Publications by authors named "Luciano J Costa"

119 Publications

Real-World Applicability of Commercial Chimeric Antigen Receptor T Cell Therapy Among Older Adults with Relapsed and/or Refractory Multiple Myeloma.

Am J Hematol 2022 Jan 19. Epub 2022 Jan 19.

Division of Hematology and Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, United States.

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http://dx.doi.org/10.1002/ajh.26472DOI Listing
January 2022

Pre-treatment neutrophil to lymphocyte ratio as a biomarker of frailty and predictor of survival among older adults with multiple myeloma.

J Geriatr Oncol 2021 Dec 16. Epub 2021 Dec 16.

Institute for Cancer Outcomes & Survivorship, University of Alabama at Birmingham, Birmingham, AL, United States.

Introduction: Neutrophil to Lymphocyte Ratio (NLR) combines a marker of inflammation and reduced cell turnover to reflect age related alterations in the immune system. Whether NLR can serve as a biomarker of frailty and predict survival among older adults with Multiple Myeloma (MM) is unknown.

Materials And Methods: We used an electronic health record-derived database to identify older adults (age ≥ 60y) with incident MM diagnosed between 1/2011 and 2/2020, with known pre-treatment absolute neutrophil and lymphocyte count up to 90 days before the start of therapy. The calculated NLR values were stratified into quartiles (Q1-Q4). We constructed a previously validated, simplified frailty index combining age, comorbidity and ECOG performance status. We measured the association between NLR quartiles and this frailty index using a logistic regression, adjusted for age, sex and race/ethnicity. We used Kaplan Meier methods and multivariable Cox regression to assess the impact of NLR on overall survival adjusting for potential confounders.

Results: We identified 1729 older adults with newly diagnosed MM, at a median age of 73y (IQR: 67-78y). The median NLR was 2.13 (IQR: 1.44 to 3.31). Of the 1135 evaluable patients, 55% met criteria for frailty. Multivariable analysis revealed a 2.1-fold higher odds of frailty (95%CI = 1.42-3.10, p < 0.001) for patients in the NLR Q4 group vs. NLR Q1 group. In a multivariable analysis, adjusting for age, sex, race/ethnicity, M-protein type, stage, high risk cytogenetics, baseline creatinine, LDH and type of first line therapy, patients in NLR Q4 group had a 1.51 times increased hazards of death (95%CI = 1.15-1.98, p 0.002) when compared to those in NLR Q1 group.

Conclusion: NLR, a readily available laboratory biomarker, is associated with frailty measured using a simplified frailty index as well as inferior overall survival among older adults with MM. Future studies should explore its value as a screening tool to identify frail older adults with MM.
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http://dx.doi.org/10.1016/j.jgo.2021.12.004DOI Listing
December 2021

Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone With Minimal Residual Disease Response-Adapted Therapy in Newly Diagnosed Multiple Myeloma.

J Clin Oncol 2021 Dec 13:JCO2101935. Epub 2021 Dec 13.

University of Wisconsin, Madison, WI.

Purpose: The MASTER trial combined daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) in newly diagnosed multiple myeloma (NDMM), using minimal residual disease (MRD) by next-generation sequencing (NGS) to inform the use and duration of Dara-KRd post-autologous hematopoietic cell transplantation (AHCT) and treatment cessation in patients with two consecutive MRD-negative assessments.

Methods: This multicenter, single-arm, phase II trial enrolled patients with NDMM with planed enrichment for high-risk cytogenetic abnormalities (HRCAs). Patients received Dara-KRd induction, AHCT, and Dara-KRd consolidation, according to MRD status. MRD was evaluated by NGS at the end of induction, post-AHCT, and every four cycles (maximum of eight cycles) of consolidation. Primary end point was achievement of MRD negativity (< 10). Patients with two consecutive MRD-negative assessments entered treatment-free MRD surveillance.

Results: Among 123 participants, 43% had none, 37% had 1, and 20% had 2+ HRCA. Median age was 60 years (range, 36-79 years), and 96% had MRD trackable by NGS. Median follow-up was 25.1 months. Overall, 80% of patients reached MRD negativity (78%, 82%, and 79% for patients with 0, 1, and 2+ HRCA, respectively), 66% reached MRD < 10, and 71% reached two consecutive MRD-negative assessments during therapy, entering treatment-free surveillance. Two-year progression-free survival was 87% (91%, 97%, and 58% for patients with 0, 1, and 2+ HRCA, respectively). Cumulative incidence of MRD resurgence or progression 12 months after cessation of therapy was 4%, 0%, and 27% for patients with 0, 1, or 2+ HRCA, respectively. Most common serious adverse events were pneumonia (6%) and venous thromboembolism (3%).

