Background Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma. MethodsIn this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0-2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing. Findings Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years [IQR 60-72]; 107 [43%] were female) and 249 to the pomalidomide group (median age 68 years [IQR 61-72]; 109 [44%] were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6•8 months (95% CI 5•0-8•5; 165 [67%] of 246 patients had an event) in the melflufen group and 4•9 months (4•2-5•7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0•79, [95% CI 0•64-0•98]; p=0•032), at a median follow-up of 15•5 months (IQR 9•4-22•8) in the melflufen group and 16•3 months (10•1-23•2) in the pomalidomide group. Median overall survival was 19•8 months (95% CI 15•1-25•6) at a median follow-up of 19•8 months (IQR 12•0-25•0) in the melflufen group and 25•0 months (95% CI 18•1-31•9) in the pomalidomide group at a median follow-up of 18•6 months (IQR 11•8-23•7; HR 1•10 [95% CI 0•85-1•44]; p=0•47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs...
295 Genetic events mediating transformation from the pre-malignant monoclonal gammopathies (MG) to myeloma (MM) are unknown. Previous FISH analyses have highlighted that most genetic lesions typical of MM are already present in MGUS. However, the genetic abnormalities characteristic of each evolving stage of MG have not been elucidated. To obtain a comprehensive genomic profile of MG cases from the early to the late stages we performed for the first time high resolution analysis on purified plasma cells from 20 MGUS, 20 Smoldering MM (SMM) and 34 MM by high density 6.0 SNP-array. Ten matched non-tumor DNA samples were also included in the analysis. We examined DNA copy number alterations (CNA), copy number neutral loss of heterozygosity (CNN-LOH) and the spectrum of minimally altered regions which could contain relevant genes. Moreover, visual inspection allowed us to detect intermediate situations which corresponded to imbalances present in minor populations (less than 50%) coexisting with the major diploid population. CNA were identified in 69 (93%) of the 74 patients analyzed with a median of 8 imbalances per abnormal case. The only 5 cases with no CNA corresponded to asymptomatic entities. We observed a progressive increase in the incidence of genomic imbalances from MGUS (median, 5/case) to SMM (media, 7.5/case) to MM (median, 12/case) (P=0.006; MGUS vs MM). In particular, gains on 1q, 3p, 6p, 9p, 11q, 19, 21q together with losses on 1p, 16q and 22q may be important genetic events associated with MGUS-MM transition, as they were less frequent in MGUS than in MM (P<0.038). Otherwise, 11p+ and 4q- would be implicated in the transition from SMM to symptomatic disease, as they were lower in SMM compared to MM (P<0.038). Chromosomal gains were usually associated with gains and losses with losses with the exception of 1q gains that were significantly associated with losses. The subclones analysis allowed us to illustrate that PC bearing CNA increased from MGUS to SMM and to MM. Thus, we observed at least one minor subclone (<50% of PC) carrying a CNA more frequently in MGUS (75% of cases with a median of 3.5 of subclones/case, range 1–12) than in SMM (30% of cases with a median of 1, range 1–19) and MM (56% of cases with a median of 1/case, range 1–16) (p=0.017, MGUS vs SMM+MM comparison). Moreover, the four abnormalities apparently exclusive of MM disease (+11q, +21q, -16q y -22q) were also found as minor subclone in MGUS samples, supporting the previous notion that karyotypic instability is initiated in MGUS (Figure 1).Figure 1Percentage of cases with CNAs as major and minor subclonesFigure 1. Percentage of cases with CNAs as major and minor subclones Overall, a total of 65 CNN-LOH were detected and 7 locus had a uniparental trisomy with a median number of genes of 188 per CNN-LOH. The frequency of CNN-LOH was higher in active MM as compared to the asymptomatic entities (MM, 53% vs SMM, 25% vs MGUS 25%; p=0.047). Most of the cases showed more than one region affected by this phenomenom. Of note, there were two identical interstitial CNN-LOH in one MGUS and one MM at 8q11.21-q11.23. We identified 12 homozygous deletions (HZD) corresponding to 5 MGUS (25%), 1 SMM (5%) and 3 MM (9%) patients, some of them containing relevant genes such as PRAME, BIRC2, BIRC3, MMPs 7 and 20. Interestingly, two couples of MGUS patients showed the same HZD at 2p22.3 and 8p11.23-p11.22. The latest contained only the gene ADAM 3A, whose function remains unknown, but its HZD has been recently reported in gliomas (Figure 2).Figure 2HZD at 8p11.23-p11.22 in two MGUS (CHAS software).Figure 2. HZD at 8p11.23-p11.22 in two MGUS (CHAS software). A strong association between genetic lesions and fragile sites (FRA) was also detected as more than one third of the focal-recurrent CNA and HZD, and more than a half of the minimal common regions and interstitial CNN-LOH overlapped with known FRA. In summary, our study shows an evolving cytogenetic profile of increasing complexity from MGUS to SMM and to MM. However, although MM display more CNA and CNN-LOH than early steps, MGUS are as genetically aberrant as MM, and the transition from MGUS to MM is not associated to a particular chromosomal imbalance but rather to an expansion of altered clones already present in MGUS. The analysis of sequential samples from the same individual evolving from MGUS and SMM to active MM is essential to confirm these results. In addition, our study reveals new chromosomal regions involved in CNA, HZD and CNN-LOH. A comprehensive investigation of the genes contained in these regions may provide new insights in MM pathogenesis. Disclosures: No relevant conflicts of interest to declare.
