Publications by authors named "Shaji K Kumar"

301 Publications

Characteristics and risk factors for thrombosis in POEMS syndrome: a retrospective evaluation of 230 patients.

Am J Hematol 2021 Nov 25. Epub 2021 Nov 25.

Division of Hematology, Mayo Clinic, Rochester, Minnesota, US.

Thromboses are prevalent in POEMS syndrome, but few risk factors for POEMS-associated thrombosis have been identified. The objective of this study is to identify novel risk factors for POEMS-associated thrombosis. In this retrospective cohort of 230 POEMS patients, 27% developed thrombosis. Arterial events were slightly more common than venous. Stroke accounted for 26% of all thromboses and 53% of arterial events. There were differences in baseline features between the thrombosis group and the no thrombosis group, and these were driven by patients with arterial thrombosis. Risk factors for arterial thrombosis included thrombocytosis, elevated hemoglobin/hematocrit, extravascular volume overload and splenomegaly. Hyperprolactinemia appeared to be a risk factor for venous thrombosis. The risk of thrombosis was most striking among men with elevated hemoglobin (32% versus 5%, p < 0.001) and hematocrit (42% versus 5%, p < 0.001) compared to men without. Most thromboses occurred prior to POEMS directed therapy, and most that occurred during therapy happened within 3 months of diagnosis. Twenty-one percent of patients with thrombosis had recurrence. In recognition of high overall rates of thrombosis in this population, all patients with POEMS syndrome should receive prophylactic antiplatelet therapy, and clinicians should consider anticoagulation in patients with risk factors for POEMS-associated thrombosis. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ajh.26422DOI Listing
November 2021

The mechanisms and therapeutic targets of ferroptosis in cancer.

Expert Opin Ther Targets 2021 Nov 25. Epub 2021 Nov 25.

Laboratory of Cancer Precision Medicine, the First Hospital of Jilin University, Changchun, Jilin, China.

Introduction: Ferroptosis, a form of programmed cell death, is mediated primarily by lipid peroxidation via a unique iron-dependent process. The mechanisms of ferroptosis involve the metabolisms of amino acids, irons, and lipids, and the regulation of antioxidant systems. Evidence supports the roles of ferroptosis in cancer, while metabolic reprogramming (a hallmark of cancer) renders tumor cells highly vulnerable to ferroptosis and thus provides a rationale for ferroptosis-targeted therapy for cancer.

Area Covered: This article examines the current understanding of the mechanisms and related signaling pathways involving ferroptosis; it focuses on novel targets in cancer and its treatment and drug resistance. The development of ferroptosis-targeted therapy, especially in combination with conventional or non-conventional therapies, are considered with dilemmas and key questions in this research area.

Expert Opinion: An increasing number of potential targets and ferroptosis inducers (FINs) have been identified to treat cancer. However, no specific FIN has entered clinical trials thus far, likely due to poor efficacy and high toxicity . Thus, new FINs with high selectivity and bioavailability are required to target tumor cells more specifically and potently. Particularly, the combination of FINs with chemotherapy, radiotherapy, targeted therapy, and immunotherapy warrants clinical investigation in the future.
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http://dx.doi.org/10.1080/14728222.2021.2011206DOI Listing
November 2021

Prognostic significance of acquired 1q22 gain in multiple myeloma.

Am J Hematol 2021 Oct 28. Epub 2021 Oct 28.

Department of Hematology, Mayo Clinic, Rochester, Minnesota, USA.

Gain of 1q22 at diagnosis portends poorer outcomes in multiple myeloma (MM), but the prognostic significance of acquired 1q22 gain is unknown. We identified 63 MM patients seen at Mayo Clinic from 1/2004 to 12/2019 without 1q22 gain at diagnosis who acquired it during follow up and compared them to 63 control patients who did not acquire 1q22 gain with similar follow up. We also compared outcomes in the acquired 1q22 gain group with outcomes in 126 patients with 1q22 gain present at diagnosis. The incidence of acquired 1q22 gain was 6.1% (median follow-up 6.8 years); median time to acquisition was 5.0 years (range: 0.7-11.5 years). Abnormalities on baseline fluorescence in situ hybridization (FISH) included trisomies (54%) and monosomy 13 (39%); 16 (25%) had high-risk (HR) translocations or del(17p). Median progression-free survival with front line therapy was 29.5 months in patients with acquired 1q22 gain, versus 31.4 months in control patients (p = .34) and 31.2 months in patients with de novo 1q22 gain (p = .04). Median overall survival (OS) from diagnosis was 10.9 years in patients with acquired 1q22 gain, versus 13.0 years in control patients (p = .03) and 6.3 years in patients with de novo 1q22 gain (p = .01). Presence of HR FISH at baseline increased risk of 1q22 gain acquisition. We demonstrate that acquisition of 1q22 gain is a significant molecular event in MM, associated with reduced OS. Among HR patients for whom this clonal evolution is determined, a risk-adapted approach and/or clinical trial should be considered.
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http://dx.doi.org/10.1002/ajh.26391DOI Listing
October 2021

