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Despite enormous advances, management of multiple myeloma (MM) remains challenging. Multiple factors impact the decision to treat or which regimen to use at MM relapse/progression. Recent major randomized controlled trials (RCTs) showed widely varying progression-free survivals (PFS), ranging from a median of 4 months (MM-003) to 23.6 months (ASPIRE). Based on these RCTs, next-generation proteasome inhibitors (carfilzomib and ixazomib), next-generation immunomodulatory agent (pomalidomide), and monoclonal antibodies (elotuzumab and daratumumab) were approved for relapsed and refractory MM. Daratumumab, targeting CD38, has multiple mechanisms of action including modulation of the immunosuppressive bone marrow micro-environment. In addition to the remarkable single agent activity in refractory MM, daratumumab produced deep responses and superior PFS in MM when combined with lenalidomide/dexamethasone, or bortezomib/dexamethasone. Other anti-CD38 antibodies, such as isatuximab and MOR202, are undergoing assessment. Elotuzumab, targeting SLAMF7, yielded superior response rates and PFS when combined with lenalidomide/dexamethasone. New combinations of these next generation novel agents and/or antibodies are undergoing clinical trials. Venetoclax, an oral BH3 mimetic inhibiting BCL2, showed single agent activity in MM with t(11;14), and is being studied in combination with bortezomib/dexamethasone. Selinexor, an Exportin-1 inhibitor, yielded promising results in quad- or penta-refractory MM including patients resistant to daratumumab. Pembrolizumab, an anti-PD1 check-point inhibitor, is being tested in combination with lenalidomide/dexamethasone or pomalidomide/dexamethasone. Chimeric antigen receptor-T cells targeting B-cell maturation antigen have yielded deep responses in RRMM. Finally, salvage autologous stem cell transplantation (ASCT) remains an important treatment in MM relapsing/progressing after a first ASCT. Herein, the clinical trial data of these agents are summarized, cautious interpretation of RCTs highlighted, and algorithm for salvage treatment of relapse/refractory MM proposed.

Following the publication of this article the authors noted that the MRD data under the Table 1 column “Remark” of Aspire should go to that of Pollux. The authors wish to apologize for any inconvenience caused. The corrected table is attached to this correction.

This phase 1 dose-escalation study evaluated pomalidomide, bortezomib (subcutaneous (SC) or intravenous (IV)) and low-dose dexamethasone (LoDEX) in lenalidomide-refractory and proteasome inhibitor-exposed relapsed or relapsed and refractory multiple myeloma (RRMM). In 21-day cycles, patients received pomalidomide (1–4 mg days 1–14), bortezomib (1–1.3 mg/m2 days 1, 4, 8 and 11 for cycles 1–8; days 1 and 8 for cycle ⩾9) and LoDEX. Primary endpoint was to determine the maximum tolerated dose (MTD). Thirty-four patients enrolled: 12 during escalation, 10 in the MTD IV bortezomib cohort and 12 in the MTD SC bortezomib cohort. Patients received a median of 2 prior lines of therapy; 97% bortezomib exposed. With no dose-limiting toxicities, MTD was defined as the maximum planned dose: pomalidomide 4 mg, bortezomib 1.3 mg/m2 and LoDEX. All patients discontinued treatment by data cutoff (2 April 2015). The most common grade 3/4 treatment-emergent adverse events were neutropenia (44%) and thrombocytopenia (26%), which occurred more frequently with IV than SC bortezomib. No grade 3/4 peripheral neuropathy or deep vein thrombosis was reported. Overall response rate was 65%. Median duration of response was 7.4 months. Pomalidomide, bortezomib and LoDEX was well tolerated and effective in lenalidomide-refractory and bortezomib-exposed patients with RRMM.

