Publications by authors named "Melissa Alsina"

85 Publications

Phase 2 multicenter trial of ofatumumab and prednisone as initial therapy of chronic graft-vs-host disease.

Blood Adv 2021 Oct 14. Epub 2021 Oct 14.

H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States.

Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal and transient responses in a significant number of patients. Safety and feasibility of anti-CD20 directed B-cell therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n=12). We now report the mature results of the phase II expansion of the trial (n=38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The combined therapy was generally well tolerated, with some anticipated infusion reactions to ofatumumab, and common toxicities of glucocorticoids. Total B-cell depletion following therapy was profound, with marginal recovery within first 12 months from initial therapy. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR=complete + partial response[CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial IS agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD. This trial is registered at www.clinicaltrials.gov as NCT01680965.
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http://dx.doi.org/10.1182/bloodadvances.2021005552DOI Listing
October 2021

Assessment of Clonotypic Rearrangements and Minimal Residual Disease in Lymphoid Malignancies: A Large Cancer Center Experience Using clonoSEQ.

Arch Pathol Lab Med 2021 Aug 3. Epub 2021 Aug 3.

Malignant Hematology (Shah, Pinilla-Ibarz, Shain), Moffitt Cancer Center, Tampa, Florida.

Context.—: Measurable (minimal) residual disease (MRD) is an independent prognostic factor for survival outcomes in patients with lymphoid and plasma cell malignancies and has been incorporated into consensus criteria regarding treatment response, strategy, and clinical trial endpoints. clonoSEQ (a next-generation sequencing [NGS]-MRD assay) uses multiplex polymerase chain reaction and NGS to identify clonotypic rearrangements at the immunoglobulin (Ig) H, IgK, IgL, T-cell receptor (TCR)-β, and TCR-γ loci, and translocated B-cell lymphoma 1/IgH and 2/IgH sequences for MRD assessment. Additionally, it can be used to confirm diagnoses of cutaneous T-cell lymphoma (CTCL).

Objective.—: To review the technical aspects of our experience using the clonoSEQ Assay in routine clinical practice.

Design.—: In this single-center experience, 390 patients with lymphoid and plasma cell malignancies were assessed with the NGS-MRD Assay at a central laboratory.

Results.—: Median time from arrival of the shipment to initiation of the assay (defined as captured in Adaptive's secure tracking system) was 2.1 hours. Overall, 317 patients had 1 or more samples submitted for sequence identification. Of these, 290 (91.5%) had trackable sequences identified. The median calibration rate of samples by malignancy (where n ≥ 10 samples, excluding CTCL samples) was 88.1%, across a variety of fresh and archived sample sources (177 of 201 samples). TCR-β and/or TCR-γ clonotypes were identified in 40 of 95 samples (42.1%) from 66 patients with suspected CTCL.

Conclusions.—: This NGS-MRD Assay is a valuable and sensitive tool for monitoring MRD in patients with plasma cell and lymphoid malignancies and assisting in the diagnosis of CTCL.
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http://dx.doi.org/10.5858/arpa.2020-0457-OADOI Listing
August 2021

Increased Infections and Delayed CD4 T Cell but Faster B Cell Immune Reconstitution after Post-Transplantation Cyclophosphamide Compared to Conventional GVHD Prophylaxis in Allogeneic Transplantation.

Transplant Cell Ther 2021 Nov 28;27(11):940-948. Epub 2021 Jul 28.

Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Post-transplantation cyclophosphamide (PTCy) is being increasingly used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic cell transplantation (allo-HCT) across various donor types. However, immune reconstitution and infection incidence after PTCy-based versus conventional GVHD prophylaxis has not been well studied. We evaluated the infection density and immune reconstitution (ie, absolute CD4 T cell, CD8 T cell, natural killer cell, and B cell counts) at 3 months, 6 months, and 1 year post-HCT in 583 consecutive adult patients undergoing allo-HCT with myeloablative (n = 223) or reduced-intensity (n = 360) conditioning between 2012 and 2018. Haploidentical (haplo; n = 75) and 8/8 HLA-matched unrelated (MUD; n = 08) donor types were included. GVHD prophylaxis was PTCy-based in all haplo (n = 75) and in 38 MUD allo-HCT recipients, whereas tacrolimus/methotrexate (Tac/MTX) was used in 89 and Tac/Sirolimus (Tac/Sir) was used in 381 MUD allo-HCT recipients. Clinical outcomes, including infections, nonrelapse mortality (NRM), relapse, and overall survival (OS), were compared across the 4 treatment groups. The recovery of absolute total CD4 T-cell count was significantly lower in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups throughout 1 year post-allo-HCT (P = .025). In contrast, CD19 B-cell counts at 6 months and thereafter were higher in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups (P < .001). Total CD8 T cell and NK cell recovery was not significantly different among the groups. Infection density analysis showed a significantly higher frequency of total infections in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups (5.0 and 5.0 vs 1.8 and 2.6 per 1000-person days; P < .01) within 1 year of allo-HCT. The cumulative incidence of cytomegalovirus reactivation/infection at 1 year post-allo-HCT was higher in the haplo-PTCy group (51%) compared with the MUD-PTCy (26%), Tac/MTX (26%), or Tac/Sir (13%) groups (P < .001). The incidence of BK, human herpesvirus 6, and other viruses were also higher in the PTCy-based groups. Overall, the treatment groups had similar 2 year NRM (P = .27) and OS (P = .78) outcomes. Our data show that PTCy-based GVHD prophylaxis is associated with delayed CD4 T cell but faster B cell immune reconstitution and a higher frequency of infections compared with conventional GVHD prophylaxis but has no impact on nonrelapse mortality or overall survival.
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http://dx.doi.org/10.1016/j.jtct.2021.07.023DOI Listing
November 2021

Impact of Total Body Irradiation-Based Myeloablative Conditioning Regimens in Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: Systematic Review and Meta-Analysis.

Transplant Cell Ther 2021 07 30;27(7):620.e1-620.e9. Epub 2021 Mar 30.

Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for patients with acute lymphoblastic leukemia (ALL). Both total body irradiation (TBI)-based and chemotherapy only-based myeloablative transplantation conditioning regimens have been applied, but the optimal regimen remains unclear. We performed a systematic review to assess the efficacy of TBI-based versus chemotherapy only-based myeloablative conditioning regimens. We searched PubMed, Embase, and Cochrane databases and meeting abstracts for all studies comparing TBI-based and chemotherapy only-based conditioning regimens in patients who underwent allo-HCT for ALL. Two authors independently reviewed all studies for inclusion and extracted data related to overall survival (OS), progression-free survival (PFS), nonrelapse mortality (NRM), relapse, and acute and chronic graft-versus-host disease (GVHD). Eight studies were included in the final analysis. The overall methodological quality of the included studies was optimal. TBI-based regimens showed evidence of benefit compared with chemotherapy only-based conditioning regimens in terms of relapse (relative risk [RR], 0.82; 95% confidence interval [CI], 0.72 to 0.94; 6 studies, 5091 patients), OS (hazard ratio [HR], 0.76; 95% CI, 0.64 to 0.89; 7 studies, 4727 patients), and PFS (HR, 0.74; 95% CI, 0.63 to 0.85; 7 studies, 4727 patients). The TBI-based regimen did not increase the likelihood of grade II-IV acute GVHD (RR, 1.12; 95% CI, 0.92 to 1.36; 5 studies, 4996 patients) or chronic GVHD (RR, 1.10; 95% CI, 1.00 to 1.21; 5 studies, 4490 patients), or NRM (RR, 0.94; 95% CI, 0.69 to 1.28; 6 studies, 4522 patients). However, TBI-based regimens were associated with an increased risk of grade III-IV acute GVHD (RR, 1.29; 95% CI, 1.01 to 1.63; 3 studies, 3675 patients). A subgroup comparison of patients age ≥16 years showed similar results. This systematic review represents evidence supporting the use of TBI-based conditioning regimen in patients undergoing allo-HCT for ALL who are candidates for myeloablative conditioning, as it offers better OS, PFS, and less relapse with acceptable NRM.
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http://dx.doi.org/10.1016/j.jtct.2021.03.026DOI Listing
July 2021

A phase 2 trial of GVHD prophylaxis with PTCy, sirolimus, and MMF after peripheral blood haploidentical transplantation.

Blood Adv 2021 03;5(5):1154-1163

Blood and Marrow Transplant and Cellular Immunotherapy, and.

The introduction of posttransplant cyclophosphamide (PTCy) made performing allogeneic hematopoietic cell transplantation (HCT) from HLA haplotype-incompatible donors possible. In a setting of PTCy and tacrolimus/mycophenolate mofetil (MMF) as a graft-versus-host disease (GVHD) prophylaxis, a peripheral blood (PB) graft source as compared with bone marrow reduces the relapse rate but increases acute GVHD (aGVHD) and chronic GVHD (cGVHD). This phase 2 trial assessed sirolimus and MMF efficacy following PTCy as a GVHD prophylaxis after PB haploidentical HCT (haplo-HCT). With 32 evaluable patients (≥18 years) enrolled, this study had 90% power to demonstrate a reduction in 100-day grade II-IV aGVHD to 20% from the historical benchmark of 40% after haplo-HCT using PTCy/tacrolimus/MMF. At a median follow-up of 16.1 months, the primary end point of the trial was met with a day-100 grade II-IV aGVHD cumulative incidence of 18.8% (95% confidence interval [CI], 7.5% to 34.0%). There were no graft-failure events and the 1-year probability of National Institutes of Health (NIH) moderate/severe cGVHD was 18.8% (95% CI, 7.4% to 34.0%), nonrelapse mortality was 18.8% (95% CI, 7.4% to 34.0%), relapse was 22.2% (95% CI, 9.6% to 38.2%), disease-free survival was 59.0% (95% CI, 44.1% to 79.0%), GVHD-free relapse-free survival was 49.6% (95% CI, 34.9% to 70.5%), and overall survival was 71.7% (95% CI, 57.7% to 89.2%) for the entire cohort. These data demonstrate that GVHD prophylaxis with sirolimus/MMF following PTCy effectively prevents grade II-IV aGVHD after PB haplo-HCT, warranting prospective comparison of sirolimus vs tacrolimus in combination with MMF following PTCy as GVHD prophylaxis after PB HCT. This trial was registered at www.clinicaltrials.gov as #NCT03018223.
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http://dx.doi.org/10.1182/bloodadvances.2020003779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948297PMC
March 2021

A phase 1b study of once-weekly carfilzomib combined with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma.

Am J Hematol 2021 02 15;96(2):226-233. Epub 2020 Dec 15.

John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, New Jersey, USA.

Twice-weekly carfilzomib with lenalidomide-dexamethasone (Rd) is an effective regimen for newly diagnosed multiple myeloma (NDMM). Here we evaluated once-weekly carfilzomib with Rd (once-weekly KRd) in NDMM patients. The NDMM patients were enrolled regardless of transplant eligibility. Patients received carfilzomib on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on carfilzomib days (also day 22 for cycles 1-8) for ≤18, 28-day cycles. Enrollment initiated in a carfilzomib 20/70 mg/m (20 mg/m on cycle one, day 1; 70 mg/m thereafter) NDMM dose-expansion arm, which was suspended because of serious adverse events. After evaluation of dose-limiting toxicities in a two-step-up dose-evaluation cohort, an NDMM dose-expansion arm (carfilzomib 20/56 mg/m ) was opened. Fifty-one NDMM patients were enrolled in dose-finding and dose-expansion cohorts. Results are presented for the carfilzomib 56 mg/m NDMM dose-expansion arm (n = 33). The grade ≥ 3 treatment-emergent AE (TEAE) rate was 63.6%. Twenty-five patients underwent stem cell collection; 18 proceeded to auto stem cell transplant, and five resumed KRd on study after autoSCT. The overall response rate (ORR) based on best overall response by cycle four was 97.0% (≥very good partial response [VGPR], 69.7%) in the NDMM 20/56 mg/m cohort. In patients who did not receive autoSCT (n = 15), the median number of cycles was 16.0; ORR was 93.3% (≥VGPR, 80.0%). At a median follow-up of 8.1 months, median progression-free survival was not reached. Once-weekly KRd (carfilzomib 56 mg/m ) had a favorable safety profile and promising activity in NDMM, supporting the use of this regimen in this setting.
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http://dx.doi.org/10.1002/ajh.26041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898514PMC
February 2021

Weekly carfilzomib, lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: A phase 1b study.

