Refractory Multiple Myeloma Pts Research Articles

Real -World Outcomes for Relapsed or Refractory Multiple Myeloma Patients Treated with Lenalidomide and Daratumumab Sparing Triplet Regimens: A United States Retrospective Cohort Study

Background: Current frontline treatment of multiple myeloma (MM) often includes lenalidomide (Len) and the anti-CD38 monoclonal antibody daratumumab (Dara), with treatment administered until disease progression. There is no singular standard of care for patients (pts) refractory to these drugs at time of relapse. With the rising need for regimens that incorporate alternate agents in relapsed and/or refractory MM (RRMM), we evaluated subsequent treatment regimens that exclude Len and Dara RRMM. This study describes the most frequent real-world use of such regimens in early RRMM and patient outcomes. Methods: A retrospective observational study of pts with RRMM was conducted using the nationwide Flatiron Health electronic health record (EHR)-derived database, a longitudinal database comprising de-identified pt-level structured and unstructured data, curated via technology-enabled abstraction (Ma et. al., 2020). Patients diagnosed with MM, ICD-9 (203.0x) or ICD-10 (C90.xx) who initiated line 2 (L2) or line 3 (L3) triplet regimens not including Len and Dara between January 2013 and December 2021 were included with follow-up through December 2022. Patients receiving one of the five most utilized (“top 5”) Len and Dara sparing L2 and L3 triplet regimens were included in the analysis. Pts could be included in both L2 and L3. Real-world overall survival (rwOS) and real-world progression free survival (rwPFS) were calculated using the Kaplan-Meier approach defined as time from initiation of L2 or L3 until death or their last visit (rwOS) and until death, last visit, Flatiron-derived progression, or initiation of next line of therapy (rwPFS), whichever occurred first. Results: Of the 6915 L2 and L3 treated RRMM pts in the database, 1023 (14.8%) received Len and Dara sparing triplet regimens with 751 (10.9%) comprising one of the top five Len and Dara sparing triplet regimens. Of those, 464 pts (6.7%) and 287 pts (4.2%) were in 2L and 3L respectively. In 2L, 259 (55.8%) were treated with bortezomib-cyclophosphamide-dexamethasone (VCy-d), 96 (20.7%) with carfilzomib-pomalidomide-dexamethasone (KPd), 52 (11.2%) with bortezomib-pomalidomide-dexamethasone (VPd), 39 (8.4%) with carfilzomib-cyclophosphamide-dexamethasone (KCy-d) and 18 (3.9%) with ixazomib-pomalidomide-dexamethasone (Ixa-Pd). Three (0.6%) pts in L2 had received frontline Dara (all 3 with Len). In 3L, 107 (37.3%) were treated with KPd, 68 (23.7%) with VCy-d, 56 (19.5%) with KCy-d, 30 (10.5%) with elotuzumab-pomalidomide-dexamethasone (Elo-Pd), and 26 (9.1%) with VPd. Of the L3 cohort, 83.6% (n=240) and 20.9% (n=60) had prior exposure to Len and Dara, respectively; 54 (18.8%) pts were double class exposed to both Len and Dara, with KPd and KCyd being the mostly used regimens (70.4%; n=38). Variation in baseline pt and disease characteristics was observed across the top five Len and Dara sparing triplet regimens in L2 and L3 and is summarized in Table 1. In L2 and L3 cohorts, overall median rwPFS was 9.0 (95% CI: 8.0-11.0) and 8.0 (95% CI: 6.0-10.0) months. Median rwOS was not reached in L2 and L3 pts, with median follow up of 25 and 18 months (Figure 1). Median rwPFS for the 54 L3 pts who were double class exposed to both Len and Dara was 6.0 (95% CI: 5.0-10.0) months. Median rwOS was not reached. Conclusions: With the evolution of MM practice, the proportion of RRMM pts exposed and refractory to Dara and Len is expected to continue growing. Efficacious Dara and Len sparing regimens with demonstrated real-world utility, such as KPd and KCy-d, are increasingly needed, especially beginning at first relapse of MM.

Elranatamab (PF-06863135), a B-Cell Maturation Antigen (BCMA) Targeted CD3-Engaging Bispecific Molecule, for Patients with Relapsed or Refractory Multiple Myeloma: Results from Magnetismm-1

Elranatamab (PF-06863135), a B-Cell Maturation Antigen (BCMA) Targeted CD3-Engaging Bispecific Molecule, for Patients with Relapsed or Refractory Multiple Myeloma: Results from Magnetismm-1

P-065: CyTOF and single cell RNA sequencing reveal altered T cell phenotypes in Multiple Myeloma patients: implications for immunotherapy

<h3>Background</h3> Immune therapies have had a major impact in multiple myeloma (MM). Responses induced in relapsed and/or refractory MM (RRMM) patients (pts) are unprecedented; however the key challenge is their durability. Most immunotherapeutic approaches rely on the fitness of pts' T cells but exposure to multiple therapies may alter immune cell numbers and function. Here we analyzed and compared the transcriptome and phenotype of T cells from healthy donors (HD), newly diagnosed MM (NDMM) and RRMM pts. <h3>Methods</h3> Peripheral Blood Mononuclear Cells (PBMCs) from age-matched HD, NDMM and RRMM pts were collected before the start of a new line of treatment. Single cell RNA sequencing (scRNAseq) was performed and proportion of cell types were inferred using a reference PBMC dataset with Seurat. Cell type proportions were also estimated with CyTOF and conventional flow cytometry <h3>Results</h3> PBMCs from 10 HDs (median age 69, range 53-79), 20 NDMM pts (median age 71, range 54-88), 20 RRMM pts (median age 71, range 54-80) were analyzed. RRMM pts were exposed to 1 (n=8), 2 (n=6) or 3 (n=6) lines of treatment. All RRMM pts were exposed to a proteasome inhibitor, 75% were exposed to an immunomodulatory drug, and 65% received autologous stem cell transplantation. 48 out of 50 samples were processed by scRNAseq, 45 by CyTOF and 33 by flow cytometry. NDMM pts demonstrated a trend towards lower frequency of CD4 T cells compared to HD. This decreased number was accompanied by a decrease in the expression of genes involved in mitochondrial oxidative phosphorylation and an increase in expression of immediate early response genes (e.g. FOS, JUN, JUNB). In the CD8 compartment, CD8 naive cells were lower in NDMM compared to HD. No differences were found on CD8 central memory, effector memory and/or terminal effector populations In RRMM, the proportion of naive CD4 cells was significantly lower compared to NDMM (p < 0.05 by scRNAseq and CyTOF). This was confirmed by conventional flow cytometry (p < 0.05). No differences in CD4 central memory, effector memory and/or terminal effector proportions were observed. Decreases in the proportion of naive CD4 cells were observed as early as after 1 line of treatment and did not correlate with age, absolute lymphocyte count, previous exposure to lenalidomide or cyclophosphamide cumulative dose. Exposure to higher melphalan doses corelated with lower proportion of CD4 naive T cells. Compared with T cells from NDMM, T cells harvested from RRMM pts expressed higher levels of activation/exhaustion markers such as PD1 (p < 0.05) and HLA-DR (p < 0.05). <h3>Conclusion</h3> T cell phenotypes in MM pts are altered, especially after treatment. These findings may provide the rationale for the investigation of immunotherapy in NDMM and less heavily pretreated MM. Ongoing functional studies will demonstrate whether these phenotypic and transcriptomic changes lead to less fit T cells with consequent impact on effectiveness of T cell directed therapies.

