortezomib-based induction (BORT) or lenalidomide-based (LEN) treatment.Methods : In the GIMEMA-MM-03-05-trial, patients were randomized to bortezomib-melphalan-prednisone-thalidomide for 9 cycles followed by maintenance with bortezomib-thalidomide (VMPT-VT) vs VMP for 9 cycles, without maintenance. In the EMN01-trial, patients were randomized to melphalan-prednisone-lenalidomide (MPR) or cyclophosphamide-prednisone-lenalidomide (CPR) or lenalidomide plus low-dose dexamethasone (Rd) for 9 cycles, followed by maintenance with lenalidomide alone or plus prednisone continuously. Results of these studies have previously been reported (Palumbo A et al JCO 2010 and 2014; Magarotto V et al Blood 2016 127(9)).Cytogenetics were assessed using FISH. Patients were categorized into cytogenetic risk groups according to International Myeloma Working Group criteria. HiR cytogenetics included del(17p), t(4;14), and t(14;16); all other patients were categorized as standard risk (StR).Subgroup analyses were performed to determine the consistency of treatment effects of BOR vs LEN in the different subgroups using interaction terms between treatment and FISH, ISS, age, sex, Karnofsky PS and LDH. The different effect of BORT vs LEN in cytogenetic subgroups was confirmed by one sensitivity analysis where the follow-up of the BORT study was reduced to make the follow-up times similar; and by another sensitivity analysis with multiple imputation method for missing cytogenetic value.Results : 902 of 1165 patients from the intent-to-treat population had available cytogenetic profiles, with 243 (27%) patients in the HiR group and 659 (73%) in the StR group. In the BORT vs LEN groups, median age was 71 vs 73 years (p<0.001), ISS3 20% vs 27% (P=0.65), HiR patients were 29% vs 26%, StR patients were 71% vs 74% (p=0.32) and the median follow-up was 72.3 and 63.6 months, respectively.In the subgroup analysis, a significant difference was found in the cytogenetic subgroup with a superior advantage of BORT versus LEN in HiR group, whereas no significant difference was found between BORT and LEN in the other subgroups analyzed (ISS, age, sex, Karnofsky PS and LDH) (interaction-p=0.01) (Fig. 1 B).BORT treatment resulted in a reduced risk of death or progression compared with LEN in patients with HiR. In HiR patients, median PFS was 30.8 with BORT compared with 14.8 months with LEN (HR: 0.54; 95% CI: 0.41-0.72); in StR, median PFS was 29.1 with BORT compared with 22.1 months with LEN (HR: 0.87; 95%; CI: 0.72-1.05) (Fig. 1 A).Considering the standard of care VMP and Rd, in the HiR group (n=95) VMP resulted in a 48% reduced risk of death or progression compared with Rd (HR: 0.53; 95% CI: 0.34-0.83), whereas no significant difference in PFS was found in the StR group (n=273) (HR: 1.00; 95% CI: 0.75-1.33), interaction-p=0.02.BORT treatment resulted in a reduced risk of death in patients with HiR cytogenetics: median OS was 62.4 months with BORT compared with 43.2 months with LEN (HR: 0.68; 95% CI: 0.47-0.96); in StR, median OS was 78.1 months with BORT and was not reached with LEN (HR: 1.06; 95% CI: 0.82-1.36), interaction-p=0.04 (Fig. 1 A).In patients with del(17p) (n=131) median PFS was 18.0 vs 12.9 months for BORT vs LEN (HR: 0.71; 95% CI: 0.49-1.04), interaction-p=0.73. In patients with t(4;14) (n=118) median PFS was 31.5 vs 15.2 months for BORT vs LEN (HR: 0.41; 95% CI: 0.27-0.62) interaction-p=0.002. In patients with t(14;16) (n=31) median PFS was 36.2 vs 9.8 months for BORT vs LEN treated patients (HR: 0.34; 95% CI: 0.16-0.76), interaction-p=0.045.Conclusions : BORT treatment resulted in a PFS and OS benefit vs LEN in patients with HiR cytogenetics. Treatment with VMP led to a significant reduction of the risk of death or progression vs Rd in HiR patients. These results support VMP induction as a standard treatment option for patients with NDMM who are ineligible for transplant with HiR cytogenetics. [Display omitted] DisclosuresLarocca:Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Offidani:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto:Janssen: Honoraria; Celgene: Honoraria. Patriarca:MSD Italia: Honoraria; Janssen: Honoraria. Corradini:Gilead: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Bosi:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Petrucci:Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding; AbbVie: Honoraria.

Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma

AbstractLenalidomide-dexamethasone improved outcome in newly diagnosed elderly multiple myeloma patients. We randomly assigned 662 patients who were age ≥65 years or transplantation-ineligible to receive induction with melphalan-prednisone-lenalidomide (MPR) or cyclophosphamide-prednisone-lenalidomide (CPR) or lenalidomide plus low-dose dexamethasone (Rd). The primary end point was progression-free survival (PFS) in triplet (MPR and CPR) vs doublet (Rd) lenalidomide-containing regimens. After a median follow-up of 39 months, the median PFS was 22 months for the triplet combinations and 21 months for the doublet (P = .284). The median overall survival (OS) was not reached in either arms, and the 4-year OS was 67% for the triplet and 58% for the doublet arms (P = .709). By considering the 3 treatment arms separately, no difference in outcome was detected among MPR, CPR, and Rd. The most common grade ≥3 toxicity was neutropenia: 64% in MPR, 29% in CPR, and 25% in Rd patients (P < .0001). Grade ≥3 nonhematologic toxicities were similar among arms and were mainly infections (6.5% to 11%), constitutional (3.5% to 9.5%), and cardiac (4.5% to 6%), with no difference among the arms. In conclusion, in the overall population, the alkylator-containing triplets MPR and CPR were not superior to the alkylator-free doublet Rd, which was associated with lower toxicity. This study was registered at www.clinicaltrials.gov as #NCT01093196.