Am J Hematol 2019 07 13;94(7):794-802. Epub 2019 May 13.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, New York.

Twice-weekly carfilzomib (27 mg/m ) with lenalidomide-dexamethasone (KRd) is a standard-of-care in relapsed or refractory multiple myeloma (RRMM). This phase 1b study evaluated KRd with once-weekly carfilzomib in RRMM. Patients received carfilzomib (30-minute infusion; 56 or 70mg/m ) on days 1, 8, and 15; lenalidomide 25 mg on days 1-21; and dexamethasone 40 mg on days 1, 8, 15, and 22 (day 22 omitted for cycles 9+) of 28-day cycles. Primary objective was safety/tolerability; efficacy was a secondary objective. Fifty-six RRMM patients enrolled: 22 during dose evaluation (56-mg/m , n = 10; 70-mg/m , n = 12) and 34 during dose expansion (all initiated dosing at 70 mg/m ). After 2 fatal adverse events (AEs) during 70-mg/m dose expansion, dosage reduction to 56 mg/m was permitted. Results are presented for carfilzomib 56-mg/m (n = 10) and 70-mg/m groups (dose evaluation/expansion; n = 46). Median carfilzomib dose was 53.2 mg/m (56-mg/m group) and 62.4 mg/m (70-mg/m group). Grade ≥3 AE rates were 70.0% (56 mg/m ) and 69.6% (70 mg/m ). Overall response rates were 90.0% (56 mg/m ) and 89.1% (70 mg/m ); ≥very good partial response rates were 50.0% (56 mg/m ) and 73.9% (70 mg/m ). Once-weekly KRd was active with acceptable toxicity in RRMM, supporting further evaluation of this regimen.
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http://dx.doi.org/10.1002/ajh.25498DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6593978PMC
July 2019

Lenalidomide-based response-adapted therapy for older adults without high risk myeloma.

Br J Haematol 2019 03 12;184(5):735-743. Epub 2018 Dec 12.

Department of Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Combined lenalidomide and dexamethasone is a standard-of-care therapy for the treatment of older adults with multiple myeloma. Lenalidomide monotherapy has not been evaluated in newly diagnosed myeloma patients. We conducted a phase II study, evaluating a response-adapted therapy for older adults newly diagnosed with multiple myeloma without high-risk features who were ineligible for high-dose therapy and stem cell transplant. Patients were started on single-agent lenalidomide, and low-dose dexamethasone was added in the event of progressive disease, in a response-adapted approach. The primary endpoint was progression-free survival (PFS), and the International Myeloma Working Group's uniform response criteria were used to assess response and progression. Twenty-seven patients were enrolled, and 20 (74%) experienced a partial response or better to this response-adapted therapy. After a median follow-up of 69 months, the median PFS was 36 months [95% confidence interval (CI), 29·8 to not reached], and the median overall survival was 65 months (95% CI, 35·3 to not reached). Grade 3/4 adverse events were mainly haematological in nature. This response-adapted therapy in this patient population is feasible and results in durable responses that compare favourably with concurrent lenalidomide and dexamethasone. These results should be validated in prospective studies.
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http://dx.doi.org/10.1111/bjh.15700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771320PMC
March 2019

Case Report of IgM Multiple Myeloma: Diagnosing a Rare Hematologic Entity.

Cancer Control 2018 Jan-Mar;25(1):1073274817744448

3 Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center, Tampa, FL, USA.

IgM multiple myeloma is an exceedingly rare hematologic entity comprising only less than 0.5% of multiple myeloma cases. Given the rarity of this disorder, it makes it a challenge to differentiate from other more prevalent hematologic disorders like Waldenstrom macroglobulinemia. These 2 diseases have the common finding of an IgM monoclonal gammopathy and distinguishing between these 2 diagnoses is of great importance given that therapy and prognosis differ significantly. This report illustrates the case of a 64-year-old man who presented with IgM lambda monoclonal gammopathy in whom signs, symptoms, laboratories, and imaging were initially thought to be consistent with Waldenstrom macroglobulinemia. Upon further analysis, which included bone marrow biopsy, flow cytometry, immunohistochemistry, fluorescence in situ hybridization, and MYD88 (L265P) gene mutation analysis, the rare diagnosis of IgM multiple myeloma was confirmed. As highlighted by this patient's case, reaching the diagnosis of IgM multiple myeloma can be a difficult task which requires a high index of suspicion and accurate diagnostic methods. By using the approach detailed in this report, more cases of IgM multiple myeloma can be diagnosed early, which in turn may lead to earlier treatment and better outcomes.
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http://dx.doi.org/10.1177/1073274817744448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811765PMC
August 2018

NCCN Guidelines Insights: Multiple Myeloma, Version 3.2018.

J Natl Compr Canc Netw 2018 01;16(1):11-20

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, evaluation, treatment, including supportive-care, and follow-up for patients with myeloma. These NCCN Guidelines Insights highlight the important updates/changes specific to the myeloma therapy options in the 2018 version of the NCCN Guidelines.
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http://dx.doi.org/10.6004/jnccn.2018.0002DOI Listing
January 2018

Recurrent cardiotoxicity potentiated by the interaction of proteasome inhibitor and immunomodulatory therapy for the treatment of multiple myeloma.

Br J Haematol 2018 01 19;180(2):271-275. Epub 2017 Oct 19.

Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.

Patients with multiple myeloma (MM) have improved treatment options, including immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). Despite their efficacy, increased rates of cardiovascular (CV) complications occur in patients exposed to some of these therapies. While previous research has focused on identifying the toxicities inherent to each specific agent, the CV side effects may be potentiated by the combination of PIs and IMiDs plus dexamethasone. We present a patient with MM with recurrent cardiotoxicity only when exposed to combination PI and IMiD-based therapy. We also review the literature in this context, and propose a potential algorithm for cardiotoxicity prevention in this population.
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http://dx.doi.org/10.1111/bjh.14970DOI Listing
January 2018

Hypoalbuminemia at Day +90 Is Associated with Inferior Nonrelapse Mortality and Overall Survival in Allogeneic Hematopoietic Cell Transplantation Recipients: A Confirmatory Study.

