Publications by authors named "Hari Parameswaran"

272 Publications

A Comprehensive Review of the Genomics of Multiple Myeloma: Evolutionary Trajectories, Gene Expression Profiling, and Emerging Therapeutics.

Cells 2021 Aug 2;10(8). Epub 2021 Aug 2.

Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.

Multiple myeloma (MM) is a blood cancer characterized by the accumulation of malignant monoclonal plasma cells in the bone marrow. It develops through a series of premalignant plasma cell dyscrasia stages, most notable of which is the Monoclonal Gammopathy of Undetermined Significance (MGUS). Significant advances have been achieved in uncovering the genomic aberrancies underlying the pathogenesis of MGUS-MM. In this review, we discuss in-depth the genomic evolution of MM and focus on the prognostic implications of the accompanied molecular and cytogenetic aberrations. We also dive into the latest investigatory techniques used for the diagnoses and risk stratification of MM patients.
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http://dx.doi.org/10.3390/cells10081961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391934PMC
August 2021

Outcomes of upfront autologous hematopoietic cell transplantation in patients with multiple myeloma who are 75 years old or older.

Cancer 2021 Aug 10. Epub 2021 Aug 10.

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

Background: Consolidative autologous hematopoietic stem cell transplantation (AHCT) is commonly used for patients with multiple myeloma (MM). We studied AHCT use and outcomes in patients with MM ≥75 years old.

Methods: Patients with MM ≥75 years old receiving AHCT between 2013 and 2017 in the United States were identified using the Center for International Blood and Marrow Transplant Research database. Relapse and/or progression (REL), progression-free survival (PFS), and overall survival (OS) were modeled using Cox proportional hazards models. Covariates used were age, sex, Karnofsky performance score (KPS), HCT-comorbidity index (HCT-CI), International Staging System and/or Durie-Salmon stage, high-risk cytogenetics, melphalan dose, and disease status at and 1 year after transplant. AHCT utilization rate using the Surveillance, Epidemiology, and End Results database was used to estimate specific incidence among ≥75 years old by race and gender.

Results: Of 360 patients, 63% were male, 84% were White, 56% had KPS <90, and 57% had HCT-CI ≥3. The 100-day transplant-related mortality was 1% (0%-2%) with a 2-year REL rate of 27% (95% confidence interval [CI], 22%-33%), PFS of 66% (95% CI, 60%-72%), and OS of 83% (95% CI, 78%-87%). On multivariate analysis, only high-risk cytogenetics was associated with REL risk and decreased PFS. In White males, transplant utilization rate was 5.2%-5.8% compared to 3.5%-4.0% in African American males (P = .02). There was 3.37-3.79% transplant utilization in White females compared to 1.88-2.12% in African American females (P < .01).

Conclusions: The use of AHCT was associated with excellent 2-year outcomes in this selected MM population ≥75 years old. Transplant utilization for patients ≥75 years old remains low with significant racial and gender disparities.
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http://dx.doi.org/10.1002/cncr.33831DOI Listing
August 2021

A new interventional home care model for COVID management: Virtual Covid IP.

Diabetes Metab Syndr 2021 Jul 23;15(5):102228. Epub 2021 Jul 23.

Department of Diabetology, Jothydev's Diabetes Research Centers, Kerala, India.

Aim: Amidst COVID-19 pandemic, the health care delivery in India faces major challenges owing to the overwhelming hospitals, exhausted healthcare workers, and shortage of crucial medical supplies such as ventilators and oxygen. The study aims to propose a novel successful interventional home care model, the Virtual COVID In-Patient (VCIP) care for effective COVID management.

Methods: The Covid-19 positive patients enrolled in VCIP were chosen for the study. A 24/7 active multidisciplinary WhatsApp group was created for each patient, for remote monitoring of temperature, blood pressure, blood glucose, respiratory and pulse rate along with the symptoms. Advice on sleep and exercises were given along with the medication via video-audio consultations. Lab facility was provided at the doorstep. Training on various devices, medications including steroids, delivering subcutaneous injections etc were given via video platforms.

Results: Among the 220 patients who availed the VCIP facility, only two were hospitalized, yielding a 99.5 % success rate in preventing hospitalizations and patients enrolled have been immensely satisfied with their experience.

