Publications by authors named "Jacob P Laubach"

84 Publications

Phase 1 open-label study of panobinostat, lenalidomide, bortezomib + dexamethasone in relapsed and relapsed/refractory multiple myeloma.

Blood Cancer J 2021 Feb 5;11(2):20. Epub 2021 Feb 5.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Additional therapeutic options are needed for relapsed and refractory multiple myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range: 50-77]) and a median of four prior regimens (range: 2-14); 85% had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]). Patients received a median of six cycles (range: 1-74) of panobinostat (10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m, and dexamethasone 20 mg (pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were reported (mostly hematological); maximum tolerated dose of panobinostat (primary endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of patients and included decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related discontinuations or mortality occurred. In evaluable patients (n = 18), overall response rate was 44%, and clinical benefit rate was 61%. Median duration of response was 9.2 months; progression-free survival was 7.4 months; overall survival was not reached. Pano-RVd proved generally well-tolerated and demonstrated potential to overcome lenalidomide and/or bortezomib resistance.
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http://dx.doi.org/10.1038/s41408-021-00407-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873303PMC
February 2021

Functional Genomics Identify Distinct and Overlapping Genes Mediating Resistance to Different Classes of Heterobifunctional Degraders of Oncoproteins.

Cell Rep 2021 Jan;34(1):108532

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.

Heterobifunctional proteolysis-targeting chimeric compounds leverage the activity of E3 ligases to induce degradation of target oncoproteins and exhibit potent preclinical antitumor activity. To dissect the mechanisms regulating tumor cell sensitivity to different classes of pharmacological "degraders" of oncoproteins, we performed genome-scale CRISPR-Cas9-based gene editing studies. We observed that myeloma cell resistance to degraders of different targets (BET bromodomain proteins, CDK9) and operating through CRBN (degronimids) or VHL is primarily mediated by prevention of, rather than adaptation to, breakdown of the target oncoprotein; and this involves loss of function of the cognate E3 ligase or interactors/regulators of the respective cullin-RING ligase (CRL) complex. The substantial gene-level differences for resistance mechanisms to CRBN- versus VHL-based degraders explains mechanistically the lack of cross-resistance with sequential administration of these two degrader classes. Development of degraders leveraging more diverse E3 ligases/CRLs may facilitate sequential/alternating versus combined uses of these agents toward potentially delaying or preventing resistance.
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http://dx.doi.org/10.1016/j.celrep.2020.108532DOI Listing
January 2021

Efficacy and safety of oral panobinostat plus subcutaneous bortezomib and oral dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma (PANORAMA 3): an open-label, randomised, phase 2 study.

Lancet Oncol 2021 01 7;22(1):142-154. Epub 2020 Dec 7.

Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Background: Improved therapeutic options are needed for patients with relapsed or relapsed and refractory multiple myeloma. Subcutaneous bortezomib has replaced intravenous bortezomib as it is associated with a more favourable toxicity profile. We investigated the activity and safety of three different dosing regimens of oral panobinostat in combination with subcutaneous bortezomib and oral dexamethasone for this indication.

Methods: PANORAMA 3 is an open-label, randomised, phase 2 study being done at 71 sites (hospitals and medical centres) across 21 countries. Patients aged 18 years or older with relapsed or relapsed and refractory multiple myeloma (as per International Myeloma Working Group 2014 criteria), who had received one to four previous lines of therapy (including an immunomodulatory agent), and had an Eastern Cooperative Oncology Group performance status of 2 or lower, were randomly assigned (1:1:1) to receive oral panobinostat 20 mg three times weekly, 20 mg twice weekly, or 10 mg three times weekly, plus subcutaneous bortezomib and oral dexamethasone. All study drugs were administered in 21-day cycles. Randomisation was done by an interactive response technology provider, and stratified by number of previous treatment lines and age. The primary endpoint was overall response rate after up to eight treatment cycles (analysed in all randomly assigned patients by intention to treat). Safety analyses included all patients who received at least one dose of any study drug. No statistical comparisons between groups were planned. This trial is ongoing and registered with ClinicalTrials.gov, NCT02654990.

Findings: Between April 27, 2016, and Jan 17, 2019, 248 patients were randomly assigned (82 to panobinostat 20 mg three times weekly, 83 to panobinostat 20 mg twice weekly, and 83 to 10 mg panobinostat three times weekly). Median duration of follow-up across all treatment groups was 14·7 months (IQR 7·8-24·1). The overall response rate after up to eight treatment cycles was 62·2% (95% CI 50·8-72·7; 51 of 82 patients) for the 20 mg three times weekly group, 65·1% (53·8-75·2; 54 of 83 patients) for the 20 mg twice weekly group, and 50·6% (39·4-61·8; 42 of 83 patients) for the 10 mg three times weekly group. Grade 3-4 adverse events occurred in 71 (91%) of 78 patients in the 20 mg three times weekly group, 69 (83%) of 83 patients in the 20 mg twice weekly group, and 60 (75%) of 80 patients in the 10 mg three times weekly group; the most common (≥20% patients in any group) grade 3-4 adverse events were thrombocytopenia (33 [42%] of 78, 26 [31%] of 83, and 19 [24%] of 83 patients) and neutropenia (18 [23%], 13 [16%], and six [8%]). Serious adverse events occurred in 42 (54%) of 78 patients in the 20 mg three times weekly group, 40 (48%) of 83 patients in the 20 mg twice weekly group, and 35 (44%) of 83 patients in the 10 mg three times weekly group; the most common serious adverse event (≥10% patients in any group) was pneumonia (nine [12%] of 78, ten [12%] of 83, and nine [11%] of 80 patients). There were 14 deaths during the study (five [6%] of 78 patients in the 20 mg three times weekly group, three [4%] of 83 in the 20 mg twice weekly group, and six [8%] of 80 in the 10 mg three times weekly group); none of these deaths was deemed treatment related.