PMCID: PMC4112539.-- International Myeloma Working Group: et al., Plasma cell leukemia (PCL) is a rare and aggressive variant of myeloma characterized by the presence of circulating plasma cells. It is classified as either primary PCL occurring at diagnosis or as secondary PCL in patients with relapsed/refractory myeloma. Primary PCL is a distinct clinic-pathological entity with different cytogenetic and molecular findings. The clinical course is aggressive with short remissions and survival duration. The diagnosis is based upon the percentage (≥20%) and absolute number (≥2 × 10 9/l) of plasma cells in the peripheral blood. It is proposed that the thresholds for diagnosis be re-examined and consensus recommendations are made for diagnosis, as well as, response and progression criteria. Induction therapy needs to begin promptly and have high clinical activity leading to rapid disease control in an effort to minimize the risk of early death. Intensive chemotherapy regimens and bortezomib-based regimens are recommended followed by high-dose therapy with autologous stem cell transplantation if feasible. Allogeneic transplantation can be considered in younger patients. Prospective multicenter studies are required to provide revised definitions and better understanding of the pathogenesis of PCL., This work has been supported in part by “Josep Font” Grant from Hospital Clínic de Barcelona and RD06/0020/0005 from Instituto de Salud Carlos III, Spain.

Anti-tumor activities of selective HSP90α/β inhibitor, TAS-116, in combination with bortezomib in multiple myeloma

e78 BP-055 Subgroup Analysis by Prior Treatment of the Efficacy and Safety of Panobinostat Plus Bortezomib and Dexamethasone in Patients With Relapsed or Relapsed and Refractory Multiple Myeloma in the PANORAMA 1 Study P.G. Richardson, V.T.M. Hungria, S.-S. Yoon, M. Beksac, M.A. Dimopoulos, A. Elghandour, W.W. Jedrzejczak, A. Guenther, T.N. Nakorn, N. Siritanaratkul, R.L. Schlossman, J. Hou, P. Moreau, S. Lonial, J.H. Lee, H. Einsele, M. Sopala, B.R. Bengoudifa, C. Corrado, J.F. San-Miguel Dana-Farber Cancer Institute, Boston, MA, USA; Irmandade da Santa Casa de Misericordia de Sao Paulo, Sao Paulo, Brazil; Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea; Ankara University School of Medicine, Ankara, Turkey; Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece; Alexandria University, Alexandria, Egypt; Medical University of Warsaw, Warsaw, Poland; Division of Stem Cell Transplantation and Immunotherapy, 2 Department of Medicine, University Hospital SchleswigHolstein and University of Kiel, Kiel, Germany; King Chulalongkorn Memorial Hospital and Chulalongkorn University, Bangkok, Thailand; Siriraj Hospital, Bangkok, Thailand; Chang Zheng Hospital, Shanghai, China; University Hospital of Nantes, Nantes, France; Winship Cancer Institute, Atlanta, GA, USA; Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Republic of Korea; Medizinische Klinik und Poliklinik II, University of Wurzburg, Wurzburg, Germany; Novartis Pharma AG, Basel, Switzerland; Clinica Universidad de Navarra, Pamplona, Spain Introduction: Panobinostat (PAN), a potent pan-deacetylase inhibitor, affects processes integral to growth and survival of multiple myeloma (MM) cells through alteration of protein metabolism and epigenetic mechanisms. In the PANORAMA 1 phase 3 trial, combination of PAN with bortezomib (BTZ) and dexamethasone (Dex; PAN-BTZ-Dex) led to a clinically significant increase in progression-free survival (PFS) of z4 mo vs placebo plus BTZ and Dex (Pbo-BTZ-Dex). This analysis examined efficacy and safety of PAN-BTZ-Dex based on prior treatment. Therapeutic options for patients (pts) who have received immunomodulatory agents (IMIDs) and protease inhibitors are limited, and with each relapse these options become progressively restricted by drug resistance or intolerance. Methods: The study design was described previously (San-Miguel JF, Lancet Oncol. 2014). A subanalysis assessed efficacy and safety of PAN-BTZ-Dex in pts based on prior treatment characteristics, including receipt of prior IMiDs, BTZ + IMiDs, and BTZ + IMiDs and 2 prior lines of therapy. Here, we focus on efficacy and safety of PAN-BTZ-Dex in pts with relapsed or relapsed and refractory MM who received 2 prior regimens, including BTZ and an IMiD (n1⁄4147). Results: Pts in the PAN-BTZ-Dex arm (n1⁄473) had improved efficacy compared with those receiving Pbo-BTZ-Dex (n1⁄474). Of note, in the studied subgroup, pts in the PAN arm had Clinical Lymphoma, Myeloma & Leukemia September 2015 a longer median PFS (12.5 mo) than those in the Pbo arm (4.7 mo, HR: 0.47 [95% CI, 0.31-0.72]; Figure). Pts in the PAN arm vs Pbo arm also showed improvements in overall response rate (ORR; 58.9% [95% CI, 46.8%-70.3%] vs 39.2% [28.0%-51.2%]) and complete response/near-complete response (CR/nCR) rate (21.9% [95% CI, 13.1%-33.1%] vs 8.1% [3.0%-16.8%]). Common grade 3/4 adverse events and laboratory abnormalities in the PAN arm vs Pbo arm included thrombocytopenia (68.1% vs 44.4%), neutropenia (40.3% vs 16.4%), diarrhea (33.3% vs 15.1%), and asthenia/fatigue (26.4% vs 13.7%). Importantly, incidence of ontreatment deaths was nearly identical in both arms (n1⁄45 [6.9%] vs n1⁄45 [6.8%]). Conclusion: This analysis identified a subpopulation of pts in whom PAN-BTZ-Dex more than doubled the PFS vs PboBTZ-Dex, with marked improvements in CR/nCR rate and ORR. The safety profile was similar to the overall population. Together, these findings support the approval of PAN-BTZ-Dex by the US FDA in pts with relapsed or relapsed and refractory MM with 2 prior regimens, including BTZ and an IMiD. BP-056 Safety Profile of Oral Ixazomib: Experience from 761 Patients (Pts) Across 14 Phase 1 or Phase 1/2 Clinical Studies S. Lonial, K. Colson, R.D. Harvey, S. Kumar, A.-M. Hui, G. Liu, D. Berg, P. Richardson Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA; Dana-Farber Cancer Institute, Boston, MA, USA; Division of Hematology, Mayo Clinic, Rochester, MN, USA; Millennium Pharmaceuticals, Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company