Biol Blood Marrow Transplant 2018 02 13;24(2):400-405. Epub 2017 Oct 13.

Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida; Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, Florida. Electronic address:

Prognostic biomarkers in allogeneic hematopoietic cell transplantation (allo-HCT) are needed to improve risk assessment and help guide therapeutic and surveillance strategies to mitigate the risk of death from the procedure. We previously identified hypoalbuminemia at day +90 post-transplantation as an independent predictor of increased nonrelapse mortality (NRM) and inferior overall survival (OS) in patients with acute myelogenous leukemia and myelodysplastic syndrome who were treated with an allo-HCT. Here, we aim to confirm the prognostic significance of day +90 hypoalbuminemia in 783 patients, median age 52 years (range, 18 to 76), who received an allo-HCT for various hematologic malignancies and bone marrow failure syndromes. Multivariate analysis for NRM demonstrated a negative effect of low serum albumin levels (<3.0 versus 3.0 to 3.5 versus >3.5 g/dL) at day +90 post-transplantation (hazard ratios, 8.03 [95% CI, 3.59 to 17.97] versus 2.84 [95% CI, 1.59 to 5.08] versus reference; P < .0001). This was also the case for OS (hazard ratios, 6.86 [95% CI, 4.24 to 11.10] versus 1.52 [95% CI, 1.05 to 2.20] versus reference; P < .0001). Patients with hypoalbuminemia at day +90 post-transplantation are more likely to die from causes other than relapse, particularly infections. This large study confirms the ability of day +90 serum hypoalbuminemia to predict worse NRM and inferior OS. Presence of hypoalbuminemia at day +90 should drive a more rigorous real-time surveillance strategy considering the anticipated high-risk of NRM and poor survival in these patients. Future studies should consider incorporating day +90 serum albumin levels in prognostic models of NRM and OS.
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http://dx.doi.org/10.1016/j.bbmt.2017.09.022DOI Listing
February 2018

Multiple Myeloma, Version 3.2017, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2017 02;15(2):230-269

Multiple myeloma (MM) is caused by the neoplastic proliferation of plasma cells. These neoplastic plasma cells proliferate and produce monoclonal immunoglobulin in the bone marrow causing skeletal damage, a hallmark of multiple myeloma. Other MM-related complications include hypercalcemia, renal insufficiency, anemia, and infections. The NCCN Multiple Myeloma Panel members have developed guidelines for the management of patients with various plasma cell dyscrasias, including solitary plasmacytoma, smoldering myeloma, multiple myeloma, systemic light chain amyloidosis, and Waldenström's macroglobulinemia. The recommendations specific to the diagnosis and treatment of patients with newly diagnosed MM are discussed in this article.
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http://dx.doi.org/10.6004/jnccn.2017.0023DOI Listing
February 2017

IL-2 promotes early Treg reconstitution after allogeneic hematopoietic cell transplantation.

Haematologica 2017 05 19;102(5):948-957. Epub 2017 Jan 19.

Department of Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, FL, USA.

Graft--host disease (GvHD) remains a major cause of transplant-related mortality. Interleukin-2 (IL-2) plus sirolimus (SIR) synergistically reduces acute GvHD in rodents and promotes regulatory T cells. This phase II trial tested the hypothesis that IL-2 would facilitate STAT5 phosphorylation in donor T cells, expand regulatory T cells, and ameliorate GvHD. Between 16 April 2014 and 19 December 2015, 20 patients received IL-2 (200,000 IU/m thrice weekly, days 0 to +90) with SIR (5-14 ng/mL) and tacrolimus (TAC) (3-7 ng/mL) after HLA-matched related or unrelated allogeneic hematopoietic cell transplantation (HCT). The study was designed to capture an increase in regulatory T cells from 16.0% to more than 23.2% at day +30. IL-2/SIR/TAC significantly increased regulatory T cells at day +30 compared to our published data with SIR/TAC (23.8% 16.0%, =0.0016; 0.052 k/uL 0.037 k/uL, =0.0163), achieving the primary study end point. However, adding IL-2 to SIR/TAC led to a fall in regulatory T cells by day +90 and did not reduce acute or chronic GvHD. Patients who discontinued IL-2 before day +100 showed a suggested trend toward less grade II-IV acute GvHD (16.7% 50%, =0.1475). We surmise that the reported accumulation of IL-2 receptors in circulation over time may neutralize IL-2, lead to progressive loss of regulatory T cells, and offset its clinical efficacy. The amount of phospho-STAT3 CD4 T cells correlated with donor T-cell activation and acute GvHD incidence despite early T-cell STAT5 phosphorylation by IL-2. Optimizing IL-2 dosing and overcoming cytokine sequestration by soluble IL-2 receptor may sustain lasting regulatory T cells after transplantation. However, an approach to target STAT3 is needed to enhance GvHD prevention. ().
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http://dx.doi.org/10.3324/haematol.2016.153072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477614PMC
May 2017

Deacetylase inhibitors: an advance in myeloma therapy?

Expert Rev Hematol 2017 Mar 1;10(3):229-237. Epub 2017 Feb 1.

a Department of Hematologic Malignancies , Dana-Farber Cancer Institute , Boston , MA , USA.

Introduction: A significant unmet need exists in patients with relapsed or refractory multiple myeloma (MM), which remains an incurable disease despite recent advances in the field. One such development was the use of deacetylase inhibitors (DACi), which exert unique antimyeloma effects through targeting of epigenetic and protein metabolism pathways. The pan-DACi panobinostat was recently approved in combination with bortezomib and dexamethasone for use in patients with relapsed or relapsed and refractory MM. Results of a phase 3 trial showed that the panobinostat-containing regimen improved the overall response rate and progression-free survival. Panobinostat-associated adverse events included thrombocytopenia, diarrhea, fatigue, and peripheral neuropathy. Research into how to maintain the benefits of DACi while improving tolerability is ongoing. Areas covered: This review focuses on the efficacy and safety of panobinostat and panobinostat-based combinations for MM. Early data from clinical trials investigating the HDAC6 inhibitor ricolinostat are also discussed. Expert commentary: DACi are a unique and effective new class of agents for the treatment of MM, with panobinostat being the first to have clinically meaningful benefit for patients with relapsed or refractory MM. Optimization of dose and schedule, novel combination strategies, and introduction of selective DACi may improve the risk-benefit profile of DACi-based regimens.
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http://dx.doi.org/10.1080/17474086.2017.1280388DOI Listing
March 2017

Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study.