Impact of Daratumumab Monotherapy on Bone Parameters in Patients with Relapsed and/or Refractory Multiple Myeloma Who Have Received at Least 2 Prior Lines of Therapy Including Lenalidomide and a Proteasome Inhibitor; Interim Analysis of a Phase 2 Study (the REBUILD Study)

Impact of Daratumumab Monotherapy on Bone Parameters in Patients with Relapsed and/or Refractory Multiple Myeloma Who Have Received at Least 2 Prior Lines of Therapy Including Lenalidomide and a Proteasome Inhibitor; Interim Analysis of a Phase 2 Study (the REBUILD Study)

Demographic Characteristics and Treatment Patterns of Relapse / Refractory Multiple Myeloma PTS: Charismma Study and Insight MM Registry in Spain

In Spain, the evidence related to the treatment of MM population according to patient's characteristics is scarce. There are no demographic studies that elucidate the impact of patient and disease characteristics on treatment selection strategies. Based on that, interim results of two studies in Spanish population have been analysed independently

Promising Clinical Efficacy and Toxicity Profile of Isatuximab Based Regimens for Treatment of Newly Diagnosed and Relapsed/Refractory Multiple Myeloma: A Systematic Review

Introduction:Despite the recent advancements in the treatment of multiple myeloma (MM), there is a constant need of newer therapies in order to treat the complex issue of the disease relapse and refractory disease. Isatuximab (ISA) is a non-Food and Drug Administration (FDA) anti-CD38 monoclonal antibody that acts through immune cell engagement and direct tumor targeting. We report efficacy & toxicity of ISA in newly diagnosed MM ((NDMM) as well as relapsed, refractory MM (RRMM) patients (pts).Methods:Following Prisma guidelines, we performed a comprehensive literature search on articles published after January 2012 using PubMed, Embase, Cochrane Library, Web of Science and Clinicaltrials.gov. On initial search, 246 articles were found and after a detailed screening, 6 completed and 11 ongoing phase I/II/III studies were included.Results:A total of 249 pts were included. Two hundred thirty-four pts had RRMM while 15 pts had NDMM, overall response rate (ORR) was 37.60% and 87% respectively. In a phase I trial involving 34 pts with RRMM, single-agent ISA (1-20 mg/kg) was given. The median age of pts was 64 years (y) [range (r) = 38-85]. The overall response rate (ORR) was 24% with a partial response (PR) in 18% pts. The most common adverse events (AEs) were nausea (34%), fatigue (49%), fever (29%) and headache (26%) and upper respiratory infection (23%). In a phase II trial, 97 pts with RRMM were stratified into 4 groups. Single-agent ISA [3mg/kg, every 2 week,(Q2W); 10 mg/kg, Q2W - every 4 weeks (Q4W); 10 mg/kg (Q2W), 20 mg/kg (QW-Q2W)] was given. The median age of pts was 62.5 y (r = 38-85). The ORR was 9%, 20%, 29% and 24% respectively. The cumulative ORR was 20.6%. The median time to first response was 1.4 months (M) while the median duration of response was 6.6 M. The most common AEs were nausea (33%), fatigue (30%), diarrhea (26%) and cough (24%). In a phase Ib trial, 57 pts with RRMM were stratified into 5 groups. ISA [3 mg/kg (Q2W); 5 mg/kg (Q2W); 10 mg/kg (Q2W); 10 mg/kg (QW-Q2W); 20 mg/kg (QW-Q2W)] in combination with lenalidomide (R) (25mg), and dexamethasone (D) (40 mg) was given. The median age of pts was 61 y (r = 42-76). The median time since the initial diagnosis was 4 y. The ORR was 33%, 67%, 63%, 50%, and 50% respectively. The cumulative ORR was 56% with complete response (CR) in 3.8 % pts, very good partial response (VGPR) in 32.7 % pts and PR in 19.2 % pts. The progression-free survival (PFS) was 8.5 M (r=4.73-16.59). The most common grade 3 and 4 AEs were neutropenia (60%), lymphopenia (58%), leukopenia (53%), anemia (25%), thrombocytopenia (38%), pneumonia (9%), fatigue (7%), and dyspnea (4%). In another phase Ib trial, 36 pts with RRMM were stratified into 3 groups. ISA (5 mg/kg; 10 mg/kg, 20 mg/kg) in combination with pomalidomide (P) (4 mg), and D (40 mg) was given. The ORR was 63%, 55%, and 50% respectively. The cumulative ORR was 55.5%. The median time to first response was 4.1 weeks (W) while the median duration of response was 33.1 W. The most common grade 3 AEs were neutropenia (81%), lymphopenia (75%), and leukopenia (75%). In another phase Ib trial involving 10 pts with RRMM, ISA (10-20 mg/kg) in combination with carfilzomib (CFZ) (27 mg) was given. The median number of prior lines of therapy was 4.5 (2-8). The ORR was 80% with VGPR in 20% pts and PR in 60% pts. The most common grade 3 and 4 AEs were lymphopenia (64%), anemia (9%), and neutropenia (9%). In a phase Ib trial involving 15 pts with NDMM, ISA (10 mg) in combination with bortezomib (V) (1.3 mg/m2) and cyclophosphamide (CY) (300 mg/m2) was given. The median age of pts was 71 y (r= 68-80). The ORR was 87% with CR in 33% pts, VGPR in 27% pts, and PR in 27% pts. The median time to first response was 1.5 M while the median duration of response was 11 M. The most common grade 3 and 4 AEs were lymphopenia (50%), leucopenia (18%), neutropenia (8%), anemia (6%) and thrombocytopenia (6%).Conclusion:In RRMM pts, ISA as a single agent has shown weaker efficacy when compared to combination regimens i.e. ORR 21% vs. 58%. The best result was seen when ISA was used in combination with CFZ demonstrating an ORR of 80%. In NDMM pts, combination regimens have shown excellent efficacy with an ORR of 87%. Nausea and fatigue were the major AEs reported with the monotherapy while neutropenia, leucopenia, and lymphopenia were the major AEs reported with the combination regimens. Further studies involving a larger population are required to gather evidence in favor of the improved efficacy and to evaluate AEs. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparative Effectiveness of Daratumumab Monotherapy Versus a Real-World Historical Control from the Czech Republic in Heavily Pretreated and Highly Refractory Multiple Myeloma Patients

BACKGROUND: The European Commission has granted conditional approval to daratumumab (DARA) as monotherapy in adult patients (pts) with relapsed or refractory multiple myeloma (MM) whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) and who have demonstrated disease progression on the last therapy. DARA was approved under an accelerated assessment based on single-arm phase 2 studies. Outcomes in these heavily pretreated pts in a real-world (RW) setting can provide evidence on the relative treatment efficacy of DARA versus physician's choice (PC).AIMS: To perform an adjusted comparison of overall survival (OS) and progression-free survival (PFS) for DARA monotherapy versus PC, as observed in a RW historical cohort of heavily pretreated and highly refractory MM pts from the Czech Republic using pt-level data.METHODS: Using RW longitudinal pt chart data from the Registry of Monoclonal Gammopathies (RMG) of the Czech Myeloma Group, pts with ≥2 prior lines of therapy previously exposed to both a PI and an IMiD were identified. Pt-level data from the RMG were pooled from pivotal DARA monotherapy studies (pts treated with DARA 16 mg/kg). Pts in the RMG could contribute information to the analysis for multiple lines of therapy, with baseline defined as the date of initiation of the actual treatment line. For the definition of PFS, missing data for the date of disease progression for pts in the RMG who initiated subsequent therapy were replaced by the conservative proxy of the date of initiation of the next treatment. OS and PFS were analysed using a Kaplan-Meier analysis. To adjust for confounding variables, a multivariate Cox proportional hazards regression was developed that included age, gender, beta-2 microglobulin levels (β2M : <3.5/3.5-5.5/>5.5 g/L), albumin levels (<3.5/≥3.5 g/L), line of therapy (3-13), prior exposure to pomalidomide/carfilzomib, refractory status (none/double/triple/quadruple), andincidence of thrombocytopenia (defined as platelet counts <150.000 per µL) as covariates. Predicted PFS and OS curves for the RMG cohort were derived from the multivariate model.RESULTS: From the RMG database, we identified 971 treatment lines in 463 pts previously exposed to both a PI and an IMID (n=206 in third line, n=256 in fourth line, n=203 in fifth line, n=307 in ≥sixth line). The dates of treatment initiation for the RMG pts ranged from March 2006 to March 2015. The most frequent treatment regimens were lenalidomide (33.4%), chemotherapy (18.1%), bortezomib (13.6%), thalidomide (8.0%), and bortezomib+thalidomide (5.3%). The number of pts treated with carfilzomib (2.5%) and pomalidomide (2.4%) was limited. DARA-treated pts (N=148) differed from the RMG cohort in median age (64 vs 62 years), median prior lines of therapy (5 vs 4), prior exposure to carfilzomib (41.2% vs 0.3%) and pomalidomide (55.4% vs 0.6%), thrombocytopenia incidence (46.9% vs 18.0%), and ≥triple refractory status (64.2% vs 5.3%). Median observed PFS and OS for DARA versus PC were 4.0 and 5.6 months, respectively, for PFS and 20.1 and 11.9 months, respectively, for OS. Older age, male sex, low albumin levels, high β2M levels, thrombocytopenia incidence, and double/triple/quadruple refractory status were all independent, statistically significant risk factors for mortality. Albumin levels, β2M levels, thrombocytopenia incidence, and refractory status were also predictive of PFS. The adjusted hazard ratio (95% confidence interval) for OS and PFS for DARA versus PC was 0.35 (0.22-0.56) and 0.79 (0.56-1.12), respectively. Figure 1 represents the predicted survival curves for the RMG cohort that were derived from the multivariate model, comparing observed PFS/OS versus predicted with DARA treatment.CONCLUSIONS:This adjusted treatment comparison suggests a significant improvement in OS and a numerical improvement in PFS for DARA compared to RW historical control data in heavily pretreated/highly refractory MM pts. The lower PFS benefit estimate for DARA compared to OS may be partly explained by limitations in the availability and comparability of data regarding progressive disease in the RMG cohort compared to clinical trial data. Adjusted comparisons between trial data and historical cohorts can provide useful insights to clinicians and reimbursement decision makers on relative treatment efficacies in the absence of head-to-head comparison studies for DARA monotherapy. [Display omitted] DisclosuresHájek:Amgen: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Spicka:BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millenium: Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Gatopoulou:Janssen Health Economics & Market Access EMEA: Employment. Vesela:Janssen Cilag s.r.o., Czech Republic: Employment. Diels:Johnson & Johnson: Employment, Equity Ownership. Besson:Janssen: Employment. Ito:Janssen: Employment, Equity Ownership.