e174 PO-162 Four phase 3 studies of the oral proteasome inhibitor (PI) ixazomib for multiple myeloma in the newly-diagnosed, relapsed/refractory, and maintenance settings: TOURMALINE-MM1, -MM2, -MM3, and -MM4 J. San Miguel, P. Moreau, V. Rajkumar, A. Palumbo, T. Facon, G. Morgan, R. Orlowski, M. Cavo, H. Einsele, F. Neumann, R. Labotka, S. Lonial, P. Richardson Clinica Universidad de Navarra, Centro Investigacion Medica Aplicada (CIMA) Pamplona, Spain; University Hospital Hotel Dieu, Nantes, France; Division of Hematology, Mayo Clinic, Rochester, MN, USA; Azienda Ospedaliero-Universitaria (AOU), University of Torino, Torino, Italy; Hopital Claude-Huriez, Lille, France; University of Arkansas for Medical Sciences (UAMS), Little Rock, AR, USA; MD Anderson Cancer Center, Houston, TX, USA; Seragnoli Institute of Haematology, University School of Medicine, Bologna, Italy; Medizinische Klinik und Poliklinik II, Julius Maximilians Universitat Wurzburg, Wurzburg, Germany; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited; Winship Cancer Institute of Emory University, Atlanta, GA, USA; Dana-Farber Cancer Institute, Boston, MA, USA Background: Triplet regimens combining a PI with an immunomodulatory drug (IMiD) plus dexamethasone (dex) have been shown to be highly effective for the treatment of multiple myeloma (MM), resulting in improved long-term outcomes. These improved outcomes have increased the focus on extended treatment, including maintenance therapy; however, the feasibility of long-term treatment with current regimens is limited due to toxicities or the need for regular clinic visits. Ixazomib is the first oral PI to be studied in the clinic, with encouraging early-phase data. A phase 1 study showed weekly administration of single-agent ixazomib to be TOURMALINE-MM1 TOURMALINE-MM Setting Relapsed/refractory MM Newly diagnosed MM Regimen Ixazomib plus Iendex vs Iendex Ixazomib plus Iendex vs Dosing Ixazomib 4 mg or placebo on days 1 ,8, and 15 Ixazomib 4 mg or plac on days 1, 8, and 1 Len 25 mg on days 1e21 Dex. 40 mg on days 1, 3, 15, and 22 Len 25 mg on days 1 Dex. 40 mg on day 1, 8,15, and 22 28-day cycles 28-day cycles Enrollment 722 patients Estimated 701 Primary end point PFS PFS Main secondary end points OS, OS in del17p, response rate, DOR, TTP, safety, PFS and OS in patients with high-risk cytogenetics OS, response rate, DOR, TTP, safety, PFS and O patients with high-ris cytogenetics Abbreviations: ASCT, autologous stem cell transplantation; dex, dexamethasone; DOR, duration of r survival; TTP, time to progression: TTR, time to response. 15th International Myeloma Workshop, September 23-26, 2015 generally well tolerated in patients with relapsed/refractory MM, with a low incidence of peripheral neuropathy (PN) (20% overall, only 1 case of grade 3 PN), and encouraging preliminary efficacy (Kumar et al Blood 2014). The feasibility of the all-oral combination of ixazomib plus lenalidomide (len) and dex has also been demonstrated, with a 90% overall response rate (including 62% VGPR) and a manageable safety profile with limited PN (6% grade 3) reported in patients with newly diagnosed MM (Kumar et al Lancet Oncol 2014). These studies, together with population pharmacokinetic results, identified the recommended ixazomib phase 3 dose as 4 mg weekly for patients with relapsed/refractory or newly diagnosed MM (Gupta et al Br J Clin Pharmacol 2015). The recommended phase 3 dose for ixazomib maintenance therapy was identified as 3 mg, increasing to 4 mg after 4 cycles if tolerated, using an exposure-safety-efficacy analysis approach (Gupta et al EHA 2014). On the basis of these preliminary data, 4 phase 3 trials of ixazomib are ongoing in the following settings: relapsed and/or refractory MM (TOURMALINE-MM1, NCT01564537), newly diagnosed MM (NDMM) (TOURMALINE-MM2, NCT01850524), MM maintenance therapy following autologous stem cell transplantation (ASCT) (TOURMALINE-MM3, NCT02181413), MM maintenance therapy after initial therapy without ASCT (TOURMALINE-MM4, NCT02312258). Methods: The four trials are shown in the Table. All are randomized, placebo-controlled, double-blind, multicenter studies. Patients in the TOURMALINE-MM1 and -MM2 studies will receive the all-oral combination of ixazomib plus len-dex, while those in the TOURMALINE-MM3 and -MM4 maintenance trials will receive single-agent ixazomib. Progression-free survival is the primary endpoint for all four trials. Recruitment for TOURMALINEMM2, -MM3, and -MM4 is ongoing The authors would like to thank Jane Saunders of FireKite, an Ashfield company, part of UDG Healthcare plc, for writing support during the development of this abstract, which was funded by Millennium Pharmaceuticals, Inc. 2 TOURMALINE-MM3 TOURMALINE-MM4 MM maintenance post-ASCT MM maintenance without ASCT Iendex Ixazomib maintenance vs placebo Ixazomib maintenance vs placebo ebo 5 Ixazomib 3 mg or placebo on days 1, 8, and 15 for cycles 1e4 Ixazomib 3 mg or placebo on days 1, 8, and 15 for cycles 1e4 -21 s Ixazomib 4 mg or placebo on days 1, 8, and 15 for cycles 5e26 Ixazomib 3 or 4 mg, or placebo on days 1 , 8, and 15 for cycles 5e26 28-day cycles 28-day cycles Estimated 652 Estimated 761

