CD38 antibodies in multiple myeloma: back to the future

CD38 is highly and uniformly expressed on multiple myeloma (MM) cells, and at relatively low levels on normal lymphoid and myeloid cells, and in some tissues of nonhematopoietic origin. CD38 is a transmembrane glycoprotein with ectoenzymatic activity, and also functions as a receptor and adhesion molecule. Altogether, this has triggered the development of several CD38 antibodies including daratumumab (fully human), isatuximab (chimeric), and MOR202 (fully human). CD38 antibodies have pleiotropic mechanisms of action including Fc-dependent immune-effector mechanisms, direct apoptotic activity, and immunomodulatory effects by the elimination of CD38+ immune-suppressor cells. CD38-targeting antibodies are generally well tolerated and induce partial response or better in ∼30% of heavily pretreated MM patients as monotherapy. Based on their distinct mechanisms of action, favorable toxicity profile, and single-agent activity, CD38 antibodies are attractive partners in combination regimens. Indeed, deep responses and prolonged progression-free survival can be achieved in relapsed/refractory MM patients when CD38 antibodies are combined with immunomodulatory agents or proteasome inhibitors. Infusion-related reactions, which typically occur during the first infusion, are the most frequent adverse events. Attention should also be paid to the interference of CD38 antibodies with certain laboratory assays, which may complicate response evaluation and blood compatibility testing. Several studies are currently examining the role of CD38-based therapies in newly diagnosed and high-risk smoldering MM. Furthermore, CD38 antibodies are currently also under investigation in other hematologic malignancies, including acute lymphoblastic leukemia, natural killer/T-cell lymphoma, and acute myeloid leukemia, as well as in solid tumors.

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Clinical efficacy and management of monoclonal antibodies targeting CD38 and SLAMF7 in multiple myeloma

Blood ◽

10.1182/blood-2015-10-646810 ◽

2016 ◽

Vol 127 (6) ◽

pp. 681-695 ◽

Cited By ~ 130

Author(s):

Niels W. C. J. van de Donk ◽

Philippe Moreau ◽

Torben Plesner ◽

Antonio Palumbo ◽

Francesca Gay ◽

...

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibodies ◽

Plasma Cells ◽

Blood Compatibility ◽

Single Agent ◽

Progression Free Survival ◽

Complete Response ◽

Therapeutic Antibody ◽

Drug Discontinuation ◽

Therapeutic Antibodies

AbstractImmunotherapeutic strategies are emerging as promising therapeutic approaches in multiple myeloma (MM), with several monoclonal antibodies in advanced stages of clinical development. Of these agents, CD38-targeting antibodies have marked single agent activity in extensively pretreated MM, and preliminary results from studies with relapsed/refractory patients have shown enhanced therapeutic efficacy when daratumumab and isatuximab are combined with other agents. Furthermore, although elotuzumab (anti-SLAMF7) has no single agent activity in advanced MM, randomized trials in relapsed/refractory MM have demonstrated significantly improved progression-free survival when elotuzumab is added to lenalidomide-dexamethasone or bortezomib-dexamethasone. Importantly, there has been no significant additive toxicity when these monoclonal antibodies are combined with other anti-MM agents, other than infusion-related reactions specific to the therapeutic antibody. Prevention and management of infusion reactions is important to avoid drug discontinuation, which may in turn lead to reduced efficacy of anti-MM therapy. Therapeutic antibodies interfere with several laboratory tests. First, interference of therapeutic antibodies with immunofixation and serum protein electrophoresis assays may lead to underestimation of complete response. Strategies to mitigate interference, based on shifting the therapeutic antibody band, are in development. Furthermore, daratumumab, and probably also other CD38-targeting antibodies, interfere with blood compatibility testing and thereby complicate the safe release of blood products. Neutralization of the therapeutic CD38 antibody or CD38 denaturation on reagent red blood cells mitigates daratumumab interference with transfusion laboratory serologic tests. Finally, therapeutic antibodies may complicate flow cytometric evaluation of normal and neoplastic plasma cells, since the therapeutic antibody can affect the availability of the epitope for binding of commercially available diagnostic antibodies.