Conclusions: With similar pandemics anticipated in near future, VCIP model may be considered for successful domiciliary treatment and overcoming the challenges.
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http://dx.doi.org/10.1016/j.dsx.2021.102228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299213PMC
July 2021

Management Strategies for Dealing With Surges of the COVID-19 Pandemic.

Cureus 2021 Jun 21;13(6):e15794. Epub 2021 Jun 21.

Diabetes and Endocrinology, Jothydev's Diabetes Research Centre, Thiruvananthapuram, IND.

The spread of COVID-19 (coronavirus disease 2019) across the world has resulted in widespread morbidity and mortality. An explosive increase in the number of cases during the surge phase of the pandemic can result in a management crisis. Therefore, we propose a simple model to manage the surges of the pandemic.
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http://dx.doi.org/10.7759/cureus.15794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293859PMC
June 2021

Budesonide Prophylaxis Reduces the Risk of Engraftment Syndrome After Autologous Hematopoietic Cell Transplantation in Multiple Myeloma.

Clin Lymphoma Myeloma Leuk 2021 Jun 18. Epub 2021 Jun 18.

Division of BMT & Cellular Therapy, Medical College of Wisconsin, Milwaukee, WI.

Background: Engraftment syndrome (ES) after autologous hematopoietic cell transplantation (AHCT) in multiple myeloma (MM) encompasses a continuum of periengraftment complications characterized by noninfectious fever, rash, diarrhea, and capillary leak features.

Patients And Methods: We analyzed the ES outcomes in 257 consecutive patients MM patients who underwent AHCT at our institution from 12/2017 to 11/2019 with budesonide prophylaxis (3 mg PO daily at day +5 post-AHCT till the time of discharge) (N = 109) and no prophylaxis (N = 148).

Results: The rates of ES were significantly higher in the no prophylaxis group versus prophylaxis group [69 (46%) vs. 23 (21%); P< .001]. There was no significant difference in length of stay (LOS) [mean 15 (±3.2) vs. 16 (±2.8); P = .27] and 30-day readmission [9 (6%) vs. 8 (7%); P = .81] between the no prophylaxis and prophylaxis groups, respectively. On adjusted analysis, budesonide prophylaxis was associated with a significantly lower risk of developing ES [odds ratio (OR) 0.29 (95% confidence interval [CI], 0.16-0.51); P< .0001]. There was no difference in the 30-day readmission rates [OR 1.12 (95% CI, 0.41-3.03); P = .81], but a trend for shorter LOS in the prophylaxis group [7.3% reduction in LOS (95% CI, -14.4% to 0%); P = .06].

Conclusion: Budesonide prophylaxis significantly reduces the risk of ES in MM patients undergoing AHCT. These promising results suggest the need for a randomized study investigate the role of budesonide for ES prophylaxis.
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http://dx.doi.org/10.1016/j.clml.2021.06.004DOI Listing
June 2021

Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study.

Lancet 2021 07 24;398(10297):314-324. Epub 2021 Jun 24.

Legend Biotech USA, Piscataway, NJ, USA.

Background: CARTITUDE-1 aimed to assess the safety and clinical activity of ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T-cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma with poor prognosis.

Methods: This single-arm, open-label, phase 1b/2 study done at 16 centres in the USA enrolled patients aged 18 years or older with a diagnosis of multiple myeloma and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who received 3 or more previous lines of therapy or were double-refractory to a proteasome inhibitor and an immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 10 CAR-positive viable T cells per kg) was administered 5-7 days after start of lymphodepletion. The primary endpoints were safety and confirmation of the recommended phase 2 dose (phase 1b), and overall response rate (phase 2) in all patients who received treatment. Key secondary endpoints were duration of response and progression-free survival. This trial is registered with ClinicalTrials.gov, NCT03548207.