Interpretation: The safety profile of panobinostat 20 mg three times weekly was more favourable than in previous trials of this regimen with intravenous bortezomib, suggesting that subcutaneous bortezomib improves the tolerability of the panobinostat plus bortezomib plus dexamethasone regimen. The overall response rate was highest in the 20 mg three times weekly and 20 mg twice weekly groups, with 10 mg three times weekly best tolerated.

Funding: Novartis Pharmaceuticals and Secura Bio.
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http://dx.doi.org/10.1016/S1470-2045(20)30680-XDOI Listing
January 2021

Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma.

J Clin Oncol 2021 Mar 9;39(7):757-767. Epub 2020 Dec 9.

Hospital Clínico Universitario de Salamanca/IBSAL/CIC, Salamanca, Spain.

Purpose: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need.

Patients And Methods: Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing.

Results: Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class-refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class-refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4.

Conclusion: Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class-refractory and extramedullary disease.
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http://dx.doi.org/10.1200/JCO.20.02259DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078327PMC
March 2021

Long-Term Follow-Up of Ibrutinib Monotherapy in Symptomatic, Previously Treated Patients With Waldenström Macroglobulinemia.

J Clin Oncol 2021 Feb 15;39(6):565-575. Epub 2020 Sep 15.

Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA.

Purpose: We report the long-term findings and final analysis of a pivotal multicenter trial of ibrutinib monotherapy in previously treated patients with Waldenström macroglobulinemia (WM).

Patients And Methods: Sixty-three symptomatic patients with median prior therapies of two (range, one to nine therapies), of whom 40% were refractory to their previous therapy, received ibrutinib at 420 mg/d. Dose reduction was permitted for toxicity.

Results: The median follow-up was 59 months, and overall and major response rates were 90.5% and 79.4%, respectively. At best response, median serum immunoglobulin M declined from 3,520 to 821 mg/dL, bone marrow disease involvement declined from 60% to 20%, and hemoglobin rose from 10.3 to 14.2 g/dL ( < .001 for all comparisons). Responses were impacted by mutated (Mut) and status. Patients with , wild-type (WT) showed higher major (97.2% 68.2%; < .0001) and very good partial (47.2% 9.1%; < .01) response rates and a shorter time to major response (1.8 4.7 months; = .02) versus patients with . Conversely, four patients who had disease showed no major responses. The median 5-year progression-free survival (PFS) rate for all patients was not reached, and was 70% and 38% for those with and WM, respectively ( = .02). In patients with , the median PFS was 0.4 years ( < .01 for three-way comparisons). The 5-year overall survival rate for all patients was 87%. Grade ≥ 3 adverse events in more than one patient at least possibly related included neutropenia (15.9%), thrombocytopenia (11.1%), and pneumonia (3.2%). Eight patients (12.7%) experienced atrial arrhythmia, and seven of the eight continued therapy with medical management.

Conclusion: Ibrutinib is highly active and produces long-term disease control in previously treated patients with WM. Treatment is tolerable. Response depth, time to major response, and PFS are impacted by and mutation status.
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http://dx.doi.org/10.1200/JCO.20.00555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078354PMC
February 2021

Phase 1 Trial Evaluating Vorinostat Plus Bortezomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma.

Clin Lymphoma Myeloma Leuk 2020 Dec 25;20(12):797-803. Epub 2020 Jul 25.

Department of Lymphoma/Myeloma, The University of Texas, MD Anderson Cancer Center, Houston, TX.

Introduction: Bortezomib plus lenalidomide and dexamethasone (VRD) is a standard induction therapy for newly diagnosed multiple myeloma (NDMM) patients. Given preclinical and clinical data suggesting the synergistic activity of the histone deacetylase inhibitor vorinostat with both bortezomib and lenalidomide for the treatment of multiple myeloma, we hypothesized that adding vorinostat to VRD (R2V2) would increase the rate and the quality of responses to induction treatment. Here we report the results of a phase 1 trial (NCT01038388) evaluating R2V2 as up-front treatment for NDMM patients.

Patients And Methods: R2V2 was tested as induction therapy in a dose-escalation phase 1 study in 30 NDMM patients deemed eligible for autologous stem-cell transplantation. Treatment consisted of 4 induction cycles with R2V2, followed by either autologous stem-cell transplantation or 4 additional R2V2 cycles and lenalidomide maintenance therapy.

Results: The maximum tolerated dose of vorinostat was 200 mg daily. The most common adverse events were gastrointestinal (87%), fatigue and peripheral neuropathy (60%), and thrombocytopenia (33%). R2V2 induced an objective response in 96% of patients, with 48% obtaining at least a complete remission. Median progression-free survival was 52 months, with 77% of patients alive at 5 years.

Conclusion: R2V2 as induction treatment for NDMM patients resulted in remarkable response rates at the cost of increased toxicity.
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http://dx.doi.org/10.1016/j.clml.2020.07.013DOI Listing
December 2020

Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant.

Nat Commun 2020 06 12;11(1):2996. Epub 2020 Jun 12.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.

Multiple myeloma (MM) is a plasma-cell neoplasm that is treated with high-dose chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. The presence of somatic mutations in the peripheral blood is termed clonal hematopoiesis of indeterminate potential (CHIP) and is associated with adverse outcomes. Targeted sequencing of the stem cell product from 629 MM patients treated by ASCT at the Dana-Farber Cancer Institute (2003-2011) detects CHIP in 136/629 patients (21.6%). The most commonly mutated genes are DNMT3A, TET2, TP53, ASXL1 and PPM1D. Twenty-one from fifty-six patients (3.3%) receiving first-line IMiD maintenance develop a therapy-related myeloid neoplasm (TMN). However, regardless of CHIP status, the use of IMiD maintenance associates with improved PFS and OS. In those not receiving IMiD maintenance, CHIP is associated with decreased overall survival (OS) (HR:1.34, p = 0.02) and progression free survival (PFS) (HR:1.45, p < 0.001) due to an increase in MM progression.
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http://dx.doi.org/10.1038/s41467-020-16805-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293239PMC
June 2020

Daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma: final results from the phase 2 GEN501 and SIRIUS trials.

