Bortezomib-refractory Patients Research Articles

Efficacy of total oral regimens containing ixazomib in patients with relapsed and refractory multiple myeloma

To investigate the efficacy and safety of total oral regimen containing ixazomib in multidrug-resistant relapsed and refractory multiple myeloma(RRMM). A total of 38 patients were retrospectively analyzed from August 2018 to January 2020 in the First Affiliated Hospital of Soochow University. The overall response rate (ORR)was 36.8%. Among them, the very good partial response (VGPR) or better rate was 23.7%, and the complete response (CR) rate was 5.3%. The ORR was 41.7% in patients receiving ixazomib-lenalidomide-dexamethasone (IRD) regimen. Median PFS was 5 months and median OS was 7.5 months. The ORR was 50% after second-line therapy, 40% after third-line therapy and 12.5% after forth-line therapy or more. The ORR was 29.0% in bortezomib-refractory patients, 38.0% in lenalidomide-refractory patients, 21.4% in bortezmoib & lenalidomide dual refractory patients. Grade 3-4 hematological adverse events (AEs) were reported in 21% patients. Common hematological AEs included lymphopenia, neutropenia, thrombocytopenia. Other usual AEs were fatigue and diarrhea. No grade 3-4 peripheral neuropathy was recorded. In the treatment of relapsed/refractory multiple myeloma patients with multidrug resistance, the total oral regimens containing ixazomib demonstrate reliable efficacy and safety. Early administration of ixazomib at first or second relapse is suggested for more favorable clinical outcome.

Prognostic Value of Resistance Proteins in Plasma Cells from Multiple Myeloma Patients Treated with Bortezomib-Based Regimens

While multiple myeloma (MM) treatment with proteasome inhibitors and other agents yields encouraging results, primary and secondary resistance remains an emerging problem. An important factor in such treatment resistance is the overexpression of several proteins. The present study comprehensively evaluates the expression of POMP, PSMB5, NRF2, XBP1, cMAF and MAFb proteins in plasma cells isolated from the bone marrow of 39 MM patients treated with bortezomib-based regimens using an enzyme-linked immunosorbent assay (ELISA). The proteins were selected on the basis of previous laboratory and clinical studies in bortezomib-treated MM patients. It was found that the expression of the investigated proteins did not significantly differ between bortezomib-sensitive and bortezomib-refractory patients. However, the expression of some proteins correlated with overall survival (OS); this was significantly shorter in patients with higher POMP expression (HR 2.8, 95% CI: 1.1–7.0, p = 0.0277) and longer in those with higher MAFB expression (HR 0.32, 95% CI: 0.13–0.80, p = 0.0147). Our results indicate that a high expression of POMP and MAFB in MM plasma cells may serve as predictors of OS in MM patients treated with bortezomib-based regimens. However, further studies are needed to determine the role of these factors in effective strategies for improving anti-myeloma therapy.

Argentine Multicentric Experience of Carfilzomib Use in Relapsed / Refractory Multiple Myeloma. Report from the GAMM (Grupo Argentino de Mieloma Multiple)