Conclusion: Dara-KRd, AHCT, and MRD response-adapted consolidation leads to high rate of MRD negativity in NDMM. For patients with 0 or 1 HRCA, this strategy creates the opportunity of MRD surveillance as an alternative to indefinite maintenance.
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http://dx.doi.org/10.1200/JCO.21.01935DOI Listing
December 2021

Comparison of Cilta-cel, an Anti-BCMA CAR-T Cell Therapy, Versus Conventional Treatment in Patients With Relapsed/Refractory Multiple Myeloma.

Clin Lymphoma Myeloma Leuk 2021 Oct 30. Epub 2021 Oct 30.

Department of Medicine, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI.

Background: In the single-arm, phase 1b/2 CARTITUDE-1 study, ciltacabtagene autoleucel (cilta-cel), an anti-B-cell maturation antigen chimeric antigen receptor T-cell (CAR-T) therapy, showed encouraging efficacy in US patients with multiple myeloma (MM) who previously received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 monoclonal antibody (triple-class exposed).

Patients And Methods: A dataset of US patients refractory to an anti-CD38 monoclonal antibody (MAMMOTH) was used to identify patients who would meet eligibility for CARTITUDE-1 and received subsequent non-CAR-T therapy. The intent-to-treat (ITT) population in CARTITUDE-1 included patients who underwent apheresis (N = 113); the modified ITT (mITT) population was the subset who received cilta-cel (n = 97). Corresponding populations were identified from the MAMMOTH dataset: ITT population (n = 190) and mITT population of patients without progression/death within 47 days (median apheresis-to-cilta-cel infusion time) from onset of therapy (n = 122). Using 1:1 nearest neighbor propensity score matching to control for selected baseline covariates, 95 and 69 patients in CARTITUDE-1 ITT and mITT populations, respectively, were matched to MAMMOTH patients.

Results: In ITT cohorts of CARTITUDE-1 vs. MAMMOTH, improved overall response rate (ORR; 84% vs. 28% [P < .001]) and longer progression-free survival (PFS; hazard ratio [HR], 0.11 [95% confidence interval (CI), 0.05-0.22]) and overall survival (OS; HR, 0.20 [95% CI, 0.10-0.39]) were observed. Similar results were seen in mITT cohorts of CARTITUDE-1 vs. MAMMOTH (ORR: 96% vs. 30% [P < .001]; PFS: HR, 0.02 [95% CI, 0.01-0.14]; OS: HR, 0.05 [95% CI, 0.01-0.22]) and with alternative matching methods.

Conclusion: Cilta-cel yielded significantly improved outcomes versus real-world therapies in triple-class exposed patients with relapsed/refractory MM.
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http://dx.doi.org/10.1016/j.clml.2021.10.013DOI Listing
October 2021

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. IV: CAR-T cell therapy for multiple myeloma patients.

Hematol Transfus Cell Ther 2021 Nov;43 Suppl 2:S30-S34

Santa Casa de Misericórdia de São Paulo, São Paulo, SP, Brazil; Clínica São Germano, São Paulo, SP, Brazil.

Extraordinary progress has been made over the last decade in the treatment of multiple myeloma with the incorporation of new drugs, particularly proteasome inhibitors, immunomodulators, and monoclonal antibodies. The combined use of innovative drugs, already in the first lines of treatment, has led to an expressive increase in the survival of these patients. However, the approach to relapse remains a great challenge, and the disease continues to be incurable. In this scenario, modern immunotherapy has gained the limelight, especially with its recent use of CAR-T cells in clinical trials, as in the case of multiple myeloma, having the BCMA as the primary target. The results are impactful in the treatment of multiple myeloma patients who have had multiple relapses and are triple- and penta-refractory. In this Consensus, we have brought together a group of experts in multiple myeloma to discuss and forward their recommendations for the future, which we hope is very near, incorporating the CAR-T in our country.
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http://dx.doi.org/10.1016/j.htct.2021.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606706PMC
November 2021

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. I: Structuring centers for the multidisciplinary clinical administration and management of CAR-T cell therapy patients.

Hematol Transfus Cell Ther 2021 Nov;43 Suppl 2:S3-S12

Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil.

Chimeric antigen receptor T-cells (CAR-T cells) are a new modality of oncological treatment which has demonstrated impressive response in refractory or relapsed diseases, such as acute lymphoblastic leukemia (ALL), lymphomas, and myeloma but is also associated with unique and potentially life-threatening toxicities. The most common adverse events (AEs) include cytokine release syndrome (CRS), neurological toxicities, such as the immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, infections, and hypogammaglobulinemia. These may be severe and require admission of the patient to an intensive care unit. However, these AEs are manageable when recognized early and treated by a duly trained team. The objective of this article is to report a consensus compiled by specialists in the fields of oncohematology, bone marrow transplantation, and cellular therapy describing recommendations on the Clinical Centers preparation, training of teams that will use CAR-T cells, and leading clinical questions as to their use and the management of potential complications.
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http://dx.doi.org/10.1016/j.htct.2021.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606713PMC
November 2021

Chromosomal 1q21 abnormalities in multiple myeloma: a review of translational, clinical research, and therapeutic strategies.