Lancet Haematol 2020 Jun;7(6):e447-e455

Winship Cancer Institute, Emory University, Atlanta, GA, USA.

Background: Daratumumab showed encouraging efficacy as monotherapy in patients with heavily pretreated multiple myeloma in the GEN501 and SIRIUS studies. Here we report a pooled, post-hoc final analysis of these two studies.

Methods: GEN501 was an open-label, multicentre, phase 1-2, dose escalation and expansion study done in the Netherlands, the USA, Sweden, and Denmark. Eligible patients had multiple myeloma and had relapsed or were refractory to 2 or more previous lines of treatment that included a proteasome inhibitor or an immunomodulatory drug. SIRIUS was an open-label, multicentre, phase 2 study done in Canada, Spain, and the USA, in which eligible patients with multiple myeloma had received 3 or more previous lines of therapy, including a proteasome inhibitor or an immunomodulatory drug, or were double refractory. In both studies, eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group performance status of 2 or less. In part 2 of GEN501, patients were given intravenous daratumumab 16 mg/kg once per week for 8 weeks, twice per month for 8 doses, and then once per month until disease progression. In part 2 of SIRIUS, patients received intravenous daratumumab 16 mg/kg once per week for 8 weeks, twice per month for 16 weeks, and once per month until disease progression. The primary endpoints (safety in GEN501 and overall response rate in SIRIUS) have previously been reported. These trials are registered on ClinicalTrials.gov, NCT00574288 (GEN501) and NCT01985126 (SIRIUS).

Findings: Patients were enrolled in GEN501 from March 27, 2008, until May 30, 2014, and in SIRIUS from Sept 30, 2013, until May 5, 2014. The combined analysis included 148 patients who received daratumumab 16 mg/kg (42 patients in GEN501 part 2; 106 patients in SIRIUS), with a median follow-up of 36·6 months (IQR 34·5-38·2). Patients had received a median of 5 previous lines of therapy (IQR 4-7), and 128 (87%) of 148 patients were double refractory. The overall response rate was 30·4% (95% CI 23·1-38·5), including 20 (14%) of 148 patients with very good partial response or better (8·5-20·1) and seven (5%) patients reporting complete response or better (1·9-9·5). Among 45 responders, the median duration of response was 8·0 months (95% CI 6·5-14·7). Median overall survival was 20·5 months (95% CI 16·6-28·1), with a 3-year overall survival rate of 36·5% (28·4-44·6). The most common grade 3-4 treatment-emergent adverse events (TEAEs) were anaemia (grade 3, 26 [18%] of 148 patients; no grade 4 events) and thrombocytopenia (grade 3, 13 [9%] of 148 patients; grade 4, 8 [5%] of 148 patients). Serious drug-related TEAEs occurred in 13 (9%) of 148 patients. There were no treatment-related deaths.

Interpretation: In this analysis, daratumumab 16 mg/kg monotherapy showed durable responses and there were no new safety concerns with longer follow-up.

Funding: Janssen Research & Development.
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http://dx.doi.org/10.1016/S2352-3026(20)30081-8DOI Listing
June 2020

Phase I/II trial of the CXCR4 inhibitor plerixafor in combination with bortezomib as a chemosensitization strategy in relapsed/refractory multiple myeloma.

Am J Hematol 2019 11 4;94(11):1244-1253. Epub 2019 Oct 4.

Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

We tested the hypothesis that using CXCR4 inhibition to target the interaction between the tumor cells and the microenvironment leads to sensitization of the tumor cells to apoptosis. Eligibility criteria included multiple myeloma (MM) patients with 1-5 prior lines of therapy. The purposes of the phase I study were to evaluate the safety and maximal-tolerated dose (MTD) of the combination. The treatment-related adverse events and response rate of the combination were assessed in the phase II study. A total of 58 patients were enrolled in the study. The median age of the patients was 63 years (range, 43-85), and 78% of them received prior bortezomib. In the phase I study, the MTD was plerixafor 0.32 mg/kg, and bortezomib 1.3 mg/m . The overall response rate for the phase II study was 48.5%, and the clinical benefit rate 60.6%. The median disease-free survival was 12.6 months. The CyTOF analysis demonstrated significant mobilization of plasma cells, CD34+ stem cells, and immune T cells in response to plerixafor. This is an unprecedented study that examines therapeutic targeting of the bone marrow microenvironment and its interaction with the tumor clone to overcome resistance to therapy. Our results indicate that this novel combination is safe and that the objective response rate is high even in patients with relapsed/refractory MM. ClinicalTrials.gov, NCT00903968.
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http://dx.doi.org/10.1002/ajh.25627DOI Listing
November 2019

Daratumumab-based regimens are highly effective and well tolerated in relapsed or refractory multiple myeloma regardless of patient age: subgroup analysis of the phase 3 CASTOR and POLLUX studies.

Haematologica 2020 31;105(2):468-477. Epub 2020 Jan 31.

National and Kapodistrian University of Athens, Athens, Greece.