Results of an Open, Non-Comparative, Phase I/II Investigator Initiated Trial (IIT) in Relapsed or Refractory Multiple Myeloma Patients Using Vorinostat, Bortezomib, Doxorubicin and Dexamethasone (VBDD)

Introduction: Multiple myeloma (MM) relapse is common and may eventually lead to highly refractory/relapsed MM (RRMM). Therefore, novel treatment combinations are crucially needed for this highly challenging subgroup of patients (pts). The aim of the here presented phase I/II IIT was to test the tolerability and activity of a novel, so-called VBDD schedule within an outpatient regimen for extensively pretreated RRMM pts. In addition to Bortezomib, Doxorubicin and Dexamethason, which are all active and approved drugs in RRMM, Vorinostat has shown promising anti-tumor effects as a histone deacetylase inhibitor (HDACi). It inhibits the enzyme activity of HDAC 1, 2, 3 and 6, thereby allowing the activation of tumor suppressor genes. MM cells have been shown to escape from bortezomib treatment by formation of aggrosomes which desensitize cells to proteasome inhibitors and by microtubule mediated protein shuttling to lysosomes, where proteins are degradaded in order to prevent cytotoxic stress and ultimately escape from apoptosis (Fig.A). Albeit vorinostat has shown moderate activity when given alone, it has promising additive effects when combined with other antimyeloma agents, and was therefore used as an add-on agent within this RRMM regimen as it blocks microtubule coppling and aggrosome building and thereby may antagonize escape mechanisms in bortezomib-refractory pts.Methods: Vorinostat was escalated from 100mg (dose level 0), to 200mg (+1) and 300mg (+2). Primary objectives (MTD; 3+3 dose escalation), secondary objectives (safety, IMWG responses, PFS, OS) and supplementary endpoints (organ function, prognostic factors, QoL, comorbidity and HDAC-activity in PBMCs/BM) were assessed throughout the trial. Dose limiting toxicities (DLTs) were defined as any possibly drug-related adverse event (AEs) ≥grade 3 (CTCAE) during the 1st cycle. After completing 6 cycles, patients could receive either a bortezomib maintenance therapy or next-line treatment (e.g. 2nd ASCT).Results: 34 pts with RRMM with a median age of 63 years (47-78) and KPS of 90% (70-100%) have been enrolled, of which 33 received therapy according to the study protocol (1 pt deceased prior to study start due to aggressive MM progression and was therefore not included in the evaluation). The number of prior therapy lines was substantial with a median of 3 (1-8; with prior bortezomib, SCT and IMiDs in 88%, 94% and 42%, respectively). 3 pts each were treated in dose levels 0 and +1, and the remaining 27 pts in dose level +2. No DLTs were observed. In our current analysis, SAEs amounted to 15 and occurred in 9/33 pts (27%): Amongst them, 2 nonfatal SAEs were judged to be related to the investigational therapy (1 bacteraemia, 1 herpes zoster), for the others, no causal relationship to VBDD was found. The response according to IMWG criteria was rewarding with best ORR (>PR) and clinical benefit rate (CBR; >SD) of 42% and 94% (Fig. B), and end of treatment (EoT) ORREoT and CBREoT of 36% and 88%, respectively (Fig.C). Our data also revealed that the response was independent of the presence or absence of unfavorable cytogenetics. Comorbidity assessments assured no decline in pts' mental or physical condition and pts reported preserved or improved QoL with this well-tolerated 4-agent treatment regimen. Pharmacodynamic analyses in peripheral blood (PB) MCs showed substantial and early HDAC downregulation between VBDD cycles 1 and 2 in 11/16 pts (69%): median HDAC activity decreased to 52% of pre-treatment levels. Thereby, we were able to distinguish 3 groups of pts with substantial, more subtle or no PB HDAC decreases in 8, 3 and 5 pts, respectively. Of note, these HDAC changes correlated well with pts' serological and clinical responses, except in 2 pts. These intriguing results are currently further assessed and will be presented at the meeting.Conclusions: VBDD demonstrated to be an effective and well-tolerated outpatient regimen with promising response rates in heavily pretreated RRMM pts. The employed VBDD regimen, with a continuous, rather than pulsed vorinostat-schedule, constitutes a promising treatment option, expands current standard therapies and, similarly to other HDACi (i.e. panobinostat), suggests HDACi as a valuable add-on within this combination schedule in order to stabilize the disease and/or bridge RRMM patients to next-line treatments (i.e. autologous/allogenic stem cell transplantation) or novel clinical trial drugs.*AK and JW contributed equally [Display omitted] DisclosuresOff Label Use: We report on results of an Phase I/II IIT, in which the HDACi Vorinostat is used to treat relapsed or refractory Multiple Myeloma pts . Engelhardt:MSD: Research Funding; Janssen-Cilag: Research Funding; Comprehensive Cancer Center Freiburg: Research Funding; German Cancer Aid: Research Funding. Wäsch:German Cancer Aid: Research Funding; Janssen-Cilag: Research Funding; Comprehensiv Cancer Center Freiburg: Research Funding; MSD: Research Funding.