Expert Rev Hematol 2021 Dec 8;14(12):1099-1114. Epub 2021 Oct 8.

Oncology Therapeutic Area, Sanofi Research and Development, Cambridge, MA, USA.

Introduction: Multiple myeloma (MM) remains an incurable disease with a median overall survival of approximately 5 years. Gain or amplification of 1q21 (1q21+) occurs in around 40% of patients with MM and generally portends a poor prognosis. Patients with MM who harbor 1q21+ are at increased risk of drug resistance, disease progression, and death. New pharmacotherapies with novel modes of action are required to overcome the negative prognostic impact of 1q21+. Areas covered: This review discusses the detection, biology, prognosis, and therapeutic targeting of 1q21+ in newly diagnosed and relapsed MM. Patients with MM and 1q21+ tend to present with higher tumor burden, greater end-organ damage, and more co-occurring high-risk cytogenetic abnormalities than patients without 1q21+. The chromosomal rearrangements associated with 1q21+ result in dysregulation of genes involved in oncogenesis. Identification and characterization of the 1q21+ molecular targets are needed to inform on prognosis and treatment strategy. Clinical trial data are emerging that addition of isatuximab to combination therapies may improve outcomes in patients with 1q21+ MM. Expert opinion: In the next 5 years, the results of ongoing research and trials are likely to focus on the therapeutic impact and treatment decisions associated with 1q21+ in MM.
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http://dx.doi.org/10.1080/17474086.2021.1983427DOI Listing
December 2021

Impact of sociodemographic factors on early mortality in acute promyelocytic leukemia in the United States: A time-trend analysis.

Cancer 2022 Jan 8;128(2):292-298. Epub 2021 Sep 8.

Division of Hematology and Oncology, Department of Pediatrics, Children's of Alabama, University of Alabama at Birmingham, Birmingham, Alabama.

Background: The survival of patients with acute promyelocytic leukemia (APL) has dramatically improved with the use of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, because of the complexity of the initial management, early mortality (EM) remains a major contributor to treatment failure. It is less known whether advances in treatment, urgent access to specialized care, and broad availability of ATRA/ATO have reduced EM in the last 2 decades. Furthermore, the influence of sociodemographic factors on the risk of EM also remains unclear.

Methods: This study used the Surveillance, Epidemiology, and End Results program to characterize the impact of sociodemographic factors on the rates of EM and overall survival (OS) in patients with APL diagnosed between 1992 and 2015.

Results: In all, 2224 cases were identified (895 who were younger than 40 years and 1329 who were 40 years old or older); 47.9% had a county-level median household income of $59,630 or higher, 49.0% belonged to counties where more than 31% of adults held at least a bachelor's degree, and 86.0% resided in urban areas. The rate of EM declined from 31.5% in 1992-1995 to 15.9% in 2012-2015 for all patients. It improved for patients younger than 40 years (27.4% in 1992-1995 vs 5.4% in 2012-2015; P < .001) and for patients 40 years old or older but not to the same extent (35.2% in 1992-1995 vs 22.2% in 2012-2015; P = .02). Importantly, improvements in EM were not seen among patients residing in rural areas, with the rate remaining higher than 20% in 2012-2015. The 3-year OS rate was 49.2% for patients with APL diagnosed in 1992-1995 and 76.4% for patients diagnosed in 2012-2015.

Conclusions: These findings confirm consistent improvements in EM and OS for patients with APL and point to the challenge of further extending these improvements in EM rates to older patients and to those living in rural areas.
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http://dx.doi.org/10.1002/cncr.33914DOI Listing
January 2022

Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma.

Blood Adv 2021 10;5(19):3748-3759

Division of Hematology and Oncology, University of Pennsylvania Abramson Cancer Center, Philadelphia, PA.

Proteins in the antiapoptotic B-cell lymphoma 2 (BCL-2) family play a role in the pathophysiology of multiple myeloma (MM). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis of MM cells, and its efficacy may be potentiated through combination with agents that increase BCL-2 dependency or have complementary mechanisms of action. The safety, tolerability, pharmacokinetics, and antitumor activity of venetoclax in combination with carfilzomib and dexamethasone (VenKd) in adults with relapsed/refractory MM (RRMM) were investigated in this phase 2 dose-escalation study. Oral venetoclax (400 or 800 mg) was administered daily in combination with intravenous carfilzomib (27, 56, or 70 mg/m2) and oral dexamethasone (20 or 40 mg) in 4 dose-finding cohorts. The expansion cohort received venetoclax 800 mg, carfilzomib 70 mg/m2, and dexamethasone 40 mg. Forty-nine patients received treatment. Median prior lines of therapy was 1 (range, 1-3), and median time in the study was 27 months. The most common treatment-emergent adverse events were diarrhea (65%), fatigue (47%), nausea (47%), and lymphopenia (35%). Serious adverse events occurred in 26 (53%) patients. Of 3 treatment-emergent deaths, 1 was considered treatment related. The overall response rate was 80% in all patients, 92% in patients with t(11;14) (n = 13), and 75% in patients without (n = 36). The rate of complete response or better was 41%. Median progression-free survival was 22.8 months. Treatment with VenKd was well tolerated and showed promising response rates in this RRMM patient population, with greater responses observed in patients with t(11;14). This trial is registered at www.clinicaltrials.gov as #NCT02899052.
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http://dx.doi.org/10.1182/bloodadvances.2020004146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8679663PMC
October 2021