The phase 3 POLLUX and CASTOR studies demonstrated superior benefit of daratumumab plus lenalidomide/dexamethasone or bortezomib/dexamethasone in relapsed/refractory multiple myeloma. Efficacy and safety of daratumumab was analyzed according to age groups of 65 to 74 years and ≥75 years. Patients received ≥1 prior line of therapy. In POLLUX, patients received lenalidomide/dexamethasone ± daratumumab (16 mg/kg weekly, cycles 1-2; every two weeks, cycles 3-6; monthly until progression). In CASTOR, patients received eight cycles of bortezomib/dexamethasone ± daratumumab (16 mg/kg weekly, cycles 1-3; every three weeks, cycles 4-8; monthly until progression). Patients aged >75 years received dexamethasone 20 mg weekly. For patients aged ≥75 years in POLLUX (median follow-up: 25.4 months), daratumumab/lenalido-mide/dexamethasone prolonged progression-free survival lenalido-mide/dexamethasone (median: 28.9 11.4 months; hazard ratio, 0.27; 95% confidence interval, 0.10-0.69; =0.0042) and increased overall response rate (93.1% 76.5%; =0.0740). Neutropenia was the most common grade 3/4 treatment-emergent adverse event (daratumumab: 44.8%; control: 31.4%). Infusion-related reactions occurred in 12 (41.4%) patients. For patients aged ≥75 years in CASTOR (median follow-up: 19.4 months), daratumumab/bortezomib/dexamethasone prolonged progression-free survival versus bortezomib/dexamethasone (median: 17.9 8.1 months; hazard ratio, 0.26; 95% confidence interval, 0.10-0.65; =0.0022) and increased overall response rate (95.0% 78.8%; =0.1134). Thrombocytopenia was the most common grade 3/4 treatment-emergent adverse event (daratumumab: 45.0%; control: 37.1%). Infusion-related reactions occurred in 13 (65.0%) patients. Similar findings were reported for patients aged 65 to 74 years in both studies. Taken together, this subgroup analysis of efficacy and safety of daratumumab was largely consistent with the overall populations.
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http://dx.doi.org/10.3324/haematol.2019.217448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012498PMC
April 2021

Ixazomib maintenance therapy in newly diagnosed multiple myeloma: An integrated analysis of four phase I/II studies.

Eur J Haematol 2019 Jun 8;102(6):494-503. Epub 2019 May 8.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Objectives: To evaluate the safety and efficacy of maintenance therapy with the oral proteasome inhibitor ixazomib in patients with newly diagnosed multiple myeloma (NDMM) not undergoing transplantation.

Methods: Data were pooled from four NDMM phase I/II studies; patients received induction therapy with once- or twice-weekly ixazomib plus lenalidomide-dexamethasone (IRd), melphalan-prednisone (IMP), or cyclophosphamide-dexamethasone (ICd), followed by single-agent ixazomib maintenance, given at the last tolerated dose during induction, until disease progression, death, or unacceptable toxicity.

Results: A total of 121 patients achieved stable disease or better after induction (weekly IRd, n = 25; twice-weekly IRd, n = 18; weekly or twice-weekly IMP, n = 35; weekly ICd, n = 43) and received ≥ 1 dose of ixazomib maintenance. Grade ≥ 3 drug-related adverse events occurred in 24% of patients during maintenance; each event was reported in ≤2% of patients. Rates of complete response were 22% after induction and 35% after maintenance. A total of 28 patients (23%) improved their response during maintenance.

Conclusions: Ixazomib maintenance following ixazomib-based induction is associated with deepening of responses and a positive safety profile with no cumulative toxicity in patients with NDMM not undergoing transplantation, suggesting that ixazomib is feasible for long-term administration. Phase III investigation of ixazomib maintenance is ongoing.
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http://dx.doi.org/10.1111/ejh.13231DOI Listing
June 2019

Ixazomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma: long-term follow-up including ixazomib maintenance.

Leukemia 2019 07 29;33(7):1736-1746. Epub 2019 Jan 29.

Dana-Farber Cancer Institute, Boston, MA, USA.

Triplet combinations containing a proteasome inhibitor are a standard of care in newly diagnosed multiple myeloma (NDMM). We examined the long-term efficacy and safety of the all-oral combination of weekly ixazomib plus lenalidomide-dexamethasone (IRd), followed by single-agent ixazomib maintenance in NDMM patients. Of 65 enrolled patients, 53 received ixazomib 4 mg (days 1, 8, and 15) plus lenalidomide 25 mg (days 1-21) and dexamethasone 40 mg (days 1, 8, 15, and 22) for up to twelve 28-day induction cycles. Twenty-three patients discontinued induction for stem cell transplantation (SCT). In the remaining 42 patients, overall response rate was 80%, including 63% ≥very good partial response (VGPR) and 32% complete responses. At a median follow-up of 56 months, median progression-free survival (PFS) was 35.4 months in the total population. Twenty-five patients received ixazomib maintenance; eight deepened their response (76% ≥VGPR), and median PFS was 37.2 months in this subgroup. Nine of 42 patients who did not proceed to SCT (14% of total population) had an adverse event requiring discontinuation. Ixazomib (median ≥ 96%) and lenalidomide (median 88-94%) relative dose intensities were maintained throughout treatment. Weekly IRd, followed by ixazomib maintenance, was highly active with acceptable toxicity, enabling long-term administration with no evidence of cumulative toxicities.
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http://dx.doi.org/10.1038/s41375-019-0384-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755968PMC
July 2019

Performance of the International Myeloma Working Group myeloma frailty score among patients 75 and older.

J Geriatr Oncol 2019 05 22;10(3):486-489. Epub 2018 Nov 22.

Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; Center for Leukemia, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA. Electronic address:

Objectives: We compared the performance of two frailty scoring systems in predicting survival among older patients with multiple myeloma: the International Myeloma Working Group (IMWG) frailty score (which includes age), and the Fried model for frailty (which does not).

Methods: From 2015 to 2018, all patients aged 75 years and older presenting at our institution with a diagnosis of multiple myeloma were approached for a frailty screening assessment. We first categorized patients' frailty using the Fried model. Then, using available deficit measures, we reclassified frailty using the IMWG approach. We compared the performance of the IMWG strategy to the Fried model in terms of association with overall survival.

