RRMM Pts Research Articles

Renal Response in Carfilzomib (K)- Versus Bortezomib (V)-Treated Patients (Pts) with Relapsed or Refractory Multiple Myeloma (RRMM) in the Real-World Practice Setting

Introduction: Renal impairment (RI) is a classic clinicopathological feature of MM, is associated with poor prognosis and shorter survival (Eleutherakis-Papaiakovou Leuk Lymphoma 2007), and can complicate drug dosing and limit treatment options. In clinical trials, the proteasome inhibitors K and V have demonstrated efficacy in RRMM pts with RI, with superior efficacy observed in K-treated pts (Dimopoulos Blood 2017). K and V have also been observed to improve renal function in RRMM pts (Dimopoulos Clin Lymphoma Myeloma 2009; Dimopoulos Blood Advances 2017). However, few studies have investigated the real-world effectiveness of K- and V-based regimens in renal rescue. This study aimed to describe and compare renal response rates in RRMM pts treated with K + dexamethasone (Kd) and V + dexamethasone (Vd) in oncology clinics. Methods: The Oncology Services Comprehensive Electronic Records (OSCER) database (Lau Clin Epidemiol 2011) contains electronic medical records (EMR) from community- and hospital-affiliated oncology clinics in the United States. MM pts aged ≥18 who entered an OSCER clinic Jan 2012‒Feb 2018; initiated Kd or Vd treatment as line 2 (2L), 3L, or 4L; and had baseline renal impairment (Modification of Diet in Renal Disease Study estimated glomerular filtration rate [eGFR] Results: 543 Kd-treated and 1005 Vd-treated pts were included. Baseline characteristics were similar between cohorts, with no difference in baseline eGFR stages. More Kd pts were Conclusions: Using one of the most complete oncology EMR databases available, we found that RRMM pts with baseline RI treated with Kd had higher rates of overall and complete renal response, and were more likely to have a renal response, compared with pts treated with Vd. A limitation of the study is that we could not account for all concomitant medications or comorbidities that affect renal function, as some may not be captured in OSCER. Disclosures Kumar:AbbVie: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity9s Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity9s Board of Directors or advisory committees, Research Funding. Fu:Amgen: Employment, Equity Ownership. Mezzi:Amgen: Employment, Equity Ownership. Braunlin:Amgen: Employment. Kim:Amgen: Employment, Equity Ownership. Iskander:Amgen: Employment, Equity Ownership. Niesvizky:Amgen Inc.: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Jagannath:Celgene: Consultancy; Novartis: Consultancy; Merck: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; Bristol-Myers Squibb: Consultancy. Boccia:Sandoz: Consultancy; Celgene: Speakers Bureau; Abbvie: Speakers Bureau; Genentech: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; BMS: Research Funding; Pfizer: Consultancy; AstraZeneca: Research Funding, Speakers Bureau. Raje:Celgene: Consultancy; Janssen: Consultancy; Merck: Consultancy; Takeda: Consultancy; AstraZeneca: Research Funding; Research to Practice: Honoraria; Medscape: Honoraria; BMS: Consultancy; Amgen Inc.: Consultancy.

Efficacy and Safety of Daratumumab, Bortezomib, and Dexamethasone (D-Vd) Versus Bortezomib and Dexamethasone (Vd) in First Relapse Patients: Two-Year Update of Castor

Efficacy and Safety of Daratumumab, Bortezomib, and Dexamethasone (D-Vd) Versus Bortezomib and Dexamethasone (Vd) in First Relapse Patients: Two-Year Update of Castor

Pharmacokinetics (PK) of Subcutaneous Daratumumab in Patients with Relapsed or Refractory (RR) Multiple Myeloma (MM): Primary Clinical Pharmacology Analysis of the Open-Label, Multicenter, Phase 1b Study (PAVO)

Pharmacokinetics (PK) of Subcutaneous Daratumumab in Patients with Relapsed or Refractory (RR) Multiple Myeloma (MM): Primary Clinical Pharmacology Analysis of the Open-Label, Multicenter, Phase 1b Study (PAVO)

Three-Year Follow up of the Phase 3 Pollux Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) Alone in Relapsed or Refractory Multiple Myeloma (RRMM)