Impact of t(11;14) as a sole and concomitant abnormality on outcomes in multiple myeloma.

Br J Haematol 2021 10 24;195(1):e113-e116. Epub 2021 Jun 24.

Department of Medicine, O'Neal Comprehensive Cancer Center, Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.

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http://dx.doi.org/10.1111/bjh.17627DOI Listing
October 2021

Maintaining the minimal: dynamics of measurable residual disease with continuous lenalidomide therapy.

Lancet Haematol 2021 06;8(6):e386-e387

O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35233, USA. Electronic address:

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http://dx.doi.org/10.1016/S2352-3026(21)00140-XDOI Listing
June 2021

Impact of insurance status on the survival of younger patients diagnosed with acute promyelocytic leukemia in the United States.

Cancer 2021 Aug 23;127(16):2966-2973. Epub 2021 Apr 23.

Division of Hematology and Oncology, Department of Pediatrics, Children's of Alabama, University of Alabama at Birmingham, Birmingham, Alabama.

Background: Survival among patients diagnosed with acute promyelocytic leukemia (APL) has significantly improved with the use of all-trans retinoic acid and arsenic trioxide. However, the need for immediate diagnosis and access to specialized care and the cost associated with APL management can potentially act as barriers for disadvantaged patients. The influence of sociodemographic factors on the outcomes of patients with APL remains unclear.

Methods: The authors used the National Cancer Institute's Surveillance, Epidemiology, and End Results program to characterize the impact of sociodemographic factors on survival in patients younger than 65 years with APL.

Results: The authors identified 1787 cases: 816 who were younger than 40 years and 971 who were 40 years old or older. Insured patients who were younger than 40 years had an improved 5-year overall survival (OS) rate in comparison with patients without insurance. Among patients who were 40 years or older, having insurance (other than Medicaid) was associated with better survival than being a Medicaid beneficiary or being uninsured, whereas patients with Medicaid had improved 5-year OS in comparison with uninsured patients. In a multivariate analysis of patients younger than 40 years, a higher risk of death was associated with being male, being diagnosed in earlier years, and being uninsured. For patients who were 40 years old or older, mortality increased with increasing age and for both Medicaid and uninsured patients in comparison with insured patients.

Conclusions: Despite the high cure rate experienced by patients with APL, patients younger than 65 years without insurance and those 40 years old or older with Medicaid are at a significant disadvantage in comparison with patients with insurance. These findings point to an opportunity to improve survival in APL by addressing access to care.
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http://dx.doi.org/10.1002/cncr.33593DOI Listing
August 2021

Survival of chronic myeloid leukemia patients in comparison to the general population in the tyrosine kinase inhibitors era: A US population-based study.

Am J Hematol 2021 07 1;96(7):E265-E268. Epub 2021 May 1.

Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.

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http://dx.doi.org/10.1002/ajh.26195DOI Listing
July 2021

Treatment of relapsed and refractory multiple myeloma: recommendations from the International Myeloma Working Group.

Lancet Oncol 2021 03;22(3):e105-e118

Rigshospitalet, Copenhagen University, Copenhagen, Denmark.

This Policy Review presents the International Myeloma Working Group's clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma. Based on the results of phase 2 and phase 3 trials, these recommendations are proposed for the treatment of patients with relapsed and refractory disease who have received one previous line of therapy, and for patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy. These recommendations integrate the issue of drug access in both low-income and middle-income countries and in high-income countries to help guide real-world practice and thus improve patient outcomes.
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http://dx.doi.org/10.1016/S1470-2045(20)30756-7DOI Listing
March 2021

Daratumumab plus RVd for newly diagnosed multiple myeloma: final analysis of the safety run-in cohort of GRIFFIN.

Blood Adv 2021 02;5(4):1092-1096

Dana-Farber Cancer Institute, Boston, MA.