Lancet Oncol 2017 01 4;18(1):112-121. Epub 2016 Dec 4.

Department of Malignant Hematology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address:

Background: Clonal haemopoiesis of indeterminate potential (CHIP) is an age-associated genetic event linked to increased risk of primary haematological malignancies and increased all-cause mortality, but the prevalence of CHIP in patients who develop therapy-related myeloid neoplasms is unknown. We did this study to investigate whether chemotherapy-treated patients with cancer who have CHIP are at increased risk of developing therapy-related myeloid neoplasms.

Methods: We did a nested, case-control, proof-of-concept study to compare the prevalence of CHIP between patients with cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not develop these neoplasms (controls). We identified cases from our internal biorepository of 123 357 patients who consented to participate in the Total Cancer Care biobanking protocol at Moffitt Cancer Center (Tampa, FL, USA) between Jan 1, 2006, and June 1, 2016. We included all individuals who were diagnosed with a primary malignancy, were treated with chemotherapy, subsequently developed a therapy-related myeloid neoplasm, and were 70 years or older at either diagnosis. For inclusion in this study, individuals must have had a peripheral blood or mononuclear cell sample collected before the diagnosis of therapy-related myeloid neoplasm. Controls were individuals who were diagnosed with a primary malignancy at age 70 years or older and were treated with chemotherapy but did not develop therapy-related myeloid neoplasms. Controls were matched to cases in at least a 4:1 ratio on the basis of sex, primary tumour type, age at diagnosis, smoking status, chemotherapy drug class, and duration of follow-up. We used sequential targeted and whole-exome sequencing and described clonal evolution in cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available. The primary endpoint of this study was the development of therapy-related myeloid neoplasm and the primary exposure was CHIP.

Findings: We identified 13 cases and 56 case-matched controls. The prevalence of CHIP in all patients (23 [33%] of 69 patients) was higher than has previously been reported in elderly individuals without cancer (about 10%). Cases had a significantly higher prevalence of CHIP than did matched controls (eight [62%] of 13 cases vs 15 [27%] of 56 controls, p=0·024; odds ratio 5·75, 95% CI 1·52-25·09, p=0·013). The most commonly mutated genes in cases with CHIP were TET2 (three [38%] of eight patients) and TP53(three [38%] of eight patients), whereas controls most often had TET2 mutations (six [40%] of 15 patients). In most (four [67%] of six patients) cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available, the mean allele frequency of CHIP mutations had expanded by the time of the therapy-related myeloid neoplasm diagnosis. However, a subset of paired samples (two [33%] of six patients) had CHIP mutations that decreased in allele frequency, giving way to expansion of a distinct mutant clone.

Interpretation: Patients with cancer who have CHIP are at increased risk of developing therapy-related myeloid neoplasms. The distribution of CHIP-related gene mutations differs between individuals with therapy-related myeloid neoplasm and those without, suggesting that mutation-specific differences might exist in therapy-related myeloid neoplasm risk.

Funding: Moffitt Cancer Center.
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http://dx.doi.org/10.1016/S1470-2045(16)30627-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771361PMC
January 2017

Subsequent primary malignancies among multiple myeloma patients treated with or without lenalidomide.

Leuk Lymphoma 2017 03 18;58(3):560-568. Epub 2016 Jul 18.

b Department of Malignant Hematology , Moffitt Cancer Center , Tampa , FL , USA.

Risk of subsequent primary malignancies (SPMs) associated with lenalidomide therapy in multiple myeloma (MM) patients, outside the context of melphalan-based therapy is not established. We assessed the risk of SPMs in lenalidomide treated MM patients (n = 1653) at Moffitt Cancer Center (2004-2012) outside the context of melphalan-based induction therapy and post-melphalan maintenance therapy, via (1) cohort analysis and (2) nested case-control study. Incident SPMs (n = 51) were matched to controls (n = 102) on age at MM diagnosis, gender, follow-up time, and date of diagnosis. Incidence of SPM differed significantly (p = 0.0038) between MM patients treated with and without lenalidomide (5-year incidence estimates of 3.2 and 6.2%, respectively), although not significant after adjustment for age and year of diagnosis (HR = 0.82, 95%CI = 0.43-1.57). Lenalidomide treatment was inversely associated with SPM in the nested case-control analysis (OR = 0.03, 95%CI = 0.002-0.34). In this large cohort of MM patients, lenalidomide treatment was not associated with an increased risk of SPM.
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http://dx.doi.org/10.1080/10428194.2016.1207763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771364PMC
March 2017

NCCN Guidelines Insights: Multiple Myeloma, Version 3.2016.

J Natl Compr Canc Netw 2016 04;14(4):389-400

National Comprehensive Cancer Network

These NCCN Guidelines Insights highlight the important updates/changes specific to the 2016 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include updated recommendations to the overall management of multiple myeloma from diagnosis and staging to new treatment options.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016087PMC
http://dx.doi.org/10.6004/jnccn.2016.0046DOI Listing
April 2016

Randomized multicenter phase 2 study of pomalidomide, cyclophosphamide, and dexamethasone in relapsed refractory myeloma.

Blood 2016 05 1;127(21):2561-8. Epub 2016 Mar 1.

Multiple Myeloma Program, Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY; and.