Mortality trends in multiple myeloma after the introduction of novel therapies in the United States.

Leukemia 2021 Oct 26. Epub 2021 Oct 26.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Advances in the understanding of disease biology, drug development, and supportive care have led to improved outcomes in multiple myeloma. Given that these improvements have been reported in clinical trial and referral center populations, questions remain about the generalizability of this observation to patients treated in the community. Contrasting the overall survival experience of 3783 patients seen at Mayo Clinic and 57,654 patients followed in the Surveillance, Epidemiology, and End Results Program (SEER) between 2004 and 2018, we observed different mortality trends across patient populations and subgroups. Early mortality decreased and estimated 5-year overall survival increased over time in both patient populations. Excess mortality (compared to the general population) declined over time in Mayo Clinic patients and remained largely unchanged in SEER patients. Improvements over time were primarily observed in patients with favorable disease characteristics and older patients with multiple myeloma remain a vulnerable population with significant excess mortality compared to the United States general population. Patients with unfavorable disease characteristics have derived disproportionately less benefit from recent advances in the field. Future efforts need to focus on the development of safe and effective therapies for these patients and on increasing timely access to specialized care for patients in the community.
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http://dx.doi.org/10.1038/s41375-021-01453-5DOI Listing
October 2021

Chimeric antigen receptor T-cells, bispecific antibodies, and antibody-drug conjugates for multiple myeloma: An update.

Am J Hematol 2021 Oct 18. Epub 2021 Oct 18.

Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Patients with multiple myeloma who are refractory to currently available effective therapies have short expected survival. Modalities harvesting the knowledge of the immune characteristics and microenvironment of myeloma such as chimeric antigen receptor (CAR) T-lymphocytes, bispecific antibodies (bsAbs), and antibody-drug conjugates (ADCs) have shown potential in early phase trials. Based on data from phase 2 studies, idecabtagene vicleucel (ide cel), an anti-B-cell maturation antigen CAR T-product and belantamab mafodotin (belamaf), an ADC are currently approved in the relapsed/refractory setting. bsAbs have shown promise with quick and deep responses. In this review, we summarize the available evidence on these treatments from clinical trials.
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http://dx.doi.org/10.1002/ajh.26379DOI Listing
October 2021

Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial.

Lancet Oncol 2021 11 13;22(11):1582-1596. Epub 2021 Oct 13.

Levine Cancer Institute/Atrium Health, Charlotte, NC, USA.

Background: In the primary analysis of the phase 3 MAIA trial (median follow-up 28·0 months), a significant improvement in progression-free survival was observed with daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in transplantation-ineligible patients with newly diagnosed multiple myeloma. Here, we report the updated efficacy and safety results from a prespecified interim analysis for overall survival.

Methods: MAIA is an ongoing, multicentre, randomised, open-label, phase 3 trial that enrolled patients at 176 hospitals in 14 countries across North America, Europe, the Middle East, and the Asia-Pacific region. Eligible patients were aged 18 years or older, had newly diagnosed multiple myeloma, had an Eastern Cooperative Oncology Group performance status score of 0-2, and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation because of their age (≥65 years) or comorbidities. Patients were randomly assigned (1:1) using randomly permuted blocks (block size 4) by an interactive web response system to receive 28-day cycles of intravenous daratumumab (16 mg/kg, once per week during cycles 1-2, once every 2 weeks in cycles 3-6, and once every 4 weeks thereafter) plus oral lenalidomide (25 mg on days 1-21 of each cycle) and oral dexamethasone (40 mg on days 1, 8, 15, and 22 of each cycle; daratumumab group) or lenalidomide and dexamethasone alone (control group). Randomisation was stratified by International Staging System disease stage, geographical region, and age. Neither patients nor investigators were masked to treatment assignment. The primary endpoint was progression-free survival, which was centrally assessed, and a secondary endpoint was overall survival (both assessed in the intention-to-treat population). The safety population included patients who received at least one dose of the study treatment. The results presented here are from a prespecified interim analysis for overall survival, for which the prespecified stopping boundary was p=0·0414. This trial is registered with ClinicalTrials.gov, NCT02252172.