Evaluation of Institutional Non-Core Chemotherapy Regimens Approved for the Treatment of Leukemia and Multiple Myeloma

The University of Wisconsin Chemotherapy Council (UWCC) monitors the uniformity and appropriateness of chemotherapy administration at the University of Wisconsin Hospital and Clinics through a peer-review process. One aspect involves approval of "patient specific requests" (PSRs) that involve treatments not included in the institution's core regimens. Providers are asked to submit published evidence, information regarding pt. comorbidities, and clinical justification to support the application. However there is no current stipulation regarding demonstration of value, although implicit in this review process is to avoid futile, expensive or potentially harmful treatments. Given the ever burgeoning chemotherapeutic choices available for patients with any stage of disease, and the complexity of selecting an optimal therapeutic regimen, we hypothesized that some approved PSRs might have provided limited benefit to the pts who received them. Therefore, we undertook an analysis of PSRs specifically submitted for patients with leukemia and multiple myeloma (MM) between 1/1/2011 and 7/31/2014 to exam reasons for the submission as well as outcomes after the new therapy was initiated. METHODSA total of 307 PSRs were reviewed by the UWCCC during this time period. Forty-one were specifically submitted and approved for patients with leukemia or MM. Reason for PSR, status at initiation, previous transplant, and days of hospitalization after PSR and 1 year survival were calculated. Table 1DiagnosisNumberStatus at time of PSRPrevious TransplantMedian No previous regimensReason for PSR submissionPSR RegimenMean Survival After PSR starts1 yr. survivalAML, relapsed8Refractory relapse88%3No SOC1Various236d (range 88-575d)12%AML, other2Remission01Nonstandard Transplant regimenTransplant regimen533 d100%CML, relapsed2RefractoryNo3Failed all previous regimensTransplant regimen289d50%ALL, newly diagnosed5UntreatedNA0Adult treated on pediatric regimen (n=3); elderly (n=2)Various551d (range 365-981d)100%ALL, relapsed5Relapsed20%3 (range 1-8)No SOC1CVP2, TKI3 based;, BFM4408d (range 167-735d)40%MM15Relapsed, refractory (n=15) 100%73% (auto)7 (range 2-10)Not core regimen (n=13) Rare subtype(n=2)PCP5 (n=3); CRD6 (n-4) other272 d ( range 74-661)60%APL4untreatedN/AN/ANot Core RegimenATRA/Arsenic, other788d (range 692-910d)100%1SOC; 2cyclophosphamide, vincristine prednisone; 3tyrosine kinase inhibitor; 4Berlin/Frankfurt/Munich; 5Pomalidomide, cyclophosphamide, prednisone; 6carfilzomib, lenalidomide dexamethasone RESULTSA total of 41 PSRs were examined. The most common reasons for submission of the PSR was request for a non-core regimen including a recently FDA approved use of an agent (n= 11); no current SOC established (n=13); salvage therapy with older regimen ((n=2). Median 1 yr. survival varied from 12% to 100% depending on diagnosis. Not surprisingly, APL pts displayed the best overall survival, followed by AML, transplanted with a nonstandard conditioning regimen. AML patients relapsing after previous allogeneic transplant had the worst survival, regardless of salvage regimen; only 1 pt. survived longer than 6 months. The median length of hospital stay in these patients following start of PSR was 43 d (range 14-54). Relapsed ALL pts also fared poorly, with 1 year survival of 40% and median days of hospitalization after PSR of 48d (range 0-117). Relapsed refractory MM pts had a variable outcome, with some pts surviving more than 3 years and others for only several months. CONCLUSIONUse of peer reviewed PSRs resulted in reasonable outcomes in most patients with leukemia and myeloma. However, pts with AML relapsing after allogeneic transplant and those with relapsed ALL fared particularly poorly despite treatment with a peer reviewed treatment plan, presumably chosen for best outcome. Furthermore, these salvage treatments were associated with lengthy hospital stays. Such patients are unlikely to benefit from any currently available regimens and may be more appropriately considered for clinical trials or supportive/ palliative care at time of relapse. DisclosuresNo relevant conflicts of interest to declare.

Selinexor Demonstrates Marked Synergy with Dexamethasone (Sel-Dex) in Preclinical Models and in Patients with Heavily Pretreated Refractory Multiple Myeloma (MM)

Introduction: The nuclear export protein exportin 1, (XPO1) is overexpressed in a wide variety of cancers including MM and often correlate with poor prognosis. Selinexor (KPT-330) is an oral Selective Inhibitor of Nuclear Export (SINE) XPO1 antagonist in Phase 1 and 2 clinical studies. Selinexor forces nuclear retention and reactivation of tumor suppressor proteins (TSPs) and reduction of many proto-oncogenes, including MDM2, MYC and Cyclin D. In addition, selinexor potently deactivates NF-κB, through forced nuclear retention of IκBα. Together these effects induce selective apoptosis in MM cells and inhibition of NF-κB dependent osteoclast activation. XPO1 is also responsible for nuclear export of the glucocorticoid receptor (GR). We hypothesized that selinexor will enhance the activity of dexamethasone (DEX)-bound GR, resulting in synergistic tumor cell killing. Methods: In vitro tumor cell viability measurements were based on MTT (CellTiter 96¨/Promega) and combination indices were calculated using CalcuSyn software. For xenograft studies, utilized NOD-SCID mice with subcutaneous inoculation of MM.1s cells. GR nuclear localization was measured with immunofluorescent anti-GR (phosphor-S211) antibody and quantitative imaging. To assess GR transcriptional activation, GR binding to a GCR consensus sequence was measured in nuclear extracts using an ELISA method (GR ELISA kit/Affymetrix). Patients (pts) with heavily pretreated refractory MM were dosed with oral selinexor at doses of up to 60 mg/m2 (8-10 doses/4 wk cycle) as part of a Phase 1 program in advanced hematological malignancies. Response we defined based on the IMWG criteria. The effect of combining DEX with selinexor was analyzed in all pts who received selinexor at moderate to high doses (30-60 mg/m2). Safety and efficacy were analyzed separately in three groups: no DEX, Disclosures Chen:Celgene: Honoraria; Janssen: Honoraria. Off Label Use: Lenalidomide maintenance therapy after ASCT. Gutierrez:Senesco: PI Other. Siegel:Celgene, Millennium, Onyx: Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau. Baz:Celgene: Research Funding; Millennium: Research Funding; Bristol Myers Squibb: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding. Kukreti:Celgene: Honoraria. Azmi:Karyopharm Therpeutics: Research Funding. Kashyap:Karyopharm Therapeutics: Employment. Landesman:Karyopharm Therapeutics: Employment. Marshall:Karyopharm Therpeutics: Employment. McCartney:Karyopharm Therpeutics: Employment. Saint-Martin:Karyopharm Therpeutics: Employment. Norori:Karyopharm Therpeutics: Consultancy. Savona:Karyopharm Therpeutics: Membership on an entity9s Board of Directors or advisory committees. Rashal:Karyopharm Therapeutics: Employment. Carlson:Karyopharm Therapeutics: Employment. Mirza:Karyopharm Therpeutics: Consultancy, Membership on an entity9s Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics Inc.: Employment, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership. Reece:Millennium: Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Merck: Research Funding; Merck: Research Funding; BMS: Research Funding; BMS: Research Funding; Novartis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen : Honoraria; Amgen : Honoraria.

The MM-021 Trial Of Lenalidomide Plus Low-Dose Dexamethasone In Chinese Patients With Relapsed and Refractory Multiple Myeloma: Impact Of Prior Therapies On Efficacy and Safety