Anti-CD19 Chimeric Antigen Receptor-Modified T Cells for Multiple Myeloma

Multiple myeloma is a disease formed by malignant plasma cells that accumulate in the bone marrow. The lifetime risk of multiple myeloma in the U.S. is 1/140, making it the second most common hematologic malignancy and it was expected that 22,350 new cases to be diagnosed in the US in 2013 [1]. In the past decade, we have witnessed dramatic changes in the treatment of multiple myeloma. Proteasome inhibitors such as bortezomib and carfilzomib target the ubiquitin pathway, resulting in cytotoxic injury due to disruption of protein degradation in myeloma cells. When compared with melphalan–prednisone–lenalidomide (MPR), combine therapy with high-dose melphalan and stem-cell transplantation significantly prolonged progression-free survival among patients with multiple myeloma who were in the age group of 65 years or younger [2]. Discovery of anti-tumor efficacy of the graft vs. myeloma response, such as CAR T cell therapy seems likely to herald the beginning of a revolution in the treatment of multiple myeloma. Several observations have fostered optimism that more specific immunotherapeutic approach such as chimeric antigen receptors (CARs) modified autologous T cells might exhibit more potent anti-myeloma activity with less toxicity. Currently all ongoing CAR studies employ firstgeneration anti-CD19 CAR and a second-generation version, usually with CD28. In pre-clinical studies, anti-myeloma second-generation CARs are developed to target the Lewis Y antigen (Ley), B Cell Maturation Antigen (BCMA), cell surface glycoprotein CS1 and CD38. Ley is overexpressed in many epithelial malignancies. In a recent study, multiple myeloma cell lines were injected into a immunocompromised mice followed by the injection of anti-Ley CAR T cells that significantly exhibited prolonged survival and delayed development of symptomatic plasmacytomas [3]. The National Cancer Institute (NCI) has recently identified BCMA which is expressed on most multiple myeloma cells. Anti-BCMA CAR is a second-generation CD28-based CAR that showed quite favourable efficacy and toxicity profiles against multiple myeloma [4]. CS1 is over-expressed in multiple myeloma cells. The CD28-based anti-CS1 CAR-modified natural killer (NK) cells revealed cytotoxicity against multiple myeloma cell lines and prolonged survival in patients with multiple myeloma [5]. CD38 is a transmembrane glycoprotein and a second-generation 4-1BB-based anti-CD38 CAR was proved to be effective against multiple myeloma cell lines [6]. In a phase I/II study, anti-CD38 antibody daratumumab showed a remarkable efficacy for the treatment of patients with multiple myeloma [7]. The most clinical experience so far has been with anti-CD19 CARs that have been utilized in several phase I trials targeting B cell malignancies. Genetically engineered CARs that couple with an anti-CD19 single chain Fv domain to intracellular T-cell signalling domains of the T-cell receptor transmit cytotoxic T lymphocytes to antigen expressing cells. CAR–mediated T-cell responses can further be enhanced with the addition of a costimulatory domain. CD3 zeta domain has been used in CARmodified T cells that lead to the activation of T-cell signal and it has been referred as a first generation CAR. In recent competitive repopulation studies, CAR designs have been executed based on the addition of a single (second generation) or multiple co-stimulatory domains (third generation) [8]. In preclinical models, it has been found that antitumor activity and in vivo persistence of chimeric antigen receptors significantly increase with the inclusion of CD137 (4-1BB) signalling domain as compared with the inclusion of CD3-zeta chain alone [9]. CTL019 is a chimeric antigen receptor that includes a CD137 (4-1BB) signalling domain and is expressed with the use of lentiviral-vector technology for gene transfer and permanent T cell modification.

Significant Survival Improvement with Maintenance in Patients Achieving a Complete Response: Pooled Analysis of 4 Italian Phase III Trials in Newly Diagnosed Multiple Myeloma Patients