Introduction: Daratumumab is a human, CD38-targeted, IgGκ monoclonal antibody with both direct on-tumor and immunomodulatory mechanisms of action. In the phase 3 POLLUX study, D-Rd reduced the risk of disease progression or death by 63% and significantly increased the overall response rate (ORR) versus Rd alone (93% vs 76%; P 3 years of median follow-up. Methods: Pts with ≥1 prior line of therapy were randomized (1:1) to receive Rd (lenalidomide 25 mg PO on Days 1-21 of each 28-day cycle; dexamethasone 40 mg per week) ± daratumumab (16 mg/kg IV QW for Cycles 1-2, Q2W for Cycles 3-6, then Q4W until disease progression). High risk cytogenetic abnormalities included t(4;14), t(14;16), and del17p. At the time of suspected CR and at 3 and 6 months after confirmed CR (and every 12 months thereafter if CR was maintained), bone marrow aspirates were assessed for MRD using clonoSEQ® V2.0 (Adaptive Biotechnologies, Seattle, WA). Sustained MRD negativity was defined as maintenance of MRD negativity at the 10-5 threshold for ≥6 or ≥12 months. PFS on subsequent line of therapy (PFS2), an exploratory endpoint, was defined as time from randomization to progression after next line of subsequent therapy or death. Results: A total of 569 pts were randomized (D-Rd, n = 286; Rd, n = 283). At a median follow-up of 39.5 months, D-Rd significantly prolonged progression-free survival (PFS) versus Rd (median, not reached [NR] vs 17.5 months; hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.35-0.55; P The median duration of treatment was 34.3 months in the D-Rd arm versus 16.0 months in the Rd arm. The most common (≥10%) grade 3/4 treatment-emergent adverse events (TEAEs) observed with D-Rd versus Rd are described in Table 2. No differences were observed for D-Rd versus Rd in discontinuations due to TEAEs (14% of pts in each treatment group) or incidences of second primary malignancies (7% of pts in each treatment group). Updated data including PFS2 will be presented at the meeting. Conclusion: After >3 years of median follow-up, D-Rd continued to demonstrate a significant PFS benefit and higher rates of deeper responses versus Rd alone in RRMM pts. The higher rate of sustained MRD negativity with D-Rd compared with Rd suggests that continued D-Rd treatment drives these deep responses and delays progression. No new safety signals were observed following a median of 34 months of D-Rd exposure. Disclosures Bahlis:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Dimopoulos:Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Takeda: Honoraria. White:Amgen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Cook:Amgen, Bristol-Myers Squibb, GlycoMimetics, Celgene, Janssen and Takeda and Sanofi: Honoraria; Celgene, Janssen and Takeda: Research Funding. Ho:Takeda: Honoraria, Other: Travel to meeting; Novartis: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Other: Travel to meeting. Moreau:Janssen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity9s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees. Krevvata:Janssen Research & Development, LLC: Employment. Chiu:Janssen Research & Development, LLC: Employment. Qin:Janssen Research & Development, LLC: Employment. Okonkwo:Janssen Research & Development, LLC: Employment. Trivedi:Janssen Research & Development, LLC: Employment. Qi:Janssen Research & Development, LLC: Employment. San-Miguel:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria.

Subcutaneous Delivery of Daratumumab in Patients (pts) with Relapsed or Refractory Multiple Myeloma (RRMM): Pavo, an Open-Label, Multicenter, Dose Escalation Phase 1b Study

Subcutaneous Delivery of Daratumumab in Patients (pts) with Relapsed or Refractory Multiple Myeloma (RRMM): Pavo, an Open-Label, Multicenter, Dose Escalation Phase 1b Study

DARATUMUMAB, LENALIDOMIDE, AND DEXAMETHASONE (DRD) VS LENALIDOMIDE AND DEXAMETHASONE (RD) IN RELAPSED OR REFRACTORY MULTIPLE MYELOMA (RRMM): EFFICACY AND SAFETY UPDATE (POLLUX)

Introduction: Daratumumab (D) is a human CD38-targeting mAb that significantly prolongs progression-free survival (PFS) when added to standard-of-care regimens in patients (pts) with RRMM. We examined updated efficacy and safety data from POLLUX (NCT02076009), a randomised phase 3 study of DRd vs Rd in RRMM. Methods: Pts with ≥1 prior line of therapy (LOT) received Rd (25 mg PO lenalidomide on days 1–21 of each q4w cycle; 40 mg dexamethasone weekly) ± D (16 mg/kg IV qw for cycles 1 and 2, q2w for cycles 3–6, then q4w until disease progression). Pts refractory to lenalidomide were ineligible. Minimal residual disease (MRD) was assessed on bone marrow samples at time of suspected complete response (CR) and at 3 and 6 months post-suspected CR at sensitivities of 10–4, 10–5, and 10–6 via next-generation sequencing (Adaptive Biotechnologies, Seattle, WA). Results: Pts received a median (range) of 1 (1–11) prior LOT. 55% received prior IMiDs (18% lenalidomide). Based on previous median follow-up of 17.3 months, DRd significantly prolonged PFS (median, not reached vs 17.5 months; HR, 0.37; 95% CI, 0.28–0.50; P < 0.0001) and significantly improved overall response rate (ORR; 93% vs 76%, P < 0.0001) vs Rd. DRd induced higher rates of deep responses vs Rd (≥very good partial response [VGPR]: 78% vs 45%; ≥CR: 46% vs 20%; all P < 0.0001) and included MRD negativity, which was >3-fold higher across all 3 sensitivity thresholds for DRd vs Rd (25% vs 6% at the 10–5 threshold). MRD-negative pts demonstrated longer PFS vs MRD-positive pts. Follow up for overall survival (OS) is ongoing (OS events: 40 [14%] in DRd and 56 [20%] in Rd). No new safety signals were identified with longer follow up. Updated efficacy and safety data based on approximately 25-month follow up will be presented at the meeting. Conclusions: DRd provided significant benefits vs Rd in terms of PFS, ORR, and MRD negativity, and the favourable safety profile of DRd was maintained with longer follow up. These data further validate the use of DRd in RRMM pts who received ≥1 prior therapy. Keywords: CD38; monoclonal antibodies (MoAb); multiple myeloma (MM).