BackgroundThe combination of lenalidomide (LEN) and low-dose dexamethasone (LoDEX) is approved in China for the treatment of multiple myeloma (MM) patients (pts) who have received at least 1 prior antimyeloma treatment. The MM-021 China registration study demonstrated the efficacy and safety of LEN + LoDEX (Rd). This sub-analysis investigated the impact of the number of prior antimyeloma therapies on treatment outcomes. MethodsMM-021 was a phase 2, multicenter, single-arm, open-label study. Relapsed and refractory MM (RRMM) pts (aged ≥ 18 yrs) were given LEN (25 mg/day on days 1-21) and LoDEX (40 mg/day on days 1, 8, 15, and 22) in 28-day treatment cycles until disease progression or discontinuation. Pts included in the pharmacokinetics cohort did not receive DEX on day 1, cycle 1. All pts received thromboprophylaxis during the study. The primary end-point was best overall response rate (ORR), defined as the percentage of pts who achieved a best response of at least partial response. Secondary end-points included progression-free survival (PFS), time to progression (TTP), overall survival (OS), and safety. Data were analyzed according to the number of therapies that pts had received prior to study screening: 1-2, 3-4, or > 4. ResultsThe analysis cut-off date was January 4, 2013, with a median follow-up of 17.6 mos. All pts in the intent-to-treat (ITT) population (N = 199) were included in the safety analysis, and 187 pts were included in the efficacy-evaluable (EE) population. At the cut-off date, 42 pts had completed treatment and 157 had discontinued. Overall, the median age of pts was 59.0 yrs (range 35-81) and 62.8% were male. The majority of pts had advanced disease (85.9% had Durie-Salmon stage III MM); 40.7% of pts (ITT population) had received > 4 prior anti-myeloma therapies; 33.2% had received 3-4, and 26.1% had received 1-2. Most pts had received prior treatment with thalidomide (THAL; 68.8%) or bortezomib (BORT; 63.8%) (Table 1). After a median treatment duration of 8.3 mos (range 0.9-24.8) or 9 treatment cycles (range 1-27), the ORR was 47.6% in the overall EE population, and highest in pts who had received 1-2 prior therapies (Table 2). Median OS, PFS, and TTP were longer in pts who had received 1-2 prior therapies compared with those who had received 3-4 and > 4 prior therapies, and compared with the overall EE population (Table 2). In the safety population, the most common grade 3-4 treatment-emergent adverse events (TEAEs) were anemia (26.1%), neutropenia (25.1%), thrombocytopenia (14.6%), pneumonia (13.1%), leukopenia (9.5%), and decreased neutrophil count (8.5%). In general, grade 3-4 TEAE rates were lower in pts who had received 1-2 prior therapies (60%), and comparable in pts who had received 3-4 (71%), > 4 prior therapies (75%), and the overall safety population (70%). There were 2 reports of grade 3-4 peripheral neuropathy. AEs resulted in discontinuation of LEN in 5.8% (n = 3), 10.6% (n = 7) and 9.9% (n = 8), of pts who had received 1-2, 3-4 and > 4 prior therapies, respectively. [Display omitted] [Display omitted] ConclusionRd is an effective treatment option for Chinese RRMM pts who have relapsed after one or more prior therapies, including THAL and/or BORT. More robust efficacy and higher ORR was observed for Rd in patients who had received 1-2 prior therapies compared to those who had received additional lines of treatment. The tolerability of Rd was similar in heavily and less heavily pretreated pts. Discontinuations were infrequent, even in heavily pretreated pts who had received > 4 prior therapies. Disclosures:Zhang:Celgene Corporation: Employment, Equity Ownership. Wortman-Vayn:Celgene Corporation: Employment, Equity Ownership. Mei:Celgene: Employment, Equity Ownership. Hou:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; J & J: Honoraria, Membership on an entity's Board of Directors or advisory committees.

PFS2 In Elderly Patients With Newly Diagnosed Multiple Myeloma (NDMM): Results From The MM-015 Study

IntroductionIn a phase 3 trial of transplant non-eligible elderly (≥ 65 yrs) patients (pts) with NDMM, the combination of melphalan-prednisone-lenalidomide (LEN) followed by LEN maintenance (MPR-R) reduced the risk of progression by 60% compared with 9 cycles of MP (HR=0.40; P < 0.001) and by 51% compared with 9 cycles of MPR (HR=0.49; P < 0.001) (Palumbo, NEJM. 2012). The progression-free survival (PFS) benefit was seen in all patient types. With a median follow-up of 53 mos, the median overall survival (OS) was similar across the 3 treatment (Tx) groups (54 mos for MPR-R vs. 52 mos for MPR vs. 55 mos for MP) (Dimopoulos, ASH 2012; abstract 944). The similar OS benefit seen across the 3 arms could be due in part to the availability of more effective Tx options in subsequent lines of therapy. Assessment of PFS2, defined as the time from initial randomization to time of objective disease progression (PD) after next-line of therapy or death from any cause, has recently been proposed as a surrogate for OS, particularly for trials evaluating maintenance Tx (EMA guideline, www.ema.europa.eu). Therefore, data from MM-015 were analyzed to estimate PFS2 in pts treated with MPR-R, MPR, or MP. MethodsThe MM-015 study design has been previously described (Palumbo, NEJM. 2012). Refractory multiple myeloma pts who progressed during MM-015 study could receive LEN 25 mg (D1–21/28-day cycle) ± dexamethasone 40 mg (on days 1–4, 9–12, and 17–20) as part of an open-label extension phase, or any other anti-myeloma Tx outside of the protocol as part of the follow-up phase. The data of PD following 2nd-line Tx was not collected prospectively; therefore, the start of 3rd-line Tx was used as a surrogate for analyzing the PFS2 endpoint. The assessment included data up to July 31, 2012 (median follow-up: 53 mos after initial randomization). ResultsA total of 459 pts were randomized to MPR-R (n= 152), MPR (n= 153), or MP (n= 154). At the time of the data cut-off, fewer pts in the MPR-R group had started 2nd-line Tx (53%) compared with the MPR and MP groups (77% and 82%, respectively) due to the improved PFS seen with MPR-R in the 1st-line setting. Most pts in the MP group “crossed over” to receive LEN as 2nd-line Tx (72%); choice of 2nd-line Tx in the MPR-R group was heterogeneous (Table). Median PFS2 was significantly higher with MPR-R (39.7 mos) vs. MP (28.5 mos; HR=0.71; log-rank P = 0.013) (Figure). The safety profile of continuous therapy with LEN was predictable and manageable with little evidence of cumulative toxicity and low second primary malignancy risk (Delforge, IMW 2013: abstract O-17). [Display omitted] ConclusionPFS2 was markedly improved in the MPR-R group vs. the MP group. LEN provided a durable progression-free interval also when including the impact of 2nd-line Tx, confirming the clinical benefits of continuous LEN Tx. The benefit of MPR-R was apparent regardless of subsequent Tx; long-term treatment with LEN did not affect the efficacy of subsequent therapy. Use of continuous LEN in the 1st-line setting in combination with MP is more beneficial than sequential use of MP and LEN. PFS and PFS2 were improved with MPR-R; OS was similar among the 3 Tx groups; the reason for this is unclear, but may be related to the impact of subsequent Tx (i.e., 3rd and 4th line), which was more frequently needed in the MPR and MP groups. Disclosures:Dimopoulos:Orthobiotech: Honoraria; Celgene Corporation: Honoraria. Off Label Use: Lenalidomide in the frontline and maintenance treatment of multiple myeloma. Petrucci:Celgene Corporation: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Catalano:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yu:Celgene Corporation: Employment, Equity Ownership. Grote:Celgene Corporation: Employment, Equity Ownership. Jacques:Celgene Corporation: Employment, Equity Ownership. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria.

Elotuzumab in Combination with Lenalidomide and Low-Dose Dexamethasone in High-Risk and/or Stage 23 Relapsed and/or Refractory Multiple Myeloma: A Retrospective Subset Analysis of the Phase 2 Study,

Elotuzumab in Combination with Lenalidomide and Low-Dose Dexamethasone in High-Risk and/or Stage 23 Relapsed and/or Refractory Multiple Myeloma: A Retrospective Subset Analysis of the Phase 2 Study,

Investigational Agent MLN9708, An Oral Proteasome Inhibitor, in Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (MM): Results From the Expansion Cohorts of a Phase 1 Dose-Escalation Study