Introduction Several trials have shown that maintenance therapy prolongs progression-free survival (PFS) in multiple myeloma (MM) patients, eligible and ineligible for autologous stem cell transplantation (ASCT); conflicting data exist about its impact on overall survival (OS). The role of maintenance in patients with a sensitive disease is still unclear. We conducted a retrospective pooled analysis to clarify the impact of continuous treatment in patients achieving a complete response (CR).Methods Data from newly diagnosed MM patientsenrolled in 4 phase III trials were analysed. Two trials included ASCT-eligible patients: RV-MM-209 [melphalan-prednisone-lenalidomide (MPR) vs melphalan 200 mg/m2 (Mel200), followed by lenalidomide maintenance vs no maintenance), RV-MM-EMN-441 (cyclophosphamide-lenalidomide-dexamethasone vs Mel200, followed by lenalidomide vs lenalidomide-prednisone maintenance). Two studies enrolled elderly, ASCT-ineligible patients: GIMEMA-MM0305 (bortezomib-melphalan-prednisone-thalidomide followed by bortezomib-thalidomide vs bortezomib-melphalan-prednisone) and EMN01 (MPR vs cyclophosphamide-prednisone-lenalidomide vs lenalidomide-dexamethasone, followed by lenalidomide vs lenalidomide-prednisone maintenance). The primary endpoint of the study was to evaluate the impact of maintenance on PFS and OS in patients who achieved CR. Univariate analyses of OS and PFS were performed. Response was considered as a time-dependent variable with a landmark point at 12 months. Lastly, a multivariate analysis was performed to evaluate the impact of maintenance and ASCT as independent variables.Results A total of 1964 patients were retrospectively analysed. Of 1503 patients who received maintenance therapy, 254 achieved a CR and 931 a very good partial response (VGPR) or partial response (PR). After a median follow-up of 41 months, a significant 5-year OS (80% vs 54%; HR 0.55, p=0.02; Figure 1) and 5-year PFS (52% vs 19%; HR 0.47, p<0.001; Figure 2) advantage was reported among CR patients who received maintenance in comparison with no maintenance.The same analysis was conducted in patients achieving a suboptimal response (VGPR or PR): the 5-year PFS advantage was confirmed in patients who received maintenance vs patients who did not (30% vs 13% HR 0.65, p<0.001); the 5-year OS was 68% vs 38% in patients who received maintenance vs no maintenance respectively (HR 0.8, p=0.2).A subgroup analysis was conducted in CR patients according to the treatment received [ASCT vs conventional chemotherapy (CC)]; the PFS benefit among patients treated with maintenance was confirmed across both the subgroups (ASCT group: HR 0.45, p=0.02; CC group: HR 0.45 P<0.001).In multivariate analysis, maintenance therapy and treatment with ASCT confirmed the favourable impact on PFS and OS in patients achieving CR.Conclusion In CR patients,maintenance therapy significantly prolongs PFS and OS. In order to optimize treatment efficacy and to prolong survival in patients with a sensitive disease, the intensification with maintenance is strongly recommended. [Display omitted] [Display omitted] DisclosuresOff Label Use: Use off-label of drugs for the dose and/or schedule and/or association. Gay:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gaidano:Novartis: Honoraria, Other: Advisory boards; Celgene: Research Funding; Karyopharm: Honoraria, Other: Advisory boards; Roche: Honoraria, Other: Advisory boards; Morphosys: Honoraria, Other: Advisory boards; GlaxoSmithKline: Honoraria, Other: Advisory boards; Amgen: Honoraria, Other: Advisory boards; Janssen: Honoraria, Other: Advisory boards. Offidani:Janssen-Cilag, Celgene, Sanofi, Amgen, Mundipharma: Honoraria. Patriarca:Janssen-Cilag, Celgene, Merck Sharp & Dohme: Honoraria. Di Raimondo:Janssen-Cilag, Celgene: Honoraria. Hájek:Janssen-Cilag: Honoraria; Celgene, Merck Sharp & Dohme: Consultancy, Honoraria. Boccadoro:Sanofi: 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; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria.

Immunoglobulin light chain amyloidosis: 2014 update on diagnosis, prognosis, and treatment.

Immunoglobulin light chain amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light chain are deposited in tissues. Clinical features depend on organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, peripheral/autonomic neuropathy, and atypical multiple myeloma. Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow biopsy or subcutaneous fat aspirate in 85% of patients. Verification that amyloid is composed of immunoglobulin light chains is mandatory. N-terminal pro-brain natriuretic peptide (NT-proBNP), serum troponin T, and difference between involved and uninvolved immunoglobulin free light chain values are used to classify patients into four groups of similar size; median survivals are 94.1, 40.3, 14.0, and 5.8 months. All patients with a systemic amyloid syndrome require therapy to prevent deposition of amyloid in other organs and prevent progressive organ failure of involved sites. Stem cell transplant (SCT) is preferred, but only 20% of patients are eligible. Requirements for safe SCT include NT-proBNP <5,000 ng/mL, troponin T <0.06 ng/mL, age <70 years, <3 organs involved, and serum creatinine ≤1.7 mg/dL. Nontransplant candidates can be offered melphalan-dexamethasone or cyclophosphamide-bortezomib-dexamethasone. Other combinations of chemotherapy with agents such as cyclophosphamide-thalidomide (or lenalidomide)-dexamethasone, bortezomib-dexamethasone, and melphalan-prednisone-lenalidomide have documented activity. Future Challenges: Late diagnosis remains a major obstacle to initiating effective therapy. Recognizing the presenting syndromes is necessary for improving survival.

Autologous Transplantation and Maintenance Therapy in Multiple Myeloma

BackgroundThis open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with melphalan–prednisone–lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma.MethodsWe randomly assigned 273 patients 65 years of age or younger to high-dose melphalan plus stem-cell transplantation or MPR consolidation therapy after induction, and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival.ResultsThe median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.32 to 0.61; P<0.001; and 4-year overall survival, 81.6% vs. 65.3%; hazard ratio for death, 0.55; 95% CI, 0.32 to 0.93; P=0.02). Median progression-free survival was significantly longer with lenalidomide maintenance than with no maintenance (41.9 months vs. 21.6 months; hazard ratio for progression or death, 0.47; 95% CI, 0.33 to 0.65; P<0.001), but 3-year overall survival was not significantly prolonged (88.0% vs. 79.2%; hazard ratio for death, 0.64; 95% CI, 0.36 to 1.15; P=0.14). Grade 3 or 4 neutropenia was significantly more frequent with high-dose melphalan than with MPR (94.3% vs. 51.5%), as were gastrointestinal adverse events (18.4% vs. 0%) and infections (16.3% vs. 0.8%); neutropenia and dermatologic toxic effects were more frequent with lenalidomide maintenance than with no maintenance (23.3% vs. 0% and 4.3% vs. 0%, respectively).ConclusionsConsolidation therapy with high-dose melphalan plus stem-cell transplantation, as compared with MPR, significantly prolonged progression-free and overall survival among patients with multiple myeloma who were 65 years of age or younger. Lenalidomide maintenance, as compared with no maintenance, significantly prolonged progression-free survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00551928.)