Daratumumab, bortezomib and dexamethasone (DVd) vs bortezomib and dexamethasone (Vd) in relapsed or refractory multiple myeloma (RRMM): Efficacy and safety update (CASTOR).

8036 Background: Daratumumab (D), a human, CD38-targeting mAb, is well tolerated and induces deep and durable responses in patients (pts) with RRMM. We provide an update of CASTOR (NCT02136134), a multicenter, phase 3, randomized study of DVd vs Vd in RRMM. Methods: All pts received ≥1 prior line of therapy (LOT) and were administered 8 cycles (Q3W) of Vd (1.3 mg/m2 SC bortezomib on days 1, 4, 8, and 11; 20 mg PO/IV dexamethasone on days 1-2, 4-5, 8-9, and 11-12) ± D (16 mg/kg IV once weekly in Cycles 1-3, every 3 weeks for Cycles 4-8, then every 4 weeks until progression). Bortezomib-refractory pts were ineligible. Minimal residual disease (MRD) was assessed upon suspected CR and at 6 and 12 months following the first dose at sensitivities of 10–4, 10–5, and 10–6using the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA). Results: Pts received a median (range) of 2 (1-10) prior LOTs. 66% were previously treated with bortezomib and 21% were refractory to lenalidomide in their last prior LOT. After a median follow-up of 13.0 months, PFS was significantly prolonged with DVd vs Vd (median: not reached vs 7.1 months; HR, 0.33; 95% CI, 0.26-0.43; P&lt; 0.0001). This PFS benefit was seen regardless of number of prior LOTs received, with greatest benefit observed in 1 prior line pts (median: not reached vs 7.9 months; HR, 0.22; 95% CI, 0.14-0.34; P&lt; 0.0001). ORR was also significantly higher for DVd vs Vd (84% vs 63%), along with ≥VGPR (62% vs 29%) and ≥CR (26% vs 10%; P&lt; 0.0001 for all). MRD-negative rates were ≥4-fold higher at all three sensitivity thresholds with DVd vs Vd (10% vs 2% at 10–5 threshold). Pts who achieved MRD negativity demonstrated prolonged PFS compared with MRD-positive pts. 37 (15%) and 58 (24%) deaths were observed in DVd vs Vd, respectively, and follow up is ongoing. The most common grade 3/4 TEAE was thrombocytopenia (45% vs 33%). Updated efficacy and safety data will be presented. Conclusions: DVd provided significant benefits with respect to PFS, ORR, depth of response, and MRD-negative rate vs Vd. No new safety signals were reported. These data continue to support the use of DVd in RRMM pts and indicate that pts with 1 prior LOT will derive the most benefit. Clinical trial information: NCT02136134.

Phase 3 ELOQUENT-2 study: Extended four year follow-up (FU) of elotuzumab plus lenalidomide/dexamethasone (ELd) vs Ld in relapsed/refractory multiple myeloma (RRMM).

8028 Background: Elotuzumab, an immunostimulatory monoclonal antibody, has a dual mechanism of action: directly activating NK cells and tagging myeloma cells for recognition/death via antibody-dependent cell-mediated cytotoxicity. In a 3-y FU, ELOQUENT-2 (NCT01239797) showed a sustained 27% reduction in risk of disease progression/death for ELd vs Ld and OS trend in favor of ELd (Dimopoulos et al, ASH 2015). Here we present extended 4-y FU data (median FU 46 mo). Methods: RRMM patients (pts) were randomized 1:1 to ELd or Ld in 28-d cycles until disease progression/unacceptable toxicity. Coprimary endpoints: PFS, ORR. Secondary endpoint: OS. Results: Of 646 RRMM pts, 321 were randomized to ELd, 325 to Ld; ~ twice as many pts remain on therapy in ELd vs Ld (17 vs 9%) at data cut-off (Oct 18, 2016). Discontinuation was mainly due to disease progression (both arms 54%). At 4-y FU, ELd had 29% reduction in risk of progression/death vs Ld (HR 0.71, 95% CI 0.59–0.86) and relative improvement of 50% in PFS (21 vs 14%). Pts with ≥VGPR (ELd 112 [35%], Ld 95 [29%]) had greatest reduction in risk of progression/death (HR 0.65, 95% CI 0.46–0.94). ORR was 79% (ELd) vs 66% (Ld). OS will be presented. G3–4 AEs in ≥5% of pts included second primary malignancies (SPMs), vascular diseases, cardiac disorders and infections (ELd vs Ld: 9 vs 6%, 10 vs 8%, 5 vs 8%, 33 vs 26%). Overall rate (any grade) of infection and SPMs was 84 vs 75% and 17 vs 11% for ELd vs Ld. However, pts had longer exposure to ELd vs Ld (median [Q1, Q3] treatment cycles (19 [9, 42] vs 14 [6, 25]). There were fewer deaths with ELd vs Ld (165 vs 186), mainly due to disease progression and infection in both arms. Conclusions: Elotuzumab in combination with Ld consistently met its efficacy objectives at 4-y FU. ELd showed durable, clinically relevant improvement in PFS, with 29% reduction in risk of progression/death, consistent with 2-y (30%) and 3-y FU (27%). Safety, including rate of SPMs, was consistent with previous findings, with minimal incremental AEs with addition of elotuzumab to Ld. These data represent the longest median FU of an immuno-oncology agent in MM. Study funding: BMS. Writing support: C Tomas, Caudex, funded by BMS. Clinical trial information: NCT01239797.