A246 VMP Results in Fewer Bone Events and Greater ALP Increases Versus MP in the VISTA Study in Front-Line MM M Delforge,1 M Kropff,1 I Spicka,2 M Petrucci,3 PG Richardson,4 R Schlag,5 N Khuageva,6 MA Dimopoulos,7 O Shpilberg,8 O Samoilova,9 MV Mateos,10 K Liu,11 W Deraedt,12 H van de Velde,13 J San Miguel14 1University of Munster, Germany; 2University Hospital, Prague, Czech Republic; 3University La Sapienza, Rome, Italy; 4Dana-Farber Cancer Institute, Boston, MA; 5Praxisklinik Dr. Schlag, Wurzburg, Germany; 6SP Botkin Moscow City Clinical Hospital, Russian Federation; 7University of Athens, School of Medicine, Athens, Greece; 8Rabin Medical Center, Petah-Tiqva, Israel; 9Nizhnii Novgorod Region Clinical Hospital, Russian Federation; 10Hospital Universitario Salamanca, CIC, IBMCC (USAL-CSIC), Spain; 11Johnson & Johnson Pharmaceutical Research & Development, L.L.C., Raritan; 12Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium; 13Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium; 14Hospital Universitario Salamanca. CIC, IBMCC (USAL-CSIC), Salamanca, Spain