Findings: Between July 16, 2018, and Oct 7, 2019, 113 patients were enrolled. 97 patients (29 in phase 1b and 68 in phase 2) received a cilta-cel infusion at the recommended phase 2 dose of 0·75 × 10 CAR-positive viable T cells per kg. As of the Sept 1, 2020 clinical cutoff, median follow-up was 12·4 months (IQR 10·6-15·2). 97 patients with a median of six previous therapies received cilta-cel. Overall response rate was 97% (95% CI 91·2-99·4; 94 of 97 patients); 65 (67%) achieved stringent complete response; time to first response was 1 month (IQR 0·9-1·0). Responses deepened over time. Median duration of response was not reached (95% CI 15·9-not estimable), neither was progression-free survival (16·8-not estimable). The 12-month progression-free rate was 77% (95% CI 66·0-84·3) and overall survival rate was 89% (80·2-93·5). Haematological adverse events were common; grade 3-4 haematological adverse events were neutropenia (92 [95%] of 97 patients), anaemia (66 [68%]), leukopenia (59 [61%]), thrombocytopenia (58 [60%]), and lymphopenia (48 [50%]). Cytokine release syndrome occurred in 92 (95%) of 97 patients (4% were grade 3 or 4); with median time to onset of 7·0 days (IQR 5-8) and median duration of 4·0 days (IQR 3-6). Cytokine release syndrome resolved in all except one with grade 5 cytokine release syndrome and haemophagocytic lymphohistiocytosis. CAR T-cell neurotoxicity occurred in 20 (21%) patients (9% were grade 3 or 4). 14 deaths occurred in the study; six due to treatment-related adverse events, five due to progressive disease, and three due to treatment-unrelated adverse events.

Interpretation: A single cilta-cel infusion at the target dose of 0·75 × 10 CAR-positive viable T cells per kg led to early, deep, and durable responses in heavily pretreated patients with multiple myeloma with a manageable safety profile. The data from this study formed the basis for recent regulatory submissions.

Funding: Janssen Research & Development and Legend Biotech.
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http://dx.doi.org/10.1016/S0140-6736(21)00933-8DOI Listing
July 2021

Laboratory Mice - A Driving Force in Immunopathology and Immunotherapy Studies of Human Multiple Myeloma.

Front Immunol 2021 2;12:667054. Epub 2021 Jun 2.

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

Mouse models of human cancer provide an important research tool for elucidating the natural history of neoplastic growth and developing new treatment and prevention approaches. This is particularly true for multiple myeloma (MM), a common and largely incurable neoplasm of post-germinal center, immunoglobulin-producing B lymphocytes, called plasma cells, that reside in the hematopoietic bone marrow (BM) and cause osteolytic lesions and kidney failure among other forms of end-organ damage. The most widely used mouse models used to aid drug and immunotherapy development rely on propagation of human myeloma cells in immunodeficient hosts (xenografting) or myeloma-like mouse plasma cells in immunocompetent hosts (autografting). Both strategies have made and continue to make valuable contributions to preclinical myeloma, including immune research, yet are ill-suited for studies on tumor development (oncogenesis). Genetically engineered mouse models (GEMMs), such as the widely known Vκ*MYC, may overcome this shortcoming because plasma cell tumors (PCTs) develop (spontaneously) in a highly predictable fashion and accurately recapitulate many hallmarks of human myeloma. Moreover, PCTs arise in an intact organism able to mount a complete innate and adaptive immune response and tumor development reproduces the natural course of human myelomagenesis, beginning with monoclonal gammopathy of undetermined significance (MGUS), progressing to smoldering myeloma (SMM), and eventually transitioning to frank neoplasia. Here we review the utility of transplantation-based and transgenic mouse models of human MM for research on immunopathology and -therapy of plasma cell malignancies, discuss strengths and weaknesses of different experimental approaches, and outline opportunities for closing knowledge gaps, improving the outcome of patients with myeloma, and working towards a cure.
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http://dx.doi.org/10.3389/fimmu.2021.667054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206561PMC
June 2021

SARS-CoV-2 receptor binding domain-specific antibodies activate platelets with features resembling the pathogenic antibodies in heparin-induced thrombocytopenia.

Res Sq 2021 Apr 26. Epub 2021 Apr 26.