The phase 2 GRIFFIN study of daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) for transplant-eligible, newly diagnosed multiple myeloma included a safety run-in phase followed by a randomized phase. The ongoing randomized phase has met its prespecified primary end point of an improved stringent complete response (sCR) rate after consolidation for D-RVd (reported elsewhere). Final analysis of the safety run-in cohort is reported herein and provides longer follow-up (median, 40.8 months) encompassing daratumumab plus lenalidomide (D-R) maintenance therapy. Patients in the safety run-in cohort (N = 16) received 4 induction cycles (D-RVd), high-dose melphalan supported by autologous stem cell transplant, 2 consolidation cycles (D-RVd), and 24 months of maintenance (D-R). By the end of consolidation, all patients had responded, with a best response of sCR in 9 (56.3%) patients; 8 (50.0%) patients were minimal residual disease (MRD) negative (10‒5 threshold). After maintenance, 15 (93.8%) patients had achieved a best response of sCR, and 13 (81.3%) patients were MRD (10‒5) negative. Estimated 36-month progression-free and overall survival rates were 78.1% and 93.8%, respectively. One death from progressive disease occurred in the patient who did not achieve sCR. Observed safety profiles were consistent with daratumumab and RVd. With >3 years of median follow-up, D-RVd achieved durable responses that deepened with D-R maintenance. This study was registered at www.clinicaltrials.gov as #NCT02874742.
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http://dx.doi.org/10.1182/bloodadvances.2020003642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903234PMC
February 2021

Caution With Routine Use of Daratumumab for Newly Diagnosed High-Risk Multiple Myeloma-Reply.

JAMA Oncol 2021 Apr;7(4):635-636

Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham.

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http://dx.doi.org/10.1001/jamaoncol.2020.8020DOI Listing
April 2021

New regimens and directions in the management of newly diagnosed multiple myeloma.

Am J Hematol 2021 03 20;96(3):367-378. Epub 2021 Jan 20.

O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, USA.

The introduction of novel agents over the last decade has rapidly expanded the therapeutic landscape of multiple myeloma (MM) for both transplant-eligible and transplant-ineligible patients. The assessment of minimal residual disease (MRD) by next-generation flow cytometry or next-generation sequencing is established as a powerful predictor of long-term outcomes. The use of MRD in response-adapted clinical trials may provide opportunities to identify candidates for treatment escalation and de-escalation. Agents with proven activity in the relapsed and refractory setting are being studied in the management of high-risk newly diagnosed MM (NDMM). Here, we summarize the most recent clinical trials that have led to the current paradigms in the management of NDMM. We also discuss how novel agents could be incorporated in the newly diagnosed setting and potential clinical trial designs that could leverage MRD information with the goal of treatment optimization.
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http://dx.doi.org/10.1002/ajh.26080DOI Listing
March 2021

Defining and Managing High-Risk Multiple Myeloma: Current Concepts.

J Natl Compr Canc Netw 2020 12 2;18(12):1730-1737. Epub 2020 Dec 2.

2Plasma Cell Disorders Division, Department of Hematologic Oncology & Blood Disorders, Levine Cancer Institute/Atrium Health, Charlotte, North Carolina.

Multiple myeloma is a very heterogeneous disease. Despite advances in diagnostics and therapeutics, a subset of patients still experiences abbreviated responses to therapy, frequent relapses, and short survival and is considered to have high-risk multiple myeloma (HRMM). Stage III diagnosis according to the International Staging System; the presence of del(17p), t(4;14), or t(14;16) by fluorescence in situ hybridization; certain gene expression patterns; high serum lactic dehydrogenase level; and the presence of extramedullary disease at diagnosis are all considered indicators of HRMM. More recent evidence shows that patients who experience response to therapy but with a high burden of measurable residual disease or persistence of abnormal FDG uptake on PET/CT scan after initial therapy also have unfavorable outcomes, shaping the concept of dynamic risk assessment. Triplet therapy with proteasome inhibitors, immunomodulatory agents, and corticosteroids and autologous hematopoietic cell transplantation remain the pillars of HRMM therapy. Recent evidence indicates a benefit of immunotherapy with anti-CD38 monoclonal antibodies in HRMM. Future trials will inform the impact of novel immunotherapeutic approaches, including T-cell engagers, CAR T cells, and nonimmunotherapeutic approaches in HRMM. Those agents are likely to be deployed early in the disease course in the setting of risk- and response-adapted trials.
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http://dx.doi.org/10.6004/jnccn.2020.7673DOI Listing
December 2020

Evaluation of Daratumumab for the Treatment of Multiple Myeloma in Patients With High-risk Cytogenetic Factors: A Systematic Review and Meta-analysis.

JAMA Oncol 2020 Nov;6(11):1759-1765

Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham.

Importance: The addition of daratumumab to backbone multiple myeloma (MM) regimens is associated with improved response rates and progression-free survival (PFS). Whether improved outcomes are also associated with this regimen among patients with cytogenetically defined high-risk MM (HRMM) remains unclear.

Objective: To measure PFS associated with adding daratumumab to backbone MM regimens among patients with HRMM.