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Efficacy of Once-Weekly Bortezomib with Daratumumab for Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-111908 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1958-1958

Author(s):

Natalia Gut ◽

Filiz Yucebay ◽

Jessica Dempsey ◽

Junan Li ◽

Don M. Benson

Keyword(s):

Multiple Myeloma ◽

Peripheral Neuropathy ◽

Hematologic Malignancy ◽

Small Sample Size ◽

Single Agent ◽

Proteasome Inhibitors ◽

Progression Free Survival ◽

Small Sample ◽

Weekly Schedule ◽

Refractory Multiple Myeloma

Abstract Background Multiple Myeloma (MM) is an essentially incurable hematologic malignancy with the goals of therapy being disease control, improved quality of life, and prolonged survival.1,2 Despite improved survival with proteasome inhibitors and immunomodulatory agents, outcomes for patients with refractory disease, resistant to these classes of therapy, are poor. Daratumumab, an anti-CD38 antibody, is a commonly utilized therapy for relapsed/refractory multiple myeloma (RRMM) as a single agent based on the SIRIUS study which resulted in adequate response and acceptable safety profiles.3,4 Currently, it is approved in various combinations including with bortezomib. The approval of daratumumab in combination with bortezomib days 1, 4, 8, and 11 of a 21-day cycle was based on the CASTOR study which resulted in high response rates and acceptable safety profiles.5With the addition of bortezomib, additional toxicities in this RRMM setting may be a concern.6 Previous studies of bortezomib in RRMM patients have demonstrated that once-weekly bortezomib is equally as efficacious and better tolerated than the standard twice-weekly schedule, with a lower incidence of peripheral neuropathy and myelosuppression.8,9 However, there are currently no published reports of combining once-weekly bortezomib with daratumumab for patients with RRMM. Methods The present study sought to evaluate the progression-free survival (PFS) of daratumumab administered with once-weekly bortezomib for patients with RRMM. Secondary objectives included evaluation of overall survival (OS), overall response rate (ORR), time to response (TTR), and toxicity of once-weekly bortezomib with daratumumab. Eighteen patients were identified in an Institutional Review Board (IRB)-approved retrospective review of our institutional experience with daratumumab and once-weekly bortezomib. The median age of patients was 65 years (range 47 - 76, Table 1). Ten patients (55.6%) had three or more prior lines of therapy. Twelve patients (66.7%) had previous autologous stem cell transplantation. Sixteen patients (88.9%) had prior proteasome inhibitor (PI) therapy. Thirteen patients (72.2%) had disease refractory to their last line of therapy. Results The median PFS was 3.5 months. Median OS was not reached and TTR were undetermined due to the small sample size. The ORR was 33.3%, with 6 out of 18 patients experiencing an objective partial response or better (Table 2). Of those that responded, 4 patients (66.7%) remained on therapy at the time of data collection.The side effect profile was more tolerable, with less thrombocytopenia (27.8% all grade) and peripheral neuropathy (33.3% all grade) than previously reported (Table 3). Conclusions Daratumumab monotherapy was approved in heavily pretreated RRMM based on the SIRIUS trial showing promising efficacy and a favorable safety profile.4 The median PFS was 3.7 months compared to our PFS of 3.5 months. The combination of daratumumab with bortezomib administered twice weekly was approved based results from the CASTOR trial showing superiority of daratumumab in combination with bortezomib and dexamethasone over bortezomib and dexamethasone.5 As depicted in Table 2, our ORR of 33.3% is similar to the ORR of 29.2% in the SIRIUS trial, however differs greatly from 82.9% in the CASTOR trial. While the present work is retrospective and hypothesis-generating, our results suggest that further prospective inquiry is necessary to determine the additional efficacy of adding once-weekly bortezomib to daratumumab. Disclosures Dempsey: Heron Therapeutics: Honoraria; TESARO: Honoraria.

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Drug Conjugated and Bispecific Antibodies for Multiple Myeloma: Improving Immunotherapies off the Shelf

Pharmaceuticals ◽

10.3390/ph14010040 ◽

2021 ◽

Vol 14 (1) ◽

pp. 40

Author(s):

Gregorio Barilà ◽

Rita Rizzi ◽

Renato Zambello ◽

Pellegrino Musto

Keyword(s):