Higher c-MYC Expression Is Associated with Ixazomib-Lenalidomide-Dexamethasone (IRd) Progression-Free Survival (PFS) Benefit Versus Placebo-Rd: Biomarker Analysis of the Phase 3 Tourmaline-MM1 Study in Relapsed/Refractory Multiple Myeloma (RRMM)

Higher c-MYC Expression Is Associated with Ixazomib-Lenalidomide-Dexamethasone (IRd) Progression-Free Survival (PFS) Benefit Versus Placebo-Rd: Biomarker Analysis of the Phase 3 Tourmaline-MM1 Study in Relapsed/Refractory Multiple Myeloma (RRMM)

Daratumumab, Bortezomib and Dexamethasone Versus Bortezomib and Dexamethasone Alone for Relapsed or Refractory Multiple Myeloma Based on Prior Treatment Exposure: Updated Efficacy Analysis of Castor

Introduction: Daratumumab is a human CD38 IgGκ monoclonal antibody that demonstrated significant activity and a manageable safety profile in combination with bortezomib and dexamethasone. In a randomized phase 3 study, daratumumab in combination with bortezomib and dexamethasone (DVd) significantly prolonged progression-free survival (PFS) versus bortezomib and dexamethasone alone (Vd) in a pre-specified interim analysis of patients (pts) with relapsed or refractory multiple myeloma (RRMM; Palumbo A. N Engl J Med 2016; in press). Herein, we examine subgroups from this study to compare the efficacy of DVd vs Vd in bortezomib-naive and bortezomib-experienced pt populations. In addition, the efficacy of DVd vs Vd in pts who were refractory to lenalidomide at last prior line of therapy was also evaluated.Methods: Pts who received ≥1 prior line of therapy were randomized (1:1) to 8 cycles (q3w) of Vd (bortezomib: 1.3 mg/m2 SC on Days 1, 4, 8, 11; dexamethasone: 20 mg PO on Days 1, 2, 4, 5, 8, 9, 11, 12) with or without daratumumab (16 mg/kg IV qw in Cycles 1-3, Day 1 of Cycles 4-8, then q4w until progression). Pts who were refractory to bortezomib were not eligible. The primary endpoint was PFS. Bone marrow aspirate samples that had been prepared with Ficoll were evaluated for minimal residual disease (MRD) using three different thresholds (10-4, 10-5, and 10-6) based on the ClonoSEQ assay (Adaptive Biotechnologies, Seattle, WA, USA).Results: Median follow-up was 7.4 months. Among bortezomib-naive pts (DVd, n=89; Vd, n=83), PFS was significantly improved with DVd vs Vd (median: not reached [NR] vs 7.5 months; HR, 0.25; 95% CI, 0.13-0.47; P<0.0001); estimated 12-month PFS rates were 72% vs 28%, respectively. ORR was 88% with DVd vs 70% with Vd (P=0.0040), with ≥very good partial response (VGPR) rates of 72% vs 42% (P<0.0001), and ≥complete response (CR) rates of 30% vs 20% (P=0.1199), respectively.For pts who previously received a bortezomib-containing regimen (DVd, n=162; Vd, n=164), PFS was also significantly longer with DVd vs Vd (median: 12.3 vs 6.7 months; HR, 0.46; 95% CI, 0.32-0.66; P<0.0001). Estimated 12-month PFS rates were 55% vs 27%, respectively. ORR was significantly higher with DVd vs Vd (80% vs 60%; P=0.0001), along with significantly higher rates of ≥VGPR (52% vs 22%; P<0.0001) and ≥CR (13% vs 3%; P=0.0019).Among pts who were refractory to lenalidomide at the last prior line of therapy (DVd, n=45; Vd, n=60), PFS was significantly longer in DVd vs Vd (median: 10.3 vs 4.4 mo; HR, 0.37; 95% CI, 0.21-0.65; P=0.0004; Figure). Within this subgroup, ORR was significantly higher for DVd vs Vd (81% vs 50%; P=0.0021), and the same trends were observed for rates of ≥VGPR (54% vs 12%; P<0.0001) and ≥CR (20% vs 5%; P=0.0261).Updated efficacy and safety data, including MRD analyses across different sensitivity thresholds (10-4, 10-5, and 10-6), will be presented at the meeting.Conclusions: These analyses confirm that addition of daratumumab to Vd significantly improves outcomes for RRMM pts regardless of prior treatment with bortezomib. Importantly, this treatment benefit of DVd vs Vd was maintained in pts who were refractory to lenalidomide at the last prior line of therapy. These data lend further support to adding daratumumab to a standard-of-care regimen in RRMM. [Display omitted] DisclosuresLentzsch:BMS: Consultancy; Foundation One: Consultancy; Celgene: Consultancy, Honoraria. Quach:Celgene: Membership on an entity’s Board of Directors or advisory committees; Janssen Cilag: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees. Ovilla:Janssen: Consultancy. Qi:Janssen: Employment. Deraedt:Janssen: Employment, Equity Ownership. Schecter:Janssen: Employment, Equity Ownership. Amin:Janssen: Employment. Qin:Janssen: Employment. Casneuf:Johnson & Johnson: Equity Ownership; Janssen R&D, Beerse, Belgium: Employment. Chiu:Janssen: Employment. Sasser:Johnson & Johnson: Equity Ownership; Janssen Pharmaceuticals R&D: Employment. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding.

