scholarly journals A Phase I Single-Agent Study of Twice-Weekly Consecutive-Day Dosing of the Proteasome Inhibitor Carfilzomib in Patients with Relapsed or Refractory Multiple Myeloma or Lymphoma

2012 ◽  
Vol 18 (17) ◽  
pp. 4830-4840 ◽  
Author(s):  
Melissa Alsina ◽  
Suzanne Trudel ◽  
Richard R. Furman ◽  
Peter J. Rosen ◽  
Owen A. O'Connor ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Proteasome Inhibitor ◽  
Single Agent ◽  
Refractory Multiple Myeloma

Phase I Study of 30-Minute Infusion of Carfilzomib As Single Agent or in Combination With Low-Dose Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma

2015 ◽  
Vol 33 (7) ◽  
pp. 732-739 ◽  
Author(s):  
Kyriakos P. Papadopoulos ◽  
David S. Siegel ◽  
David H. Vesole ◽  
Peter Lee ◽  
Steven T. Rosen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Concentration ◽  
Phase I ◽  
Phase I Study ◽  
Low Dose ◽  
Single Agent ◽  
Phase Iii ◽  
Maximum Plasma ◽  
Irreversible Inhibitor ◽  
Refractory Multiple Myeloma

Purpose Carfilzomib is an irreversible inhibitor of the constitutive proteasome and immunoproteasome. This phase I study evaluated the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carfilzomib administered as a 30-minute intravenous (IV) infusion. Safety and efficacy of carfilzomib as a single agent or in combination with low-dose dexamethasone were assessed. Patients and Methods Patients with relapsed and/or refractory multiple myeloma (MM) were administered single-agent carfilzomib on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle one day 1 and 2 doses were 20 mg/m2, followed thereafter by dose escalation to 36, 45, 56, or 70 mg/m2. Additionally, carfilzomib was combined with low-dose dexamethasone (40 mg/wk). Results Thirty-three patients were treated with single-agent carfilzomib. Dose-limiting toxicities in two patients at 70 mg/m2 were renal tubular necrosis and proteinuria (both grade 3). The MTD was 56 mg/m2. Nausea (51.5%), fatigue (51.5%), pyrexia (42.4%), and dyspnea and thrombocytopenia (each 39.4%) were the most common treatment-related toxicities. Overall response rate (ORR) was 50% (56-mg/m2 cohort). Increasing carfilzomib dosing from 20 to 56 mg/m2 resulted in higher area under the plasma concentration-time curve from time zero to last sampling and maximum plasma concentration exposure with short half-life (range, 0.837 to 1.21 hours) and dose-dependent inhibition of proteasome chymotrypsin-like activity. In 22 patients treated with 45 or 56 mg/m2 of carfilzomib plus low-dose dexamethasone, the ORR was 55% with a safety profile comparable to that of single-agent carfilzomib. Conclusion Carfilzomib administered as a 30-minute IV infusion at 56 mg/m2 (as single agent or with low-dose dexamethasone) was generally well tolerated and highly active in patients with relapsed and/or refractory MM. These data have provided the basis for the phase III randomized, multicenter trial ENDEAVOR.

scholarly journals Quantitative PK/PD Prediction of the Efficacious and Safe Dose Ranges of the LMP7 Inhibitor M3258 for Phase I Application in Relapsed/Refractory Multiple Myeloma Patients

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5582-5582
Author(s):  
Florian Lignet ◽  
Christina Esdar ◽  
Manja Friese-Hamim ◽  
Andreas Becker ◽  
Elise Drouin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research And Development ◽  
Phase I ◽  
Dose Escalation ◽  
Single Agent ◽  
Proteasome Inhibitors ◽  
Refractory Multiple Myeloma ◽  
Oral Application ◽  
Development Institute ◽  
Safe Dose