Background:Carfilzomib is a selective proteasome inhibitor recently approved in Argentina for the treatment of relapsed and refractory multiple myeloma (RRMM) in patients previously treated with bortezomib and immunomodulatory drugs. Carfilzomib has shown to be an effective drug in this difficult to treat population with an acceptable toxicity profile. In this multicentre experience, we decided to report the results of the first patients (not participating in clinical trials) treated with this second class proteasome inhibitor in our country.Methods:Retrospective cohort study. We evaluated the efficacy and toxicity of carfilzomib based treatments in RRMM patients from 29 centers in Argentina from April 2013 till April 2017. Patients were follow from first treatment day till death or lost to follow up. The primary endpoint was best response rate and secondary endpoints were progression free survival (PFS) and overall survival (OS). The international uniform response criteria (IMWG 2006) were used to assess response rates. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events version 4.OS and PFS were estimated using the Kaplan Meier method using Stata13 program. Hazard ratios were estimated by means of a stratified Cox proportional-hazards model.The study complies with guiding principles for experimental procedures found in the declaration of Helsinki.Results:Data on 106 patients was analyzed. Median of previous treatment lines was 3 (IQR 2-4). The median age of patients were 62 years (IQR 57-68) with a median time from diagnosis to start of treatment of 4 years (IQR 3-7). Thirteen out of 106 (12%) patients were considered as high risk according to cytogenetics abnormalities and 33/106 (31%) patients had ISS score of 3. All patients have been previously treated with bortezomib and immunomodulatory drugs, 52 patients (49%) were refractory to at least one of these drugs and 35 patients (33%) were double refractory.Fifty patients (47%) received carfilzomib + dexametasone (Kd), 40 patients (38%) carfilzomib + lenalidomide + dexametasone (KRd) and 16 patients (15%) carfilzomib + other agents (Koa) with a median of 6 (IQR 3-7) cycles.The overall response rate (ORR) (≥ partial response) for the complete cohort was 57% (60 patients), complete response was found in 10% (11 patients) and very good partial response in 13% (14 patients). There was a trend towards better ORR when carfilzomib was associated with Rd or other agents, although not statistically significant (p:0.195).In the univariate analysis lenalidomide refractory patients (55/106), bortezomib refractory patients (52/106) and double refractory patients (35/106) had a lower chance of achieveing ≥ partial response [hazard ratio (HR): 2.23 (CI 95%: 0.01-4.89), HR: 2.74; 95% (C I95%: 1.29-6.06 and HR: 2.76 (CI 95%: 1.19-6.35) respectively]. In the multivariate analysis only bortezomib refractory patients had lower chance of achieving ≥ partial response [HR: 2.29 (CI 95%: 0.98-5.33).Median progression free survival (PFS) for the complete cohort was 14 months (CI 95% 10-20) and the median overall survival (OS) was 22 months (CI 95% 14-36). The median PFS was 5 months (CI 95% 4-8) for not responders and 21 months (CI 95% 15-27) for responders (p:0.001). The median OS was 9 months (CI 95% 5-20) for non responders vs 30 months (CI 95% 16-36) for responders (p:0.001).Double refractory patients had a median PFS of 11 months (CI 95% 6-15) vs 18 months (CI 95% 8-33) for the rest of the patients (p:0.19). Twenty nine patients (27%) discontinued treatment due to adverse events (AE) related to carfilzomib. The more commons AE (any grade) were hematological: anemia 42/106 (40%), thrombocytopenia 31/106 (29%) and neutropenia 30/106 (28%), The most frequent non hematological AE (any grade) were: cardiovascular 23/106 (22%), infections 12/106 (12%) and gastrointestinal 6/106 (6%). Interestingly, 13/29 patients (45%) that discontinued treatment due to AE, were because of cardiovascular events.Conclusion:This is the first report of carfilzomib use for the treatment of RRMM in South America as far as our knowledge. Our results were comparable with the reports published in the literature. Carfilzomib alone or in combination with other agents has shown efficacy for the treatment of RRMM patients with an acceptable toxicity. Cardiovascular toxicity should be carefully evaluated in patients treated with carfilzomib. DisclosuresSchutz:varifarma: Speakers Bureau. Duarte:Janssen: Consultancy, Speakers Bureau; varifarma: Other: conferences; gador: Consultancy. Shanley:Gador: Speakers Bureau. Corzo:Raffo: Consultancy, Speakers Bureau. Enrico:BMS: Consultancy, Speakers Bureau. Riveros:BMS: Speakers Bureau; Raffo: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Fantl:varifarma: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Raffo: Speakers Bureau.

Efficacy of Lenalidomide As Salvage Therapy for Patients with AL Amyloidosis

Current treatment approach to AL amyloidosis aims at the elimination of the plasma cell clone that produces the amyloidogenic light chains. Bortezomib-based regimens are used in most centers as primary treatment; however, there are limited data on the outcomes of patients with AL who fail bortezomib. Lenalidomide is a standard treatment for patients with myeloma who fail bortezomib. In patients with AL amyloidosis there data from mixed cohorts of previously untreated and pretreated patients, indicating that lenalidomide with dexamethasone with or without a third agent (cyclophosphamide or melphalan) is active but is not well tolerated at standard doses; however, data regarding the efficacy of lenalidomide specifically in patients with relapsing or refractory AL, especially after bortezomib, are limited. The aim of the current study was to evaluate lenalidomide as salvage therapy in consecutive patients with pretreated AL amyloidosis, in order to assess its efficacy and toxicity in this setting.This analysis included 50 consecutive patients who received at least one dose of lenalidomide for relapsed/refractory AL amyloidosis; all were diagnosed, treated and followed in the Department of Clinical Therapeutics, Athens, Greece. Definition of hematologic and organ response and progression was based on consensus criteria.The median age was 63 years (range 42-82) and 67% were males. Heart was involved in 72%, kidneys in 75%, peripheral nerve in 33% and liver in 24%. At the time of initiation of lenalidomide, median eGFR was 53 ml/min/1.73 m2 and 12% were on dialysis; median NTproBNP was 2369 pg/ml and 21% were Mayo stage -1, 41% stage -2 and 38% stage -3. Median time from the start of primary therapy to lenalidomide was 14 months (range 1 to 108) and the median number of prior therapies was 1 (range 1-4), while, 72% of the patients had prior bortezomib: 42% were bortezomib refractory and 30% were potentially bortezomib sensitive (i.e. had responded to bortezomib and relapsed > 6 months after last bortezomib dose).On intention to treat, hematologic response rate was 57% (5% CRs, 24% VGPRs and 28% PRs); was similar for patients with and without prior bortezomib (56% vs 58%) and was 38% vs 62% for bortezomib refractory vs non-refractory patients (p=0.084).Organ responses were recorded in 10% of evaluable patients and included 11% renal responses and 8% liver responses; however, no cardiac responses were recorded based on NTproBNP criteria, probably due to increase of NTproBNP in most patients after start of lenalidomide therapy. Among patients not in dialysis, 10 (20%) eventually progressed to end stage renal disease requiring dialysis.Median overall survival post lenalidomide initiation was 29 months. There was no difference in the survival of patients who were potentially bortezomib sensitive vs refractory (p=0.395); however, bortezomib naive patients had better survival, even after adjustment for Mayo stage (p=0.028).Median dose of lenalidomide was 10 mg (range 5 to 15); no patient received the 25 mg dose. Median duration of lenalidomide therapy was 7.2 months (7 cycles) and 46% of the patients discontinued lenalidomide before completion of planned therapy. Main reasons to discontinue lenalidomide were disease progression/no response in 10%, toxicity in 26%, patient's or physician's decision in 10%, while 17% died while on therapy with lenalidomide due to AL-related complications. Common hematologic toxicities (≥Gr3) included thrombocytopenia in 6%, anemia in 15%, neutropenia in 6%. Most common non hematologic toxicities (≥Gr3) that led to dose reduction or early discontinuation of therapy were diarrhea in 9%, fatigue in 15%, skin rash in 15%, pneumonitis in 4%. Transient increases in serum creatinine (up to Gr1) were common; however, in 8% this was associated with acute renal failure.We conclude that lenalidomide is a major salvage option for patients with relapsed/refractory AL amyloidosis, with hematologic responses in 57% of patients, including patients who are refractory to bortezomib. However, organ responses were poor, probably because of the prolonged disease course which may have affected the ability of organ function recovery, at the time of initiation of lenalidomide, while NTproBNP based cardiac response criteria are challenging to use with IMiDs-based therapies. The toxicity of lenalidomide in patients with AL amyloidosis is significant and dose adjustments are commonly required. DisclosuresKastritis:Amgen: Honoraria; Genesis Pharma: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Prothena: Honoraria. Terpos:BMS: Honoraria; Janssen: Honoraria, Research Funding; Genesis/Celgene: Honoraria, Other: DMC member, Research Funding; Takeda: Honoraria, Other: SC member, Research Funding; Amgen: Honoraria, Other: SC member, Research Funding; Abbvie: Honoraria; GSK: Honoraria. Dimopoulos:Genesis Pharma: Research Funding; Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology: Consultancy, Honoraria, Other: Advisory Committee: Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Onyx Pharmaceuticals, an Amgen subsidiary, Takeda Oncology; Novartis: Consultancy, Honoraria.