Factors that influence health-related quality of life in newly diagnosed patients with multiple myeloma aged ≥ 65 years treated with melphalan, prednisone and lenalidomide followed by lenalidomide maintenance: results of a randomized trial

In the MM-015 trial, melphalan–prednisone–lenalidomide followed by lenalidomide maintenance (MPR-R) significantly prolonged progression-free survival versus melphalan–prednisone (MP) in newly diagnosed patients with multiple myeloma aged ≥ 65 years. Health-related quality of life (HRQoL), a secondary endpoint of MM-015, was also improved with MPR-R. This sub-analysis evaluated the impact of individual predictive factors on HRQoL. Patients completed HRQoL questionnaires at baseline, every third cycle and at progressive disease (PD)/treatment discontinuation. In a mixed-effects model female gender, advanced age and PD negatively affected HRQoL while better treatment responses showed positive effects. Compared to PD, HRQoL during MPR-R treatment was statistically significantly better in two of six preselected domains both of which were also clinically meaningful. HRQoL scores at end of treatment were all either improved or not statistically significantly different versus baseline. In conclusion, continuous treatment with MPR-R, which delays PD, appears to be associated with clinically meaningful improvements in HRQoL.

Maintenance Therapy With Lenalidomide Significantly Improved Survival Of Yong Newly Diagnosed Multiple Myeloma Patients

▪ BackgroundHigh-dose chemotherapy (HDT) with autologous stem cell transplant improves outcome of multiple myeloma (MM) patients in comparison to conventional chemotherapy. The incorporation of new drugs into induction, consolidation and maintenance therapy is changing the treatment paradigm and is questioning the role of HDT in newly diagnosed MM (NDMM) patients <65 years. Previous finding have been presented (Boccadoro, ASCO 2013) and this analysis provides a longer follow-up. AimsTo compare in a prospective randomized trial melphalan-prednisone-lenalidomide (MPR) with tandem melphalan (200 mg/m2) (MEL200) both followed by maintenance with lenalidomide or no maintenance in NDMM patients. MethodsA 2x2 factorial randomized trial was designed. The induction treatment consisted of four 28-day cycles of lenalidomide (25 mg d 1-21) and low-dose dexamethasone (40 mg d 1,8,15,22) (Rd). As consolidation, patients were randomized to MPR (N=202) [six 28-day cycles of melphalan (0.18 mg/k g d 1-4), prednisone (2 mg/kg d 1-4) and lenalidomide (10 mg d 1-21)] or MEL200 (N=200)[tandem melphalan 200 mg/m2 with stem-cell support]. Patients were further randomized, within each group, to receive lenalidomide maintenance (10 mg, days 1-21, N=198) or no maintenance (N=204). Primary study endpoint was progression free survival (PFS). The secondary study endpoints included response rates, safety and overall survival (OS). Data were analyzed in the intent-to-treat (ITT) population. ResultsFrom November 2007 to July 2009, 402 patients with NDMM <65 years of age were enrolled. All patients were stratified according to International Staging System (ISS) and age. Patient characteristics were well balanced in all groups. In the MPR group, the Very Good Partial Response (VGPR) rate was 50% with 13% of Complete Response (CR) while the VGPR rate was 52% including 19% of CR in the MEL200 group. In the MPR group the CR rate improved from 13% after consolidation to 17% after maintenance. In the MEL200 group the CR rate improved from 19% after consolidation to 25% after maintenance.After a median follow-up of 48 months, the median PFS was 24.2 months in MPR group and 38.6 months in MEL200 group ( P< 0.0001).A multivariate analysis confirms the PFS benefit associated with MEL200 across all subgroups of patients defined by stratification factors and baseline characteristics.The 5-year OS rate was similar between MPR (62%) and MEL200 (71%; P= 0.27). In a landmark analysis, lenalidomide maintenance significantly extended PFS from the start of maintenance (median 42,7 months) compared with no maintenance (median 17.5 months; P<.0001). The 4-year OS rate from the start of maintenance was higher in patients who received lenalidomide maintenance (80%) compared with patients who did not (62%; P= 0,01). No significant interaction was detected between MPR/MEL200 (P=0.704) and maintenance/observation (P=0.984) effects.During consolidation, the incidence of grade 3-4 adverse events (AEs) between MPR and MEL200 were as follow: neutropenia (50% vs. 90%), thrombocytopenia (8% vs. 89%), infections (1% vs. 15%) and gastrointestinal (0% vs. 18%), with complications being higher with MEL200.During the maintenance phase, grade 3-4 hematologic AEs were reported in 17% of patients receiving lenalidomide (16% neutropenia). For individual group comparisons during maintenance, grade 3-4 hematologic AEs were observed in 20% of patients receiving MPR plus lenalidomide maintenance compared with 15% receiving MEL200 plus lenalidomide maintenance. Second primary malignancies were observed in 11 patients (3%), and were mainly solid tumors. Four solid tumors were observed in the MEL200 group and one in the MPR group in the maintenance arm, while three solid tumors were observed in the MEL200 group and three in the MPR group in no maintenance arm. ConclusionThe administration of MPR was significantly inferior to MEL200 in terms of PFS. Toxicities were significantly higher in MEL200 group, but manageable. OS is similar between MPR and MEL200. Lenalidomide maintenance significantly reduced the risk of progression and of death independently from the previous treatment. Disclosures:Gay:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Caravita:Celgene: Honoraria, Research Funding. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