Severe COVID-19 is associated with unprecedented thromboembolic complications. We found that hospitalized COVID-19 patients develop immunoglobulin Gs (IgGs) that recognize a complex consisting of platelet factor 4 and heparin similar to those developed in heparin-induced thrombocytopenia and thrombosis (HIT), however, independent of heparin exposure. These antibodies activate platelets in the presence of TLR9 stimuli, stimuli that are prominent in COVID-19. Strikingly, 4 out of 42 antibodies cloned from IgG1 RBD-binding B cells could activate platelets. These antibodies possessed, in the heavy-chain complementarity-determining region 3, an RKH or Y motif that we recently described among platelet-activating antibodies cloned from HIT patients. RKH and Y motifs were prevalent among published RBD-specific antibodies, and 3 out of 6 such antibodies tested could activate platelets. Features of platelet activation by these antibodies resemble those by pathogenic HIT antibodies. B cells with an RKH or Y motif were robustly expanded in COVID-19 patients. Our study demonstrates that SARS-CoV-2 infection drives the development of a subset of RBD-specific antibodies that can activate platelets and have activation properties and structural features similar to those of the pathogenic HIT antibodies.
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http://dx.doi.org/10.21203/rs.3.rs-462080/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132233PMC
April 2021

Immunotherapy in Multiple Myeloma-Time for a Second Major Paradigm Shift.

JCO Oncol Pract 2021 07 18;17(7):405-413. Epub 2021 May 18.

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

Multiple myeloma (MM) is a genetically heterogenous disease and remains mostly incurable with a small group of patients achieving long-term disease remission. The past decade witnessed enormous efforts to break the circulus vitiosus of tumor-induced immunosuppression and to re-engage the immune system to fight cancer. The first-in-class anti-CD38 monoclonal antibody, daratumumab, has shown unprecedented responses especially in combination with other novel agents in both newly diagnosed and relapsed MM. There has been great interest in harnessing the power of T cells with bispecific antibodies and chimeric antigen receptor T-cell therapies in hematologic malignancies including MM. These immune-based approaches have shown notable antimyeloma effects with deeper, durable responses in early clinical trials of heavily pretreated patients with MM with limited therapeutic options. Several trials are underway investigating both single and combinatorial immune therapies at different stages with a hope to bring major transformation in MM. In the current review, we summarize how an immunologic approach offers promise for the treatment of MM and is setting the stage for second major paradigm shift 2 decades after the emergence of thalidomide and novel therapeutics.
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http://dx.doi.org/10.1200/OP.21.00032DOI Listing
July 2021

KD-PACE Salvage Therapy for Aggressive Relapsed Refractory Multiple Myeloma, Plasma Cell Leukemia and Extramedullary Myeloma.

Clin Lymphoma Myeloma Leuk 2021 Aug 6;21(8):526-535. Epub 2021 Apr 6.

Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Patients with advanced/aggressive multiple myeloma have limited treatment options to achieve rapid disease control. In eligible patients, bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide is often used. However, many patients are refractory to or have toxicities from bortezomib and there is a need for bridging therapy. We have used a modified regimen incorporating the second-generation proteasome inhibitor carfilzomib (carfilzomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide [KD-PACE]) instead of bortezomib for relapsed/refractory multiple myeloma.

Patients And Methods: This 2-center retrospective study included consecutive patients receiving KD-PACE for relapsed or refractory multiple myeloma, plasma cell leukemia, or extramedullary myeloma. The primary outcome was the feasibility of KD-PACE as a bridging therapy to a more definitive treatment option.

Results: Fifty-two patients were included. The median age was 57 years, and 67% were male. Thirty-one patients were bridged with KD-PACE to autologous hematopoietic stem cell transplant (29%), allogenic hematopoietic stem cell transplant (27%), or a clinical trial (12%). Patients bridged to autologous hematopoietic stem cell transplant, allogenic hematopoietic stem cell transplant, or a clinical trial had a superior progression-free survival (8.3 months vs 2.3 months in the nonbridged group; P < .001) and overall survival (median, 16.7 months vs 4.3 months in the nonbridged group; P < .001). No unexpected toxicities occurred from the treatment regimen.

Conclusion: KD-PACE is a promising treatment option for select patients with advanced/aggressive forms of myeloma requiring rapid disease control before a more definitive salvage therapy such as auto/allotransplantation or a clinical trial.
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http://dx.doi.org/10.1016/j.clml.2021.03.013DOI Listing
August 2021

Pulmonary Lymphangitic Spread of Multiple Myeloma as Early Relapse after Autologous Stem Cell Transplantation.

Case Rep Hematol 2021 3;2021:5590975. Epub 2021 Apr 3.