The Prognostic Value of Whole-Blood PSMB5, CXCR4, POMP, and RPL5 mRNA Expression in Patients with Multiple Myeloma Treated with Bortezomib.

Simple SummaryThe mRNA expression of nine previously described genes that may affect resistance to multiple myeloma (MM), viz., ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1, was compared between bortezomib-refractory and bortezomib-sensitive patients. RPL5 was the only gene to be significantly down-regulated in MM patients compared with non-MM individuals, while POMP was significantly up-regulated in the bortezomib-refractory patients. Multivariate analysis found the best independent predictors of progression-free survival to be high PSMB5 and CXCR expression and autologous stem cell transplantation, and that high expression of POMP and RPL5 were associated with shorter survival.Proteasome inhibitors, like bortezomib, play a key role in the treatment of multiple myeloma (MM); however, most patients eventually relapse and eventually show multiple drug resistance, and the molecular mechanisms of this resistance remain unclear. The aim of our study is to assess the expression of previously described genes that may influence the resistance to bortezomib treatment at the mRNA level (ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1) and prognosis of MM patients. mRNA expression was determined in 73 MM patients treated with bortezomib-based regimens (30 bortzomib-sensitive and 43 bortezomib-refractory patients) and 11 healthy controls. RPL5 was significantly down-regulated in multiple myeloma patients as compared with healthy controls. Moreover, POMP was significantly up-regulated in MM patients refractory to bortezomib-based treatment. In multivariate analysis, high expression of PSMB5 and CXCR and autologous stem cell transplantation were independent predictors of progression-free survival, and high expression of POMP and RPL5 was associated with shorter overall survival.

A comprehensive overview of daratumumab and carfilzomib and the recently approved daratumumab, carfilzomib and dexamethasone regimen in relapsed/refractory multiple myeloma

ABSTRACT Introduction: Novel, effective regimens are needed in patients with relapsed and refractory myeloma (RRMM) who inevitably relapse after PI and IMID containing treatment. Areas covered: Pre-clinical data, early clinical and pivotal trials relevant to the development of the two backbone drugs of carfilzomib and daratumumab, and the two important recent trials, EQUULEUS and CANDOR leading to the FDA approval of the combination regimen of daratumumab, carfilzomib, and dexamethasone (DKd) for RRMM are detailed in this review. Expert opinion: EQUULEUS and CANDOR have established the efficacy of the DKd regimen in the landscape of bortezomib and lenalidomide refractory patients. The split dosing schedule of the first dose of daratumumab was approved by the FDA based on EQUULEUS, significantly improving patient convenience. Subcutaneous daratumumab is being evaluated in this combination to further improve tolerance and convenience. Further studies are needed to evaluate and optimally sequence the many effective and potent drugs available in RRMM.