Findings: Between March 18, 2015, and Jan 15, 2017, 952 patients were assessed for eligibility, of whom 737 patients were enrolled and randomly assigned to the daratumumab group (n=368) or the control group (n=369). At a median follow-up of 56·2 months (IQR 52·7-59·9), median progression-free survival was not reached (95% CI 54·8-not reached) in the daratumumab group versus 34·4 months (29·6-39·2) in the control group (hazard ratio [HR] 0·53 [95% CI 0·43-0·66]; p<0·0001). Median overall survival was not reached in either group (daratumumab group, 95% CI not reached-not reached; control group, 95% CI 55·7-not reached; HR 0·68 [95% CI 0·53-0·86]; p=0·0013). The most common (>15%) grade 3 or higher treatment-emergent adverse events were neutropenia (197 [54%] patients in the daratumumab group vs 135 [37%] patients in the control group), pneumonia (70 [19%] vs 39 [11%]), anaemia (61 [17%] vs 79 [22%]), and lymphopenia (60 [16%] vs 41 [11%]). Serious adverse events occurred in 281 (77%) patients in the daratumumab group and 257 (70%) patients in the control group. Treatment-related deaths occurred in 13 (4%) patients in the daratumumab group and ten (3%) patients in the control group.

Interpretation: Daratumumab plus lenalidomide and dexamethasone increased overall survival and progression-free survival in patients ineligible for stem-cell transplantation with newly diagnosed multiple myeloma. There were no new safety concerns. Our results support the frontline use of daratumumab plus lenalidomide and dexamethasone for patients with multiple myeloma who are ineligible for transplantation.

Funding: Janssen Research & Development.
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http://dx.doi.org/10.1016/S1470-2045(21)00466-6DOI Listing
November 2021

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

Expert Rev Hematol 2021 Oct 8:1-16. 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
October 2021

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
October 2021

Decoding DNA methylation in epigenetics of multiple myeloma.

Blood Rev 2021 Jul 31:100872. Epub 2021 Jul 31.

Laboratory of Cancer Precision Medicine, the First Hospital of Jilin University, 519 Dongminzhu Street, Changchun, Jilin 130061, China. Electronic address:

Dysregulation of DNA methylation in B cells has been observed during their neoplastic transformation and therefore closely associated with various B-cell malignancies including multiple myeloma (MM), a malignancy of terminally differentiated plasma cells. Emerging evidence has unveiled pronounced alterations in DNA methylation in MM, including both global and gene-specific changes that can affect genome stability and gene transcription. Moreover, dysregulated expression of DNA methylation-modifying enzymes has been related with myelomagenesis, disease progression, and poor prognosis. However, the functional roles of the epigenetic abnormalities involving DNA methylation in MM remain elusive. In this article, we review current understanding of the alterations in DNA methylome and DNA methylation modifiers in MM, particularly focusing on DNA methyltransferases (DNMTs) and tet methylcytosine dioxygenases (TETs). We also discuss how these DNA methylation modifiers may be regulated and function in MM cells, therefore providing a rationale for developing novel epigenetic therapies targeting DNA methylation in MM.
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http://dx.doi.org/10.1016/j.blre.2021.100872DOI Listing
July 2021

Minimal Residual Disease in Myeloma: Application for Clinical Care and New Drug Registration.

Clin Cancer Res 2021 Jul 28. Epub 2021 Jul 28.

Departamento de Hematologia, Hospital Universitario de Salamanca.