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

These Clinical Practice Guidelines are endorsed by the Japanese Society of Medical Oncology (JSMO) incidence and epidemiology Multiple myeloma (MM) accounts for 1% of all cancers and ∼10% of all haematological malignancies. The incidence in Europe is 4.5–6.0/100 000/year with a median age at diagnosis of between 65 and 70 years; the mortality is 4.1/100 000/year. Almost all patients with MM evolve from an asymptomatic pre-malignant stage termed monoclonal gammopathy of undetermined significance (MGUS). MGUS progresses to MM at a rate of 1% per year. In some patients, an intermediate asymptomatic but more advanced pre-malignant stage termed smouldering (or indolent) multiple myeloma (SMM) can be recognised. SMM progresses to myeloma at a rate of 10% per year over the first 5 years following diagnosis, 3% per year over the following 5 years and 1.5% per year thereafter [1]. diagnosis Diagnosis of MM should be based on the following tests: [1] -Detection and evaluation of the monoclonal (M-) component by serum and/or urine protein electrophoresis (concentrate of 24 h urine collection); nephelometric quantification of IgG, IgA and IgM immunoglobulins; characterisation of the heavy and light chains by immunofixation; and serum-free light-chain (FLC) measurement; -Evaluation of bone marrow (BM) plasma cell infiltration: BM aspiration and/or biopsies are the standard options to evaluate the number and characteristics. Moreover, the BM sample should be used for cytogenetic/fluorescence in situ hybridization (FISH) studies and also has the potential for immunophenotypic and molecular investigations; -Evaluation of lytic bone lesions: a radiological skeletal bone survey, including spine, pelvis, skull, humeri and femurs is necessary. A magnetic resonance imaging (MRI) or computed tomography (CT) scan may be needed to evaluate symptomatic bony sites, even if the skeletal survey is negative and the patient has symptoms suggesting bone lesions. Moreover, MRI provides greater detail and is recommended whenever spinal cord compression is suspected. Fluorodeoxyglucose positron emission tomography is currently under evaluation but should not be systematically used; -Complete blood cell count, with differential serum creatinine and calcium level.

Pharmacoeconomic Implications of Lenalidomide Maintenance Therapy in Multiple Myeloma and the Impact On Survival

AbstractAbstract 601 Background:Despite therapeutic advances and availability of novel agents, multiple myeloma (MM) remains an incurable malignant disorder and strategies to improve survival are being actively sought. One such approach is the use of maintenance therapy with lenalidomide (Revlimid®; R), which has shown PFS benefit, without conclusive evidence of OS benefit except in a selected population (CALGB100104). Shrinking resources with rising healthcare costs warrant careful assessment of the financial impact of expensive anticancer therapeutics in context with the true benefit to patients. Methods:This analysis was not supported or solicited by any pharmaceutical industry. For our pharmacoeconomic study we selected the MM-015 trial; a large (n=459) double-blind, randomized, placebo-controlled phase III study that investigated the efficacy of continuous R maintenance after initial therapy with melphalan/prednisone/lenalidomide (MPR) in a uniform cohort of patients (≥65 years, newly diagnosed MM, transplant ineligible). The three study arms were MP, MPR and MPR followed by R maintenance (MPR-R). The cost-effectiveness model included medical costs (drugs, office visits, laboratory tests) and costs of treatment-related adverse events (AEs) for an individual patient. Drug costs were calculated from the average wholesale price, using average US adult weight of 80kg. Office visit and laboratory test costs were obtained using Medicare reimbursement fees. Costs of AEs were obtained from peer-reviewed publications. Incidence of AEs was obtained from the published MM-015 trial. Costs were valued in 2011 US dollars. Cost calculations included: (1) computing distribution of the numbers of induction and maintenance courses completed by patients treated with each of these regimens; (2) computing the per-course probabilities of the occurrence of individual AEs during induction and maintenance for each of these toxicities; (3) combining these data with the treatment costs and costs of individual AEs to compute cumulative cost of treatment through 40 maintenance cycles and cumulative cost of treatment per progression-free survivor. Summary measures computed for each treatment: (1) average cumulative cost per patient (ACCP) treated; (2) average cumulative cost per progression free survivor (ACCPFS), representing the average cumulated cost/patient who is progression free at that time. The distribution of courses received was obtained from the MM-015 publication. Data on subsequent therapy at the time of disease progression was not available. Results:Median follow up reported in the published study was 30 months. Median PFS was 13 months (MP), 14 months (MPR) and 31 months (MPR-R) in the three arms. Table 1 summarizes the calculated ACCP and the ACCPFS of each regimen for induction and maintenance treatment. MPR-R was the most expensive of the three arms in terms of total cumulative costs, with an ACCP of $231,314, compared to $166,211 for MPR and $17,972 for MP. However, taking the efficacy of each regimen into account (ACCPFS), MPR greatly exceeds both MPR-R and MP ($1,540,139 vs. $516,322 vs. $309,346), while the difference between MPR-R and MP was less distinct. Figure 1 illustrates the exponential increase in ACCPFS of MPR, compared to MPR-R and MP.Table 1TreatmentACCPACCPFSMPMPRMPR-RMPMPRMPR-RInduction (9 cycles)Medical2,18541,57541,5752,61448,27248,273AE7,88555,08155,0819,43163,95463,956Total10,07196,65696,65612,045112,226112,229Maintenance (36 cycles)Medical3,98971,392139,53668,660661,532311,461AE13,98394,81991,778240,686878,607204,861Total17,972166,211231,314309,3461,540,139516,322 [Display omitted] Conclusions:From a cost-effectiveness perspective, if MPR is used as the induction regimen, maintenance with R should be strongly considered, as MPR without maintenance does not confer any significant benefit over MP, while incurring a much higher cost. However, the overall cost of MPR-R is substantial with no reported OS benefit at present. In the absence of clear survival benefit the financial burden of prolonged treatment becomes an important factor to consider prior to adopting this therapeutic strategy in MM. As part of a global strategy for addressing healthcare costs, it is important to consider this in appropriate medical decision making for patients, and to include cost-effectiveness analyses as a part of large prospective clinical trial efforts. Disclosures:No relevant conflicts of interest to declare.