DREAMM-6: Safety, Tolerability and Clinical Activity of Belantamab Mafodotin (Belamaf) in Combination with Bortezomib/Dexamethasone (BorDex) in Relapsed/Refractory Multiple Myeloma (RRMM)

DREAMM-6: Safety, Tolerability and Clinical Activity of Belantamab Mafodotin (Belamaf) in Combination with Bortezomib/Dexamethasone (BorDex) in Relapsed/Refractory Multiple Myeloma (RRMM)

SP-23 - Therapeutic modulation of pleural effusion environment: the Next-Gen immunotherapy

Oprozomib is an oral proteasome inhibitor with activity in multiple myeloma (MM). Our phase 1b/2 study examined the safety and efficacy of oprozomib with dexamethasone in patients with relapsed and refractory MM. Oprozomib was administered with a 5/14 or 2/7 schedule with dexamethasone. Phase 1b primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of oprozomib; phase 2 primary objectives were to determine overall response rate (ORR) and safety/tolerability of the RP2D. Between July 2, 2013, and August 29, 2016, data were available on 65 enrolled patients (5/14 schedule, n = 19; 2/7 schedule, n = 46). In phase 1b, MTD was 180 mg (5/14 schedule) and not reached (2/7 schedule); RP2D was 300 mg (2/7 schedule). In phases 1b and 2, ORR across dosing cohorts (210–330 mg) for the 2/7 schedule was 58.7% overall and 46.4% for bortezomib-refractory patients (n = 28). All patients reported ≥1 treatment-emergent adverse event (AE); the most common AEs were gastrointestinal. Grade ≥3 AEs occurred in 78.9% and 82.6% of patients on the 5/14 and 2/7 schedules, respectively. The oprozomib and dexamethasone combination has encouraging activity and could be an important MM therapy if gastrointestinal tolerability is improved.

OP-48 - Measurable residual diseases in haematological malignancies: current applications and future direction

Oprozomib is an oral proteasome inhibitor with activity in multiple myeloma (MM). Our phase 1b/2 study examined the safety and efficacy of oprozomib with dexamethasone in patients with relapsed and refractory MM. Oprozomib was administered with a 5/14 or 2/7 schedule with dexamethasone. Phase 1b primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of oprozomib; phase 2 primary objectives were to determine overall response rate (ORR) and safety/tolerability of the RP2D. Between July 2, 2013, and August 29, 2016, data were available on 65 enrolled patients (5/14 schedule, n = 19; 2/7 schedule, n = 46). In phase 1b, MTD was 180 mg (5/14 schedule) and not reached (2/7 schedule); RP2D was 300 mg (2/7 schedule). In phases 1b and 2, ORR across dosing cohorts (210–330 mg) for the 2/7 schedule was 58.7% overall and 46.4% for bortezomib-refractory patients (n = 28). All patients reported ≥1 treatment-emergent adverse event (AE); the most common AEs were gastrointestinal. Grade ≥3 AEs occurred in 78.9% and 82.6% of patients on the 5/14 and 2/7 schedules, respectively. The oprozomib and dexamethasone combination has encouraging activity and could be an important MM therapy if gastrointestinal tolerability is improved.

Efficacy and safety results from a phase 1b/2, multicenter, open-label study of oprozomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma

Oprozomib is an oral proteasome inhibitor with activity in multiple myeloma (MM). Our phase 1b/2 study examined the safety and efficacy of oprozomib with dexamethasone in patients with relapsed and refractory MM. Oprozomib was administered with a 5/14 or 2/7 schedule with dexamethasone. Phase 1b primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of oprozomib; phase 2 primary objectives were to determine overall response rate (ORR) and safety/tolerability of the RP2D. Between July 2, 2013, and August 29, 2016, data were available on 65 enrolled patients (5/14 schedule, n = 19; 2/7 schedule, n = 46). In phase 1b, MTD was 180 mg (5/14 schedule) and not reached (2/7 schedule); RP2D was 300 mg (2/7 schedule). In phases 1b and 2, ORR across dosing cohorts (210–330 mg) for the 2/7 schedule was 58.7% overall and 46.4% for bortezomib-refractory patients (n = 28). All patients reported ≥1 treatment-emergent adverse event (AE); the most common AEs were gastrointestinal. Grade ≥3 AEs occurred in 78.9% and 82.6% of patients on the 5/14 and 2/7 schedules, respectively. The oprozomib and dexamethasone combination has encouraging activity and could be an important MM therapy if gastrointestinal tolerability is improved.

Oncolytics Virus Replication Using Pelareorep (Reolysin) and Carfilzomib in Relapsed Myeloma Patients Increases PD-L1 Expression with Clinical Responses