TPS227 Background: The development of novel agents, including the proteasome inhibitor bortezomib (BTZ), has resulted in significant improvements in survival for patients (pts) with multiple myelom...

8014 Background: Elotuzumab is a humanized monoclonal IgG1 antibody targeting human CS1, a cell surface glycoprotein. CS1 is highly and uniformly expressed on multiple myeloma (MM) cells, with limi...

8016 Background: Bortezomib (VELCADE, Bz) or lenalidomide (REVLIMID, Len) plus dexamethasone (dex) demonstrate substantial activity in front-line MM; the three-drug combination has shown efficacy in the relapsed setting. This was the first prospective study of the three-drug regimen in front-line MM. Methods: Patients (pts) received eight 3-wk cycles of Bz 1.0–1.3 mg/m2 (d 1, 4, 8, 11), Len 15–25 mg (d 1–14), and dex 40 or 20 mg (d 1, 2, 4, 5, 8, 9, 11, 12) at 5 dose levels (phase I) and the maximum tolerated/planned dose (MTD; phase II). Responding pts could receive maintenance therapy or ASCT. Pts received prophylactic anticoagulants and anti-viral therapy. Primary endpoints were MTD and response rate. Results: 66 pts were treated (35 in phase II). Median age was 58 (range 22–86); 55% were men; 44%/47%/9% had ISS stage I/II/III MM; 68%/23%/9% had IgG/IgA /light chain MM; 57% had any of del 13q, del 17p, t(4;14), and t(11;14). Pts received a median of 10 cycles, including medians of 8, 10, and 8 cycles o...

TPS308 Background: BTZ, a backbone of novel therapy for patients (pts) with MM, is an effective agent but pts will relapse and ultimately become refractory to BTZ-based therapy as well as other novel agents, thereby constituting a high unmet medical need. Panobinostat (PAN; LBH589) is a potent pan-deacetylase inhibitor (pan-DACi) that targets HDAC6, disrupts aggresome and HSP90 activity, and promotes MM cell death. Combination with BTZ has shown synergistic cytotoxicity in preclinical studies. In a phase Ib MM study, combination of oral PAN with iv BTZ displayed a predictable and manageable safety profile with limited neurotoxicity and clinical efficacy seen with CR + PR + MR in 68% of pts, including 8 of 13 (62%) BTZ-refractory pts. Hence this combination is to be further evaluated in the PANORAMA program (PANobinostat ORAl in Multiple myelomA) Phase III (PANORAMA 1) and Phase II (PANORAMA 2) studies. PANORAMA 2is a U.S.-based, multicenter, single-arm study to evaluate the efficacy of PAN + BTZ + DEX in ...

8032 Background: Lenalidomide (Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or relapsed/refractory multiple myeloma (MM) patients following ≥1 prior therapy. RAD001, an m...

8140 Background: Aminobisphosphonates (aBP) are standard of care for myeloma related bone disease and are recommended every 3-4 weeks. Our previous data suggests altered bone remodeling in osteonec...