Data Sources: For this systematic review and meta-analysis, MEDLINE, Embase, PubMed, Scopus, Web of Science Core Collection, Cochrane Library, clinical trials registries, and meeting libraries were searched from inception to January 2, 2020, using terms reflecting multiple myeloma and daratumumab.

Study Selection: Included studies were phase 3 randomized clinical trials that compared backbone MM regimens with the same regimen plus daratumumab in newly diagnosed or relapsed or refractory MM, such that the only difference between the intervention and control groups was use of daratumumab and reported outcomes by cytogenetic risk. High-risk MM was defined as the presence of t(4;14), t(14;16), or del(17p).

Data Extraction And Synthesis: Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline, 2 investigators independently extracted study data, with disagreements resolved by a third investigator. Quality was assessed by the Cochrane risk-of-bias method.

Main Outcomes And Measures: Data on effectiveness were extracted using hazard ratios (HRs) for PFS. Relative log-HRs were pooled using a DerSimonian-Laird random-effects model. Heterogeneity was assessed using the Cochran Q and the I2 statistic.

Results: Of 5194 studies screened, 6 phase 3 trials were eligible, including 3 trials for newly diagnosed MM (2528 patients; 358 with HRMM) and 3 trials for relapsed or refractory MM (1533 patients; 222 with HRMM). Among patients with newly diagnosed HRMM, the addition of daratumumab to backbone regimens was associated with improved PFS (pooled HR, 0.67; 95% CI, 0.47-0.95; P = .02), with little evidence of heterogeneity (Cochran Q, P = .77; I2 = 0%). Similar results were seen among patients with relapsed or refractory HRMM (pooled HR, 0.45; 95% CI, 0.30-0.67; P < .001), again with little evidence of heterogeneity (Cochran Q, P = .63; I2 = 0%).

Conclusions And Relevance: This study suggests that incorporating daratumumab to backbone regimens may be associated with improved PFS among patients with newly diagnosed HRMM or relapsed or refractory HRMM.
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http://dx.doi.org/10.1001/jamaoncol.2020.4338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516804PMC
November 2020

Age is just a number, the wrong number.

Cancer 2020 12 23;126(23):5014-5016. Epub 2020 Sep 23.

Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.

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http://dx.doi.org/10.1002/cncr.33170DOI Listing
December 2020

Outcomes of Autologous Hematopoietic Cell Transplantation in Diffuse Large B Cell Lymphoma Refractory to Firstline Chemoimmunotherapy.

Transplant Cell Ther 2021 01 17;27(1):55.e1-55.e7. Epub 2020 Sep 17.

CIBMTR (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; BMT & Cellular Therapy Program, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address:

Outcomes of patients with primary refractory diffuse large B cell lymphoma (DLBCL) are dismal. The role of autologous hematopoietic cell transplant (autoHCT) in this population is not well defined in the modern era. Most data sets combine these patients with those with relapsed disease. We report the outcomes of autoHCT in patients with primary refractory DLBCL that subsequently demonstrated chemosensitive disease with salvage therapies, using the Center for International Blood and Marrow Transplant Research registry. Between 2003 and 2018, 169 patients met the inclusion criteria. The median age of the cohort was 54 years, and 64% were male. The patients had advanced stage disease (73%) at diagnosis, 27% patients had stable disease, and 73% had progressive disease after frontline chemoimmunotherapy. Following salvage therapy, 36% patients were in complete remission (CR) and 64% in partial remission (PR). Nonrelapse mortality, progression/relapse, progression-free survival (PFS), and overall survival of this cohort at 4 years were 10.8% (95% confidence interval [CI], 6% to 13%), 47.8% (95% CI, 41% to 52%), 41.4% (95% CI, 38% to 50%), and 49.6% (95% CI, 44% to 56%), respectively. On univariate analysis, patients with progressive disease after frontline chemoimmunotherapy did just as well as those with stable disease. Patients achieving CR with salvage therapy had a lower cumulative incidence of progression/relapse at 1 year (30% versus 46.9%; P = .02) and experienced superior 1-year PFS compared to patients in PR (63.2% versus 46.7%; P = .03). AutoHCT provides durable disease control and should remain the standard of care in patients with primary refractory DLBCL who respond to salvage therapies.
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http://dx.doi.org/10.1016/j.bbmt.2020.09.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965782PMC
January 2021

International harmonization in performing and reporting minimal residual disease assessment in multiple myeloma trials.

Leukemia 2021 01 11;35(1):18-30. Epub 2020 Aug 11.

Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.