The development of novel agents has transformed the treatment paradigm for multiple myeloma (MM), with minimal residual disease (MRD) negativity now achievable across the entire disease spectrum. Bone marrow-based technologies to assess MRD, including approaches using next-generation flow and next-generation sequencing, have provided real-time clinical tools for the sensitive detection and monitoring of MRD in MM patients. Complementary liquid biopsy-based assays are now quickly progressing with some, such as mass spectrometry methods, being very close to clinical use, while others utilizing nucleic acid-based technologies are still developing and will prove important to further our understanding of the biology of MRD. On the regulatory front, multiple retrospective individual patient and clinical trial level meta-analyses have already shown and will continue to assess the potential of MRD as a surrogate for patient outcome. Given all this progress, it is not surprising that a number of clinicians are now considering using MRD to inform real world clinical care of patients across the spectrum from smoldering myeloma to relapsed refractory MM, with each disease setting presenting key challenges and questions that will need to be addressed through clinical trials. The pace of advances in targeted and immune therapies in MM is unprecedented, and novel MRD-driven biomarker strategies are essential to accelerate innovative clinical trials leading to regulatory approval of novel treatments and continued improvement in patient outcomes.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1059DOI Listing
July 2021

Perspectives on Drug Development in Multiple Myeloma-Looking Forward to 2025.

Clin Cancer Res 2021 Jul 27. Epub 2021 Jul 27.

FDA, Office of the Commissioner, Office of Medical Products and Tobacco, Oncology Center of Excellence, Silver Spring, Maryland.

The multiple myeloma treatment landscape has evolved considerably over the last 20 years with the development of multiple therapies with novel mechanisms of action and new combination regimens. However, the recent failure of several large phase III trials, coupled with an increased understanding of the mutational landscape of multiple myeloma has provided opportunities to explore optimal strategies for future multiple myeloma drug development. The Office of Oncologic Diseases at the FDA held an educational symposium, "Drug Development in MM-Project 2025," in November 2019. The symposium brought together select U.S.-based academic thought leaders in the field of multiple myeloma to explore issues relevant to regulatory science in the field, including considerations for trial design, combination strategies, control arms, and precision medicine. This article summarizes the highlights of this educational symposium held at the FDA, including discussions on the future development of novel drugs and drug combinations and biomarker-directed therapies for patients with multiple myeloma.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-1069DOI Listing
July 2021

Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, MAIA.

Blood 2021 Jul 21. Epub 2021 Jul 21.

Dana-Farber Cancer Institute, Boston, Massachusetts, United States.

We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible newly diagnosed multiple myeloma (TIE NDMM) using data from four phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD-negativity rates and reduced the risk of disease progression or death by approximately half versus standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response (CR) or better with MRD-negative status, and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10‒5 threshold). Patient-level data were pooled from all four studies, and for patients with TIE NDMM plus patients with RRMM who received ≤2 prior lines of therapy (≤2PL). PFS was evaluated by response and MRD status. Median follow-up (months) was: POLLUX, 54.8; CASTOR, 50.2; ALCYONE, 40.1; and MAIA, 36.4. Patients who achieved ≥CR and MRD negativity had improved PFS versus those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM ≤2PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.ClinicalTrials.gov: NCT02076009/NCT02136134/NCT02195479/NCT02252172.
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http://dx.doi.org/10.1182/blood.2021011101DOI Listing
July 2021

Sustained Minimal Residual Disease Negativity With Daratumumab in Newly Diagnosed Multiple Myeloma: MAIA and ALCYONE.

Blood 2021 Jul 16. Epub 2021 Jul 16.

Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, Canada.

In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone; D-Rd) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone; D-VMP). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10-5) occurred for patients achieving complete response (CR) or better, and after ≥CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving ≥CR. In MAIA, (D-Rd, n=368; Rd, n=369), and ALCYONE (D-VMP, n=350; VMP, n=356), the median duration of follow-up was 36.4 months and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS versus control groups. In a pooled analysis, patients who were MRD negative had improved PFS versus patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. ClinicalTrials.gov identifier NCT02252172 (MAIA); NCT02195479 (ALCYONE).
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http://dx.doi.org/10.1182/blood.2020010439DOI Listing
July 2021

Treatment and outcome of newly diagnosed multiple myeloma patients > 75 years old: a retrospective analysis.

Leuk Lymphoma 2021 Dec 15;62(12):3011-3018. Epub 2021 Jul 15.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.