Phase 1 MMRC Trial of Selinexor, Carfilzomib (CFZ), and Dexamethasone (DEX) in Relapsed and Relapsed/Refractory Multiple Myeloma (RRMM)

Phase 1 MMRC Trial of Selinexor, Carfilzomib (CFZ), and Dexamethasone (DEX) in Relapsed and Relapsed/Refractory Multiple Myeloma (RRMM)

Oprozomib, Pomalidomide, and Dexamethasone (OPomd) in Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): Initial Results of a Phase 1b Study (NCT01999335)

Oprozomib, Pomalidomide, and Dexamethasone (OPomd) in Patients (Pts) with Relapsed and/or Refractory Multiple Myeloma (RRMM): Initial Results of a Phase 1b Study (NCT01999335)

A Phase 1/2 Trial of Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin for Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

BackgroundImmunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM.MethodsThe phase 1 portion enrolled MM pts w/progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who previously received POM treatment were ineligible. POM was administered orally on days 1-21 of a 28-day cycle, while DEX (40 mg) and PLD (5mg/m2) were both infused on days 1, 4, 8, and 11. During phase 1 enrollment, three cohorts were enrolled at 2, 3 and 4 mg doses of POM, and DEX and PLD were both administered at fixed doses. Phase 2 enrollment commenced once the MTD was established from the phase 1 portion of the study.ResultsAs of August 1, 2015, 70 pts were screened, 68 were enrolled in the trial (with the pre-planned enrollment goal reached) and had received study drug, and a total of 50 pts were evaluable for safety and efficacy. Among all enrolled pts, 60pts discontinued treatment and 8 remain active. Pts had received a median of 4 prior treatments (range 1-18). Median number of cycles for all pts was 4 (range 1-8), with a median follow-up time of 5.5 months (range 0-22).During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled.Among the 57 pts enrolled in phase 2, 53% percent were refractory to LEN and steroids with or without other agents and 31% had previously received PLD. A median of 4 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Fifty-five pts were evaluable for response as 2 pts are active but have not yet had any post-baseline disease assessment. Among all evaluable pts (n=55) enrolled in phase 2, the overall response rate (ORR) was 33% (CR= 5%, VGPR= 5% and PR=23%) and clinical benefit rate (CBR) was 47% with 11 pts (26%) showing stable disease and 5 pts (12%) demonstrating progressive disease. For all evaluable pts enrolled in phase 2, the median follow-up time was 3.6 months (range 0-12 months) and the median PFS was 4.2 months (range 0.3- 29.0+). ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (36% and 51%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose.Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (49 pts; 72.0%), lymphopenia (36 pts; 52.9%), leukopenia (33 pts; 48.5%), hyponatremia (27 pts; 39.7%), and hypokalemia (26pts; 38.2%). One pt died of grade 5 sepsis.ConclusionsThis phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. DisclosuresNo relevant conflicts of interest to declare.