M3258 is an orally bioavailable, potent, selective, reversible inhibitor of the large multifunctional peptidase 7 (LMP7, β5i, PSMB8) proteolytic subunit of the immunoproteasome; a crucial component of the cellular protein degradation machinery, which is highly expressed in malignant hematopoietic cells including multiple myeloma. M3258 was previously shown to deliver strong in vivo preclinical efficacy in multiple myeloma xenograft models, as well as a more benign non-clinical safety profile compared to approved pan-proteasome inhibitors, exemplified by a lack of effects on the central and peripheral nervous systems and cardiac and respiratory organs. Here we describe preclinical PK/PD and PK/efficacy modelling which led to a prediction of the PK profile, and the efficacious and safe dose ranges of M3258 in human which were used to guide the design of the phase I dose-escalation trial of M3258 in >3 line relapsed/refractory multiple myeloma (RRMM) patients. Mouse, rat, dog and monkey PK, plasma protein binding and intrinsic clearance data were used to estimate a half-life of approximately 6 hours for M3258 in human. The human total clearance and volume of distribution for M3258 were predicted to be 0.033 L/h/kg and 0.28 L/kg, respectively, whilst oral bioavailability was estimated to be above 80%. LMP7 proteolytic activity was assessed as a PD readout in human multiple myeloma tumor cells xenografted to mice as well as in dog peripheral blood mononuclear cells (PBMCs). A strong PK/PD relationship was observed for M3258 across both species. LMP7 inhibition by M3258 also correlated strongly with anti-tumor efficacy in multiple myeloma xenografts, with maximal efficacy observed at M3258 exposure delivering sustained inhibition of tumor LMP7 activity. Quantitative PK/PD/efficacy modeling predicted the biologically efficacious dose (BED) of M3258 upon oral application to be between 10 - 90 mg daily in human. By incorporating data from nonclinical safety studies, these data suggest an attractive human PK profile of M3258, enabling oral application, as well as an improved human therapeutic index compared to approved pan-proteasome inhibitors. M3258 is being investigated in a phase I, first-in-man, 2-part, open label clinical study designed to determine the safety, tolerability, PK, PD and early signs of efficacy of M3258 as a single agent (dose-escalation) and co-administered with dexamethasone (dose-expansion) in participants with RRMM whose disease has progressed following > 3 prior lines of therapy and for whom no effective standard therapy exists. Integration of these data will guide the selection of the BED for potential further clinical development of M3258. Disclosures Lignet: Merck Healthcare KGaA: Employment. Esdar:Merck Healthcare KGaA: Employment. Friese-Hamim:Merck Healthcare KGaA: Employment. Becker:Merck Healthcare KGaA: Employment, Other: Holding shares with a value below 1000-USD. Drouin:EMD Serono Research and Development Institute: Employment. El Bawab:Merck Healthcare KGaA: Employment. Goodstal:EMD Serono Research and Development Institute: Employment. Gimmi:Merck Healthcare KGaA: Employment. Haselmayer:Merck Healthcare KGaA: Employment. Jährling:Merck Healthcare KGaA: Employment. Sanderson:Merck Healthcare KGaA: Employment. Sloot:Merck Healthcare KGaA: Employment. Stinchi:Merck Healthcare KGaA: Employment. Victor:Merck Healthcare KGaA: Employment. Walter:Merck Healthcare KGaA: Employment. Rohdich:Merck Healthcare KGaA: Employment.

An Open-Label Phase I Study of the Safety and Efficacy of RAD001 in Combination with Lenalidomide in the Treatment of Patients with Relapsed and Relapsed/Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3856-3856 ◽  
Author(s):  
Noopur Raje ◽  
Paul Richardson ◽  
Parameswaran N Hari ◽  
Anuj Mahindra ◽  
Sarah Kaster ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Single Agent ◽  
Oral Steroid ◽  
High Dose ◽  
Advisory Committees ◽  
Refractory Multiple Myeloma ◽  
Grade 3