Pomalidomide and low-dose dexamethasone (PomDex) is standard treatment of lenalidomide refractory myeloma patients who have received >2 prior therapies. We aimed to assess the safety and efficacy of the addition of oral weekly cyclophosphamide to standard PomDex. We first performed a dose escalation phase 1 study to determine the recommended phase 2 dose of cyclophosphamide in combination with PomDex (arm A). A randomized, multicenter phase 2 study followed, enrolling patients with lenalidomide refractory myeloma. Patients were randomized (1:1) to receive pomalidomide 4 mg on days 1 to 21 of a 28-day cycle in combination with weekly dexamethasone (arm B) or pomalidomide, dexamethasone, and cyclophosphamide (PomCyDex) 400 mg orally on days 1, 8, and 15 (arm C). The primary end point was overall response rate (ORR). Eighty patients were enrolled (10 in phase 1 and 70 randomized in phase 2: 36 to arm B and 34 to arm C). The ORR was 38.9% (95% confidence interval [CI], 23-54.8%) and 64.7% (95% CI, 48.6-80.8%) for arms B and C, respectively (P = .035). As of June 2015, 62 of the 70 randomized patients had progressed. The median progression-free survival (PFS) was 4.4 (95% CI, 2.3-5.7) and 9.5 months (95% CI, 4.6-14) for arms B and C, respectively (P = .106). Toxicity was predominantly hematologic in nature but was not statistically higher in arm C. The combination of PomCyDex results in a superior ORR and PFS compared with PomDex in patients with lenalidomide refractory multiple myeloma. The trial was registered at www.clinicaltrials.gov as #NCT01432600.
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http://dx.doi.org/10.1182/blood-2015-11-682518DOI Listing
May 2016

Multiple Myeloma, Version 2.2016: Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw 2015 Nov;13(11):1398-435

Multiple myeloma (MM) is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. Recent statistics from the American Cancer Society indicate that the incidence of MM is increasing. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) included in this issue address management of patients with solitary plasmacytoma and newly diagnosed MM.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891187PMC
http://dx.doi.org/10.6004/jnccn.2015.0167DOI Listing
November 2015

Primary plasmacytoma involving mediastinal lymph nodes: A diagnostic mimicry of primary mediastinal lymphoma.

Hematol Oncol Stem Cell Ther 2016 Mar 8;9(1):26-9. Epub 2015 Jul 8.

Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Department of Oncologic Sciences, University of South Florida College of Medicine, Tampa, FL, USA.

Plasmacytomas could involve any organ, and at times might pose a diagnostic challenge when the site of involvement is unusual, or if the presentation is similar to other diseases. We describe a 48-year-old man presenting with worsening shortness of breath and chest discomfort with radiologic evidence of mediastinal enlargement, mimicking a lymphoma with mediastinal involvement. An excisional biopsy of a mediastinal lymph node showed a plasma-cell infiltrate strongly positive for CD138, with a flow-cytometry analysis showing a population of lambda-restricted neoplastic plasma cells. He failed to respond to 50Gy involved-field radiotherapy, but achieved a partial response to combination chemotherapy. He underwent high-dose chemotherapy with melphalan (200mg/m(2)) followed by lenalidomide maintenance, and is in complete remission 18months postautografting. This case illustrates a unique and rare presentation of primary lymph-node plasmacytomas involving the mediastinum potentially mistaken as lymphoid malignancy. Clinicians should be aware of the plasma-cell origin of the mediastinal neoplastic process.
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http://dx.doi.org/10.1016/j.hemonc.2015.06.007DOI Listing
March 2016

A comparison of salvage infusional chemotherapy regimens for recurrent/refractory multiple myeloma.

Cancer 2015 Oct 6;121(20):3622-30. Epub 2015 Jul 6.

Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Background: Despite the impact of proteasome inhibitors and immunomodulatory agents, infusional chemotherapy regimens continue to be used for patients with multiple myeloma. To the authors' knowledge, contemporary data regarding salvage chemotherapy regimens are sparse, with no direct comparisons.

Methods: The authors performed a single-institution study comparing 3 salvage chemotherapy regimens in 107 patients with recurrent/refractory multiple myeloma: dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) in 52 patients; bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide (VTD-PACE) in 22 patients; and cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) in 33 patients.

Results: Differences between treatment groups existed, including higher baseline creatinine for patients treated with CVAD (P<.001) and greater prior use of infusional chemotherapy for those receiving VTD-PACE (P<.001). There was no significant difference in response noted among the 3 regimens: 55% overall (P = .18). For the intent-to-transplant population, a similar percentage were successfully bridged to transplant without further therapy (62%; P = .9). There was no difference in survival observed across the 3 regimens, with an overall median progression-free survival of 4.5 months (95% confidence interval, 3.6-5.5 months [P = .8]) and a median overall survival of 8.5 months (95% confidence interval, 6.1-11 months [P = .8]). Furthermore, there was no statistically significant difference noted among clinically relevant adverse events, although there was a suggestion of fewer adverse events with DCEP. Patients treated with the intent to transplant had superior outcomes for response (odds ratio, 3.40; P = .01), progression-free survival (hazard ratio, 0.28; P<.001), and overall survival (hazard ratio, 0.19; P<.001).

Conclusions: The 3 salvage regimens demonstrated similar responses, survival, and adverse events. Given the short response durations observed in the recurrent/refractory disease setting, infusional chemotherapy is best suited for cytoreduction before more definitive therapy is administered.
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http://dx.doi.org/10.1002/cncr.29533DOI Listing
October 2015

Panobinostat: a novel pan-deacetylase inhibitor for the treatment of relapsed or relapsed and refractory multiple myeloma.

Expert Rev Anticancer Ther 2015 7;15(7):737-48. Epub 2015 Jun 7.

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

Outcomes for patients with multiple myeloma (MM) have improved significantly over the past decade. Despite these advances, MM remains incurable and an unmet medical need remains for patients who are relapsed and/or refractory. Panobinostat is a potent, oral pan-deacetylase inhibitor that elicits anti-myeloma activity through epigenetic modulation of gene expression and disruption of protein metabolism. Preclinical data demonstrated that panobinostat has synergistic effects on myeloma cells when combined with bortezomib and dexamethasone. In a Phase III clinical trial evaluating bortezomib and dexamethasone in combination with panobinostat or placebo in patients with relapsed or relapsed and refractory MM (PANORAMA 1), panobinostat led to a significant increase in median progression-free survival. Panobinostat is currently under regulatory review with a recent accelerated approval granted for the treatment of relapsed disease, in which both bortezomib and immunomodulatory drugs have failed. Here, we summarize the preclinical, pharmacokinetic and clinical data for panobinostat in MM.
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http://dx.doi.org/10.1586/14737140.2015.1047770DOI Listing
April 2016

Prolonged sirolimus administration after allogeneic hematopoietic cell transplantation is associated with decreased risk for moderate-severe chronic graft-versus-host disease.