Minimal residual disease (MRD) assessment is incorporated in an increasing number of multiple myeloma (MM) clinical trials as a correlative analysis, an endpoint or even as a determinant of subsequent therapy. There is substantial heterogeneity across clinical trials in how MRD is assessed and reported, creating challenges for data interpretation and for the design of subsequent studies. We convened an international panel of MM investigators to harmonize how MRD should be assessed and reported in MM clinical trials. The panel provides consensus on which MM trials should include MRD, the recommended time points for MRD assessment, and expected analytical validation for MRD assays. We subsequently outlined parameters for reporting MRD results implementing the intention-to-treat principle. The panel provides guidance regarding the incorporation of newer peripheral blood-based and imaging-based approaches to detection of residual disease. Recommendations are summarized in 13 consensus statements that should be followed by sponsors, investigators, editors, and reviewers engaged in designing, performing, and interpreting MM trials.
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http://dx.doi.org/10.1038/s41375-020-01012-4DOI Listing
January 2021

Second primary malignancy among older adults with multiple myeloma receiving first-line lenalidomide-based therapy: A population-based analysis.

J Geriatr Oncol 2021 03 17;12(2):256-261. Epub 2020 Jul 17.

Alpert Medical School of Brown University, Providence, RI, United States of America; Division of Hematology-Oncology, Lifespan Cancer Institute, Providence, RI, United States of America.

Objectives: Clinical trials have suggested that patients with myeloma treated with lenalidomide may have an increased risk of second primary malignancies (SPM). Whether such risks are of significant relevance in the real-world clinical practice, particularly among older patients receiving first-line lenalidomide based therapy, remains unclear.

Methods: Using Surveillance Epidemiology and End Results-Medicare database, we identified adults ≥ 65 years with plasma cell myeloma diagnosed in 2007-2015 who received at least one oral anti-myeloma agent. We defined first-line lenalidomide-containing therapy as use within 90 days of diagnosis. SPM was defined as a malignancy reported to a cancer registry > 90 days after myeloma diagnosis. We computed cumulative incidence of SPM (with death being a competing event) and compared SPM rates between patients treated with or without first-line lenalidomide using a Fine-Gray's model, adjusting for age, sex, race, ethnicity, prior malignancy, and histologic subtype.

Results: Of 9850 Medicare beneficiaries, 4009 (41%) received first-line lenalidomide. During median follow up of 5.0 years, 423 patients (4.3%) developed SPM, including 361 solid tumors (85%) and 61 hematologic malignancies (14%). The cumulative incidence of any SPM at 5 years was similar among those who received first-line lenalidomide and those who did not (5.3% vs 4.4%; sub-hazard ratio, SHR 1.06, P = .53). Consistent results were seen in the risk of solid tumor (4.7% vs 3.6%; SHR 1.13, P = .24) or hematologic malignancy (4.7 vs 3.6%, SHR 0.73; P = .72).

Conclusion: First-line lenalidomide therapy among older adults with myeloma was not associated with a significantly increased risk of any SPM.
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http://dx.doi.org/10.1016/j.jgo.2020.07.007DOI Listing
March 2021

Summary of the 2019 Blood and Marrow Transplant Clinical Trials Network Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling.

Biol Blood Marrow Transplant 2020 10 24;26(10):e247-e255. Epub 2020 Jun 24.

Roswell Park Comprehensive Cancer Center, Buffalo, New York.

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Myeloma Intergroup has organized an annual workshop focused on minimal residual disease (MRD) testing and immune profiling (IP) in multiple myeloma since 2016. In 2019, the workshop took place as an American Society of Hematology (ASH) Friday Scientific Workshop titled "Immune Profiling and Minimal Residual Disease Testing in Multiple Myeloma." This workshop focused on 4 main topics: the molecular and immunologic evolution of plasma cell disorders, development of new laboratory- and imaging-based MRD assessment approaches, chimeric antigen receptor T cell therapy research, and statistical and regulatory issues associated with novel clinical endpoints. In this report, we provide a summary of the workshop and discuss future directions.
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http://dx.doi.org/10.1016/j.bbmt.2020.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529908PMC
October 2020

Recent survival trends in diffuse large B-cell lymphoma--Have we made any progress beyond rituximab?

Cancer Med 2020 08 18;9(15):5519-5525. Epub 2020 Jun 18.

Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.

Background: Population-based studies previously showed an improvement in overall survival (OS) for patients with diffuse large B-cell lymphoma (DLBCL) who received chemoimmunotherapy with rituximab. However, there is limited data (especially at the population level) that show a similar trend in OS improvement, in the most recent time period. We hypothesized that survival for DLBCL patients diagnosed in the United States has continued to improve in recent years and intended to measure outcome improvements.

Methods: Using the SEER-18 registries, we compared the incidence and relative survival rates (RSRs) of DLBCL patients between 2002-2007 and 2008-2013 (availability of novel agents, broader use of autologous hematopoietic cell transplantation and improvement in supportive care). Multivariable Cox regression models were used to assess associations between the year of diagnosis and OS while controlling for age, gender, stage, and ethnicity.