Abstract 301 Background: The investigational agent MLN9708 is the first oral proteasome inhibitor (PI) to enter clinical investigation in MM pts. MLN9708 has shown antitumor activity in solid tumor and hematologic malignancy xenograft models, including in vivo models of MM. The primary objectives of this study (NCT00932698) were to determine safety/tolerability, maximum tolerated dose (MTD), and recommended phase 2 dose of oral MLN9708 in pts with relapsed and/or refractory MM. Secondary objectives included evaluation of response rate and characterization of pharmacokinetics (PK, of MLN2238, the biologically active hydrolysis product) and pharmacodynamics (20S proteasome inhibition in blood). Methods: Pts aged ≥18 years with measurable disease and no grade ≥2 peripheral neuropathy (PN) were eligible. For the dose-escalation phase (3+3 design), pts required ≥2 prior therapies, which must have included bortezomib, thalidomide or lenalidomide, and corticosteroids. Pts could have received other PIs. At the MTD, pts were enrolled to four expansion cohorts: relapsed and refractory cohort (progressive disease [PD] on therapy or Results: As of June 29 2011, 53 pts have been enrolled (53% male). Median age was 66 years (range 50–86), median time since initial MM diagnosis was 4.6 years (range 1.1–24.3), and median number of prior therapies was 4 (range 1–28); 55% of pts had received stem cell transplant, 92%, 80%, 56%, and 4% had prior bortezomib, lenalidomide, thalidomide, and carfilzomib, respectively, and 47% were refractory to last therapy, including 28% who were bortezomib-refractory. During dose escalation, 27 pts received MLN9708 0.24–2.23 mg/m2; the MTD was determined as 2.0 mg/m2. To date, 32 pts have been enrolled to the expansion cohorts (including 6 from the dose-escalation phase): 17, 11, and 4 to the relapsed and refractory, bortezomib-relapsed, and PI-naive cohorts, respectively. Overall, pts have received a median of 3 cycles (range 1–17), with 6 (11%) receiving ≥12 cycles. At data cut-off, 58% of pts had discontinued, mainly due to PD (36%). Safety profiles appeared similar between dose-escalation and expansion cohorts. Overall, 87% of pts experienced drug-related AEs, the most common being fatigue (45%), thrombocytopenia (30%), nausea (26%), diarrhea (25%), vomiting, and rash (each 23%). Only four (8%) pts had drug-related PN (three grade 1, one grade 2); all had grade 1 PN (n=3) or paresthesias (n=1) at baseline. Overall, 58% had grade ≥3 AEs, 21% had dose reductions, and 6% discontinued due to AEs (thrombocytopenia, arthralgia, hypoxia). Two pts died on study due to PD and a cardiac disorder, considered unrelated. To date, of 36 evaluable pts, six have achieved minimal response or better, including two with partial responses (in the 1.2 and 2.23 mg/m2 cohorts), with duration of disease control of up to 11.3 months; all 6 pts remain in response. Another 22 pts have achieved stable disease, which also proved durable with stabilization for up to 9.9 months. MLN9708 was rapidly absorbed with MLN2238 Tmax of 0.5–1.25 hours and terminal half-life of approximately 4–5 days after multiple MLN9708 dosing. MLN2238 plasma exposure appeared to increase proportionally with increasing MLN9708 dose from 0.8–2.23 mg/m2. Maximal 20S proteasome inhibition in blood was immediate and dose-dependent. Conclusions: Current data suggest that single-agent MLN9708 may result in clinical activity in heavily pretreated relapsed and/or refractory MM pts, including durable disease control, and is generally well tolerated, with infrequent PN. Updated information for all cohorts, plus data from an analysis of candidate biomarkers of responsiveness to treatment with MLN9708, will be presented. Disclosures: Richardson:Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Johnson & Johnson: Consultancy. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed and/or refractory multiple myeloma. Baz:Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Orthobiotech: Research Funding. Wang:Millennium Pharmaceuticals, Inc.: Research Funding. Jakubowiak:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho Biotech: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria. Berg:Millennium Pharmaceuticals, Inc.: Employment. Liu:Millennium Pharmaceuticals, Inc.: Employment. Gupta:Millennium Pharmaceuticals, Inc.: Employment. Di Bacco:Millennium Pharmaceuticals, Inc.: Employment. Hui:Millennium Pharmaceuticals, Inc.: Employment. Lonial:Millennium Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy.

Phase I study of combined vorinostat (V), lenalidomide (L), and dexamethasone (D) in patients (pts) with relapsed or refractory multiple myeloma (MM).

8031 Background: MM remains incurable despite recent therapeutic advances. Although novel treatment combinations have improved outcome, new combinations are urgently needed. V, an oral histone deacetylase inhibitor, enhances anti-MM activity of other small molecule pro-apoptotics, with preclinical synergy seen when combined with L. This ongoing phase I multicenter, open-label study evaluated V plus L and D. Maximum tolerated dose (MTD; primary objective), safety, tolerability, and response rate (RR) were assessed. Methods: Relapsed and/or refractory MM pts were enrolled into 1 of 5 escalating doses of combination regimen using standard 3+3 design. Toxicity and response were evaluated using NCI c3.0 CTC and EBMT/UC. Results: Median prior therapies was 3 (range 1-12, N=31). Most pts received prior bortezomib (65%), thalidomide (68%), or L (45%). The majority ofadverse events(AEs) were mild/moderate; most common ≥G3 drug-related AEs (all cycles) were neutropenia (23%), thrombocytopenia (16%), diarrhea (13%), and fatigue (10%). One dose-limiting toxicity was seen (Table), with MTD not reached. Of 30 pts evaluable for efficacy, 26 (87%) experienced ≥ stable disease (SD); best single responses were 2 complete, 2 very good partial (VGPR), 10 partial (PR), 5 minimal (MR), 7 SD, and 4 progressive disease, for RR (≥ MR) of 63%. Of 13 evaluable pts who received prior L, ≥ SD was seen in 9 (69%), with 1 VGPR, 3 PR, 1 MR, and 4 SD, for RR (≥MR) of 38%. Conclusions: Preliminary results suggest V, L, and D may be a convenient, effective, and generally well tolerated oral regimen for relapsed/refractory MM pts. Activity was also seen in pts who received prior L. Further analysis of this study is ongoing and a phase II study is planned. Dosing Dose level (DL) V(mg qd)7 days on 7 off(days 1-7 and 15-21) L(mg qd)× 21 days(day 1-21) D(mg qd)(days 1, 8, 15, and 22) Evaluable for DLT† Maximum cycles‡ DLT 1 300 10 40 3 19 0 2 400 10 40 3 15 0 3 400 15 40 3 11 0 4 400 20 40 3 12 0 5 400 25 40 6 (+10§) 12 Diarrhea (G3) Cycles: 28 days. Concomitant daily aspirin recommended. † 10/31 pts (across all DLs) remain ongoing. ‡ Maximum treatment cycle for which ≥1 pt received ≥1 dose. § 10-pt expansion cohort enrolled at DL 5 with no formal DLT assessment. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Celgene, Dana-Farber Cancer Institute, Merck Bristol-Myers Squibb, Celgene, Merck, Millennium, Novartis, Ortho Biotech, Pharmion Merck Celgene, Janssen-Ortho, Merck, Millennium, Novartis, Onyx, Ortho Biotech, Pharmion Celgene, Gloucester Pharmaceuticals, Merck, Merck Serono, Millennium, Novartis

Phase I Study of Carfilzomib in Patients (Pts) with Relapsed and Refractory Multiple Myeloma (MM) and Varying Degrees of Renal Insufficiency.