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

Clinical relapses early after autologous stem cell transplantation portrays an inferior clinical outcome. Early relapse in this setting with extramedullary disease (EMD) of lung involvement in multiple myeloma is rare. To our knowledge, this is the first reported case of lymphangitic spread of myeloma with pulmonary parenchymal and pleural involvement occurring at first relapse.
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http://dx.doi.org/10.1155/2021/5590975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041536PMC
April 2021

PD-1 blockade after bispecific LV20.19 CAR-T modulates CAR T-cell immunophenotype without meaningful clinical response.

Haematologica 2021 Apr 15. Epub 2021 Apr 15.

BMT and Cellular Therapy Program, Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI.

Not available.
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http://dx.doi.org/10.3324/haematol.2021.278461DOI Listing
April 2021

Bortezomib-Based Induction Is Associated with Superior Outcomes in Light Chain Amyloidosis Patients Treated with Autologous Hematopoietic Cell Transplantation Regardless of Plasma Cell Burden.

Transplant Cell Ther 2021 03 16;27(3):264.e1-264.e7. Epub 2020 Dec 16.

Center for International Blood and Marrow Transplant Research, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin. Electronic address:

The benefits of pre-transplant induction chemotherapy in light chain (AL) amyloidosis, a low burden plasma cell (PC) neoplasm associated with multiorgan dysfunction, is debatable, although with the availability of bortezomib, this approach is being increasingly pursued. We analyzed the outcomes of AL amyloidosis patients undergoing autologous hematopoietic cell transplant between 2014 and 2018 that were reported to the Center for International Blood and Marrow Transplant Research database. Of 440 patients, 294 received bortezomib-based induction, and 146 received no induction. Patients receiving induction had greater PC burden compared to no induction (PC 10% or more, 39% versus 11%; P < .01). At 2 years, the induction group compared to no induction had lower relapse/progression: 13% (9% to 18%) versus 23% (16% to 32%) (P = .02); better progression-free survival (PFS): 82% (77% to 87%) versus 69% (61% to 77%) (P < .01); and similar overall survival (OS): 92% (88% to 95%) versus 89% (84% to 94%) (P = .22), findings that were confirmed on multivariate analysis. A subset analysis limited to patients with <10% PC also showed superior relapse/progression (hazard ratio [HR], .43; 95% confidence interval [CI], .24 to .78; P < .01) and PFS (HR, .43; 95% CI, .26 to .72; P < .01) for induction compared to no induction. Thus, we conclude that pre-transplant bortezomib-based induction was associated with improved relapse/progression and PFS in AL amyloidosis. Longer survival follow-up is warranted, as OS was excellent in both cohorts at 2 years.
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http://dx.doi.org/10.1016/j.jtct.2020.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010222PMC
March 2021

Plegia to walking: AHSCBMT in severe NMOSD relapse.

BMJ Neurol Open 2020 26;2(2):e000073. Epub 2020 Oct 26.

Neurology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Objectives: Neuromyelitis optica is a devastating, relapsing, inflammatory, autoimmune disorder characterised in large part by attacks of optic neuritis and transverse myelitis causing blindness and plegia in many patients. Eighty-three per cent of patients with transverse myelitic attacks and 67% of patients with optic neuritis attacks have no or a partial recovery.

Methods: Results from The European Group for Blood and Marrow Transplantation Autoimmune Diseases Working Party imply failure of autologous haematopoietic stem cell bone marrow transplantation.

Results And Conclusion: We present a case that despite eventual relapse, made a remarkable functional recovery after bone marrow transplantation which may justify bone marrow transplantation in severe cases.
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http://dx.doi.org/10.1136/bmjno-2020-000073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903183PMC
October 2020

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

Novel prognostic scoring system for autologous hematopoietic cell transplantation in multiple myeloma.

Br J Haematol 2020 11 23;191(3):442-452. Epub 2020 Oct 23.

CIBMTR® (Center for International Blood and Marrow Transplant Research), Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.