Haematologica 2015 Jul 3;100(7):970-7. Epub 2015 Apr 3.

Blood and Marrow Transplantation, Moffitt Cancer Center, USA Oncologic Sciences, College of Medicine at University of South Florida, USA.

Effective pharmacological strategies employed in allogeneic hematopoietic cell transplantation should prevent serious chronic graft-versus-host disease and facilitate donor-recipient immune tolerance. Based on demonstrated pro-tolerogenic activity, sirolimus (rapamycin) is an agent with promise to achieve these goals. In a long-term follow-up analysis of a randomized phase II trial comparing sirolimus/tacrolimus versus methotrexate/tacrolimus for graft-versus-host disease prevention in matched sibling or unrelated donor transplant, we examined the impact of prolonged sirolimus administration (≥ 1 year post-transplant). Median follow-up time for surviving patients at time of this analysis was 41 months (range 27-60) for sirolimus/tacrolimus and 49 months (range 29-63) for methotrexate/tacrolimus. Sirolimus/tacrolimus patients had significantly lower National Institutes of Health Consensus moderate-severe chronic graft-versus-host disease (34% vs. 65%; P=0.004) and late acute graft-versus-host disease (20% vs. 43%; P=0.04). While sirolimus/tacrolimus patients had lower prednisone exposure and earlier discontinuation of tacrolimus (median time to tacrolimus discontinuation 368 days vs. 821 days; P=0.002), there was no significant difference in complete immune suppression discontinuation (60-month estimate: 43% vs. 31%; P=0.78). Prolonged sirolimus administration represents a viable approach to mitigate risk for moderate-severe chronic and late acute graft-versus-host disease. Further study of determinants of successful immune suppression discontinuation is needed.
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http://dx.doi.org/10.3324/haematol.2015.123588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4486232PMC
July 2015

Ofatumumab in combination with glucocorticoids for primary therapy of chronic graft-versus-host disease: phase I trial results.

Biol Blood Marrow Transplant 2015 Jun 21;21(6):1074-82. Epub 2015 Mar 21.

Blood and Marrow Transplantation, Moffitt Cancer Center, Tampa, Florida; Oncologic Sciences, College of Medicine at University of South Florida, Tampa, Florida.

Standard primary therapy for chronic graft-versus-host disease (GVHD) is incompletely effective. Based on biologic insights implicating pathogenic B cells, we conducted a phase I trial examining the combination of standard (1 mg/kg/day prednisone) glucocorticoid therapy with ofatumumab, a humanized anti-CD20 monoclonal antibody, for primary chronic GVHD therapy. Patients ages ≥ 18 with National Institutes of Health Consensus moderate-to-severe chronic GVHD newly requiring 1 mg/kg/day prednisone were treated at 3 escalating dose levels (300 mg, 700 mg, and 1000 mg) of i.v. ofatumumab on days 1 and 14 of initial glucocorticoid therapy. Dose-limiting toxicity (DLT) was defined by grade 4 infusion reactions, related grade 4 constitutional symptoms, related grade ≥ 3 organ toxicities, or grade 4 neutropenia lasting > 14 days. A total of 12 patients (median age 54; range, 25 to 72) were treated (dose level 1: n = 3; level 2: n = 3; level 3: n = 6). At enrollment, overall chronic GVHD was moderate (n = 7) or severe (n = 5), with diverse organ involvement (skin: n = 8; mouth: n = 8; eye: n = 8; lung: n = 4; gastrointestinal: n = 3; liver: n = 5; genital: n = 2; joint/fascia: n = 5). Infusion of ofatumumab was well tolerated, and no DLT was observed. From the total number of adverse events (n = 29), possibly related adverse events (n = 4) included grade 1 fatigue, grade 1 transaminitis, and 2 infusion reactions (grades 2 and 3). Infectious complications were expected, and there were no cases of hepatitis B reactivation or progressive multifocal leukoencephalopathy. Ofatumumab in combination with prednisone is safe and a phase II examination of efficacy is ongoing.
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http://dx.doi.org/10.1016/j.bbmt.2015.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5757506PMC
June 2015

An open-label phase I/II study of cyclophosphamide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed myeloma.

Eur J Haematol 2015 Nov 12;95(5):426-35. Epub 2015 Mar 12.

Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

We conducted a phase 1/2 trial evaluating the combination of cyclophosphamide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (CVDD) for newly diagnosed multiple myeloma (MM). The primary objective of the phase 1 was to evaluate the safety and tolerability of maximum planned dose (MPD) and the phase 2 was to assess the overall response rate. Patients received 6-8 cycles of CVDD at four dose levels. There were no dose-limiting toxicities. The MPD was cyclophosphamide 750 mg/m(2) IV on day 1, bortezomib 1.3 mg/m(2) IV on days 1, 4, 8, 11, pegylated liposomal doxorubicin 30 mg/m(2) IV on day 4, and dexamethasone 20 mg orally on the day of and after bortezomib (21-d cycle). Forty-nine patients were treated at the MPD of which 22% had high-risk myeloma. The most common grade ≥3 toxicities included myelosuppression, infection, and fatigue. Overall response and complete response rates were 91% and 26% in standard-risk, and 100% and 58% in high-risk cohort, respectively. After a median follow-up of 34 months, the median progression-free survival was 31.3 months. The 2-yr overall survival was 91.1% in the standard-risk and 88.9% in the high-risk cohort, respectively. CVDD regimen was well tolerated and was highly active in newly diagnosed MM.
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http://dx.doi.org/10.1111/ejh.12509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508238PMC
November 2015

Lenalidomide maintenance for high-risk multiple myeloma after allogeneic hematopoietic cell transplantation.

Biol Blood Marrow Transplant 2014 Aug 21;20(8):1183-9. Epub 2014 Apr 21.

Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, Wisconsin.