Abstract Abstract 3856 Poster Board III-792 Background Lenalidomide (Revlimid®, Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (MM) patients following ≥1 prior therapy. mTOR inhibitor RAD001 has been studied as a single agent in MM, and although well tolerated, did not have single agent activity. Given the increased toxicity noted with pulsed high dose steroids, we sought to study a non-steroid containing oral regimen for the treatment of relapsed MM predicated upon our previous studies which demonstrated synergistic anti-MM activity of mTOR inhibitors when combined with len. Here, we extended our in vitro observations to a phase I clinical trial combining RAD001 with len in patients with relapsed or refractory MM. The primary objective was to assess toxicity of this combination and to determine the maximum tolerated dose (MTD). The secondary objective was to determine the activity of this combination. Methods Patients with relapsed and refractory MM were assigned to len and RAD001 to be taken for 21 days of a 28 day cycle. Dose escalation followed a modified Fibonacci design. Patients were allowed to continue therapy until disease progression or unacceptable toxicity. Patients received concomitant anti-thrombotic (aspirin 81 or 325 mg/day) therapy. Response was assessed according to modified EBMT and Uniform Criteria, and toxicities were assessed using NCI CTCAE v3.0. Results Eighteen MM patients have been enrolled to date. One patient in cohort 1 (Len: 10mg and RAD001: 5 mg x 21 days) developed grade 3 neutropenia requiring expansion of the cohort. Cohort 2 (Len: 15mg and RAD001: 5 mg x 21 days) also required expansion because of grade 4 thrombocytopenia noted in 1 patient. Dose limiting toxicities included grade 4 neutropenia and thrombocytopenia in 2/3 patients in cohort 3 (Len: 20mg and RAD001: 5 mg x 21 days). The MTD for patients with MM was therefore declared at 15 mg of len and 5mg of RAD001 for 21 days with a 7 day rest period. Apart from the hematological toxicities expected with the combination, patients otherwise tolerated the regimen well. Most common (≥10%) grade 1 / 2 events included nausea, fatigue, dyspnea, diarrhea, constipation, neuropathy and muscle cramps, all of which were manageable with supportive care. No thromboembolic events were noted. Grade 3 / 4 adverse events ≥ 5% included thrombocytopenia (11%) and neutropenia (22%). Fifteen patients have finished at least 2 cycles of therapy: 8 of 15 patients have either stable disease (SD: 1), minimal response (MR: 5) or a partial response (PR: 2), including 7 of 9 patients treated at the recommended MTD for an overall response rate (MR or better) of 50% (90% CI: [30.76%]). One patient with SD continued therapy for a total of 10 cycles, without significant toxicities. Conclusions The combination of Len plus RAD001 is a well tolerated regimen with predictable hematological toxicities. Promising responses were noted in this heavily pretreated patient population. This combination provides an oral steroid free combination alternative strategy which warrants future evaluation in phase II studies. Disclosures: Raje: Astrazeneca : Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: RAD001 not labelled for use in myeloma. Richardson:Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hari:Celgene: Research Funding, Speakers Bureau. Laubach:Novartis:. Ghobrial:Millennium: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Adams:Novartis: Employment. Makrides:Celgene: Employment.

Phase I/II Study with Single Agent Everolimus (RAD001) in Patients with Relapsed or Refractory Multiple myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3850-3850 ◽  
Author(s):  
Andreas Guenther ◽  
Philipp Baumann ◽  
Renate Burger ◽  
Wolfram Klapper ◽  
Ralf Schmidmaier ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Research Funding ◽  
Cell Cancer ◽  
Single Agent ◽  
Study Drug ◽  
Fixed Dose ◽  
Bone Marrow Biopsies ◽  
Refractory Multiple Myeloma ◽  
Dose Levels

Abstract Abstract 3850 Poster Board III-786 Introduction The mammalian target of rapamycin (mToR) plays an important role in multiple myeloma (MM), since it is involved in the PI3K-AKT pathway which can be activated by stimulation with growth and survival factors such as interleukin-6 (IL-6) and insulin-like growth factor-1 (IGF-1) or the loss of the tumor suppressor PTEN. Inhibition of mToR blocked myeloma cell growth in vitro as well as in preclinical animal models. The mToR inhibitor everolimus (RAD001) is approved for immunosuppression and for the treatment of renal cell cancer. In an investigator-initiated phase I/II open label trial, patients ≥ 18 years with relapsed or refractory multiple myeloma (MM) were included after at least two lines of previous treatment. The patients received a fixed dose of oral everolimus for six months. The cohorts had 3 to 6 participants. The phase I part of the trial followed a classical dose-escalation design with three planned dose levels (5 mg, 7.5 mg and 10 mg). Patient benefiting from study drug were allowed to continue with treatment. To obtain insights into the biological activity of everolimus, serum dose levels were monitored and bone marrow biopsies and aspirates were performed three times (at screening, after four weeks and after six months of treatment). Results The primary endpoint of the phase I part was safety. Currently, 12 patients were screened and 11 enrolled in the trial (10 male and 1 female, age from 52 to 71 years). One patient withdrew his consent in the first four weeks of treatment and had to be replaced for safety and efficacy assessment. Since no DLT were observed, the intended final daily dose of 10 mg everolimus could be reached. Only one of four SAE during treatment was assessed to be possibly related to the study drug. Except for one grade 4 thrombocytopenia, no > grade 3 AE were observed during treatment. Remarkably, few infectious complications (≤grade 2) were seen despite the known immunosuppressive activity of everolimus. Anti-myeloma activity was documented in 5 out of 7 evaluable patients. One partial response in a heavily pre-treated patient and stable disease in four additional patients were seen. The observed rate of responses and clinical benefit fulfills the criteria defined in the protocol to enter the phase II part of the trial after completing phase I. The individual serum dose levels varied widely and response seemed to correlate to the achieved everolimus dose level. Conclusion Everolimus given orally at doses of 5 mg to 10 mg daily showed an acceptable safety profile in heavily pre-treated multiple myeloma patients and the observed responses even at suboptimal dose levels are promising. Further evaluation of everolimus, alone and in combination with other drugs, is warranted. Disclosures: Guenther: Novartis: Consultancy, Research Funding. Off Label Use: Everolimus is not approved for multiple myeloma. Baumann:Novartis: Consultancy, Research Funding. Schmidmaier:Novartis: Consultancy, Research Funding. Gramatzki:Novartis: Consultancy, Research Funding, Speakers Bureau.