Multiple Myeloma ◽

Advanced Disease ◽

Clonal Selection ◽

Single Agent ◽

Proteasome Inhibitors ◽

Mechanisms Of Action ◽

Bispecific Antibodies ◽

Antibody Drug Conjugate ◽

Best Response ◽

Incurable Condition

The impressive improvement of overall survival in multiple myeloma (MM) patients in the last years has been mostly related to the availability of new classes of drugs with different mechanisms of action, including proteasome inhibitors (PI), immunomodulating agents (IMiDs), and monoclonal antibodies. However, even with this increased potence of fire, MM still remains an incurable condition, due to clonal selection and evolution of neoplastic clone. This concept underlines the importance of immunotherapy as one of the most relevant tools to try to eradicate the disease. In line with this concept, active and passive immunotherapies represent the most attractive approach to this aim. Antibody-drug conjugate(s) (ADCs) and bispecific antibodies (BsAbs) include two innovative tools in order to limit neoplastic plasma cell growth or even, if used at the time of the best response, to potentially eradicate the tumoral clone. Following their promising results as single agent for advanced disease, at the recent 62nd ASH meeting, encouraging data of several combinations, particularly of ADC(s) with PI or IMiDs, have been reported, suggesting even better results for patients treated earlier. In this paper, we reviewed the characteristics, mechanism of action, and clinical data available for most relevant ADC(s) and BsAbs.

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A dose-finding Phase 2 study of single agent isatuximab (anti-CD38 mAb) in relapsed/refractory multiple myeloma

Leukemia ◽

10.1038/s41375-020-0857-2 ◽

2020 ◽

Vol 34 (12) ◽

pp. 3298-3309 ◽

Cited By ~ 4

Author(s):

Joseph Mikhael ◽

Joshua Richter ◽

Ravi Vij ◽

Craig Cole ◽

Jeffrey Zonder ◽

...

Keyword(s):

Multiple Myeloma ◽

Single Agent ◽

Proteasome Inhibitors ◽

Progression Free Survival ◽

Dose Finding ◽

Upper Respiratory Tract ◽

Phase 2 ◽

Refractory Multiple Myeloma ◽

Prior Therapy ◽

Tract Infections

AbstractA Phase 2 dose-finding study evaluated isatuximab, an anti-CD38 monoclonal antibody, in relapsed/refractory multiple myeloma (RRMM; NCT01084252). Patients with ≥3 prior lines or refractory to both immunomodulatory drugs and proteasome inhibitors (dual refractory) were randomized to isatuximab 3 mg/kg every 2 weeks (Q2W), 10 mg/kg Q2W(2 cycles)/Q4W, or 10 mg/kg Q2W. A fourth arm evaluated 20 mg/kg QW(1 cycle)/Q2W. Patients (N = 97) had a median (range) age of 62 years (38–85), 5 (2–14) prior therapy lines, and 85% were double refractory. The overall response rate (ORR) was 4.3, 20.0, 29.2, and 24.0% with isatuximab 3 mg/kg Q2W, 10 mg/kg Q2W/Q4W, 10 mg/kg Q2W, and 20 mg/kg QW/Q2W, respectively. At doses ≥10 mg/kg, median progression-free survival and overall survival were 4.6 and 18.7 months, respectively, and the ORR was 40.9% (9/22) in patients with high-risk cytogenetics. CD38 receptor density was similar in responders and non-responders. The most common non-hematologic adverse events (typically grade ≤2) were nausea (34.0%), fatigue (32.0%), and upper respiratory tract infections (28.9%). Infusion reactions (typically with first infusion and grade ≤2) occurred in 51.5% of patients. In conclusion, isatuximab is active and generally well tolerated in heavily pretreated RRMM, with greatest efficacy at doses ≥10 mg/kg.

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Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma

Blood ◽

10.1182/blood-2008-12-196238 ◽

2009 ◽

Vol 114 (4) ◽

pp. 772-778 ◽

Cited By ~ 110

Author(s):

Paul Richardson ◽

Sundar Jagannath ◽

Mohamad Hussein ◽

James Berenson ◽

Seema Singhal ◽

...

Keyword(s):

Multiple Myeloma ◽

Single Agent ◽

Progression Free Survival ◽

Prior Treatment ◽

Once Daily ◽

Free Survival ◽

Refractory Multiple Myeloma ◽

Treatment Regimens ◽

Common Grade ◽

Grade 3

Abstract Lenalidomide plus dexamethasone is effective for the treatment of relapsed and refractory multiple myeloma (MM); however, toxicities from dexamethasone can be dose limiting. We evaluated the efficacy and safety of lenalidomide monotherapy in patients with relapsed and refractory MM. Patients (N = 222) received lenalidomide 30 mg/day once daily (days 1-21 every 28 days) until disease progression or intolerance. Response, progression-free survival (PFS), overall survival (OS), time to progression (TTP), and safety were assessed. Overall, 67% of patients had received 3 or more prior treatment regimens. Partial response or better was reported in 26% of patients, with minimal response 18%. There was no difference between patients who had received 2 or fewer versus 3 or more prior treatment regimens (45% vs 44%, respectively). Median values for TTP, PFS, and OS were 5.2, 4.9, and 23.2 months, respectively. The most common grade 3 or 4 adverse events were neutropenia (60%), thrombocytopenia (39%), and anemia (20%), which proved manageable with dose reduction. Grade 3 or 4 febrile neutropenia occurred in 4% of patients. Lenalidomide monotherapy is active in relapsed and refractory MM with acceptable toxicities. These data support treatment with single-agent lenalidomide, as well as its use in steroid-sparing combination approaches. The study is registered at http://www.clinicaltrials.gov as NCT00065351.