Results: Of the 98 (92%) patients who consented to a baseline frailty assessment, we found 57% discordance among frailty classification between the two scoring systems. Using the IMWG strategy, 9% of the cohort was "fit," 29% "intermediate-fit," and 62% "frail." Using the Fried model, 29% of the cohort was "robust," 52% "pre-frail," and 19% "frail." Frailty category in the Fried model was predictive of overall survival among our cohort, while frailty category in the IMWG strategy was not (log-rank p = 0.04 vs. 0.34).

Conclusion: Among our cohort of older patients with myeloma (aged 75 and higher), the Fried model appears to be a better predictor of survival compared to the IMWG strategy. These results suggest that using age as a criterion to identify frailty in older patients with multiple myeloma may limit treatment options for the functionally vigorous.
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http://dx.doi.org/10.1016/j.jgo.2018.10.010DOI Listing
May 2019

The power of proteasome inhibition in multiple myeloma.

Expert Rev Proteomics 2018 12 14;15(12):1033-1052. Epub 2018 Nov 14.

b Medical Oncology , Dana-Farber Cancer Institute , Boston , MA , USA.

Introduction: Proteasome inhibitors (PIs) are therapeutic backbones of multiple myeloma treatment, with PI-based therapies being standards of care throughout the treatment algorithm. Proteasome inhibition affects multiple critical signaling pathways in myeloma cells and interacts synergistically with mechanisms of action of other conventional and novel agents, resulting in substantial anti-myeloma activity and at least additive effects. Areas covered: This review summarizes the biologic effects of proteasome inhibition in myeloma and provides an overview of the importance of proteasome inhibition to the current treatment algorithm. It reviews key clinical data on three PIs, specifically bortezomib, carfilzomib, and ixazomib; assesses ongoing phase 3 trials with these agents; and looks ahead to the increasingly broad role of both approved PIs and PIs under investigation in the frontline and relapsed settings. Expert commentary: Progress to date with PIs in multiple myeloma has been impressive, but there remain unmet needs and challenges, as well as increasing opportunities to optimize the use of these agents. Understanding discrepancies between PIs in terms of efficacy and safety profile is a key goal of ongoing research, along with proteomics-based efforts to identify potential biomarkers of sensitivity and resistance, thereby enabling increasingly personalized treatment approaches in the future.
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http://dx.doi.org/10.1080/14789450.2018.1543595DOI Listing
December 2018

Ixazomib for the treatment of multiple myeloma.

Expert Opin Pharmacother 2018 Dec 13;19(17):1949-1968. Epub 2018 Nov 13.

g Hematology & Medical Oncology , Winship Cancer Institute, Emory University , Atlanta , GA , USA.

Introduction: Proteasome inhibitors (PIs) are among the backbones of multiple myeloma (MM) treatment; however, their long-term use can be limited by parenteral administration and treatment-related toxicities. Ixazomib, the first oral PI to enter the clinic, is approved around the world, in combination with lenalidomide and dexamethasone, for the treatment of patients with MM who have received at least one prior therapy. Areas covered: This review summarizes the clinical data leading to approval of ixazomib; its pharmacology, efficacy, and safety. Building on the data in relapsed/refractory MM (RRMM), it also reviews the available clinical trial data for ixazomib across the MM treatment algorithm in newly diagnosed MM, RRMM, and as maintenance therapy, and looks ahead to ongoing clinical trials and the expanding role of ixazomib in these indications. Expert opinion: Ixazomib is an efficacious and well-tolerated addition to the treatment armamentarium for RRMM, with benefit as a long-term, continuous therapy for all patients, including 'poor prognosis' patients, such as those with advanced stage disease, high-risk cytogenetic abnormalities, and elderly and frail patients. Data from ongoing clinical studies are expected to expand the role of ixazomib across the MM treatment algorithm and in a broader range of combination regimens.
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http://dx.doi.org/10.1080/14656566.2018.1528229DOI Listing
December 2018

Interpreting clinical trial data in multiple myeloma: translating findings to the real-world setting.

Blood Cancer J 2018 11 9;8(11):109. Epub 2018 Nov 9.

Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Substantial improvements in survival have been seen in multiple myeloma (MM) over recent years, associated with the introduction and widespread use of multiple novel agents and regimens, as well as the emerging treatment paradigm of continuous or long-term therapy. However, these therapies and approaches may have limitations in the community setting, associated with toxicity burden, patient burden, and other factors including cost. Consequently, despite improvements in efficacy in the rigorously controlled clinical trials setting, the same results are not always achieved in real-world practice. Furthermore, the large number of different treatment options and regimens under investigation in various MM settings precludes the feasibility of obtaining head-to-head clinical trial data, and there is a temptation to use cross-trial comparisons to evaluate data across regimens. However, multiple aspects, including patient-related, disease-related, and treatment-related factors, can influence clinical trial outcomes and lead to differences between studies that may confound direct comparisons between data. In this review, we explore the various factors requiring attention when evaluating clinical trial data across available agents/regimens, as well as other considerations that may impact the translation of these findings into everyday MM management. We also investigate discrepancies between clinical trial efficacy and real-world effectiveness through a literature review of non-clinical trial data in relapsed/refractory MM on novel agent-based regimens and evaluate these data in the context of phase 3 trial results for recently approved and commonly used regimens. We thereby demonstrate the complexity of interpreting data across clinical studies in MM, as well as between clinical studies and routine-care analyses, with the aim to help clinicians consider all the necessary issues when tailoring individual patients' treatment approaches.
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http://dx.doi.org/10.1038/s41408-018-0141-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226527PMC
November 2018

A Phase I/II Study of Evofosfamide, A Hypoxia-activated Prodrug with or without Bortezomib in Subjects with Relapsed/Refractory Multiple Myeloma.

Clin Cancer Res 2019 01 2;25(2):478-486. Epub 2018 Oct 2.

Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Purpose: The presence of hypoxia in the diseased bone marrow presents a new therapeutic target for multiple myeloma. Evofosfamide (formerly TH-302) is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard, which is selectively activated under hypoxia. This trial was designed as a phase I/II study investigating evofosfamide in combination with dexamethasone, and in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma.

Patients And Methods: Fifty-nine patients initiated therapy, 31 received the combination of evofosfamide and dexamethasone, and 28 received the combination of evofosfamide, bortezomib, and dexamethasone. Patients were heavily pretreated with a median number of prior therapies of 7 (range: 2-15). All had previously received bortezomib and immunomodulators. The MTD, treatment toxicity, and efficacy were determined.

Results: The MTD was established at 340 mg/m evofosfamide + dexamethasone with dose-limiting mucositis at higher doses. For the combination of evofosfamide, bortezomib, and dexamethasone, no patient had a dose-limiting toxicity (DLT) and the recommended phase II dose was established at 340 mg/m. The most common ≥grade 3 adverse events (AE) were thrombocytopenia (25 patients), anemia (24 patients), neutropenia (15 patients), and leukopenia (9 patients). Skin toxicity was reported in 42 (71%) patients. Responses included 1 very good partial response (VGPR), 3 partial response (PR), 2 minor response (MR), 20 stable disease (SD), and 4 progressive disease (PD) for evofosfamide + dexamethasone and 1 complete response (CR), 2 PR, 1 MR, 18 SD, and 5 PD for evofosfamide + bortezomib + dexamethasone. Disease stabilization was observed in over 80% and this was reflective of the prolonged overall survival of 11.2 months.

Conclusions: Evofosfamide can be administered at 340 mg/m twice a week with or without bortezomib. Clinical activity has been noted in patients with heavily pretreated relapsed refractory multiple myeloma.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335171PMC
January 2019

Practical Considerations for Antibodies in Myeloma.

Am Soc Clin Oncol Educ Book 2018 May;38:667-674

From the Department of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, MA; Department of Hematology, VU University Medical Center, Amsterdam, the Netherlands; Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR; International Myeloma Foundation, North Hollywood, CA.

The development of the monoclonal antibodies daratumumab and elotuzumab has expanded treatment options for multiple myeloma and led to great improvement in patient outcomes. These agents have favorable safety profiles and synergize effectively with established agents used in the management of myeloma, namely immunomodulatory drugs and proteasome inhibitors. This article reviews the rationale for use of monoclonal antibodies in myeloma, current approved indications for daratumumab and elotuzumab, the manner in which these agents are used in the overall management of myeloma, and specific challenges associated with their use in the clinic. It also highlights other, emerging drug combinations that incorporate daratumumab or elotuzumab and profiles new therapeutic antibodies currently under development.
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http://dx.doi.org/10.1200/EDBK_205443DOI Listing
May 2018

The evolving role of transplantation in multiple myeloma: the need for a heterogeneous approach to a heterogeneous disease.

Clin Adv Hematol Oncol 2018 Aug;16(8):564-574

Dana-Farber Cancer Institute, Boston, Massachusetts.

Autologous stem cell transplant (ASCT) is an established frontline standard of care for the younger, fitter patients with newly diagnosed multiple myeloma (NDMM) who are eligible for the procedure, and has contributed to improved overall survival. In the current era of novel therapies, the treatment landscape and prognosis have changed. The outstanding efficacy seen with regimens based on novel agents has led to a questioning of the frontline treatment paradigm with respect to ASCT. A key current question is whether to use transplant early or to collect stem cells early but save ASCT for salvage therapy. In this review, we evaluate the clinical data for each approach as well as the arguments in favor of early or delayed ASCT. We also consider the clinical/clonal heterogeneity of myeloma and review the evidence regarding which patient subgroups may benefit most from each approach. We summarize current treatment guidelines for transplant-eligible patients with NDMM and review the evolving role of minimal residual disease evaluation and its potential effect on the debate over early vs delayed ASCT. We conclude that frontline ASCT remains a standard of care for a substantial proportion of patients; however, delayed/salvage ASCT is increasingly being used in the context of highly active frontline regimens based on novel agents and the ongoing personalization of myeloma treatment.
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August 2018

Geographic Disparities in Reported US Amyloidosis Mortality From 1979 to 2015: Potential Underdetection of Cardiac Amyloidosis.

JAMA Cardiol 2018 09;3(9):865-870

Cardiac Amyloidosis Program, Division of Cardiology, Department of Medicine, Heart & Vascular Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Importance: Cardiac amyloidosis is an underdiagnosed disease and is highly fatal when untreated. Early diagnosis and treatment with the emerging novel therapies significantly improve survival. A comprehensive analysis of amyloidosis-related mortality is critical to appreciate the nature and distribution of underdiagnosis and improve disease detection.

Objective: To evaluate the temporal and regional trends in age-adjusted amyloidosis-related mortality among men and women of various races/ethnicities in the United States.

Design, Setting, And Participants: In this observational cohort study, death certificate information from the Centers for Disease Control and Prevention's Wide-ranging ONline Data for Epidemiologic Research database and the National Vital Statistics System from 1979 to 2015 was analyzed. A total of 30 764 individuals in the United States with amyloidosis listed as the underlying cause of death and 26 591 individuals with amyloidosis listed as a contributing cause of death were analyzed.

Exposures: Region of residence.

Main Outcomes And Measures: Age-adjusted mortality rate from amyloidosis per 1 000 000 population stratified by year, sex, race/ethnicity, and state and county of residence.

Results: Of the 30 764 individuals with amyloidosis listed as the underlying cause of death, 17 421 (56.6%) were men and 27 312 (88.8%) were 55 years or older. From 1979 to 2015, the reported overall mean age-adjusted mortality rate from amyloidosis as the underlying cause of death doubled from 1.77 to 3.96 per 1 000 000 population (2.32 to 5.43 in men and 1.35 to 2.80 in women). Black men had the highest mortality rate (12.36 per 1 000 000), followed by black women (6.48 per 1 000 000). Amyloidosis contributed to age-adjusted mortality rates as high as 31.73 per 1 000 000 in certain counties. Most southern states reported the lowest US mortality rates despite having the highest proportions of black individuals.