Vorinostat, Bortezomib, Cyclophosphomide, Thalidomide, and Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients

The combination of vorinostat, a histone deacetylase (HDAC) inhibitor, is synergistic with proteasome inhibitors and IMIDs based upon preclinical and clinical data. Phase III trials with vorinostat in relapsed myeloma failed to demonstrate benefit due to excess toxicity that precluded chronic administration of the agent allowing patients to realize the clinical benefits. Herein we report on our experience combining vorinostat, or adding vorinostat to current treatments in the context of refractory myeloma.Methods: Forty RRMM pts that received vorinostat (V) (200mg orally daily on days 1-14) and bortezomib (B) (1.3 mg/m2 IV/SQ days 1,4,8, and 11) combinations, every 28 days from May 2008 until May 2014 at Emory University were reviewed. Cohort 1 consisted of 22 RRMM pts that received VBCyTD regimen (V,B, cyclophosphamide (Cy) (300 mg orally flat dose days 1, 8 and 15), thalidomide (T) (100 mg daily) and dexamethasone (D) 40 mg orally weekly), while cohort 2 consisted of 18 RRMM pts that received other combinations (VBCyD+lenalidomide (R): 4 pts; VBRD: 4 pts; VBCyD: 2 pts; VBD: 4 pts; VBTD: 4 pts and VCyTD+carfilzomib (Ca): 2 pts). The objectives are response assessment by IMWG criteria, progression-free survival (PFS) and overall survival (OS). Drug related adverse events (AEs) ≥grade 3 (CTCAE v3.0) were summarized.Results: Twenty-one males and nineteen females (median age at diagnosis: 56 years [range 28-89], median age at initiation of V treatment: 62 years [range 33-91]) that were heavily pretreated (median lines of therapy: 7 [range 3-14] were included in the analysis. Ninety-five percent of pts were B refractory and 85% pts were R refractory; 97.5% and 15% of pts underwent prior autologous and allogeneic SCT, respectively. High risk cytogenetic abnormalities were seen in 40% of pts. Time from diagnosis to initiation of V combination therapy is 58.5 months (range 18-138). The overall clinical benefit rate (≥SD) was 72.5%. Figure 1 illustrates response rates from both cohorts. Median PFS for cohort 1 is 3 months (95% CI 0.5-5.51) and for cohort 2 is 2 months (95% CI 0.8-3.2), respectively. At a median follow-up of 26 months from the time of V initiation, median OS for cohort 1 is 6 months (95% CI 0-13.6) and for cohort 2 is 3 months (95% CI 1.4-4.7). Median overall survival from diagnosis for these cohorts is 80 months (95% CI 70.2-89.8) and 70 (95% CI 55.6-84.4) months, respectively. ≥Grade 3 AEs include fatigue (15%); generalized weakness (12.5%); neutropenia (15%); and thrombocytopenia (35%).Conclusions: In heavily pretreated relapsed/refractory multiple myeloma patients with limited therapeutic options, vorinostat and bortezomib combination therapy offers clinical benefit with good response rates and acceptable tolerability, likely due to lower doses of vorinostat used. This data further supports the activity of HDAC inhibitors in the context of refractory myeloma. [Display omitted] DisclosuresGleason:Celgene: Consultancy; Novartis: Consultancy. Heffner:Amgen: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Dana Farber CI: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Idera: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Spectrum: Honoraria, Research Funding; Talon Therapeutics: Honoraria, Research Funding. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

Pomalidomide Plus Low-Dose Dexamethasone (POM + LoDEX) for Relapsed and Refractory Multiple Myeloma (RRMM): Results from a Pharmacoeconomic Evaluation