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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 ◽

10.1182/blood-2019-126972 ◽

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.

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Single-agent belantamab mafodotin for relapsed/refractory multiple myeloma: analysis of the lyophilised presentation cohort from the pivotal DREAMM-2 study

Blood Cancer Journal ◽

10.1038/s41408-020-00369-0 ◽

2020 ◽

Vol 10 (10) ◽

Cited By ~ 1

Author(s):

Paul G. Richardson ◽

Hans C. Lee ◽

Al-Ola Abdallah ◽

Adam D. Cohen ◽

Prashant Kapoor ◽

...

Keyword(s):

Multiple Myeloma ◽

Single Agent ◽

Pathological Finding ◽

Progression Free Survival ◽

Antibody Drug Conjugate ◽

Open Label ◽

Blurred Vision ◽

Refractory Multiple Myeloma ◽

Open Label Phase ◽

Duration Of Response

Abstract DREAMM-2 (NCT03525678) is an ongoing global, open-label, phase 2 study of single-agent belantamab mafodotin (belamaf; GSK2857916), a B-cell maturation antigen-targeting antibody-drug conjugate, in a frozen-liquid presentation in patients with relapsed/refractory multiple myeloma (RRMM). Alongside the main study, following identical inclusion/exclusion criteria, a separate patient cohort was enrolled to receive belamaf in a lyophilised presentation (3.4 mg/kg, every 3 weeks) until disease progression/unacceptable toxicity. Primary outcome was independent review committee-assessed overall response rate (ORR). Twenty-five patients were enrolled; 24 received ≥1 dose of belamaf. As of 31 January 2020, ORR was 52% (95% CI: 31.3–72.2); 24% of patients achieved very good partial response. Median duration of response was 9.0 months (2.8–not reached [NR]); median progression-free survival was 5.7 months (2.2–9.7); median overall survival was not reached (8.7 months–NR). Most common grade 3/4 adverse events were keratopathy (microcyst-like corneal epithelial changes, a pathological finding seen on eye examination [75%]), thrombocytopenia (21%), anaemia (17%), hypercalcaemia and hypophosphatemia (both 13%), neutropenia and blurred vision (both 8%). Pharmacokinetics supported comparability of frozen-liquid and lyophilised presentations. Single-agent belamaf in a lyophilised presentation (intended for future use) showed a deep and durable clinical response and acceptable safety profile in patients with heavily pre-treated RRMM.

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Discovery and Characterization of Macrocyclic Thiopeptide Proteasome Inhibitors for Hematologic Malignancies

Blood ◽

10.1182/blood.v112.11.3669.3669 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3669-3669

Author(s):

Sridevi Ponduru ◽

Raymond Moellering ◽

Edward Greenberg ◽

John Paul Ying-Ching Shen ◽

Benjamin Z Stanton ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Protein Degradation ◽