Abstract 3877Poster Board III-813 BackgroundRenal impairment affects 20% of newly diagnosed MM pts and over 50% during the course of their disease. Renal impairment confers shorter survival due to high tumor load and the difficulty in delivering adequate doses of active drugs, such as alkylating agents and immunomodulatory drugs (IMiDs) due to enhanced side effects (Kyle, Mayo Clin 2003). Pts with renal insufficiency have been traditionally excluded from clinical trials. Carfilzomib (CFZ) is a novel peptide epoxyketone proteasome inhibitor designed to have a high level of selectivity for the proteasome. In previous Phase 2 studies, CFZ has demonstrated single agent activity in heavily pretreated MM pts including those with mild renal insufficiency. The primary objective of this study was to evaluate the tolerability and pharmacokinetic properties of CFZ in MM pts with renal insufficiency, including those on dialysis. MethodsIn this multicenter study, MM pts who had relapsed after at least two prior therapies were enrolled into 4 cohorts based on renal impairment: normal (CrCl > 80mL/min), mild (CrCl 50–80 mL/min), moderate (CrCl 30–49 mL/min), and severe (CrCl < 30 mL/min) including dialysis pts. The primary and secondary objectives of the study included pharmacokinetics (PK), safety, pharmacodynamics (PDn; proteasome inhibition in blood) and efficacy endpoints: ORR (overall response rate, ≥ PR) CBR (clinical benefit response, ≥ MR), duration of response (DOR) and time to progression (TTP). Pts received CFZ at a dose of 15 mg/m2 IV on day (D) 1, 2, 8, 9, 15 and 16 every 28 d for cycle (C) 1, with dose escalation to 20 mg/m2 in C2 and 27 mg/m2 in C3 and thereafter if tolerated. Pts received 40 mg of dexamethasone (Dex) in cycle 3 if they had less than a partial response (PR). Pts were followed for toxicity and efficacy over the course of the study. EKG changes from baseline including QT/QTc effects were assessed in C1 and C2. PK was measured on C1 D1,15 and C2 D15 and PDn was measured on C1 D1,2,8 and C2 D1. ResultsNineteen pts received at least 1 dose of CFZ and were evaluable for safety; 18 pts completed at least 1 C of CFZ and were evaluable for response and PK/PDn. All pts had refractory MM and 42% had progressed during their last therapy. The median number of prior therapies was 5 (range 2–10). All pts had received bortezomib and 26% were refractory; all pts received at lease one IMiD (90% thalidomide and 85% lenalidomide). Seventy percent had prior stem cell transplant. To date, pts have received a median of 3 cycles (range 1–7+) of CFZ; 9 pts have completed ≥ 6 cycles. The most common adverse events were fatigue, anemia, back pain and fever. There was no appreciable difference in the safety profile between the 4 cohorts either in frequency of events or in CTC-AE grade. Two deaths from disease progression with 1 complicated by a parainfluenza upper respiratory tract infection occurred while on study. No treatment emergent QT/QTc prolongations were observed during C1 and C2 in any group. Sixteen pts had grade 1 or 2 peripheral neuropathy at study entry and no cases of newly emergent or exacerbations occurred on study. Two pts discontinued drug due to worsening renal failure, one in the mild and one in the moderate cohort; both were related to disease progression. In all cohorts, CFZ was cleared with a t½ of 30–60 minutes and reached undetectable levels in plasma within 3 hours. There was no accumulation of CFZ after two cycles. Proteasome inhibition measured 1 hr post-dose in whole blood and PBMC ranged from 75–89% at doses of 15–20 mg/m2. PK and PDn were similar between the cohorts of pts with varying degrees of renal impairment. The ORR was 16.6% and CBR was 33.3%. Two BTZ-refractory pts achieved PR. An additional 38.9% had stable disease across all groups despite entering the study with progressive disease. Seven of 18 pts received Dex in ≥ C3 with 2 exhibiting an upgraded response (1 PR and 1 MR). ConclusionsCFZ can be administered to MM pts with substantial renal dysfunction and does not require dose adjustment. CFZ toxicities in this study were manageable and importantly, exacerbation of pre-existing PN or myelosuppression was not observed in these renally impaired MM patients. Responses in relapsed and refractory MM pts with renal insufficiency are encouraging. Further evaluation of CFZ in renally impaired patients is ongoing, including in patients receiving hemodialysis. Disclosures:Vij:Proteolix, Inc.: Consultancy, Research Funding. Zonder:Celgene: Speakers Bureau; Pfizer: Consultancy; Seattle Genetics, Inc.: Research Funding; Amgen: Consultancy; Millennium: Research Funding. Woo:Proteolix, Inc.: Employment. Wang:Proteolix, Inc.: Employment. Lee:Proteolix, Inc.: Employment. Wong:Proteolix, Inc.: Employment. Niesvizky:Millenium: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Seattle Genetics, Inc: Research Funding; Proteolix: Research Funding, data monitoring committee.

Final results of PX-171–003-A0, part 1 of an open-label, single-arm, phase II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM)

8504 Background: CFZ is a novel proteasome inhibitor of the epoxyketone class that exhibits a high level of proteasome selectivityand demonstrates antitumor activity in bortezomib (BTZ)-resistant MM pts in phase I studies. Methods: PX-171–003-A0 was an open-label, multicenter study that enrolled MM pts who relapsed from &gt;2 prior therapies, failed BTZ and at least 1 immunomodulatory agent [thalidomide (THAL) or lenalidomide (LEN)], and were refractory to last treatment [progressing on or within 60 d of last therapy or &lt;25% response to last therapy]. Pts received CFZ 20 mg/m2 IV d 1, 2, 8, 9, 15 and 16 every 28 d for up to 12 cycles (C). Clinical benefit response (CBR) was defined as MR or better. Results: 46 pts were enrolled, including 78% with progression on or within 60 d of last therapy and 22% with no response to last therapy. 39 pts completed at least 1 C of CFZ, had measurable M-protein, and were evaluable for response. Median prior therapies was 5 (range 2–15). 100% of pts received prior BTZ, 91% prior THAL, 89% prior LEN, and 83% prior stem cell transplant (SCT) and all had failed combinations including anthracyclines (80%) and/or alkylating agents (94%). Pts received a median of 3 C (range 1–12); 13 pts completed ≥6 C. CBR was 26% (10/39 eval pts), including 5 pts achieving PR and 5 pts achieving MR. 5 BTZ-refractory pts achieved MR or PR. Median TTP was 6.2 mo, the median DOR for the MR + PR was 7.4 mo. 8/10 pts achieved response during C1. 16 additional pts achieved SD for at least 6 wks. The most common adverse events were fatigue, anemia, thrombocytopenia, nausea, upper respiratory infection, increased creatinine and diarrhea. Peripheral neuropathy occured in &lt; 10% of pts with 1 Gr 3 in a pt with pre-existing Gr 2. Conclusions: Single-agent CFZ achieved a TTP of &gt; 6 mo in relapsed and refractory MM pts who failed available therapies. 26% of patients had at least an MR and median duration of &gt;7 mo with this steroid- and anthracycline-sparing regimen. CFZ toxicities were manageable and importantly, exacerbation of pre-existing PN was rare. The study has been expanded to enroll an additional 250 pts in this unmet medical need population at an escalated dose, and treatment has been extended beyond a year. [Table: see text]

Lenalidomide, Bortezomib, and Dexamethasone in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Encouraging Response Rates and Tolerability with Correlation of Outcome and Adverse Cytogenetics in a Phase II Study.

Background: Bortezomib (VELCADE®, Bz) is approved for the treatment of multiple myeloma (MM). Lenalidomide (Revlimid®, Len) plus dexamethasone (Dex) is approved for the treatment of relapsed MM pts following ≥ 1 prior therapy. In a phase 1 study, Len/Bz (maximum tolerated dose [MTD] 15 mg/1.0 mg/m2) with or without Dex (20–40 mg) was well tolerated and resulted in a response rate (CR+PR+MR) of 58% in relapsed and/or refractory MM pts. The aim of this multi-center phase 2 study was to evaluate the efficacy and safety of Len/Bz/Dex (RVD) at the phase 1 MTD.Methods: Pts with relapsed or relapsed and refractory MM with 1–3 prior lines of therapy received up to eight 21-day cycles of Bz 1.0 mg/m2 (days 1, 4, 8, 11) Len 15 mg (days 1–14) and Dex 40/20 mg (cycles 1–4/5–8) on days of/after Bz dosing. After cycle 8, pts with stable or responding disease received maintenance therapy on a 21-day cycle; Bz (days 1 and 8) and Len (days 1–14) at the dose levels tolerated at the end of cycle 8, with Dex at 10 mg (days 1, 2, 8, 9) until disease progression or unacceptable toxicity. Pts received concomitant anti-thrombotic (aspirin 81 or 325 mg/day) and anti-viral prophylaxis. Pts with Grade (G) ≥ 2 peripheral neuropathy (PNY) were excluded. Response was assessed according to modified EBMT and Uniform Criteria with toxicities assessed using NCI CTCAE v3.0. Primary end point was time to progression (TTP).Results: 64 pts have been enrolled; 38 (59%) with relapsed and 26 (41%) with relapsed and refractory MM. Median number of prior therapies was two, including Len (8%), Bz (55%), Dex (92%), thalidomide (77%), and stem cell transplant (SCT; 36%). Pts received a median of 8 cycles; 31 (48%) completed 8 cycles, 24 continue on maintenance. 4 pts proceeded to stem cell collection (median CD34+ yield of 4.58x106/kg after median of 8 cycles of therapy) and 3 pts proceeded to stem cell transplant, with the 4th pt currently undergoing salvage therapy to restore disease control. 19 pts discontinued prior to completing 8 cycles due to: progressive disease (10), toxicities (3) or other reason (2). Toxicities were manageable, consisting primarily of G1–2 myelosuppression. Attributable non-hematologic toxicities included deep vein thrombosis (two pts; attributed to Len, both pts remain on-study after antithrombotic therapy), and two episodes of atrial fibrillation (G3) prompting Dex dose reduction. G3 PNY was reported in one pt attributed to Bz and leading to treatment discontinuation despite Bz dose reduction. Dose reductions were required for: Len (13 pts); Bz (9 pts) and Dex (26 pts). One on-study death (thought to be due to fungal pneumonia) was reported during cycle 3: this was not attributed to either Bz or Len, but possibly Dex. In 63 response-evaluable pts, the overall response rate (CR/nCR+VGPR+ PR+ MR) is currently 86%, including 24% CR/nCR and 67% CR/nCR/VGPR/PR. Response rates according to baseline cytogenetics, disease stage, and prior therapies showed no significant differences according to adverse risk (Table). Similarly, analysis of evaluable pts with chromosome 13 deletion by FISH showed no significant difference in response rate compared to those without. Median DOR in responding pts is 21 weeks; range 6–72 weeks. Median TTP and overall survival have not yet been reached.Conclusions: RVD is very active and well tolerated in pts with relapsed and/or refractory MM, including pts who have received prior Len, Bz, thalidomide, and SCT. Responses appeared independent of adverse cytogenetics, advanced disease stage at diagnosis, prior treatment, and being refractory to prior therapy. Durable responses have been observed. Surrogates and correlative studies are in progress.Response rates* by baseline cytogenetics, disease stage at diagnosis, and prior treatmentCytogenetics (n= 60)ORR (≥ MR)≥ PR≥ VGPRCR/nCRNormal (n=38)84%63%29%18%Abnormal† (n=22)91%73%41%32%ISS disease stage (n=44)Stage l (n=15)80%67%40%33%Stage ll (n=15)87%67%20%13%Stage lll (n=14)86%71%57%36%Response to RVD according to type of prior therapyBortezomib (n=35)77%57%31%17%Len/Thalidomide (n=54)81%57%22%15%Response by Relapsed/RefractoryRelapsed (n=38)84%66%34%26%Relapsed/Refractory (n=26)85%65%31%19%* Response assessed by Uniform Criteria.†Abnormal cytogenetics by metaphase analysis