8003 Background: Elotuzumab is a humanized antibody against a cell surface glycoprotein, CS1, which is highly expressed in multiple myeloma (MM). This phase I study was designed to determine MTD, safety, PK and response of elotuzumab in combination with bortezomib in relapsed/refractory MM patients (pts) following 1-3 prior therapies. Methods: Four escalating doses of elotuzumab (2.5 mg/kg to 20 mg/kg) were administered on D 1 and 11 and bortezomib (1.3 mg/m2) on D 1, 4, 8 and 11 of a 21-day cycle. Pts with ≥ stable disease after 4 cycles continued treatment until progression. Key entry criteria included age ≥ 18 years; confirmed MM diagnosis with 1 to 3 prior therapies including prior bortezomib and refractory MM; measurable M-protein in serum and/or urine. Results: In this fully enrolled study, 28 MM pts were treated; 3 each at 2.5, 5 and 10 mg/kg and 19 at 20 mg/kg elotuzumab. The 26 pts with completed analysis had a median of 3.4 years from initial MM diagnosis and a median of 2 prior lines of therapy...

8125 Background: Outcome of patients (pts) with multiple myeloma (MM) has improved with the introduction of the immunomodulatory drugs (IMiD; thalidomide, lenalidomide) and the proteasome inhibitor...

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 deac...

8110 Background: Bortezomib is an effective treatment for both multiple myeloma (MM) and Waldenstrom Macroglobulinemia (WM), whose activity is attributed to blocking elimination of ubiquitin tagged...

8503 Background: Tanespimycin (Tan) disrupts HSP90, a key molecular chaperone for signal transduction proteins critical to myeloma (MM) growth, survival and drug resistance. Preclinical data show anti-tumor synergy between Tan and bortezomib (Bz) and suggest Tan may be neuroprotective, including reversibility of Bz-induced peripheral neuropathy (PN). A phase I study of single agent Tan in advanced MM showed favorable tolerability and modest activity. Methods: 72 patients (pts) with relapsed/refractory MM received 0.7 - 1.3 mg/m2 Bz as IVB followed by 1-hr infusion of 100 -340 mg/m2 Tan on days 1, 4, 8,11 q 21d, with 42 pts receiving the highest dose of both drugs as part of a phase II expansion. Toxicities were assessed by CTCAE v3 and response by modified EBMT criteria. Results: Of 72 pts, 72% had IgG subtype with a median age of 60 yo. Median time since MM diagnosis was 50 mos with median of 5 (1–15) prior regimens. Prior treatments included stem cell transplant (69%), thalidomide (74%), Bz (69%), lenalidomide (28%) and Hsp90 inhibitors (13%). 58 pts with measurable disease were treated at 1 or 1.3 mg/m2 Bz. Response rates (≥ MR) were 41%, 20% and 14% in the Bz-naive, -pretreated and -refractory pts respectively. In the subgroup with 1–3 prior therapies and who were Bz-naive, the response rate was 56%. Median duration of response (DOR) for all pts with response (n=14) was 10.7 mos, including 3 Bz-refractory pts who had durable PR through mos 12, 22 and 28. 3 other pts remain in response through 24 mos. Of the 72 pts, the most frequent AEs were diarrhea (60%), nausea (49%), fatigue (49%), thrombocytopenia (40%) and AST elevation (28%), which proved manageable with dose reduction and supportive care. Most frequent G3–4 AEs included thrombocytopenia (25%), diarrhea, anemia and fatigue (7% each), as well as back pain and AST elevation (4% each). Only 21% of pts had G1–2 PN; no G3–4 PN was seen. Conclusions: Tan + Bz is active and well tolerated in relapsed/refractory MM, with durable responses in Bz-naive, -pretreated and -refractory pts. Median DOR for the combination compares favorably to Bz monotherapy. Final PFS data will be presented. No severe PN has been observed, consistent with Tan's neuroprotective effect in pre-clinical models. A phase III study of Tan + Bz vs Bz is ongoing. [Table: see text]