scholarly journals Clinical Efficacy of Intracellular Molecular Inhibitors for Relapsed, Refractory Multiple Myeloma: A Systematic Review of Early Clinical Data

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1950-1950
Author(s):  
Shehroz Aslam ◽  
Mustafa Nadeem Malik ◽  
Abdul Rafae ◽  
Rida Riaz ◽  
Muhammad Jahanzeb Khalil ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Phase Ii ◽  
Clinical Efficacy ◽  
Nuclear Export ◽  
Single Agent ◽  
Phase Iii ◽  
Refractory Multiple Myeloma ◽  
Best Response ◽  
Combination Regimens

Abstract Introduction: Intracellular molecular inhibitors act by inducing apoptosis due to inhibition of intracellular proteins like 20S proteasome subunit, histone deacetylases (HDAC's), exportin 1 (XPO1), cyclin-dependent kinases (CDKs) and kinesin spindle protein (KSP). These proteins are involved in the regulation of cell cycle. The aim of our analysis is to report published literature on the clinical efficacy of intracellular molecular inhibitors in relapsed and refractory multiple myeloma (RRMM) patients. Methods: Following Prisma guidelines, we performed a comprehensive literature search on articles published after 2011. Four hundred eighty-nine articles were identified using the following five databases (Pubmed, Embase Cochrane, Web of Science and Clinical Trials.gov). After a detailed screening, we finalized 13 studies involving 902 RRMM patients. We included phase I/II, II and III studies. The studies involving drugs approved by the US Food and Drug Administration were excluded. Results:Selective inhibitor of nuclear export (SINE) compounds: Selinexor A total of 112 RRMM patients were included. Thirty-three patients were in phase I/II while 79 patients were in phase II. All patients received selinexor (60-100 mg) in different combination regimens. Forty-eight patients were quad-refractory (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide) while 31 patients were penta-refractory (including isatuximab/daratumumab). In 110 evaluable patients, the pooled overall response rate (ORR) was 35.45%. The ORR in the subset of quad-refractory and penta-refractory patients was 21% and 20% respectively. The best response was seen when selinexor was used in combination with bortezomib (V) and dexamethasone (d) i.e. 77%.HDAC inhibitors: Vorinostat and Ricolinostat A total of 562 RRMM patients were included. Seventy-seven patients were in phase I/II, 168 patients in phase II, and 317 patients were in phase III. Five hundred and eighteen patients received vorinostat (100-400 mg) in different combination regimens while 44 patients received ricolinostat (160-240mg) in combination with Vd. The median follow-up period was 13.2-30.8 months. In 560 evaluable patients, the pooled ORR was 42.83% and 31.81% in patients who received vorinostat and ricolinostat, respectively. The best response was seen when vorinostat was used in combination with V, doxorubicin (DX) and d i.e. 67%.Proteasome inhibitors: Oprozomib and Marizomib A total of 117 RRMM patients were included. Hundred and two patients were in phase I/II while 15 patients were in phase II. Twenty-seven, 34 and 41 patients received single-agent oprozomib in the dose of 240 mg, 150-180 mg, and 240-300 mg respectively while 15 patients received single-agent marizomib (0.5 mg/m2). Out of 107 evaluable patients, the pooled ORR was 27.65% in patients who received oprozomib while no response was seen in patients who received marizomib however stable disease was seen in 31% of patients.KSP inhibitor: Filanesib A total of 50 RRMM patients were included. All patients were in phase II. Thirty-two patients received single-agent filanesib (1.5mg/m2) while 18 patients received filanesib (1.5mg/m2) in combination with d. The pooled ORR was 22%. The ORR was 19% when filanesib was used as a single agent while it was 28% when filanesib was used in combination with d.CDK inhibitors: Dinaciclib and Palbociclib A total of 61 RRMM patients were included. All patients were in phase I/II. Twenty-nine patients received single-agent dinaciclib (30-50 mg/m2) while 32 patients received palbociclib (100mg) in combination with Vd. In 52 evaluable patients, the ORR in patients who received dinaciclib was 11% while the ORR in patients who received palbociclib was 20%. Conclusion: In RRMM patients, vorinostat and selinexor when used in combination regimens demonstrated a weak efficacy with a pooled ORR of 43% and 36% respectively. The best response was seen in combination with Vd i.e. 67% and 77% respectively. The data on other intracellular molecular inhibitors (ricolinostat, oprozomib, marizomib, filanesib, dinaciclib, and palbociclib) when used either as single agents or in combination regimens, suggested a poor efficacy with an ORR of < 35%. However, future randomized well designed prospective clinical trials involving a larger population are required to further explore the efficacy of these agents in RRMM patients. Disclosures No relevant conflicts of interest to declare.