Rationale: Immune checkpoint inhibitors, including those targeting programmed cell death protein 1 (PD-1), are tempting in immunosuppressive cancers such as multiple myeloma (MM). PD-1 inhibition alone has not been effective (Lesokhin, JCO, 2016). Evidence suggests that tumor response is determined by tumor PD-L1 expression and presence of infiltrating cytotoxic T-cell lymphocytes (CTLs). Intravenous Pelareorep (Reolysin), the infusible form of reovirus (RV), has been shown to upregulate IFN-regulated gene expression, CTL infiltration, and the PD1/PD-L1 axis in myeloma cell lines (Kelly KR et al, Leukemia, 2018) and in patients with brain tumors (Samson A et al, Sci Trans Med, 2018).Introduction:Viral oncolytic therapy with Pelareorep is supported by preclinical data indicating that its antitumor activity results from direct cytolysis and immune responses against infected MM cells. Our phase 1 single agent Reolysin trial in patients with relapsed MM confirmed the tolerability of Pelareorep and demonstrated preferential infection into myeloma cells but not microenvironmental cells in the marrow by intracellular staining for RV genome. In PART ONE of our follow-up trial, Carfilzomib (Kyprolis)-sensitive patients were accrued. Correlative studies included bone marrow aspirate pretreatment on cycle 1 day 1 and day 9 to assess RV infection of myeloma cells, replication within myeloma cells, and PD-L1 expression on myeloma cell surface. Pelareorep, Carfilzomib, and 20 mg IV Dexamethasone were all infused per the standard Carfilzomib schedule on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle.Part ONE: Carfilzomib-sensitive patients were infused at dose level one with Pelareorep 3 x 1010TCID50/day and Carfilzomib 20 mg/m2 on days 1 and 2 of cycle 1 and 27 mg/m2 thereafter, on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. The MTD will be determined as the highest dose combination with fewer than 33% DLTs observed in cycle 1. There were 2 VGPRs, 2 PRs, 1 MR, and one patient with stable disease after cycle 1. All evaluable patients showed RV infection and replication in the post-treatment BM aspirates. In the 4 bortezomib-refractory patients in the first cohort, all have shown viral replication, and this correlated directly with activated caspase-3 in the MM cells and clinical response.Part TWO: Carfilzomib-refractory patients were treated with Carfilzomib 20 mg/m2 on days 1 and 2 of cycle 1, and 56 mg/m2 thereafter. Seven patients have been enrolled to date. In 3 patients processed to date with both pre- and post-treatment biopsies available, RV infection was detected in myeloma cells (2 patients) and endothelial cells (one patient). Replication was not seen. In these patients there was no strong evidence of increased activated caspase-3 expression in myeloma cells, nor was there a statistically significant increased CD8 cell infiltration or checkpoint protein expression after treatment.Conclusion: An increase in viral infection, viral replication, and PD-L1 expression on the surface of myeloma cells has been demonstrated in patients that had a clinical response to protocol therapy. A future study to assess the safety and tolerability of PD-1 inhibition in relapsed myeloma patients is now open to accrual (NCT03605719). Dose escalation is ongoing and the effects of the addition of Reolysin to Carfilzomib/Dexamethasone will be determined in this trial. DisclosuresHofmeister:Bristol-Myers Squibb: Research Funding; Adaptive biotechnologies: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Nuovo:Oncolytics Biotech Inc: Research Funding. Lonial:Amgen: Research Funding. Kaufman:Roche: Consultancy; Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy; BMS: Consultancy. Nooka:GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Adaptive technologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Heffner:Pharmacyclics: Research Funding; ADC Therapeutics: Research Funding; Genentech: Research Funding; Kite Pharma: Research Funding.

Efficacy of lenalidomide as salvage therapy for patients with AL amyloidosis

We retrospectively evaluated 55 consecutive patients who received at least one dose of lenalidomide for relapsed/refractory AL amyloidosis. Their median age was 63 years; 72% had heart and 75% kidney involvement and 13% were on dialysis; while 20%, 46% and 34% had Mayo stage -1, -2 and -3 disease, respectively. Median time from start of primary therapy to lenalidomide was 15 months (range 2–100) and median number of prior therapies was 1 (range 1–4); 73% of the patients had prior bortezomib and 42% were bortezomib-refractory. On intent to treat, haematologic response rate was 51% (5.5% CRs, 20% VGPRs) and was 56% versus 40% for patients with and without prior bortezomib and 47% versus 62.5% for bortezomib refractory versus non-refractory patients (p = .351). Organ response was achieved by 16% of evaluable patients (22% renal, 7% liver and 3% cardiac); however, 10 (21%) patients progressed to dialysis. Median survival post lenalidomide was 25 months. Bortezomib-refractory patients had worse outcome (median survival of 10.5 versus 25 months for bortezomib-sensitive patients versus not reached for bortezomib-naive patients, p = .011). Median lenalidomide dose was 10 mg and no patient received the 25 mg dose; however, in 60% a dose reduction was required. Median duration of lenalidomide therapy was 7.2 months and 46% discontinued lenalidomide before completion of planned therapy, mainly due to toxicity (26%) or disease progression/no response (13%). We conclude that although lenalidomide is a major salvage option for patients with relapsed/refractory AL amyloidosis, its toxicity in patients with AL amyloidosis is significant and doses should be adjusted for optimal tolerability.

Full Standard Doses of Lenalidomide in Bortezomib-Refractory Multiple Myeloma Patients Affected by Renal Failure: A Real-Life Experience

Full Standard Doses of Lenalidomide in Bortezomib-Refractory Multiple Myeloma Patients Affected by Renal Failure: A Real-Life Experience

Bortezomib resistance in multiple myeloma is associated with increased serine synthesis

BackgroundThe proteasome inhibitor bortezomib (BTZ) is successfully applied in the treatment of multiple myeloma, but its efficacy is restricted by the wide-spread occurrence of resistance. Metabolic alterations play an important role in cancer development and aid in the cellular adaptation to pharmacologically changed environments. Metabolic changes could therefore play an essential role in the development of drug resistance. However, specific metabolic pathways that can be targeted to improve bortezomib therapy remain unidentified.MethodsWe elucidated the metabolic mechanisms underlying bortezomib resistance by using mass spectrometry-based metabolomics and proteomics on BTZ-sensitive and BTZ–resistant multiple myeloma cell lines as well as in a set of CD138+ cells obtained from multiple myeloma patients.ResultsOur findings demonstrate that a rewired glucose metabolism sustains bortezomib resistance. Mechanistically, this results in higher activity of both the pentose phosphate pathway and serine synthesis pathway, ultimately leading to an increased anti-oxidant capacity of BTZ-resistant cells. Moreover, our results link both serine synthesis pathway activity and expression of 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of serine synthesis, to bortezomib resistance across different BTZ-resistant multiple myeloma cell lines. Consistently, serine starvation enhanced the cytotoxicity of bortezomib, underscoring the importance of serine metabolism in the response to BTZ. Importantly, in CD138+ cells of clinically bortezomib refractory multiple myeloma patients, PHGDH expression was also markedly increased.ConclusionsOur findings indicate that interfering with serine metabolism may be a novel strategy to improve bortezomib therapy and identify PHGDH as a potential biomarker for BTZ resistance.