Background: Multiple myeloma remains an incurable disease, placing a significant burden on patients (pts), families, and healthcare systems. Bortezomib (BORT) and IMiDs® immunomodulatory agents (thalidomide and lenalidomide [LEN]) have improved progression-free survival (PFS), time to progression, and overall survival (OS). However, over time, nearly all pts become refractory which greatly impacts prognosis (median OS, 3-9 mos). In the absence of approved treatments, guidelines recommend clinical trials or retreatment with agents that were previously effective, but published data in the appropriate pt population for current care (CC) options are limited to those from small, observational, early-phase studies. There is a need for newer effective treatments; however, access is increasingly being determined by the demonstration of both clinical and economic value. POM + LoDEX demonstrated a significant OS benefit vs. high-dose dexamethasone (HiDEX) in the pivotal phase 3 MM-003 study (San Miguel, Lancet Oncol, 2013). POM + LoDEX has EU approval in RRMM pts in whom BORT and LEN failed.Objective: Explore the cost-effectiveness of POM + LoDEX vs. CC from a UK and Ireland healthcare payer perspective.Methods: A de novo pharmacoeconomic evaluation was conducted to compare costs and outcomes of POM + LoDEX to CC in the UK and Ireland. CC included BORT retreatment (intravenous [IV] or subcutaneous), LEN (oral), and bendamustine (IV) regimens. Efficacy data were sourced from MM-003 and 2 observational studies: a dataset for CC (Gooding, 2013; n = 30 pts primarily treated with BORT, bendamustine, or LEN; 100% received prior BORT and LEN) and a dataset for BORT + LEN (Jimenez-Zepeda, 2013; n = 30, 80% received prior BORT, 73% prior LEN). Validation of the approach and all model assumptions was achieved through extensive clinical and health economic expert consultation and by comparing comparator arm outcomes from observational data to the MM-003 (HiDEX) control arm data. The health economic model used a partitioned survival structure with OS and PFS parametric curves fitted to the datasets to estimate the number of pts at each time point expected to be preprogression, postprogression, or dead. Time to treatment failure curves were estimated to allow treatment discontinuation modelling. EQ-5D data, collected as part of MM-003, were used to inform quality of life (QOL) weights. A utility regression equation was developed to account for important covariates and allow utility to vary over time. The economic evaluation included the cost of treatment, administration, monitoring, tests, adverse events (AEs), blood transfusions, concomitant medication, and terminal care. Costs are presented in US dollars using an exchange rate of 0.74 per € and 0.58 per £. Costs and outcomes were modeled to estimate cost per life year (LY) and cost per quality-adjusted life year (QALY) gained over a lifetime horizon.Results: In the base-case analysis, POM + LoDEX was associated with a total incremental cost of $59,250 per pt over a lifetime horizon compared with CC (Table 1). Pts who receive POM + LoDEX are predicted to live for a mean of 2.2 years, compared with 1.2 years with CC. This represents an additional 0.6 QALYs. The model predicts a deterministic incremental cost-effectiveness ratio (ICER) of $100,920/QALY compared with CC, while the probabilistic ICER obtained through 1000 probabilistic model runs was consistent at $101,947/QALY.Table 1 :Base-Case Cost-Effectiveness ResultsModel ResultsPOM + LoDEXCCDifferenceClinical outcomesMedian OS, mos12.75.57.2Mean predicted life-years (over a pt lifetime)2.21.21.0QALYs1.30.70.6Cost outcomes, US dollarsMedication and administration$84,698$29,880$54,818Monitoring$8230$4489$3741AE management (outpatient visits and hospitalization)$7135$6444$691Total$100,063$40,813$59,250ICER—Cost/LY$58,112ICER—Cost/QALY$100,920Conclusion: There are limited alternative treatment options available in the UK and Ireland for RRMM pts. None have a proven effect on survival leaving pts to face potentially ineffective retreatments. End-of-life drugs that significantly improve survival and QOL and address unmet need can be considered to be cost-effective at a higher “willingness to pay” threshold. POM, an oral therapy with significant PFS, survival, and QOL with a known safety profile, is likely to be a cost-effective use of healthcare resources. DisclosuresDhanasiri:Celgene Corp: Employment, Equity Ownership. Lee:Celgene Corp: Consultancy. Sternas:Celgene Corp: Employment, Equity Ownership. Yu:Celgene Corp: Employment, Equity Ownership. Zaki:Celgene Corp: Employment, Equity Ownership. Elvidge:Celgene Corp: Consultancy.

A Phase 1/2 Trial of Pomalidomide, Dexamethasone and Pegylated Liposomal Doxorubicin for Patients with Relapsed/Refractory Multiple Myeloma