Avascular necrosis of the jaw in multiple myeloma (MM) patients (pts) treated with bisphosphonates (BP)

18538 Background: Oral cavity avascular bone necrosis (ABN) has been recently reported as an emerging serious complication in pts receiving BP for the treatment of hypercalcemia related to MM or metastatic solid tumors. Methods: We report the cases of 6 pts with MM treated initially with pamidronate and later with zoledronic acid (ZA). Results: Pts characteristics : M/F 3/3; mean age 58.4 (46–78); 4 IgG κ,1 γ and 1 κ MM; 5 St IIIA and 1 IIIB; mean history of disease 61.3 mo. (23–103); 5 pts had a relapsing MM refractory to several lines of therapy but 1 pt had received only high dose dexametazone (D); 2 pts had received autologous stem cell transplantation and 1 pt allogenic bone marrow transplantation; mean n.° of BP doses was 41.3 (17–81). At the time of ABN onset all pts were receiving ZA along with, respectively: D (2 pts); cyclophosphamide plus D (1 pt), bortezomib plus D (2 pts) and oral melphalan (1 pt). ABN was localized in 2 pts at alveolar bone of the right maxilla and presented as an inflammation of the gum, followed by a painful bone exposure. In the other 4 pts ABN was localized at mandible and presented as dental abscesses followed in 2/4 pts by cutaneous fistulization. Treatment has included in all pts discontinuation of ZA, antibiotics, chlorhexidine mouthwashes, pain control, minor regional débridement, and bone trimming. In 1 pt a more aggressive surgical approach was attempted at an other Institution and postoperative course was complicated by massive haemorrhage and complete loss of chewing. Four pts dead with progressive disease with a mean overall survival after ABN presentation of 6 mo.; 2 pts are alive after 3 and 4 mo. after ABN presentation; however in all pts ABN significantly worsened quality of life. Conclusions: Oral cavity ABN is a severe complication in refractory MM pts receiving BP. Mechanisms of action of BP that determine a reduction in osteoclastic activity and an accumulation of nonvital osteocytes with microfractures of old mineral matrix appear to play an important role. However other causes may be involved as a long history of disease; an uncontrolled progressive disease; type and doses of previous and present therapies, primarily steroids; status of oral cavity and teeth of pts and possibly the n.° of doses of BP. No significant financial relationships to disclose.

A Multicenter Phase 1 Clinical Trial of Tanespimycin (KOS-953) + Bortezomib (BZ): Encouraging Activity and Manageable Toxicity in Heavily Pre-Treated Patients with Relapsed Refractory Multiple Myeloma (MM).

Background: Tanespimycin (KOS-953, 17-AAG) disrupts the function of Hsp90, a molecular chaperone of MM client proteins such as IL-6, IGF-1R that are key to growth, survival and drug resistance. In vitro, BZ + KOS-953 show additive cytotoxicity against MM cells. Single-agent KOS-953 produced durable MR and SD (ASH 2005 A#361) in relapsed and refractory MM pts with an MTD ≥ 420 mg/m2.Objectives: Define a phase 2 dose of BZ+KOS-953 in pts with relapsed, refractory MM. Determine PK of KOS-953 and its active metabolite. Evaluate proteasome inhibition in whole blood lysates. Explore changes in intracellular signaling proteins in PBMCs and CD138+ MM cells.Methods: Pts receive BZ as IVB followed by 1-hr infusion KOS-953 (in a Cremophor formulation) D1,4,8,11 q 21d. Dose escalation occurred in a step-wise manner (KOS-953: 100, 150, 220, 275 and 340 mg/m2; BZ: 0.7, 1.0 and 1.3 mg/m2). Collection of PK and surrogates occurs after D1, 11 dosing. Toxicity is assessed by NCI CTCAE v3.0 and response by EBMT criteria.Results: 40 pts were enrolled in 7 dose levels: 22F/18M; median age/KPS 59y/90; all rel/refy; median # of prior regimens 4 (range 2–16); 97% dex; 73% prior BZ; 87% prior thalidomide; 7% prior lenalidomide; 67% prior SCT. Pts received a median of 4 cycles (range: 1 – 19+). Three episodes of DLT potentially related to KOS-953 were observed (KOS-953/BZ dose): grade (g) 3 pancreatitis (150/1.3); g4 metabolic acidosis with GI hemorrhage secondary to GI amyloidosis (275/1.3); and g3 myalgias/cramps (340/1.3). Other g3–4 toxicity: anemia, back pain and thrombocytopenia (all reversible). Common toxicities (>10%): fatigue, diarrhea, constipation, thrombocytopenia and nausea (predominantly g1-2). Significant cardiotoxicity, peripheral neurotoxicity and DVT were not reported. KOS-953 PK: similar to single-agent trial with no change in clearance on this schedule. Dose (mg) vs exposure to [parent + metabolite] was linear (R2=0.87). 20S proteasome inhibition was similar to published BZ single-agent values. Hsp70 induction was observed in PBMCs prior to D11 infusion, suggesting sustained Hsp90 inhibition on this schedule. Responses (CR+PR+MR) were seen in all dose levels of KOS-953 with BZ ≥ 1.0 mg/m2: BZ-naive pts (5/7 pts; 71%); BZ-refractory pts (defined as PD on BZ-containing regimen prior to study or no response to prior BZ; 2/6 pts; 33%) and BZ-pretreated pts (5/13 pts; 38%); 4 pts were non-evaluable having received ≥ 2 infusions and 10 pts (Cohort 7) are not yet assessable for response.Conclusions: Encouraging anti-MM activity has been observed in all dose groups with KOS-953 with BZ ≥ 1.0 mg/m2. The dose group of 1.3 mg/m2 BZ + 340 mg/m2 KOS-953 is being expanded to assess tolerability; one pt out of 10 experienced DLT at this dose level to date. To date, no additive toxicity or PK interactions are seen. A phase 2 study of the combination in relapsed, refractory MM and a registrational phase 2/3 trial in MM pts in 1st relapse comparing BZ to BZ+KOS-953 are planned.