Efficacy and tolerability of the histone deacetylase inhibitor panobinostat in clinical practice.

The histone deacetylase inhibitor panobinostat has shown efficacy in phase-II and phase-III trials for multiple myeloma and has recently received market approval in combination with bortezomib and dexamethasone. Here, we retrospectively report our single center experience with panobinostat/bortezomib/dexamethasone (FVD) in a heavily pretreated patient population (n=24) with a high degree of refractoriness to proteasome inhibitors (PI) and immunomodulatory drugs (IMiD). Median age was 67years (range 49-87) and the median number of prior therapies was 5 (range 2-17). Fourteen patients (58%) had high-risk cytogenetic aberrations. Thirteen (54%) and 21 (88%) patients were refractory to PIs and IMiDs, respectively. Twelve patients (50%) were refractory to bortezomib and 7 (29%) to carfilzomib; 6 patients (25%) were refractory to both bortezomib and carfilzomib. In 21 patients evaluable for response, overall response rate (ORR; ≥PR) was 33% (7/21) and 81% (17/21) achieved at least stable disease. Median progression-free survival (PFS) and overall survival were 3.5 and 9.8months, respectively. Significant differences between bortezomib-sensitive and -refractory patients were observed. In bortezomib-sensitive patients, median PFS was 6.3months compared to 2.3months in bortezomib-refractory patients (P<.001). Median overall survival was not reached vs 4.8months (P=.046) in bortezomib-sensitive and bortezomib-refractory patients, respectively. The only patient refractory to carfilzomib but sensitive to bortezomib achieved very good partial remission and PFS of 6.3months, suggesting discrete mechanisms of resistance to different PIs. As expected, thrombocytopenia and fatigue/asthenia occurred in nearly all patients (96% and 83%, respectively). Diarrhea was observed in only 19% of patients which compares favorably with the high rates of diarrhea reported in the PANORAMA trials. With panobinostat dose reductions in 67% of patients, FVD was tolerated by the majority of patients. In conclusion, FVD showed efficacy in a heavily pretreated, high-risk multiple myeloma population with a high degree of patients refractory to novel agents including PIs.

Efficacy and Tolerability of the Histone-Deacetylase Inhibitor Panobinostat in Clinical Practice: a Single Center Experience

Efficacy and Tolerability of the Histone-Deacetylase Inhibitor Panobinostat in Clinical Practice: a Single Center Experience

Efficacy of Daratumumab, Lenalidomide and Dexamethasone Versus Lenalidomide and Dexamethasone Alone for Relapsed or Refractory Multiple Myeloma Among Patients with 1 to 3 Prior Lines of Therapy Based on Previous Treatment Exposure: Updated Analysis of Pollux