Immunoglobulin light chain amyloidosis: 2012 update on diagnosis, prognosis, and treatment

AbstractDisease Overview: Immunoglobulin (Ig) light chain amyloidosis is a clonal but nonproliferative plasma cell disorder in which fragments of an Ig light chain are deposited in tissues. The clinical features depend on the organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, and peripheral/autonomic neuropathy.Diagnosis: Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple‐green birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow biopsy or subcutaneous fat aspirate in 85% of patients. Prognosis: N‐terminal pro–brain natriuretic peptide and serum troponin T values are used to classify patients into three groups of approximately equal size; median survivals are 26.4, 10.5, and 3.5 months, respectively. Therapy: All patients with a visceral amyloid syndrome require therapy to prevent deposition of amyloid in other viscera and to prevent progressive organ failure of involved sites. Stem cell transplant (SCT) is a preferred technique, but only 20% of patients are eligible. Requirements for safe SCT include mild or no cardiac involvement, troponin T value &lt;0.06 ng/mL, age &lt;70 years, &lt;3 organs involved, and serum creatinine value ≤1.7 mg/dL. Nontransplant candidates can be offered melphalan–dexamethasone. Pomalidomide appears to have activity, as do other combinations of chemotherapy with agents such as cyclophosphamide–thalidomide–dexamethasone, bortezomib–dexamethasone, and melphalan–prednisone–lenalidomide. Future Challenges: Late diagnosis remains a major obstacle to initiating effective therapy when organ dysfunction is still recoverable. Recognizing the presenting syndromes is necessary for improvement in survival. Am. J. Hematol., 2011. © 2011 Wiley Periodicals, Inc.

Melphalan/Prednisone/Lenalidomide (MPR) Versus High-Dose Melphalan and Autologous Transplantation (MEL200) in Newly Diagnosed Multiple Myeloma (MM) Patients

Abstract 3069▪FN2▪This icon denotes a clinically relevant abstract Background:High-dose chemotherapy with haemopoietic stem-cell improves outcome in multiple myeloma (MM). The introduction of novel agents questions the role of autologous stem-cell transplantation (ASCT) in MM patients. Aims:In this prospective randomized study, we compared conventional melphalan-prednisone-lenalidomide (MPR) with tandem high-dose melphalan (MEL200) in newly diagnosed MM patients younger than 65 years. Methods:All patients (N=402) received four 28-day cycles of lenalidomide (25 mg, d1-21) and low-dose dexamethasone (40 mg, d1, 8, 15, 22) (Rd) as induction. As consolidation, patients were randomized to MPR (N=202) consisting of six 28-day cycles of melphalan (0.18 mg/kg d1-4), prednisone (2 mg/kg d1-4) and lenalidomide (10 mg d1-21); or tandem melphalan 200 mg/m2 MEL200 (N=200) with stem-cell support. All patients enrolled were stratified according to International Staging System (stages 1 and 2 vs. stage 3) and age (<60 vs. ≥60 years). Progression-free survival (PFS) was the primary end point. Data were analyzed in intention-to-treat. Results:Response rates were similar: at least very good partial response (≥VGPR) rate was 60% with MPR vs. 58% with MEL200 (p=.24); the complete response (CR) rate was 20% with MPR vs. 25% with MEL200 (p=.49). After a median follow-up of 26 months, the 2-year PFS was 54% in MPR and 73% in MEL200 (HR=0.51, p<.001). The 2-year overall survival (OS) was similar in the two groups: 87% with MPR and 90% with MEL200 (HR 0.68, p=.19). In a subgroup analysis, MEL200 significantly prolonged PFS in both standard-risk patients without t(4;14) or t(14;16) or del17p abnormalities (2-year PFS was 46% in the MPR group vs. 78% in the MEL200 group, HR=0.57, p=.007) and high-risk patients with t(4;14) or t(14;16) or del17p abnormalities (2-year PFS was 27% for MPR vs. 71% for MEL200, HR=0.32, p=.004). In patients who achieved CR, the 2-year PFS was 66% for MPR vs. 87% for MEL200 (HR 0.26; p<.001); in those who achieved a partial response (PR), the 2-year PFS was 56% for MPR vs. 77% for MEL200 (HR 0.45; p<.001). In the MPR and MEL200 groups, G3-4 neutropenia was 55% vs. 89% (p<.001); G3-4 infections were 0% vs. 17% (p<.001); G3-4 gastrointestinal toxicity was 0% vs. 21% (p<.001); the incidence of second tumors was 0.5% in MPR patients and 1.5% in MEL200 patients (p=.12). Deep vein thrombosis rate was 2.44% with MPR vs. 1.13% with MEL200 (p=.43). Conclusions:PFS was significantly prolonged in the MEL200 group compared to MPR. This benefit was maintained in the subgroup of patients with standard- or high-risk cytogenetic features. Toxicities were significantly higher in the MEL200 group. This is the first report showing a PFS advantage for ASCT in comparison with conventional therapies including novel agents. These data will be updated at the meeting.TableClinical outcome after MPR or MEL200 consolidationMPRMEL200P valueAll patientsCR20%25%.49≥VGPR60%58%.242-year PFS54%73%<.0012-year OS87%90%.19Standard-risk patients2-year PFS46%78%.007High-risk patients2-year PFS27%71%.004Patients who achieved CR2-year PFS66%87%<.001Patients who achieved PR2-year PFS56%77%<.001 Disclosures:Palumbo:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavallo:Celgene: Honoraria; Janssen-Cilag: Honoraria. Cavo:celgene: Honoraria. Ria:celgene: Consultancy. Caravita Di Toritto:Celgene: Honoraria, Research Funding. Di Raimondo:celgene: Honoraria. Boccadoro:celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Second Primary Malignancies in Newly Diagnosed Multiple Myeloma Patients Treated with Lenalidomide: Analysis of Pooled Data in 2459 Patients