Results: There were a total of 53 439 patients with DLBCL who were diagnosed between 2002 and 2013. Of these, 25 810 were diagnosed during time period-1 and 27 629 diagnosed during time period-2. There was a slight decline in incidence of DLBCL (time period-1 vs time period-2), 7.75 (95% CI = 7.66-7.84) vs 7.43 (95% CI = 7.34-7.52) cases per 100 000 persons, respectively (P < .0001). Overall, there was a modest improvement in DLBCL RSRs, with 5-year RSR improving from 61% (time period-1) to 64% (time period-2) and the improvement was noted across all subsets of patients. On multivariable analysis, patients diagnosed in time period-2 had lower mortality relative to time period-1 (HR = 0.87, 95% CI = 0.85-0.89).

Conclusions: Our study shows an improvement in the outcomes of DLBCL patients beyond the introduction of rituximab, although the magnitude of improvement is small. It will be interesting to see the impact of chimeric antigen receptor-T cell therapy translating to population-level survival in the next 5 years.
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http://dx.doi.org/10.1002/cam4.3237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402846PMC
August 2020

Clinical trial material.

Authors:
Luciano J Costa

Lancet Haematol 2020 May;7(5):e368

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http://dx.doi.org/10.1016/S2352-3026(20)30118-6DOI Listing
May 2020

Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial.

Blood 2020 08;136(8):936-945

Dana-Farber Cancer Institute, Boston, MA.

Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab (D) to RVd (D-RVd) in transplant-eligible NDMM patients was evaluated. Patients (N = 207) were randomized 1:1 to D-RVd or RVd induction (4 cycles), ASCT, D-RVd or RVd consolidation (2 cycles), and lenalidomide or lenalidomide plus D maintenance (26 cycles). The primary end point, stringent complete response (sCR) rate by the end of post-ASCT consolidation, favored D-RVd vs RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval, 0.87-2.82; 1-sided P = .068) and met the prespecified 1-sided α of 0.10. With longer follow-up (median, 22.1 months), responses deepened; sCR rates improved for D-RVd vs RVd (62.6% vs 45.4%; P = .0177), as did minimal residual disease (MRD) negativity (10-5 threshold) rates in the intent-to-treat population (51.0% vs 20.4%; P < .0001). Four patients (3.8%) in the D-RVd group and 7 patients (6.8%) in the RVd group progressed; respective 24-month progression-free survival rates were 95.8% and 89.8%. Grade 3/4 hematologic adverse events were more common with D-RVd. More infections occurred with D-RVd, but grade 3/4 infection rates were similar. Median CD34+ cell yield was 8.2 × 106/kg for D-RVd and 9.4 × 106/kg for RVd, although plerixafor use was more common with D-RVd. Median times to neutrophil and platelet engraftment were comparable. Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT02874742.
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http://dx.doi.org/10.1182/blood.2020005288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7441167PMC
August 2020

Long-term survival of 1338 MM patients treated with tandem autologous vs. autologous-allogeneic transplantation.

Bone Marrow Transplant 2020 09 14;55(9):1810-1816. Epub 2020 Apr 14.

University of Torino, Torino, Italy.

Contrary to tandem autologous transplant (auto-auto), autologous followed by reduced intensity conditioning allogenic transplantation (auto-allo) offers graft-versus-myeloma (GVM) effect but with higher toxicity. Trials comparing these two strategies relied on availability of HLA-matched sibling donors for arm allocation (biological randomization) and yielded conflicting results. A pooled analysis of multiple trials with extended follow up provides an opportunity to compare these strategies. We obtained individual patient data from participants of four trials comparing auto-auto vs. auto-allo after induction therapy. There were 899 patients in auto-auto and 439 in auto-allo. Median follow up of survivors was 118.5 months. Median overall survival (OS) was 78.0 months in auto-auto and 98.3 months in auto-allo (HR = 0.84, P = 0.02). OS was 36.4% vs. 44.1% at 10 years (P = 0.01) for auto-auto and auto-allo, respectively. Progression-free survival was also improved in auto-allo (HR = 0.84, P = 0.004). Risk of non-relapse mortality was higher in auto-allo (10 year 8.3% vs. 19.7%, P < 0.001), while risk of disease progression was higher in auto-auto (10 year 77.2% vs. 61.6%, P < 0.001). Median post relapse survival was 41.5 months in auto-auto and 62.3 months in auto-allo (HR = 0.71, P < 0.001). This supports the existence of durable GVM effect enhancing myeloma control with subsequent therapies.
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http://dx.doi.org/10.1038/s41409-020-0887-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483973PMC
September 2020

Consensus Recommendations for the Clinical Management of Patients With Multiple Myeloma Treated With Selinexor.

Clin Lymphoma Myeloma Leuk 2020 06 7;20(6):351-357. Epub 2020 Mar 7.

Division of Hematology and Oncology, Department of Medicine, Columbia University, New York, NY.

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http://dx.doi.org/10.1016/j.clml.2019.12.026DOI Listing
June 2020
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