High Throughput ◽

Active Sites ◽

Proteasome Inhibitors ◽

Hematologic Malignancies ◽

Bone Marrow Stroma ◽

Shh Signaling ◽

Marrow Stroma

Abstract The ubiquitin proteasome pathway comprises a coordinated, dynamic cellular system critical to cellular metabolism, signaling and proliferation. The expanding clinical utility of the peptide boronate, bortezomib, in the treatment of patients with multiple myeloma and other hematologic malignancies has established the human 26S proteasome as a validated target in cancer. Still, only one FDA-approved proteasome inhibitor presently exists. Restricted activity against one enzymatic function of the proteasome and dose-limiting toxicities associated with bortezomib warrant further discovery efforts aimed at the identification of structurally and functionally distinct protein degradation inhibitors (PDIs). Here, we report a novel family of natural product proteasome inhibitors discovered by high-throughput, high-content screening at the National Cancer Institute Initiative for Chemical Genetics. A primary screen of 14,000 small molecules was performed in 384-well plate format using a cell line stably transfected with a destabilized fluorescent protein chimera. Assay positives were retested in the primary screen in dose-response format. Thiostrepton was selected for further characterization due to its unique macrocyclic chemical structure, the recent publication of its total synthesis, reports of anticancer properties and the lack of prior annotation as a PDI. First, thiostrepton was linked to previously characterized molecules acting on the protein degradation pathways by transcriptional small molecule connectivity mapping (CMAP). Subsequent cell-state analyses confirmed strong induction of functional and annotated gene sets associated with misfolded protein stress and proteasome inhibition. Mechanism of action was confirmed by biochemical profiling of human 20S proteasome active site inhibition and specificity using homogeneous assays and selective substrates for each of three catalytic active sites. Importantly, inhibitory activity of thiostrepton differs from bortezomib by blocking both the chymotryptic-like and PGPH active sites with sub-micromolar potencies. Dose-dependent inhibition of multiple myeloma cell growth was observed, with a concomitant increase in polyubiquitinated protein stress and induction of apoptosis. Inhibition of conferred proliferation by bone marrow stroma was confirmed using a novel miniaturized high-content assay modeling the bone marrow stroma-multiple myeloma microenvironment. Structurally related compounds to thiostrepton, nosiheptide and siomycin, were confirmed also as proteasome inhibitors as above. Our discovery of this class of natural products as proteasome inhibitors and a recent report of siomycin inhibition of Sonic Hedgehog (Shh) signaling begged the question whether established proteasome inhibitors would inhibit Shh signaling in human cancer. This hypothesis was confirmed in a set of reporter-gene assays. In sum, these studies identify thiopeptide macrocycles as a class of naturally-occurring proteasome inhibitors poised for clinical development in hematologic malignancies, establish novel high-throughput assays for modeling MM-stroma microenvironment interactions and pave the way for the development of proteasome inhibitors in disease states where Shh signaling is central to pathogenesis.

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Bortezomib and Dexamethasone as Maintenance therapy in Relapse/Refractory multiple myeloma Patients

Blood ◽

10.1182/blood.v112.11.2771.2771 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2771-2771 ◽

Cited By ~ 1

Author(s):

Giulia Benevolo ◽

Alessandra Larocca ◽

Patrizia Pregno ◽

Francesca Gay ◽

Barbara Botto ◽

...

Keyword(s):

Multiple Myeloma ◽

Maintenance Therapy ◽

Median Time ◽

Salvage Therapy ◽

Univariate Analysis ◽

Single Agent ◽

Haemoglobin Concentration ◽

Progression Free Survival ◽

Median Number

Abstract Background: Despite the advances in the treatment for multiple myeloma (MM) in the past decade, it still remains an incurable haematological disease and the majority of patients still experience relapse. Bortezomib is a novel proteasome inhibitor approved for the treatment of MM patients. Several studies have demonstrated its efficacy as front-line therapy and in relapsed, advanced MM but no data are available as maintenance therapy (MT) in refractory/relapsed MM. Patients and methods: The aim of this study is to evaluate the safety and the efficacy of bortezomib/dexamethasone MT (1.3 mg/mq bortezomib on days 1 and 15; 20 mg dexamethasone on days 1–2 and 15–16 in a 28-day cycle for a total of 6 cycles) in patients with refractory/relapse MM who responded to salvage therapy. Results: From October 2004 until April 2008, 40 MM patients have been enrolled. The characteristics of the patients were as follows: 20 males and 20 females, median age was 70 years (IQR:66–75). Median haemoglobin value was 10.85 (IQR:10.175–12.225) and 7 (18%) patients had a renal failure. Skeletal disease was present in 27 (68%) patients. The median number of prior therapies was 2 (1–4). The salvage therapy included bortezomib as single agent or in combination with steroids and/or thalidomide in 12 patients (30%). Median time from diagnosis to the first dose of MT was 41 months (IQR:26–59). The median number of bortezomib infusion was 8 (1–18). After a median follow up of 13 months (IQR:6–31), 10 patients died for PD and 4 patients for infections. The MT improved the quality of response and converted in 1 CR and 4 VGPR the PR after salvage therapy in 5 patients; moreover, we observed a remarkable decreased of M component in 11 patients. The median time to progression was 23 months (95%CI: 8-not reached) with a progression free-survival at 1 year of 69% (95%CI: 50–82). The overall survival at 1 years was 63% and the cumulative incidence of death due to PD adjusted for competitive risk event was 25% (95%IC:10–41). In a univariate analysis the response rate to MT was not significantly affected by age, sex, number or type of previous therapy and haemoglobin concentration. Non-dose-limiting toxicities included neuropathy grade 1 (12 pts), herpes zoster reactivation (2 pts) and gastrointestinal affections (1 pts). Conclusion: The combination bortezomib/dexamethasone can be safely administered as a maintenance therapy in relapse/refractoy MM. These preliminary data suggest that bortezomib/dexametasone MT can improve remission duration and also quality of response with an acceptable toxicity.