Abstract 996 Background:The risk of developing a tumor is 2.1% per year of life in the general population older than 65 years. In MGUS, the incidence of AML/MDS is increased 8 fold compared with normal population, this observation supports a role for non-treatment related factors in the causation of AML/MDS in plasma-cell dyscrasias (Blood, July 27,2011). In multiple myeloma (MM) patients, the risk of second primary malignancy (SPM) is influenced by age and the use of alkylating agents. Methods:We examined SPM incidence rates (IRs) per 100 person-years in 2459 newly diagnosed MM patients, enrolled in 9 experimental trials of the European Myeloma Network (RVMM EMN 01, RVMM EMN 441, RVMM PI 026, RVMM PI 302, RVMM PI 209, GIMEMA MM 03 05, GIMEMA MM 04 05, GISMM 2001, HOVON 87). 287 patients received cyclophosphamide-lenalidomide-corticosteroids (CRC), 685 melphalan-prednisone-lenalidomide (MPR), 484 high-dose melphalan followed by lenalidomide maintenance (MEL200-R), 164 melphalan-prednisone (MP), 328 MP-thalidomide (MPT), 257 MP-bortezomib (MPV), 254 MP-bortezomib-thalidomide (VMPT). This post hoc analysis was restricted on pooled data from 1798 patients with at least 1 year of follow-up. Results:As of March 2011 cut-off, median follow-up was 28 months. Median age was 69 years, 49% of patients were aged 65–74 years, and 19% aged ≥75 years. Total cases of SPMs were 30/1798 (IR 0.72), including 8 hematologic (acute leukemia) and 22 solid cancers (gastrointestinal, lung, breast, skin, gynecologic). No cases of SPMs were reported in patients receiving cyclophosphamide and lenalidomide.CRC/MPR (N=534)MEL200-R (N=366)MP/MPT/MPV/VMPT (N=898)Total invasive SPM6717Incidence rate*0.660.870.67Hematologic SPM107Incidence rate*0.1100.28Solid tumor SPM5710Incidence rate*0.550.870.39*Incidence rate per 100 person-years.SPM: second primary malignancy; CRC: cyclophosphamide-lenalidomide-corticosteroids; MPR: melphalan-prednisone-lenalidomide; MEL200-R: high-dose melphalan followed by lenalidomide maintenance; MP: melphalan-prednisone; MPT: MP-thalidomide; MPV: MP-bortezomib; VMPT: MP-bortezomib-thalidomideIn patients receiving lenalidomide and alkylating agents (CRC/MPR/MEL200-R), the cumulative incidence of death for MM and diagnosis of SPMs at 3 years was 13.8% and 2.0%, respectively. In patients not receiving lenalidomide (MP/MPT/MPV/VMPT), the cumulative incidence of death and SPMs at 3 years was 26.1% and 1.1%, respectively. In the analysis restricted to Italian patients treated with lenalidomide and alkylating agents, we report 11 cases of SPMs. This figure is lower than the 15.6 cases expected from the age/sex adjusted incidence derived form the Italian Cancer Registry, with a standardized incidence ratio of 0.70. Conclusions:SPM incidence was lower than expected in all treatment groups. At present, the benefits of continuous therapy with lenalidomide outweigh the potential risk of SPMs. Longer follow-up is needed to definitively assess the risk of SPMs in patients receiving lenalidomide with alkylating agents. With the limitation of a short follow-up, the numbers currently support a role for non-treatment related factors as causes of SPMs. Updated data will be presented at the meeting. Disclosures:Palumbo:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Honoraria; Amgen: Honoraria. Larocca:Janssen-Cilag: Honoraria. Zweegman:Celgene: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding. Musto:Celgene: Consultancy, Honoraria, Research Funding. Lokhorst:Celgene: Consultancy; Genmab: Consultancy. Ria:celgene: Consultancy. Patriarca:Celgene: Honoraria; Schering-Plough: Honoraria. Bringhen:Celgene: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria; Merck Sharp & Dhome: Membership on an entity’s Board of Directors or advisory committees. Hajek:Merk: payment for educational presentation; celgene: Honoraria; Janssen-Cilag: Honoraria. Spencer:Janssen: 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; Amgen: Honoraria, Membership on an entity’s Board of Directors or advisory committees. 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. Sonneveld:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity’s Board of Directors or advisory committees.