Phase I and II pharmacokinetic and pharmacodynamic study of the proteasome inhibitor bortezomib in Japanese patients with relapsed or refractory multiple myeloma

2007 ◽  
Vol 0 (0) ◽  
pp. 071029014002001-??? ◽  
Author(s):  
Yoshiaki Ogawa ◽  
Kensei Tobinai ◽  
Michinori Ogura ◽  
Kiyoshi Ando ◽  
Takahide Tsuchiya ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Proteasome Inhibitor ◽  
Japanese Patients ◽  
Refractory Multiple Myeloma ◽  
Pharmacodynamic Study ◽  
Phase I And Ii

scholarly journals The role of carfilzomib in relapsed/refractory multiple myeloma

2021 ◽  
Vol 12 ◽  
pp. 204062072110196
Author(s):  
Andrew J. Yee
Keyword(s):  
Multiple Myeloma ◽  
Adverse Event ◽  
Proteasome Inhibitor ◽  
Single Agent ◽  
Adverse Event Profile ◽  
Future Role ◽  
Refractory Multiple Myeloma ◽  
Renal Adverse Event ◽  
Relapsed Disease

Carfilzomib is the second proteasome inhibitor approved for relapsed multiple myeloma. Since its approval in 2012, carfilzomib has been an active and versatile drug, based on its efficacy as a single agent; superiority as a doublet with dexamethasone compared with bortezomib and dexamethasone; and as a partner in diverse three drug combinations such as with lenalidomide or daratumumab. While it has an established place in relapsed disease, clinicians should be aware of its cardiovascular and renal adverse event profile, which is manageable, in order to optimize outcomes. This review will provide a perspective on the current and future role of carfilzomib in relapsed/refractory multiple myeloma.

scholarly journals A Phase I Dose Escalation Study of PT-112 in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 9-10
Author(s):  
Taxiarchis Kourelis ◽  
Sikander Ailawadhi ◽  
Dan T. Vogl ◽  
Dennis Cooper ◽  
Tyler D Ames ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Dose Escalation ◽  
Research Funding ◽  
Single Agent ◽  
Private Company ◽  
Dose Escalation Study ◽  
Refractory Multiple Myeloma ◽  
Car T ◽  
Grade 3