Conclusions And Relevance: The increased reported mortality over time and in proximity to amyloidosis centers more likely reflects an overall increase in disease diagnosis rather than increased lethality. The reported amyloidosis mortality is highly variable in different US regions. The lack of higher reported mortality rates in states with a greater proportion of black residents suggests underdiagnosis of amyloidosis, including cardiac forms of the disease, in many areas of the United States. Better understanding of the determinants of geographic and racial disparity in the reporting of amyloidosis deaths are warranted.
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http://dx.doi.org/10.1001/jamacardio.2018.2093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233639PMC
September 2018

Investigational agents in immunotherapy: a new horizon for the treatment of multiple myeloma.

Br J Haematol 2018 05 10;181(4):433-446. Epub 2018 May 10.

Dana Farber Cancer Institute, Harvard Medical School, Jerome Lipper Multiple Myeloma Center, Boston, MA, USA.

The treatment of multiple myeloma (MM) has gone through several major advances over the last 5 years with the introduction of next generation proteasome inhibitors (PI; carfilzomib, ixazomib) and immunomodulatory derivatives (IMiD; pomalidomide), with these new agents having a substantial impact on patient outcome. However, despite these advances, MM remains a highly resistant disease given its propensity for clonal heterogeneity and its complex interaction with the surrounding bone marrow microenvironment. Almost all patients eventually relapse despite therapeutic responses to a PI, IMiD or both. With the regulatory approval of the monoclonal antibodies Daratumumab and Elotuzumab in 2015, impressive and durable responses are being observed, even in heavily pre-treated patients who have exhausted other therapeutic options, suggesting immunological approaches in this setting have real merit. This review will focus on newer monoclonal antibodies and chimeric-antigen receptor (CAR) T cell strategies currently under investigation and in various stages of clinical development.
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http://dx.doi.org/10.1111/bjh.15116DOI Listing
May 2018

A phase 2 study of modified lenalidomide, bortezomib and dexamethasone in transplant-ineligible multiple myeloma.

Br J Haematol 2018 07 8;182(2):222-230. Epub 2018 May 8.

Massachusetts General Hospital Cancer Center, Boston, MA, USA.

We sought a regimen that incorporates optimal novel agents and balances efficacy with toxicity in transplant-ineligible multiple myeloma (MM) patients. Our study evaluated modified lenalidomide-bortezomib-dexamethasone (RVD lite) in this population and was administered over a 35-day cycle. Lenalidomide 15 mg was given orally on days 1-21; bortezomib 1·3 mg/m weekly subcutaneously on days 1, 8, 15 and 22; and dexamethasone 20 mg orally was given on the day of and day after bortezomib for 9 cycles followed by 6 cycles of consolidation with lenalidomide and bortezomib. The primary objective was to evaluate the overall response rate (ORR); secondary objectives included safety, progression-free survival (PFS) and overall survival (OS). Fifty-three eligible patients were screened between April 2013 and May 2015; 50 received at least one dose of therapy. Median age at study entry was 73 years (range 65-91). The ORR was 86% and 66% of patients achieved a very good partial response or better. Median PFS was 35·1 months (95% confidence interval 30·9-not reached) and median OS was not reached at a median follow-up of 30 months. Peripheral neuropathy was reported in 31 (62%) patients with only 1 patient experiencing grade 3 symptoms. RVD lite is a well-tolerated and highly effective regimen, with robust PFS and OS, in the transplant-ineligible MM population.
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http://dx.doi.org/10.1111/bjh.15261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6074026PMC
July 2018

Ibrutinib alone or with dexamethasone for relapsed or relapsed and refractory multiple myeloma: phase 2 trial results.

Br J Haematol 2018 03 13;180(6):821-830. Epub 2018 Feb 13.

Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Novel therapies with unique new targets are needed for patients who are relapsed/refractory to current treatments for multiple myeloma. Ibrutinib is a first-in-class, once-daily, oral covalent inhibitor of Bruton tyrosine kinase, which is overexpressed in the myeloma stem cell population. This study examined various doses of ibrutinib ± low-dose dexamethasone in patients who received ≥2 prior lines of therapy, including an immunomodulatory agent. Daily ibrutinib ± weekly dexamethasone 40 mg was assessed in 4 cohorts using a Simon 2-stage design. The primary objective was clinical benefit rate (CBR; ≥minimal response); secondary objectives included safety. Patients (n = 92) received a median of 4 prior regimens. Ibrutinib + dexamethasone produced the highest CBR (28%) in Cohort 4 (840 mg + dexamethasone; n = 43), with median duration of 9·2 months (range, 3·0-14·7). Progression-free survival was 4·6 months (range, 0·4-17·3). Grade 3-4 haematological adverse events included anaemia (16%), thrombocytopenia (11%), and neutropenia (2%); grade 3-4 non-haematological adverse events included pneumonia (7%), syncope (3%) and urinary tract infection (3%). Ibrutinib + dexamethasone produced notable responses in this heavily pre-treated population. The encouraging efficacy, coupled with the favourable safety and tolerability profile of ibrutinib, supports its further evaluation as part of combination treatment.
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http://dx.doi.org/10.1111/bjh.15058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873373PMC
March 2018

Safety of live-attenuated measles-mumps-rubella and herpes zoster vaccination in multiple myeloma patients on maintenance lenalidomide or bortezomib after autologous hematopoietic cell transplantation.