Introduction: Daratumumab is an anti-CD38 IgGκ monoclonal antibody that has been combined successfully with lenalidomide and dexamethasone. The combination of daratumumab with lenalidomide and dexamethasone (DRd) has been compared with lenalidomide and dexamethasone alone (Rd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM) in a randomized phase 3 study (Dimopoulos MA, et al. N Engl J Med 2016; in press). In a pre-specified interim analysis, the DRd combination demonstrated significantly longer progression-free survival (PFS) in addition to deep and durable responses compared with the Rd arm. We performed subgroup analyses to further examine these efficacy data according to prior treatment exposure.Methods: Pts who received ≥1 prior line of therapy were randomized (1:1) to Rd (lenalidomide: 25 mg PO on Days 1-21 of each 28-day cycle; dexamethasone: 40 mg PO weekly) with or without daratumumab (16 mg/kg IV qw for 8 weeks, q2w for 16 weeks, then q4w until progression). The primary endpoint was PFS. Pts who were refractory to lenalidomide were not eligible. All analyses were performed in pts who received 1 to 3 prior lines of therapy.Results: Median follow-up was 13.5 months. Pts who were lenalidomide-naive prior to the start of study treatment (DRd, n=226; Rd, n=219) demonstrated significantly longer PFS with DRd vs Rd (median: not reached [NR] vs 18.4 months; HR, 0.36; 95% CI, 0.25-0.52; P<0.0001), with estimated 12-month PFS rates of 83.0% vs 59.9%, respectively. ORR was significantly higher with DRd vs Rd (96% vs 79%), with ≥VGPR rates of 76% vs 47% and ≥CR rates of 44% vs 21%, respectively (P<0.0001 for all). In the lenalidomide-exposed subgroup (DRd, n=46; Rd, n=45), median PFS was NR in both treatment groups (HR, 0.49; 95% CI, 0.22-1.12; P=0.0826); estimated 12-month PFS rates were 84.1% vs 63.1%, respectively. ORR was higher with DRd vs Rd but did not reach statistical significance (87% vs 71%; P=0.0729); however, rates of ≥VGPR (78% vs 38%; P=0.0001) and ≥CR (44% vs 12%; P=0.0011) were significantly improved with DRd vs Rd, respectively.For bortezomib-naive pts (DRd, n=44; Rd, n=45), PFS was significantly longer with DRd vs Rd (median: NR vs 15.8 months; HR, 0.34; 95% CI, 0.13-0.86; P=0.0170), with estimated 12-month PFS rates of 85.4% vs 69.2%, respectively. ORR was significantly higher with DRd vs Rd (98% vs 82%; P=0.0158), with trends toward increased rates of ≥VGPR (74% vs 55%; P=0.0544) and ≥CR (42% vs 23%; P=0.0576). In the bortezomib-exposed pts (DRd, n=228; Rd, n=219), median PFS was NR in DRd vs 18.4 months in Rd (HR, 0.35; 95% CI, 0.24-0.50 P<0.0001); estimated 12-month PFS rates were 82.8% vs 58.7%, respectively. Significant differences in ORR (93% vs 77%), rate of ≥VGPR (77% vs 43%) and rate of ≥CR (44% vs 19%) were observed with DRd vs Rd, respectively (P<0.0001 for all).Among bortezomib-refractory patients (DRd, n=54; Rd, n=49), the PFS benefit of DRd compared with Rd was maintained (median: NR vs 10.3 mo, respectively; HR, 0.46; 95% CI, 0.25-0.85; P=0.0117; Figure). The estimated 12-month PFS rates were 70.8% vs 44.4%, respectively. Similar to bortezomib-exposed pts, ORR (92% vs 68%; P=0.0024), rate of ≥VGPR (75% vs 36%; P=0.0001), and rate of ≥CR (46% vs 13%; P=0.0003) were all significantly higher with DRd vs Rd for bortezomib-refractory pts.Updated data will be presented at the meeting.Conclusions: Among pts who received 1 to 3 prior lines of therapy, significantly longer PFS and higher ORR were observed with DRd vs Rd among pts who previously received bortezomib or were refractory to bortezomib or were lenalidomide-naive. Higher rates of deeper responses were observed in pts who previously received lenalidomide or bortezomib. Follow-up is ongoing to assess PFS in pts who received 1 to 3 prior lines of therapy and previously received lenalidomide. These results further strengthen the significant benefit of combining daratumumab with Rd for RRMM. [Display omitted] DisclosuresMoreau:Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Kaufman:Pharmacyclics: Consultancy; Incyte: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Sutherland:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Lalancette:Celgene: Honoraria; BMS: Honoraria. Iida:Celgene: Honoraria, Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding. Prince:Janssen: Honoraria; Celgene: Honoraria. Cochrane:BMS: Other: Received sponsorship to attend international meetings; Novartis: Other: Received sponsorship to attend international meetings; Celgene: Other: Received sponsorship to attend international meetings; Takeda: Other: Received sponsorship to attend international meetings. Khokhar:Janssen: Employment. Guckert:Johnson & Johnson: Equity Ownership; Janssen: Employment. Qin:Janssen: Employment. Oriol:Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

Selinexor Shows Synergy in Combination with Pomalidomide and Low Dose Dexamethasone in Patients with Relapsed / Refractory Multiple Myeloma

Introduction - The nuclear export protein exportin 1, (XPO1) is overexpressed in a wide variety of cancers including multiple myeloma (MM). Selinexor is a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that binds and inactivates XPO1. Selinexor forces nuclear retention and reactivation of tumor suppressor proteins (TSPs; NF-kB, p53 and FOXO) and reduction of many proto-oncogenes, including MDM2, MYC and Cyclin D. In murine MM models, the combination of selinexor with IMIDs shows synergistic anti-MM activity with good tolerability.Methods - This phase 1b/2 dose escalation study (NCT02343042) using the standard 3+3 design, is designed to determine the tolerability, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and preliminary efficacy of selinexor in combination with pomalidomide and dexamethasone (SdP). Patients (pts) with relapsed/refractory MM who received ≥ 2 prior therapies including lenalidomide and a proteasome inhibitor (PI) were enrolled. Selinexor is dose escalated once-weekly (QW, starting at 80 mg) or twice-weekly (BIW, starting at 60 mg), pomalidomide 4 mg PO daily, days 1 -21 and dexamethasone (dex) 40 mg PO weekly in a 28 day cycle.Results - As of 25-Jul-2016, 11 pts (7 male / 4 female) have been enrolled. The median age is 58 years (range, 43 - 76), with a median of 5 (range, 2 - 9) prior treatment regimens. Eight pts had MM refractory to lenalidomide and 7 pts to bortezomib; including 5 pts with MM refractory to both. For the once-weekly selinexor cohort, the 80 mg dose level has been cleared and the 100 mg dose level is on going. For the twice-weekly cohort, the 60 mg dose level has been cleared and 80 mg dose level is on going. Common related grade 1/2 adverse events (AEs) include: nausea 7pts (64%), altered taste 5pts (45%), anorexia 3pts (27%), and diarrhea 3pts (27%). Grade 3/4 AEs include: neutropenia 8pts (73%), thrombocytopenia 4pts (36%), and leukopenia 3pts (27%). There was no febrile neutropenia or bleeding reported to date. No dose limiting toxicities have been observed and MTD has not been reached. Ten pts were evaluable for response including, 1 complete response (CR), 5 partial responses (PR), 3 minor responses (MR), and 1 stable disease (SD). The overall response rate (ORR) is 60% with a clinical benefit rate of 90% (ORR + MR). Responses are rapid in onset, with at least MR achieved by cycle 2 day 1. In lenalidomide and bortezomib refractory patients the ORR was 50%. One pt was deemed not evaluable due to non-compliance with study procedures. Eight pts are still on study, (range <1 - 7+ months) including 4 pts maintaining their response for > 3 months.Conclusions - The all oral combination of selinexor, pomalidomide and low dose dex (SdP) has significant clinical activity (ORR 60%) in pts with heavily pretreated MM. Responses are rapid in onset even with the lower dose cohorts tested thus far, CR can be achieved. No additive toxicities over monotherapy of either pomalidomide or selinexor have been observed. This novel treatment regimen therefore holds promise in addressing the urgent need to induce meaningful and durable responses in patients with IMiD and PI relapsed/refractory MM. DisclosuresChen:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Research Funding. Sebag:Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Sutherland:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. White:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Venner:Takeda: Honoraria; Celgene: Honoraria, Research Funding; J+J: Research Funding; Janssen: Honoraria; Amgen: Honoraria. Kouroukis:Karyopharm: Research Funding; Amgen: Research Funding; Janssen: Research Funding. McCurdy:Celgene: Honoraria. Lalancette:BMS: Honoraria; Celgene: Honoraria. Bensinger:Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Acetylon: Research Funding; Bayer: Research Funding; Takeda: Honoraria, Research Funding. Lentzsch:Celgene: Consultancy, Honoraria; BMS: Consultancy. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Jeha:Karyopharm: Employment. Picklesimer:Karyopharm: Employment. Saint-Martin:Karyopharm: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment. Bahlis:BMS: Honoraria; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria.