3045 Background: Lenalidomide is an oral IMiD® immunomodulatory compound with a dual mechanism of action, namely tumoricidal and immunomodulatory activity, and established clinical efficacy and safety in patients with multiple myeloma (MM). Lenalidomide plus dexamethasone (Len + Dex) was well tolerated and demonstrated significant improvements in response and favorable overall survival (OS) compared with Placebo + Dex in 2 pivotal phase 3 registration trials in patients with relapsed/refractory MM (RRMM; Weber et al, NEJM 2007; Dimopoulos et al, NEJM 2007). Previously, in a phase 3, multicenter, single-arm, open-label, expanded-access study (MM-018), Len + Dex demonstrated a predictable safety profile that can preserve patient quality of life (QoL) (Yong et al Haematologica 2010 [abstract #0944]). Here we report efficacy, safety, and QoL data for patients enrolled in the Spanish cohort of MM-018. Methods: Patients with progressive disease after > 2 cycles of antimyeloma treatment, or after relapse from treatment, with ECOG performance status ≤ 2 received 28-day cycles of Len (25 mg/day, D 1–21) plus Dex (40 mg/day, D 1–4, 9–12, and 17–20 for cycles 1–4; D 1–4 in subsequent cycles). Endpoints included overall response (≥ partial response [PR] by European Group for Blood and Marrow Transplantation criteria) and QoL assessments measured by EORTC QLQ C-30 and EORTC QLQ MY-20 questionnaires at baseline and week 24. All prophylaxis was administered at the investigator's discretion. Results: Sixty-three patients receiving ≥ 1 dose of Len + Dex were evaluated for efficacy, safety, and QoL. Median age was 62 years (21 [33.3%] were > 65 years). Prior therapies included thalidomide (n = 15, 24%) and bortezomib (n = 37, 59%). Additionally, 5 (8%) patients had a history of deep vein thrombosis (DVT), and 23 (37%) had a history of peripheral neuropathy. A PR or better was observed in 49 (78%) patients, including complete response (CR) in 13 (21%), very good partial response (VGPR) in 13 (21%), and PR in 23 (37%) patients. Median time to first response and best response was 2.7 and 4.5 months, respectively. Median duration of response was 18.4 months. Response depth improved after long-term treatment with Len + Dex, and 32/63 (51%) patients received >12 cycles of therapy. Beyond 12 cycles of therapy, 8 patients achieved VGPR and 12 patients achieved CR; compared with 5 patients and 1 patient, respectively, prior to 12 cycles. Median time to progression and progression-free survival were both 13.3 months; median OS has not yet been reached. Forty-two (67%) patients remained on study at 6 months. Compliance to QoL assessment questionnaires was ≥ 80%. Patient-reported improvements in QoL and disease symptoms measured by both questionnaires were observed in nearly all scales. EORTC QLQ C-30 scores revealed clinically meaningful improvement (> 5 points) for global QoL (n = 15, 40%), fatigue (n = 16, 42%), emotional function (n = 15, 40%), physical function (n = 12, 32%), role function (n = 11, 29%), social function (n = 11, 29%), cognitive function (n = 10, 26%), and pain (n = 9, 24%) at 6 cycles compared with baseline. Preservation of QoL in role function, emotional function, social function, and pain scores was observed at 6 cycles when compared with baseline in responders (≥ PR). EORTC QLQ MY-20 results revealed no relevant median change (> 5 points) from baseline in all scales for all patients completing questionnaires at baseline and 6 cycles, except for a meaningful improvement in future perspective scores (median 11.1-point change). Adverse events observed in this study were consistent with those previously reported with Len + Dex. Grade 3/4 hematologic events were experienced by 40 (64%) patients, and included neutropenia (n = 32, 51%), thrombocytopenia (n = 11, 17%), anemia (n = 10, 18%), and febrile neutropenia (n = 4, 6%). DVT (all grades) was experienced by 5 (8%) patients, and only one grade 3/4 new-onset peripheral neuropathy was observed after 6 cycles of treatment. Conclusions: Len + Dex treatment in this expanded-access study demonstrated efficacy and predictable safety, consistent with that of previously published trials for patients with RRMM. More patients achieved VGPR and CR after long-term therapy compared with those receiving < 12 cycles of therapy. Furthermore, QoL assessments at baseline and 6 months revealed that patients treated with Len + Dex showed meaningful improvements in certain QoL and symptom scores. Disclosures: Oriol-Rocafiguera: Celgene: Consultancy; Janssen-Cilag: Consultancy; Novartis: Consultancy. García-Laraña:Celgene: Consultancy; Janssen-Cilag: Consultancy. Mateos:Celgene: Honoraria. Cibeira:Celgene: Honoraria for Lectures; Janssen-Cilag: Honoraria for Lectures; Pharmion: Honoraria for Lectures. Knight:Celgene: Employment. Rosettani:Celgene Corporation: Employment.