Bone Marrow Transplant 2018 07 9;53(7):942-945. Epub 2018 Feb 9.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Attenuated live virus vaccinations are generally recommended 24 months following hematopoietic cell transplantation (HCT) in patients not receiving immunosuppressive therapy. To date, there are no data regarding the safety of live-attenuated herpes zoster or measles-mumps-rubella (MMR) vaccinations in multiple myeloma patients on maintenance lenalidomide or bortezomib following autologous HCT. One hundred thirty-seven multiple myeloma patients on maintenance lenalidomide or bortezomib post-auto-HCT who received either MMR or herpes zoster vaccine were analyzed and any adverse events documented in the medical record in the 42 days following vaccination were recorded. Patients were vaccinated a median of 25 months (range, 18-62) post transplant. The most common post-vaccination adverse event was upper respiratory tract infection (18/137 patients); no rash attributed to vaccine strains or other adverse outcomes potentially related to the vaccines were identified. MMR and herpes zoster vaccination were safe and well-tolerated in this cohort.
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http://dx.doi.org/10.1038/s41409-018-0112-xDOI Listing
July 2018

Prevalence of Monoclonal Gammopathy in Wild-Type Transthyretin Amyloidosis.

Mayo Clin Proc 2017 Dec;92(12):1800-1805

Cardiac Amyloidosis Program, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. Electronic address:

Objective: To evaluate the prevalence of monoclonal gammopathy (MG) in patients with wild-type transthyretin amyloidosis (ATTRwt) (formerly known as senile amyloidosis).

Patients And Methods: We retrospectively analyzed the serum protein electrophoresis and serum immunofixation results, free light chain (FLC) levels, and renal function of 113 consecutive patients with ATTRwt seen at the Brigham and Women's Hospital's Cardiac Amyloidosis Program between February 21, 2006, and November 9, 2016. Monoclonal gammopathy was defined as a monoclonal protein present in the serum. Light chain MG was defined as an abnormal serum FLC κ/λ ratio with an elevated FLC level in the absence of a monoclonal protein. In patients with renal dysfunction, the renal FLC reference range was used.

Results: The mean age of the population was 75 years, 3 of the 113 patients (3%) were female, and 110 (97%) were white. Monoclonal gammopathy was present in 26 patients (23%), 24 of whom had monoclonal protein present and 2 others who met criteria for light chain MG. Most clones (12 of 20 [60%]) were λ restricted. Another 7 patients had an abnormal FLC κ/λ ratio in the setting of renal dysfunction.

Conclusion: In this study, MG was present in 23% of patients with ATTRwt. The finding of MG or an abnormal FLC κ/λ ratio in an elderly man may cause diagnostic confusion during subtyping of amyloidosis. A high degree of clinical suspicion for ATTRwt and precise tissue typing using mass spectrometry may overcome such diagnostic challenges.
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http://dx.doi.org/10.1016/j.mayocp.2017.09.016DOI Listing
December 2017

The proteasome and proteasome inhibitors in multiple myeloma.

Cancer Metastasis Rev 2017 12;36(4):561-584

Dana-Farber Cancer Institute, 44 Binney Street, Dana 1B02, Boston, MA, 02115, USA.

Proteasome inhibitors are one of the most important classes of agents to have emerged for the treatment of multiple myeloma in the past two decades, and now form one of the backbones of treatment. Three agents in this class have been approved by the United States Food and Drug Administration-the first-in-class compound bortezomib, the second-generation agent carfilzomib, and the first oral proteasome inhibitor, ixazomib. The success of this class of agents is due to the exquisite sensitivity of myeloma cells to the inhibition of the 26S proteasome, which plays a critical role in the pathogenesis and proliferation of the disease. Proteasome inhibition results in multiple downstream effects, including the inhibition of NF-κB signaling, the accumulation of misfolded and unfolded proteins, resulting in endoplasmic reticulum stress and leading to the unfolded protein response, the downregulation of growth factor receptors, suppression of adhesion molecule expression, and inhibition of angiogenesis; resistance to proteasome inhibition may arise through cellular responses mediating these downstream effects. These multiple biologic consequences of proteasome inhibition result in synergistic or additive activity with other chemotherapeutic and targeted agents for myeloma, and proteasome inhibitor-based combination regimens have become established as a cornerstone of therapy throughout the myeloma treatment algorithm, incorporating agents from the other key classes of antimyeloma agents, including the immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors. This review gives an overview of the critical role of the proteasome in myeloma and the characteristics of the different proteasome inhibitors and provides a comprehensive summary of key clinical efficacy and safety data with the currently approved proteasome inhibitors.
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http://dx.doi.org/10.1007/s10555-017-9707-8DOI Listing
December 2017

New developments in the management of relapsed/refractory multiple myeloma - the role of ixazomib.

J Blood Med 2017 22;8:107-121. Epub 2017 Aug 22.

Hematology Department, University Hospital Hotel-Dieu, Nantes, France.

Ixazomib is the first oral proteasome inhibitor to be approved, in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was on the basis of results from the phase 3, double-blind, placebo-controlled TOURMALINE-MM1 study, which demonstrated a 35% improvement in progression-free survival with the all-oral combination of ixazomib plus lenalidomide-dexamethasone versus lenalidomide-dexamethasone alone (median: 20.6 vs 14.7 months; hazard ratio: 0.74, =0.012; median follow-up 14.7 months). The addition of ixazomib to the lenalidomide-dexamethasone regimen was associated with limited additional toxicity and had no adverse impact on patient-reported quality of life. Common grade ≥3 adverse events with ixazomib include gastrointestinal adverse events, rash, and thrombocytopenia. Here, we review the efficacy, safety, pharmacokinetics, and patient-reported quality of life data seen with ixazomib, and discuss the role of this oral agent in the treatment of patients with relapsed/refractory multiple myeloma, including in patients with high-risk cytogenetic abnormalities and those with multiple prior therapies.
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http://dx.doi.org/10.2147/JBM.S102328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573039PMC
August 2017