We studied 2,528 patients with upfront autologous haematopoietic cell transplantation (AHCT) for multiple myeloma (MM) from 2008-2017 to develop a prognostic model to predict outcomes. High-risk cytogenetics included t(4;14), t(14;16), t(14;20), del13q on karyotype, del17p, +1q or 1pdel. A Cox model identified factors prognostic of progression/relapse in a training subset (n = 1,246). A weighted score using these factors was assigned to a validation cohort (n = 774). Presence of high-risk cytogenetics [hazard ratio, (HR) 1·68 (1·3-2·17)] and pre-AHCT bone marrow plasma cells (BMPCs) ≥10% [1·68 (1·33-2·12)] were assigned 4 points each; albumin at diagnosis <3·5 g/dl [1·31 (1·07-1·61)] 2; standard risk cytogenetics 1, and no cytogenetics abnormality, BMPCs <10% at AHCT and albumin ≥3·5 g/dl at diagnosis 0 points each. A three-category system with low risk (0-3), intermediate risk (4-8) and high risk (9-10) showed 3-year progression-free survival in the low vs. intermediate vs. high risk of 58% (95% CI: 52-63) vs. 49% (95% CI: 43-56) vs. 31% (95% CI: 12-51), P < 0.001 respectively, and 3-year OS in low vs. intermediate vs. high risk of 88% (95% CI: 84-91) vs. 81% (95% CI: 76-86) vs. 64% (95% CI: 39-80); P < 0·001. Our prognostic scoring system can identify MM patients at risk for early relapse after AHCT.
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http://dx.doi.org/10.1111/bjh.16987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990054PMC
November 2020

Bispecific anti-CD20, anti-CD19 CAR T cells for relapsed B cell malignancies: a phase 1 dose escalation and expansion trial.

Nat Med 2020 10 5;26(10):1569-1575. Epub 2020 Oct 5.

BMT & Cellular Therapy Program, Division of Hematology & Oncology, Medical College of Wisconsin, Milwaukee, WI, USA.

Chimeric antigen receptor (CAR) T cells targeting CD19 are a breakthrough treatment for relapsed, refractory B cell malignancies. Despite impressive outcomes, relapse with CD19 disease remains a challenge. We address this limitation through a first-in-human trial of bispecific anti-CD20, anti-CD19 (LV20.19) CAR T cells for relapsed, refractory B cell malignancies. Adult patients with B cell non-Hodgkin lymphoma or chronic lymphocytic leukemia were treated on a phase 1 dose escalation and expansion trial (NCT03019055) to evaluate the safety of 4-1BB-CD3ζ LV20.19 CAR T cells and the feasibility of on-site manufacturing using the CliniMACS Prodigy system. CAR T cell doses ranged from 2.5 × 10-2.5 × 10 cells per kg. Cell manufacturing was set at 14 d with the goal of infusing non-cryopreserved LV20.19 CAR T cells. The target dose of LV20.19 CAR T cells was met in all CAR-naive patients, and 22 patients received LV20.19 CAR T cells on protocol. In the absence of dose-limiting toxicity, a dose of 2.5 × 10 cells per kg was chosen for expansion. Grade 3-4 cytokine release syndrome occurred in one (5%) patient, and grade 3-4 neurotoxicity occurred in three (14%) patients. Eighteen (82%) patients achieved an overall response at day 28, 14 (64%) had a complete response, and 4 (18%) had a partial response. The overall response rate to the dose of 2.5 × 10 cells per kg with non-cryopreserved infusion (n = 12) was 100% (complete response, 92%; partial response, 8%). Notably, loss of the CD19 antigen was not seen in patients who relapsed or experienced treatment failure. In conclusion, on-site manufacturing and infusion of non-cryopreserved LV20.19 CAR T cells were feasible and therapeutically safe, showing low toxicity and high efficacy. Bispecific CARs may improve clinical responses by mitigating target antigen downregulation as a mechanism of relapse.
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http://dx.doi.org/10.1038/s41591-020-1081-3DOI Listing
October 2020

African Americans with translocation t(11;14) have superior survival after autologous hematopoietic cell transplantation for multiple myeloma in comparison with Whites in the United States.

Cancer 2020 01 23;127(1):82-92. Epub 2020 Sep 23.

Division of Hematological Malignancy and Cellular Therapeutics, University of Kansas Health System, Kansas City, Kansas.