This is a retrospective study of patients with multiple myeloma (MM) who were >75 years old. We identified 394 patients and for non-trial patients ( = 350), immunomodulatory drug (IMiD)+dex (32%) was the most commonly used regimen followed by alkylator with steroids or other therapy (21%), alkylator + proteasome inhibitor (PI)+steroid (18%), and IMiD + PI + dex (13%). Overall, achieving ≥ very good partial response was more in patients receiving a triplet compared to other therapies (46% vs. 21%,  < 0.0001). Also, the median overall survival (OS) was significantly longer in patients who were treated with a triplet (median OS: 50.2 vs. 32.8 months,  = 0.0006). In a multivariate for OS, receiving a triplet (HR: 0.65,  = 0.02), not having an R-ISS stage 3 (HR: 0.36,  = 0.0003), and bone marrow plasma cell percentage <60% (HR: 0.69,  = 0.03) were predictive. In conclusion, being able to receive triplet therapy was associated with better survival in our MM patients >75 years old.
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http://dx.doi.org/10.1080/10428194.2021.1950708DOI Listing
December 2021

The Prognostic Role of Structural Variants Identified by NGS and FISH in Multiple Myeloma.

Clin Cancer Res 2021 Jul 7. Epub 2021 Jul 7.

Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Purpose: Structural variants (SV) of the gene region are common in multiple myeloma and influence disease progression. However, the prognostic significance of different SVs in multiple myeloma has not been clearly established.

Experimental Design: We conducted a retrospective study of multiple myeloma comparing SV subtypes identified by next-generation sequencing (NGS) and FISH to expression and disease survival using 140 cases from Mayo Clinic and 658 cases from the MMRF CoMMpass study.

Results: SVs were found in 41% of cases and were classified into nine subtypes. A correlation between the presence of a SV and increased expression was identified. Among the nine subtypes, the non-immunoglobulin (non-Ig) insertion subtype was independently associated with improved outcomes, while the Ig insertion subtype, specifically involving the IgL gene partner, was independently associated with poorer outcomes compared with other SV subtypes. Although the FISH methodology failed to detect approximately 70% of all SVs, those detected by FISH were associated with elevated gene expression and poor outcomes suggesting a different pathogenic role for FISH-detected subtypes compared with other subtypes.

Conclusions: Understanding the impact of different SVs on disease outcome is necessary for the reliable interpretation of SVs in multiple myeloma. NGS approaches should be considered as a replacement technique for a more comprehensive evaluation of the multiple myeloma clone.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0005DOI Listing
July 2021

Dual Primary IGH Translocations in Multiple Myeloma: A Novel Finding.

Clin Lymphoma Myeloma Leuk 2021 09 9;21(9):e710-e713. Epub 2021 May 9.

Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN. Electronic address:

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http://dx.doi.org/10.1016/j.clml.2021.05.001DOI Listing
September 2021

Initial Therapeutic Approaches to Patients with Multiple Myeloma.

Adv Ther 2021 07 18;38(7):3694-3711. Epub 2021 Jun 18.

Division of Hematology, Department of Medicine, Mayo Clinic College of Medicine, Mayo Clinic, 200 First st SW, Rochester, MN, 55905, USA.

Multiple Myeloma (MM) is part of a spectrum of plasma cell disorders that may result in end organ damage. MM is subclassified into high and standard risk based on cytogenetic and laboratory markers. The treatment of newly diagnosed multiple myeloma is constantly changing with the advent of novel therapies. Recent advances in therapies have resulted in longer time to remission and overall survival. the introduction of targeted therapy with monoclonal antibodies such as Daratumumab has improved stringent complete response to 39%. In this review, we outline the current approach to diagnosis, prognosis, and management of newly diagnosed multiple myeloma in both transplant eligible and ineligible patients.
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http://dx.doi.org/10.1007/s12325-021-01824-5DOI Listing
July 2021

Venetoclax for the treatment of multiple myeloma: Outcomes outside of clinical trials.