8517 Background: Three-drug combinations with lenalidomide (Revlimid, Rev) and bortezomib (Velcade, Vel) are highly active in previously untreated multiple myeloma (MM). Among the most active are RVD (Revlimid, Velcade, Dexamethasone) and VDD (Velcade, Doxil, Dexamethasone) with ≥ PR rate of 100% and 93%, and a CR/nCR rate of 44% and 40%, respectively. Pre-clinical evaluations suggest that adding pegylated liposomal doxorubicin hydrochloride (Doxil, Dox) to RVD (RVDD) may have higher activity. This phase I/II study was designed to determine the maximum tolerated dose (MTD) of RVDD, assess safety and evaluate efficacy of this 4-drug regimen in newly diagnosed MM. Methods: Four dose levels are being evaluated: Rev 15–25 mg (days 1–14), Vel 1.3 mg/m2 (days 1, 4, 8, 11), dexamethasone (Dex) 20/10 mg (cycles 1–4/5–8; days of and after Vel), Dox 20 and 30 mg/m2 (day 4), with dose assignment for patients (pts) according to the TITE-CRM algorithm. Eight 21-day cycles are planned with 38 pts to be treated at the MTD in phase II. Pts who achieve ≥ PR can proceed to autologus stem cell transplant (ASCT) after ≥ 4 cycles, while all others receive 21-day maintenance cycles with Rev (days 1–14), Vel (day 1 and 8), and Dex (days of and after Vel) at the doses tolerated by the end of initial treatment. Results: The study has enrolled 23 pts to date. Four pts received level 1 (Rev/Dox 15/20), 11 pts level 2 (Rev/Dox 20/20, and 8 pts level 3 (Rev/Dox 25/20). Nineteen pts are evaluable for toxicity after completion of a median of 4 cycles (range 1–8). Two pts developed DLT at dose level 2, consisting of grade (G) 3 asymptomatic neutropenia and G3 elevation of transaminase. The MTD has not been reached. Overall, toxicities have been manageable with no additional G3 hematologic events. There have been 4 additional G3 non-hematologic events including one case each of pneumonia, DVT, fatigue, and hypotension. After a median of 12 (range 3–24) weeks of treatment, preliminary response rates by modified EBMT/UC in 19 evaluable pts are: 95% ≥ PR, 47% ≥ VGPR, 26% CR/nCR. Conclusions: RVDD is well tolerated in newly diagnosed MM and appears highly active with an overall response (≥ PR) of 95%. Accrual is ongoing, with updated toxicity and efficacy data to be presented at the meeting. [Table: see text]

8505 Background: NPI-0052 produces rapid, broad and prolonged inhibition of all 3 catalytic activities of the 20S proteasome. NPI-0052 has a non-peptide based structure that appears to result in a unique proteasome inhibition (PI), signal transduction and safety profile. Preclinical data suggest NPI-0052 may demonstrate an improved therapeutic ratio, with significant activity in hematologic and solid tumor malignancies including MM resistant to bortezomib (BZ) and other agents. Methods: This phase I dose escalation study of NPI-0052 was conducted in patients (pts) with r/r MM, including after BZ and/or lenalidomide. Pts were treated with NPI-0052 IV weekly for 3 weeks in 4-week cycles. The dose of NPI-0052 was escalated utilizing a combination of accelerated titration and 3+3 designs. PI and PK were assayed after the 1st and 3rd doses. Results: 17 patients have been treated at doses ranging from 0.025 mg/m2 to 0.6 mg/m2 without reaching a MTD. One patient experienced reversible creatinine elevation associated with progression of light chain nephropathy at 0.075 mg/m2. Drug- related adverse events have consisted principally of mild-to-moderate fatigue, nausea and diarrhea. In this study at dose levels 0.75 and 0.15 mg/m2, the half-life = 0.5 - 5.0 min; clearance = 4.8 ± 5.2 L/min and Vz = 22.6 ± 44.2 L. PI in whole blood demonstrates dose-dependent chymotrypsin-like inhibition up to 26% at 0.075 mg/m2. Of note, 2 patients remained on study for over 6 months and one year with stable disease and no significant toxicity. Importantly, NPI-0052 does not appear to induce peripheral neuropathy or myelosuppression. Conclusions: NPI-0052 was well tolerated in this study with escalation continuing to a recommended phase II dose (RP2D) for r/r MM. The RP2D (0.7 - 0.8 mg/m2), PI and safety profiles of NPI-0052 have been defined in other diagnoses, and appear unique from BZ in spite of up to 100% proteasome inhibition. In this study, NPI-0052 has effects on PD, PK and may potentially confer clinical benefit at doses which are well below the MTD determined in the other trials. Additional trials in MM are being initiated, including with lenalidomide. [Table: see text]