BackgroundImmunomodulatory drugs (IMiD), such as thalidomide and lenalidomide (LEN) and its newest derivative pomalidomide (POM), have shown great promise for the treatment of multiple myeloma (MM) patients (pts). POM has in vitro anti-MM potency and has shown efficacy for the treatment of relapsed/refractory (RR) MM pts. POM with dexamethasone (DEX) induces responses even for MM pts who are refractory to bortezomib (BORT) and LEN (Richardson et al, 2012). Pegylated liposomal doxorubicin (PLD) with BORT is FDA-approved for the treatment of MM pts who have received one prior therapy not containing BORT. The combination of PLD and LEN or thalidomide has shown efficacy for both RR and frontline MM pts (Offidani et al, 2006; 2007). We have also demonstrated that both the efficacy and tolerability of LEN in combination with DEX, PLD and BORT (DVD-R) may be improved by changing the doses and schedules of these drugs (Berenson et al, 2012). Based on these results, we hypothesized that the combination of POM, DEX and PLD would be effective for the treatment of RRMM pts. Thus, we conducted the first study investigating the safety and efficacy of POM in combination with intravenous (IV) DEX and PLD as a phase 1/2 trial using a modified dose, schedule and longer 28-day cycles for pts with RRMM.MethodsThe phase 1 portion enrolled MM pts w/ progressive disease whereas those enrolled in phase 2 also had to be refractory to LEN (single-agent or in combination), as demonstrated by progressive disease while receiving their last LEN-containing regimen or relapsed within 8 weeks of their last dose of this IMiD. Pts who have previously received POM treatment were ineligible. In the phase 1 portion, POM was administered at 2, 3 or 4 mg daily in three cohorts on days 1-21 of a 28-day cycle and DEX (40 mg) and PLD (5 mg/m2) were fixed and given intravenously on days 1, 4, 8, and 11.ResultsAs of June 20th, 2014, 48 pts were enrolled in the trial and a total of 47 pts had received study drug. Pts had received a median of 4 prior treatments (range 1-18), with a median of 2 prior IMiD-containing regimens (range, 0-8). Fifty-three percent of the pts had received a prior PLD-containing regimen and 21% had received a prior IMiD and PLD combination treatment. Among all enrolled pts, 40 pts discontinued treatment and seven remain active. Pts completed a median of 3 cycles (range: 1-8), with a median follow-up time of 5.4 months (range: 0-22).During the phase 1 portion of the trial, the maximum tolerated dose (MTD) of POM was established at 4 mg. Enrollment of pts into the phase 2 portion of the trial began at the MTD. However, neutropenia ≥ grade 3 was observed at this dose in 10/17 (58.8%) phase 2 pts; and, as a result, the protocol was amended so that the MTD was lowered to 3 mg for all pts subsequently enrolled.Among the 36 pts enrolled in phase 2, 78% percent were refractory to LEN and steroids with or without other agents and 47% had previously received PLD. A median of 2 cycles (range, 1 to 8) were administered among the pts enrolled in phase 2. Thirty-five pts were evaluable for response as one pt was active but had not yet had any post-baseline disease assessments. Among all pts enrolled in phase 2, the overall response rate (ORR) and clinical benefit rate (CBR) were 29% and 49%, respectively, with 6 pts (17%) showing stable disease and 12 pts (34%) demonstrating progressive disease. For all pts enrolled in phase 2, the median follow-up time was 4.7 months (range 0-12) and the median PFS was 5.3 months.ORR and CBR for pts in the phase 2 were higher among pts receiving POM at 3 mg (32% and 58%, respectively) than among pts receiving POM at 4 mg (25% and 37%, respectively). Pts receiving the 4 mg dose of POM experienced more toxicities resulting in discontinuations, which likely explains the lower ORR and CBR observed among pts receiving this POM dose.Common ≥ grade 3 adverse events observed throughout the trial were neutropenia (21 pts; 44.7%), lymphopenia (10 pts; 21.3%), and hyponatremia (4 pts; 8.5%). One pt died of grade 5 sepsis.ConclusionsThis phase 1/2 trial is the first evaluating POM with PLD and DEX and demonstrates that the combination of POM at 3 mg, PLD and DEX using a modified 28-day cycle schedule is safe and effective for the treatment of MM pts refractory to LEN. DisclosuresBerenson:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Swift:Celgene: Consultancy, Honoraria. Vescio:Celgene: Honoraria.

Patient Outcomes By Prior Therapies and Depth Of Response: Analysis Of MM-003, a Phase 3 Study Comparing Pomalidomide + Low-Dose Dexamethasone (POM + LoDEX) Vs High-Dose Dexamethasone (HiDEX) In Relapsed/Refractory Multiple Myeloma (RRMM)

Patient Outcomes By Prior Therapies and Depth Of Response: Analysis Of MM-003, a Phase 3 Study Comparing Pomalidomide + Low-Dose Dexamethasone (POM + LoDEX) Vs High-Dose Dexamethasone (HiDEX) In Relapsed/Refractory Multiple Myeloma (RRMM)

Final Analysis, Cytogenetics, Long-Term Treatment, and Long-Term Survival In MM-003, A Phase 3 Study Comparing Pomalidomide + Low-Dose Dexamethasone (POM + LoDEX) Vs High-Dose Dexamethasone (HiDEX) In Relapsed/Refractory Multiple Myeloma (RRMM)

Final Analysis, Cytogenetics, Long-Term Treatment, and Long-Term Survival In MM-003, A Phase 3 Study Comparing Pomalidomide + Low-Dose Dexamethasone (POM + LoDEX) Vs High-Dose Dexamethasone (HiDEX) In Relapsed/Refractory Multiple Myeloma (RRMM)

MM-005: A Phase 1 Trial Of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone (PVD) In Relapsed and/Or Refractory Multiple Myeloma (RRMM)

MM-005: A Phase 1 Trial Of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone (PVD) In Relapsed and/Or Refractory Multiple Myeloma (RRMM)

MM-003 Phase 3 Study Of Pomalidomide In Combination With Low-Dose Dexamethasone (POM + LoDEX) Vs High-Dose Dexamethasone (HiDEX) In Relapsed/Refractory Multiple Myeloma (RRMM): POM + Lodex Is Beneficial For Elderly Patients (> 65 Years of Age)

MM-003 Phase 3 Study Of Pomalidomide In Combination With Low-Dose Dexamethasone (POM + LoDEX) Vs High-Dose Dexamethasone (HiDEX) In Relapsed/Refractory Multiple Myeloma (RRMM): POM + Lodex Is Beneficial For Elderly Patients (> 65 Years of Age)