Allogeneic hematopoietic cell transplantation (alloHCT) with reduced-intensity conditioning is an appealing option for patients with high-risk multiple myeloma (MM). However, progression after alloHCT remains a challenge. Maintenance therapy after alloHCT may offer additional disease control and allow time for a graft-versus-myeloma effect. The primary objective of this clinical trial was to determine the tolerability and safety profile of maintenance lenalidomide (LEN) given on days 1 to 21 of 28 days cycles, with intrapatient dose escalation during 12 months/cycles after alloHCT. Thirty alloHCT recipients (median age, 54 years) with high-risk MM were enrolled at 8 centers between 2009 and 2012. The median time from alloHCT to LEN initiation was 96 days (range, 66 to 171 days). Eleven patients (37%) completed maintenance and 10 mg daily was the most commonly delivered dose (44%). Most common reasons for discontinuation were acute graft-versus-host disease (GVHD) (37%) and disease progression (37%). Cumulative incidence of grades III to IV acute GVHD from time of initiation of LEN was 17%. Outcomes at 18 months after initiation of maintenance were MM progression, 28%; transplantation-related mortality, 11%; and progression-free and overall survival, 63% and 78%, respectively. The use of LEN after alloHCT is feasible at lower doses, although it is associated with a 38% incidence of acute GVHD. Survival outcomes observed in this high-risk MM population warrant further study of this approach.
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http://dx.doi.org/10.1016/j.bbmt.2014.04.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5036168PMC
August 2014

A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/refractory myeloma.

Blood 2014 Mar 15;123(10):1461-9. Epub 2014 Jan 15.

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

In this prospective, multicenter, phase 2 study, 64 patients with relapsed or relapsed and refractory multiple myeloma (MM) received up to 8 21-day cycles of bortezomib 1.0 mg/m(2) (days 1, 4, 8, and 11), lenalidomide 15 mg/day (days 1-14), and dexamethasone 40/20 mg/day (cycles 1-4) and 20/10 mg/day (cycles 5-8) (days of/after bortezomib dosing). Responding patients could receive maintenance therapy. Median age was 65 years; 66% were male, 58% had relapsed and 42% had relapsed and refractory MM, and 53%, 75%, and 6% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Forty-eight of 64 patients (75%; 90% confidence interval, 65-84) were alive without progressive disease at 6 months (primary end point). The rate of partial response or better was 64%; median duration of response was 8.7 months. Median progression-free and overall survivals were 9.5 and 30 months, respectively (median follow-up: 44 months). Common treatment-related toxicities included sensory neuropathy (53%), fatigue (50%), and neutropenia (42%); common grade 3/4 treatment-related toxicities included neutropenia (30%), thrombocytopenia (22%), and lymphopenia (11%). Grade 3 motor neuropathy was reported in 2 patients. Lenalidomide-bortezomib-dexamethasone appears effective and tolerable in patients with relapsed or relapsed and refractory MM, demonstrating substantial activity among patients with diverse prior therapies and adverse prognostic characteristics. This trial is registered with www.clinicaltrials.gov as #NCT00378209.
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http://dx.doi.org/10.1182/blood-2013-07-517276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4123434PMC
March 2014

Phase II study of pegylated liposomal doxorubicin, low-dose dexamethasone, and lenalidomide in patients with newly diagnosed multiple myeloma.

Am J Hematol 2014 Jan;89(1):62-7

Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Our previous phase I/II trial of pegylated liposomal doxorubicin (PLD), low-dose dexamethasone, and lenalidomide in patients with relapsed and refractory myeloma showed an overall response rate of 75%, with 29% achieving ≥ VGPR. Here, we investigated this combination (PLD 30 or 40 mg/m(2) intravenously, day 1; dexamethasone 40 mg orally, days 1-4; lenalidomide 25 mg orally, days 1-21; administered every 28 days) in a phase II study in patients with newly diagnosed symptomatic multiple myeloma to determine its efficacy and tolerability (ClinicalTrials.gov NCT00617591). At best response, patients could proceed with high-dose melphalan or with maintenance lenalidomide and dexamethasone. In 57 patients, we found that the overall response rate and rate of very good partial response and better on intent-to-treat, our primary endpoints, were 77.2% and 42.1%, respectively, with responses per the International Myeloma Working Group. Median progression-free survival was 28 months (95% CI 18.1-34.8), with 1- and 2-year overall survival rates of 98.1 and 79.6%. During induction, grade 3/4 toxicities were neutropenia (49.1%), anemia (15.8%), thrombocytopenia (7%), fatigue (14%), febrile neutropenia (8.8%), and venous thromboembolic events (8.8%). During maintenance, grade 3/4 toxicities were mainly hematologic. We found this combination to be active in patients with newly diagnosed myeloma, with results comparable to other lenalidomide-based induction strategies without proteasome inhibition. In addition, maintenance therapy with lenalidomide was well tolerated.
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http://dx.doi.org/10.1002/ajh.23587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522918PMC
January 2014

Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma.

Blood 2013 Oct 6;122(18):3122-8. Epub 2013 Sep 6.

MD Anderson Cancer Center, Houston, TX;

We previously reported a phase 1b dose-escalation study of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) in relapsed or progressive multiple myeloma where the maximum planned dose (MPD) was carfilzomib 20 mg/m2 days 1 and 2 of cycle 1 and 27 mg/m2 days 8, 9, 15, 16, and thereafter; lenalidomide 25 mg days 1 to 21; and dexamethasone 40 mg once weekly on 28-day cycles. Herein, we present results from the phase 2 dose expansion at the MPD, focusing on the 52 patients enrolled in the MPD cohort. Median follow-up was 24.4 months. In the MPD cohort, overall response rate (ORR) was 76.9% with median time to response of 0.95 month (range, 0.5-4.6) and duration of response (DOR) of 22.1 months. Median progression-free survival was 15.4 months. ORR was 69.2% in bortezomib-refractory patients and 69.6% in lenalidomide-refractory patients with median DOR of 22.1 and 10.8 months, respectively. A median of 9.5 (range, 1-45) carfilzomib cycles were started with 7.7% of patients requiring carfilzomib dose reductions and 19.2% discontinuing CRd due to adverse events (AEs). Grade 3/4 AEs included lymphopenia (48.1%), neutropenia (32.7%), thrombocytopenia (19.2%), and anemia (19.2%). CRd at the MPD was well tolerated with robust, rapid, and durable responses.
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http://dx.doi.org/10.1182/blood-2013-07-511170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3814729PMC
October 2013
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