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Vorinostat Overcomes Lenalidomide-Dexamethasone and Lenalidomide-Bortezomib-Dexamethasone Resistance In Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v116.21.3065.3065 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3065-3065 ◽

Cited By ~ 6

Author(s):

David Samuel diCapua Siegel ◽

Laura McBride ◽

Elizabeth Bilotti ◽

Linda Schmidt ◽

Zhijie Gao ◽

...

Keyword(s):

Multiple Myeloma ◽

Phase I ◽

Histone Deacetylases ◽

Single Agent ◽

Proteasome Inhibitors ◽

Retrospective Chart Review ◽

Advisory Board ◽

Cell Transplants ◽

Dexamethasone Resistance

Abstract Abstract 3065 Introduction: Significant improvements have been made in the treatment of relapsed/refractory (RR) multiple myeloma (MM), although the disease remains incurable. Recently, a number of clinical trials have evaluated the efficacy of vorinostat (Zolinza®), an oral inhibitor of Class I and II histone deacetylases. Vorinostat has been evaluated as a single agent, showing minimal activity. In vitro studies demonstrated synergy between vorinostat and other pro-apoptotic agents. This led to Phase I and II trials of vorinostat in combination with both proteasome inhibitors and IMiDs. Based upon the positive phase I data, large, multinational phase II and III trials combining vorinostat (Z) and bortezomib (V) are ongoing. Previously presented Phase I data on the combination of lenalidomide (R), dexamethasone and vorinostat has been encouraging. To date, no large experience with this combination in patients previously found to be refractory to lenalidomide and dexamethasone (RD) has been reported. Here we report our single institution experience of 28 consecutive patients with RD refractory myeloma or VRD refractory myeloma treated with the RDZ or VRDZ respectively. Materials and Methods: This is a retrospective chart review of patients who received commercially available oral vorinostat 300 mg or 400 mg once daily (days 1–7 and days 15–21) and lenalidomide 10–25mg (days 1–21) in a 28-day cycle. Ten patients also received bortezomib 1.3 mg/m2 as an intravenous bolus on days 1, 4, 8, and 11. Subjects: All patients were refractory to prior RD. Most of the patients were relapsed and refractory not only to RD, but also to VRD. (Please refer to the table below.) All of the patients treated with VRDZ were R/R to prior VRD. 23/28 of these patients had previous autologous peripheral blood stem cell transplants (ASCT). 11 had two transplants, 1 had three and 5 had previous allogeneic transplants. The median prior lines of therapy were 4 (2-10) and median prior regimens was 5 (2-11). Results: An overall response rate (ORR) of 43% was noted. This included 8 partial responses (PRs) and 4 very good partial responses (VGPRs) or better. An additional 5 showed minimal responses (MRs) and 8 showed stable disease (SD). The overall clinical benefit rate (including MRs and SD) was 89%. The duration of response ranged from two months to 23+ months. The most common toxicities were GI, mostly diarrhea and cramping. Cytopenias were also experienced, but were not different from those expected for this population treated with lenalidomide-based therapy alone. We will report on additional patients, more complete toxicity data, event-free (EFS) and overall survival (OS), as well as a limited subgroup analysis. Conclusions: These results suggest that this convenient oral regimen of vorinostat combined with lenalidomide and dexamethasone is well tolerated in patients with heavily pretreated, RD relapsed/refractory MM. These results further demonstrate the ability of vorinostat to overcome resistance to RD and VRD. Disclosures: Siegel: Celgene: Advisory board, Speakers Bureau; Merck: Advisory board; Millennium: Advisory Board, Speakers Bureau. Off Label Use: vorinostat for multiple myeloma. Bilotti:Celgene: Advisory Board, Speakers Bureau; Merck: Honoraria; Millennium: Advisory Board, Speakers Bureau. McNeill:Celgene: Advisory Board, Speakers Bureau; Millennium: Advisory Board, Speakers Bureau. Graef:Merck Research Laboratories: Employment. Vesole:Celgene: Speakers Bureau; Millennium Pharmaceuticals, Inc.: Speakers Bureau.

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