Management of older patients with multiple myeloma

For many years, the oral combination melphalan–prednisone (MP) has been considered the standard of care for patients with multiple myeloma (MM) not eligible for autologous stem cell transplantation. In the era of novel agents, the introduction of immunomodulatory drugs and proteasome inhibitors has challenged the role of MP and led to new standards of care for this disease. Five randomized phase III studies compared the traditional MP with the MP plus thalidomide (MPT). All these studies showed a prolonged time to progression (TTP) with the 3-drug combination. However, in only two of these trials this advantage translated into an improvement in overall survival (OS). In another randomized trial, MP plus bortezomib (VMP) was correlated with an increase in both TTP and OS compared with MP. Preliminary data showed the superiority of the association of VMP plus thalidomide followed by bortezomib–thalidomide maintenance (VMPT-VT) vs VMP and melphalan–prednisone–lenalidomide followed by lenalidomide maintenance (MPR-R) compared to MP. Promising results have also been reported with the combination of lenalidomide plus low-dose dexamethasone. The availability of different efficacious regimens provided clinicians with the opportunity of tailoring the proper and specific approach for each patient. The choice should be based on patients' comorbidities and biologic age, while taking into account the expected toxicity profiles of each treatment regimen. Moreover, an accurate management of therapy-related adverse events and a gentler approach, particularly for patients older than 75 years, with appropriate age-adjusted dose reductions, should be considered to further improve outcome.

Lenalidomide plus dexamethasone vs. lenalidomide plus melphalan and prednisone: a retrospective study in newly diagnosed elderly myeloma

The goal of this retrospective study was to compare the efficacy and toxicity of lenalidomide-dexamethasone (len/dex) vs. melphalan-prednisone-lenalidomide (MPR) as upfront therapy for newly diagnosed elderly patients with myeloma. Data from 51 patients enrolled in an Italian phase I/II trial and treated with MPR were analyzed and compared with data from 38 patients, seen at the Mayo Clinic, treated with len/dex and enrolled in phase II/III trials. On intention-to-treat analysis, time to progression (median: 24.7 vs. 27.5 months in MPR and len/dex groups, respectively, P = 0.903), progression-free survival (median: 24.7 vs. 27.5 months in MPR and len/dex groups, respectively, P = 0.926), and overall survival (2-yr overall survival: 86.2% in MPR vs. 89.1% in len/dex, P = 0.730) were not significantly different between the two groups. Results were confirmed when the analysis was restricted to MPR and len/dex matched pair mates. Hematologic grade 3-4 toxicities were more common with MPR (neutropenia: 66.7% vs. 21.1%, P < 0.001; thrombocytopenia: 31.4% vs. 2.6%, P < 0.001). Grade 3-4 gastrointestinal events (13.2% vs. 3.9%, P = 0.132), thrombotic events (13.2% vs. 5.9%, P = 0.279), and fatigue (10.5% vs. 3.9%, P = 0.395) were more common with len/dex. Results show that both MPR and len/dex are efficacious regimens for elderly patients with myeloma. Randomized trials are needed to confirm these results.

Frontline Treatment in Elderly Patients With Multiple Myeloma

Melphalan-prednisone-thalidomide (MPT) and melphalan-prednisone-bortezomib (MPV) currently appear to be the treatments of choice for a large proportion of elderly multiple myeloma (MM) patients ineligible for autologous stem cell transplantation (ASCT). It seems certain that in the near future cyclophosphamide-thalidomide-dexamethasone, with an attenuated dose of dexamethasone (CTDa), and melphalan-prednisone-lenalidomide (MPR) will also be proved superior to MP, thus providing four therapeutic options in this patient group. These options could lead to more personalized treatment approaches, based on patient comorbidities, as the three novel agents have somewhat different toxicity profiles. MP would be appropriate for only a minority of patients with poor performance status and/or significant comorbidities. Questions regarding the relative efficacy of different melphalan-based regimens or melphalan-based regimens versus dexamethasone-based regimens with low-dose dexamethasone will require further trials. Additionally, the important issue of maintenance treatment needs to be investigated. These new and emerging therapies provide multiple effective treatment options for MM patients and greatly enhanced treatment strategies for clinicians, all offering promise that has been sorely lacking over the past four decades.

Frontline treatment of multiple myeloma in elderly patients

Until 2007, frontline chemotherapy with melphalan and prednisone (MP) was considered as the standard of care in the treatment of elderly patients with multiple myeloma (MM). Recently, several prospective randomized studies comparing MP with the same combination plus new agents such as thalidomide (MPT) or bortezomib (MPV) clearly showed that MPT and MPV were superior to MP in terms of progression-free and overall survival. Melphalan-prednisone-lenalidomide (MPR) is currently compared to MP in one prospective trial and will also probably be superior to MP. Lenalidomide plus low-dose dexamethasone is a promising combination. Thus, at least four highly active new treatment options are now available to treat elderly patients with MM. The goal of future trials will be to determine the best treatment strategy in this group of patients.