Preclinical Evidence for the Therapeutic Potential of CD38-Targeted Immuno-Chemotherapy in Multiple Myeloma Patients Refractory to Lenalidomide and Bortezomib.

Novel therapeutic agents have significantly improved the survival of patients with multiple myeloma. Nonetheless, the prognosis of patients with multiple myeloma who become refractory to the novel agents lenalidomide and bortezomib is very poor, indicating the urgent need for new therapeutic options for these patients. The human CD38 monoclonal antibody daratumumab is being evaluated as a novel therapy for multiple myeloma. Prompted with the encouraging results of ongoing clinical phase I/II trials, we now addressed the potential value of daratumumab alone or in combination with lenalidomide or bortezomib for the treatment of lenalidomide- and bortezomib-refractory patients. In ex vivo assays, mainly evaluating antibody-dependent cell-mediated cytotoxicity, and in an in vivo xenograft mouse model, we evaluated daratumumab alone or in combination with lenalidomide or bortezomib as a potential therapy for lenalidomide- and bortezomib-refractory multiple myeloma patients. Daratumumab induced significant lysis of lenalidomide/bortezomib-resistant multiple myeloma cell lines and of primary multiple myeloma cells in the bone marrow mononuclear cells derived from lenalidomide- and/or bortezomib-refractory patients. In these assays, lenalidomide but not bortezomib, synergistically enhanced daratumumab-mediated multiple myeloma lysis through activation of natural killer cells. Finally, in an in vivo xenograft model, only the combination of daratumumab with lenalidomide effectively reduced the tumorigenic growth of primary multiple myeloma cells from a lenalidomide- and bortezomib-refractory patient. Our results provide the first preclinical evidence for the benefit of daratumumab plus lenalidomide combination for lenalidomide- and bortezomib-refractory patients.

Meta-analysis of the efficacy and safety of bortezomib re-treatment in patients with multiple myeloma.

Bortezomib is administered for a finite course; thus, patients might remain sensitive to bortezomib-based therapy at relapse. We report a meta-analysis of bortezomib-based retreatment in relapsed/refractory myeloma. A systematic literature review identified studies of bortezomib-based retreatment in relapsed/refractory myeloma. Proportions of bortezomib-refractory patients and additional prognostic factors were extracted and used in weighted stratified analyses of TTP and OS. Random-effect pooled estimates were calculated for overall response rate (ORR) and rates of common AEs. Twenty-three studies (n= 1051 patients) were identified. Bortezomib was administered intravenously in all studies. Across studies in which data were available, pooled, weighted average ORR was 39.1% (95% confidence interval, 30.8%-47.4%), and pooled, weighted average median TTP and OS were 7.5 and 16.6 months, respectively. Patients with fewer previous therapies (≤ 4) and relapsed (not refractory) patients achieved higher ORRs, of 43.4% and 57.2%, respectively. Random-effects meta-regression analysis confirmed that relapsed patients were associated with a higher ORR by 28 to 41 percentage points versus refractory patients. In relapsed patients, median TTP and OS were 8.5 and 19.7 months, respectively. Common Grade 3/4 AEs included thrombocytopenia (35%), neutropenia (15%), anemia (14%), pneumonia (10%), and peripheral neuropathy (3%). Based on these findings, bortezomib retreatment is well tolerated and appears efficacious in relapsed patients. In an era of new and emerging treatment options for relapsed and/or refractory myeloma, these data indicate that bortezomib retreatment might be a highly effective option in previously treated patients.