Background: PT-112 is a novel pyrophosphate-platinum conjugate with a multi-modal mechanism of action that induces immunogenic cell death and is not susceptible to DNA-repair drug resistance pathways. In phase I studies in solid tumors, PT-112 demonstrated safety and efficacy as single agent and in combination with PD-L1 checkpoint inhibitor avelumab, crossing a range of dose levels (DL) and tumor types, including in heavily pre-treated patients (pts) non-responsive to immunotherapy and refractory to other modalities. Non-clinical, in vivo research using advanced imaging technology demonstrated that PT-112 reached the highest concentrations in bone tissue (osteotropism). Moreover, PT-112 was highly active in the orthotopic, immune-competent Vk*MYC mouse model of multiple myeloma, including drug-resistant transplant variants. Thus, a rationale for PT-112 as an investigational candidate in multiple myeloma was established. Here, we present results of a phase I dose escalation study of PT-112 in pts with relapsed or refractory multiple myeloma (RRMM). Methods: A 3+3 design was used to determine the recommended phase 2 dose (RP2D) for PT-112 (28-day cycle IV days 1, 8, 15) in pts with evaluable RRMM who had exhausted available therapies (Tx), with adequate bone marrow (abs neutrophil count ≥ 1.0 x 109/L; platelet count ≥ 50 x 109/L; and hemoglobin ≥ 8.0 g/dL) and renal function (calculated creatinine clearance ≥ 30 mL/min), and ECOG PS 0-2. Results: A total of 24 pts were treated with PT-112 monotherapy across 6 DLs: 125 mg/m2, 3 pts; 180 mg/m2, 4 pts; 250 mg/m2, 5 pts; 300 mg/m2, 4 pts; 360 mg/m2, 4 pts; 420 mg/m2, 4 pts. Patients had a median age of 72 years and were heavily pre-treated, with a median of 8 prior lines of systemic Tx: 22 (92%) pts were triple-class refractory with 19 (79%) pts penta-refractory, and 3 (13%) pts refractory to BCMA-based therapies. The most common treatment-related adverse events (TRAEs) were thrombocytopenia (58%), neutropenia (42%), diarrhea (38%), and nausea (38%). 38% of pts had ≥1 grade 3 non-hematologic TRAE, with no grade 4 non-hematologic TRAEs reported. One dose-limiting toxicity (DLT) of grade 4 neutropenia occurred at the 420 mg/m2 DL. In addition, due to frequent dose reductions and modifications at this DL, the safety committee declared 360 mg/m2 as the RP2D. Among 8 patients who received a starting dose at / above the RP2D, 2 had stable disease and 4 experienced responses to PT-112 Tx. These included a confirmed partial response (PR) achieved in a 79-year-old pt with kappa free light chain (FLC) disease treated at 360 mg/m2, whose previous Tx included combination regimens with most approved therapies (penta-refractory) and stem cell transplantation. FLC levels declined by 65% from baseline on PT-112 therapy and the pt remained progression free for 4.5 months. A 72-year-old pt treated at the 420 mg/m2 DL, reduced to 250mg/m2 every other week over the course of Tx due to grade 3-4 cytopenias, had a confirmed minor response. Prior Tx with multiple lines given over 9 years included stem cell transplantation, most approved therapies (penta-refractory), prior investigational antibody and CAR-T cell Tx (primary refractory to CAR-T). The patient was M-protein negative, kappa FLC levels declined by 32% following the first dose reduction, and the pt remained progression free and clinically stable without complaints for 4.5 months. Additionally, two transient, unconfirmed PRs occurred in patients at the 420mg/m2 DL: in a triple-class-refractory 82-year-old previously treated with 5 lines of Tx, with 70% reduction in kappa FLC during cycle 1; and in a penta-refractory 85-year-old, who experienced disappearance of M-protein during cycle 1 and Gr 4 neutropenia (DLT). Conclusions: PT-112 monotherapy was feasible and well tolerated in this heavily pre-treated, multi-refractory multiple myeloma population, and the Phase I clinical data appear to validate the developmental hypothesis, built upon activity in the Vk*MYC mouse model of multiple myeloma. Responses were confirmed in 25% of patients treated at / above the RP2D using single-agent PT-112, an encouraging result in a dose escalation trial conducted in heavily refractory patients. Activity of PT-112 in RRMM patients may be explained by its osteotropism and its unique mechanism of action compared to other drug classes used to treat this disease. Further clinical study of PT-112 in RRMM is warranted in a phase 2 clinical trial. Disclosures Ailawadhi: Celgene: Honoraria; Janssen: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; Medimmune: Research Funding; BMS: Research Funding; Cellectar: Research Funding; Phosplatin: Research Funding; Takeda: Honoraria. Vogl:Janssen: Consultancy; Celgene: Consultancy; MorphoSys: Consultancy; Takeda: Consultancy; Active Biotech: Consultancy, Research Funding; Oncopeptides: Consultancy; Karyopharm: Consultancy. Ames:Phosplatin Therapeutics: Current Employment, Current equity holder in private company. Yim:Phosplatin Therapeutics: Current Employment, Current equity holder in private company. Price:Phosplatin Therapeutics: Current Employment, Current equity holder in private company. Jimeno:Phosplatin Therapeutics: Current Employment, Current equity holder in private company.

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