4041 Several new agents have recently been incorporated to the treatment of Multiple Myeloma (MM), which have shown increased anti-tumor activity and remarkable improvements in clinical outcomes. However, novel agents and therapies are still needed for patients relapsing/refractory to these new agents. PM00104 is a novel marine-derived compound with marked in vitro and in vivo pre-clinical activity in MM cell lines and patient cells (Ocio et al., Blood, 2009). It promotes DNA double-strand breaks in malignant plasma cells, as well as over-expression of p53 in p53 wild–type cell lines. Moreover, PM00104 induces toxicity on mature normal hematopoietic cells, but not on immature hematopoietic stem cells. On the basis of the observed activity, we designed this multicenter, open label, single arm, non-comparative, phase II clinical trial in order to determine the recommended dose (RD) to be administered as 1-hour (h) intravenous (i.v) infusion on days 1, 8 and 15 every 4 weeks (q4wk) in relapsed/refractory MM patients. We report herein data from the optimization phase only of this study. Only adult patients with relapsed/refractory disease having received at least 2 but no more than 5 prior therapeutic regimens were included in the study. The study was divided in two phases: an initial optimization phase, with the primary objective of finding the RD of PM00104 by using a classical dose escalation phase I scheme, followed by an expansion phase with the objective of analyzing the efficacy of PM00104 in the treatment of MM at the RD established in the previous phase. A total of 55 patients were expected to participate, 18 in the optimization and 37 in the expansion phase. Patients showing disease progression (PD) after 2 cycles or stable disease (SD) after 4 cycles could have dexamethasone (40 mg weekly) added to their treatment exclusively during the expansion phase. Only data from the optimization phase (i.e. without dexamethasone) are presented here. Secondary study objectives included the assessment of the safety, tolerability and efficacy of PM00104 in MM patients, as well as the collection of pharmacokinetic (PK) and pharmacogenomic (PGx) information. Twenty two patients were treated in the optimization phase, median age was 61 years (range, 40–74), median number of prior therapy lines was 3 lines (range, 2–5) and prior treatment with bortezomib and lenalidomide was received by 96% and 68% patients, respectively. Seventy-seven percent (77%) of patients received prior autologous stem-cell transplantation (ASCT) and 13% of patients received an allogeneic transplantation. The median number of cycles at dose level (DL) 1 (2 mg/m2) was 2 cycles (range, 1–7), at DL 2 (2.5 mg/m2) was 3 cycles (range, 1–12) and at DL 3 (2.2 mg/m2) was 2 cycles (range, 1–5). Two patients out of 6 had DLTs at DL 2: one patient had grade 4 neutropenia lasting > 7 days, another patient had febrile neutropenia, grade 4 neutropenia lasting more than 7 days and grade 4 thrombocytopenia with pulmonary hemorrhage. Two patients out of 4 had DLTs at DL 3: febrile neutropenia and grade 4 thrombocytopenia. After dose escalation, DL 1 was declared as the RD. The main toxicity at the RD was hematological: grade 3/4 thrombocytopenia and grade 3/4 neutropenia, observed in 66% and 67% of patients, respectively. Non-hematological toxicity was mostly mild/moderate and consisted of grade 1/2 nausea (41%), vomiting (36%), pyrexia (32%), anorexia (23%) and grade 1 transitory liver enzymes elevation (40%). Grade 3/4 creatinine elevation occurred in 14% of cases. Table 1 shows overall response (OR): sixteen patients were evaluable for efficacy. One patient (6.0%) had a PR, 4 patients (25%) had MR and 9 patients (56%) achieved SD, 3 of which for longer than 4 months. The median duration of response (DR) was 4 months. Table 1. Overall response of PM00104 Overall response DL 1 DL 2 DL 3 Total n n n n % PR - 1 - 1 6.0 MR - 3 1 4 25.0 SD 3 3 3 9 56.0 PD 1 - 1 2 13.0 Total 4 7 5 16 100 DL, dose level; MR, minimal response; NE, not evaluable; PD, disease progression; PR, partial response. PM00104 is a novel agent with an interesting activity in patients relapsing/refractory to new anti-myeloma agents and shown here to be safe. The RD of PM00104 administered as a 1-h i.v. infusion on days 1, 8 and 15 q4wk has been established at 2 mg/m2. The expansion phase of this study is currently ongoing, yet on the basis of the observed preliminary therapeutic efficacy, combination of PM00104 with other anti-myeloma agents is warranted. Disclosures: Ocio: PharmaMar: Patents & Royalties, Research Funding. De La Rubia:Celgene, Janssen: Consultancy, Speakers Bureau. Blade:Celgene, Janssen: Honoraria for lectures from Celgene And Janssen and grant support from Janassen Other. Rodriguez:PharmaMar: Employment. Coronado:PharmaMar: Employment. San-Miguel:PharmaMar: Research Funding.
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