Background: Multiple myeloma (MM) with the translocation t(11;14) may have inferior outcomes in comparison with other standard-risk MM, and it has been suggested to portend a worse prognosis in African Americans in comparison with Whites. This study used the Center for International Blood and Marrow Transplant Research (CIBMTR) database to examine the impact of t(11;14) on the clinical outcomes of patients with MM of African American and White descent.

Methods: This study evaluated 3538 patients who underwent autologous hematopoietic cell transplantation (autoHCT) for MM from 2008 to 2016 and were reported to the CIBMTR. Patients were analyzed in 4 groups: African Americans with t(11;14) (n = 117), African Americans without t(11;14) (n = 968), Whites with t(11;14) (n = 266), and Whites without t(11;14) (n = 2187).

Results: African Americans with t(11;14) were younger, had lower Karnofsky scores, and had more advanced stage MM with a higher Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI). Fewer African Americans with t(11;14) (21%) had a coexistent high-risk marker in comparison with Whites with t(11;14) (27%). In a multivariate analysis, race and t(11;14) had no association with progression-free survival. However, overall survival was superior among African Americans with t(11;14) in comparison with Whites with t(11;14) (hazard ratio, 0.53; 95% confidence interval, 0.30-0.93; P = .03). Survival was also associated with female sex, stage, time from diagnosis to transplant, a low HCT-CI, and receipt of maintenance.

Conclusions: Race may have a differential impact on the survival of patients with t(11;14) MM who undergo autoHCT and needs to be further studied.
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http://dx.doi.org/10.1002/cncr.33208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736245PMC
January 2020

Age no bar: A CIBMTR analysis of elderly patients undergoing autologous hematopoietic cell transplantation for multiple myeloma.

Cancer 2020 12 23;126(23):5077-5087. Epub 2020 Sep 23.

The University of Texas M.D. Anderson Cancer Center, Houston, Texas.

Background: Upfront autologous hematopoietic stem cell transplantation (AHCT) remains an important therapy in the management of patients with multiple myeloma (MM), a disease of older adults.

Methods: The authors investigated the outcomes of AHCT in patients with MM who were aged ≥70 years. The Center for International Blood and Marrow Transplant Research (CIBMTR) database registered 15,999 patients with MM in the United States within 12 months of diagnosis during 2013 through 2017; a total of 2092 patients were aged ≥70 years. Nonrecurrence mortality (NRM), disease recurrence and/or progression (relapse; REL), progression-free survival (PFS), and overall survival (OS) were modeled using Cox proportional hazards models with age at transplantation as the main effect. Because of the large sample size, a P value <.01 was considered to be statistically significant a priori.

Results: An increase in AHCT was noted in 2017 (28%) compared with 2013 (15%) among patients aged ≥70 years. Although approximately 82% of patients received melphalan (Mel) at a dose of 200 mg/m overall, 58% of the patients aged ≥70 years received Mel at a dose of 140 mg/m . On multivariate analysis, patients aged ≥70 years demonstrated no difference with regard to NRM (hazard ratio [HR] 1.3; 99% confidence interval [99% CI], 1-1.7 [P = .06]), REL (HR, 1.03; 99% CI, 0.9-1.1 [P = 0.6]), PFS (HR, 1.06; 99% CI, 1-1.2 [P = 0.2]), and OS (HR, 1.2; 99% CI, 1-1.4 [P = .02]) compared with the reference group (those aged 60-69 years). In patients aged ≥70 years, Mel administered at a dose of 140 mg/m was found to be associated with worse outcomes compared with Mel administered at a dose of 200 mg/m , including day 100 NRM (1% [95% CI, 1%-2%] vs 0% [95% CI, 0%-1%]; P = .003]), 2-year PFS (64% [95% CI, 60%-67%] vs 69% [95% CI, 66%-73%]; P = .003), and 2-year OS (85% [95% CI, 82%-87%] vs 89% [95% CI, 86%-91%]; P = .01]), likely representing frailty.

Conclusions: The results of the current study demonstrated that AHCT remains an effective consolidation therapy among patients with MM across all age groups.
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http://dx.doi.org/10.1002/cncr.33171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063213PMC
December 2020

Propylene Glycol-Free Melphalan versus PG-Melphalan as Conditioning for Autologous Hematopoietic Cell Transplantation for Myeloma.

Biol Blood Marrow Transplant 2020 12 11;26(12):2229-2236. Epub 2020 Sep 11.

Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin; Blood and Marrow Transplant & Cellular Therapy Program, Medical College of Wisconsin, Milwaukee, Wisconsin; Center for International Blood and Marrow Transplant Research, Milwaukee Campus, Milwaukee, Wisconsin. Electronic address:

High-dose melphalan (Mel) conditioning before autologous hematopoietic cell transplantation (autoHCT) is standard of care for patients with transplantation-eligible multiple myeloma. The traditional lyophilized Mel formulation has inadequate solubility and stability after reconstitution, leading to the use of propylene glycol (PG) as a solubilizing agent. A newer PG-free Mel preparation (Evomela) uses beta cyclodextrin captisol as a solubilizing agent and was approved by the United States Food and Drug Administration as a conditioning agent based on a single-phase IIb study showing bioequivalence. We compared the outcomes of consecutive patients with myeloma undergoing autoHCT using the 2 formulations of Mel for conditioning as our center switched from using the older formulation (PG-Mel) to the newer one (PGF-Mel). Of 294 autoHCT recipients, 162 received PG-Mel conditioning and 132 received PGF-Mel conditioning. The PGF-Mel group was older and had a lower average Karnofsky Performance Status score. PGF-Mel was associated with faster neutrophil recovery (median, 12 days versus 13 days; P < .001), fewer grade 3-4 infections within 30 days of autoHCT (1.5% versus 8.0%; P = .048), and a lower 30-day rehospitalization rate (6.8% versus 17.9%; P = .04), as confirmed by propensity-weighted analysis. No significant between-group differences were detected in mucositis, organ toxicity, myeloma response, or 100-day mortality.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.030DOI Listing
December 2020

Busulfan, melphalan, and bortezomib compared to melphalan as a high dose regimen for autologous hematopoietic stem cell transplantation in multiple myeloma: long term follow up of a novel high dose regimen.

Leuk Lymphoma 2020 12 31;61(14):3484-3492. Epub 2020 Aug 31.

Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.

Melphalan at a dose of 200 mg/m (MEL200) remains the standard high dose therapy before autologous stem cell transplantation (ASCT) for multiple myeloma (MM). Intensifying the high dose regimen has shown promising results. We report here 7-year follow up of our novel high dose regimen of busulfan and melphalan followed by bortezomib (BuMelVel). Forty-three MM patients received BuMelVel high dose therapy with pharmacokinetic adjusted busulfan. Outcomes were compared to a matched control cohort from the CIBMTR database ( = 162) receiving MEL200. The primary endpoint was progression free survival. Five year PFS was 47% v 30% (95% CI; 32-62) in favor or the BuMelVel group (95% CI; 23-37) ( = 0.05). In multivariate analysis for PFS, BuMelVel (HR 0.65; 95% CI 0.44-0.97)( = 0.036) was predictive. Similar to recent reports of double alkylator therapy, although depth of response was similar between the BuMelVel group and MEL200, the BUMELVEL group experienced an improved PFS.
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http://dx.doi.org/10.1080/10428194.2020.1811275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786301PMC
December 2020

Autonomic nervous system control of multiple myeloma.

Blood Rev 2021 03 11;46:100741. Epub 2020 Aug 11.

Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee 53226, WI, USA. Electronic address:

The autonomic nervous system (ANS), which consists of antagonistic sympathetic (adrenergic) and parasympathetic (cholinergic) arms, has emerged as an important regulator of neoplastic development, yet little is known about its role in multiple myeloma (MM). Clinical findings that anti-adrenergic β-blocker intake reduces risk of disease-specific death and overall mortality in patients with MM have indicated that adrenergic input may worsen myeloma outcome. However, preclinical studies using β-adrenergic receptor agonists or antagonists produced controversial results as to whether sympathetic pathways promote or inhibit myeloma. Retrospective outcome data demonstrating that high message levels of cholinergic receptor genes predict inferior survival in the Multiple Myeloma Research Foundation CoMMpass trial suggest that parasympathetic input may drive myeloma progression in a subset of patients. Here we review the ill-defined role of the ANS in MM, put myeloma in the context of other cancers, and discuss knowledge gaps that may afford exciting research opportunities going forward.
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http://dx.doi.org/10.1016/j.blre.2020.100741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876165PMC
March 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
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