Am J Hematol 2021 09 5;96(9):1131-1136. Epub 2021 Jul 5.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Multiple myeloma (MM) remains an incurable disease despite incorporation of novel agents. Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor is approved for some hematologic malignancies but not yet for MM, although clinical trials have shown efficacy in patients with MM, particularly those harboring t(11;14). We reviewed the medical records of relapsed and/or refractory MM patients to study the efficacy and safety of venetoclax used outside of clinical trials at Mayo Clinic between December, 2016 and March, 2019. The data cut-off date was August 06, 2020. We identified 56 patients of whom 42 (75%) harbored t(11;14). The median number of prior therapies was six (range 1-15) and 14% of patients had received ≥10 prior lines of therapy. Fifty-three (95%) patients were refractory to an immunomodulatory drug and proteasome inhibitor. Venetoclax was used as monotherapy or doublet, in combination with dexamethasone in 55% (n = 31) and a triplet or quadruplet in 45% of patients. No patient experienced tumor lysis syndrome. Overall response rate in 52 evaluable patients was 44%. The median time to best response was 2 months and median duration of response was 13.6 months. The median PFS for the entire cohort was 5.8 (95% CI 4.9-10.3) months and median OS was 28.4 (95% CI 14.6-not reached) months. The presence of t(11;14) was associated with improved PFS (median 9.7 months vs. 4.2 months, p = 0.019) and OS (median not reached vs. 10.8 9 months, p = 0.015). Venetoclax demonstrates encouraging activity in heavily-treated patients with relapsed/refractory MM, particularly the t(11;14) patient-population.
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http://dx.doi.org/10.1002/ajh.26269DOI Listing
September 2021

Belantamab mafodotin detection by MASS-FIX and immunofixation.

Clin Chem Lab Med 2021 Oct 11;59(11):e430-e433. Epub 2021 Jun 11.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

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http://dx.doi.org/10.1515/cclm-2021-0326DOI Listing
October 2021

Final Overall Survival Analysis of the TOURMALINE-MM1 Phase III Trial of Ixazomib, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma.

J Clin Oncol 2021 08 11;39(22):2430-2442. Epub 2021 Jun 11.

University Hospital Hôtel Dieu, Nantes, France.

Purpose: The double-blind, placebo-controlled, phase III TOURMALINE-MM1 study demonstrated a statistically significant improvement in progression-free survival with ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd in patients with relapsed or refractory multiple myeloma. We report the final analyses for overall survival (OS).

Patients And Methods: Patients were randomly assigned to ixazomib-Rd (n = 360) or placebo-Rd (n = 362), stratified by number of prior therapies (1 2 or 3), previous proteasome inhibitor (PI) exposure (yes no), and International Staging System disease stage (I or II III). OS (intent-to-treat population) was a key secondary end point.

Results: With a median follow-up of 85 months, median OS with ixazomib-Rd versus placebo-Rd was 53.6 versus 51.6 months (hazard ratio, 0.939; = .495). Lower hazard ratios, indicating larger magnitude of OS benefit with ixazomib-Rd versus placebo-Rd, were seen in predefined subgroups: refractory to any (0.794) or last (0.742) treatment line; age > 65-75 years (0.757); International Staging System stage III (0.779); 2/3 prior therapies (0.845); high-risk cytogenetics (0.870); and high-risk cytogenetics and/or 1q21 amplification (0.862). Following ixazomib-Rd versus placebo-Rd, 71.7% versus 69.9% of patients received ≥ 1 anticancer therapy, of whom 24.7% versus 33.9% received daratumumab and 71.8% versus 76.9% received PIs (next-line therapy: 47.5% 55.8%). Rates of new primary malignancies were similar with ixazomib-Rd (10.3%) and placebo-Rd (11.9%). There were no new or additional safety concerns.

Conclusion: Median OS values in both arms were the longest reported in phase III studies of Rd-based triplets in relapsed or refractory multiple myeloma at the time of this analysis; progression-free survival benefit with ixazomib-Rd versus placebo-Rd did not translate into a statistically significant OS benefit on intent-to-treat analysis. OS benefit was greater in subgroups with adverse prognostic factors. OS interpretation was confounded by imbalances in subsequent therapies received, especially PIs and daratumumab.
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http://dx.doi.org/10.1200/JCO.21.00972DOI Listing
August 2021

Treatment of AL Amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Statement 2020 Update.

Mayo Clin Proc 2021 06;96(6):1546-1577

Division of Hematology, Mayo Clinic, Rochester, MN.

Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder leading to progressive and life-threatening organ failure. The heart and the kidneys are the most commonly involved organs, but almost any organ can be involved. Because of the nonspecific presentation, diagnosis delay is common, and many patients are diagnosed with advanced organ failure. In the era of effective therapies and improved outcomes for patients with AL amyloidosis, the importance of early recognition is further enhanced as the ability to reverse organ dysfunction is limited in those with a profound organ failure. As AL amyloidosis is an uncommon disorder and given patients' frailty and high early death rate, management of this complex condition is challenging. The treatment of AL amyloidosis is based on various anti-plasma cell therapies. These therapies are borrowed and customized from the treatment of multiple myeloma, a more common disorder. However, a growing number of phase 2/3 studies dedicated to the AL amyloidosis population are being performed, making treatment decisions more evidence-based. Supportive care is an integral part of management of AL amyloidosis because of the inherent organ dysfunction, limiting the delivery of effective therapy. This extensive review brings an updated summary on the management of AL amyloidosis, sectioned into the 3 pillars for survival improvement: early disease recognition, anti-plasma cell therapy, and supportive care.
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http://dx.doi.org/10.1016/j.mayocp.2021.03.012DOI Listing
June 2021

IGVL gene region usage correlates with distinct clinical presentation in IgM vs non-IgM light chain amyloidosis.

Blood Adv 2021 04;5(8):2101-2105

Division of Hematology.

Patients with immunoglobulin M (IgM) light chain (AL) amyloidosis have a distinct clinical presentation compared with those with non-IgM amyloidosis. We hypothesized that differential immunoglobulin light-chain variable region (IGVL) gene usage may explain the differences in organ involvement, because IGVL usage correlates with organ tropism. IGVL usage was evaluated by mass spectrometry of amyloid deposits (IgM, n = 45; non-IgM, n = 391) and differed across the 2 groups. In the λ family, LV2-08 (13% vs 2%; P < .001) and LV2-14 (36% vs 10%; P < .001) usage was more common in IgM vs non-IgM amyloidosis, whereas LV1-44 (0% vs 10%; P = .02) and LV6-57 (2% vs 18%; P = .004) usage was less common. In the κ family, there was a trend toward higher KV4-01 (11% vs 4%; P = .06) usage in IgM amyloidosis. IGVL usage correlated with disease characteristics/organ tropism. LV2-14 (more common in IgM amyloidosis) has historically been associated with peripheral nerve involvement and lower light chain burden, which were more frequent in IgM amyloidosis. LV1-44 (less common in IgM), associated with cardiac involvement, was less frequent in IgM patients. LV6-57 (less common in IgM) is associated with t(11;14), which was less frequent in IgM patients. In conclusion, IGVL gene usage differs in patients with IgM vs non-IgM amyloidosis and may explain the distinct clinical presentation.
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http://dx.doi.org/10.1182/bloodadvances.2020003671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095150PMC
April 2021

Second Stem Cell Transplantation for Relapsed Refractory Light Chain (AL) Amyloidosis.

Transplant Cell Ther 2021 07 8;27(7):589.e1-589.e6. Epub 2021 Apr 8.

Division of Hematology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Autologous stem cell transplantation (ASCT) is an effective treatment modality in light chain (AL) amyloidosis but can be offered only to a subset of patients. The feasibility, benefit, and risks of second ASCT (ASCT2) have been rarely reported. The objective of this study was to assess the utility of ASCT2 in AL amyloidosis and to identify the target population with the greatest benefit. This retrospective study examined all AL patients who underwent ASCT2 for relapsed refractory disease between 2003 and 2020. Twenty-six patients were included. The use of ASCT2 has increased over time, from 2.5% of all ASCTs from 2003 to 2011 to 5% from 2012 to 2020 (P = .056). The median time between the first ASCT (ASCT1) and ASCT2 was 7.2 years (range, 0.6 to 17.7). Fifty-four percent of patients received at least one line of therapy between ASCTs. Second stem cell mobilization prior to ASCT2 was required in 42% of patients. Full-dose melphalan (200 mg/m) was given to 73% of patients. Two patients had failed to engraft by day 100 but eventually recovered to normal blood counts. Both had second stem cell mobilization prior to ASCT2 with prior melphalan exposure. Four patients (15%) died before day 100. Progression-free and overall survival were significantly longer from ASCT2 for those who had durable remission after ASCT1 (≥5 years) and for those who did not receive therapy between ASCTs. ASCT2 is feasible and can produce favorable outcomes, especially among those with durable response to ASCT1. ASCT2, if chosen, should preferably be performed after durable response to ASCT1 and at first progression.
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http://dx.doi.org/10.1016/j.jtct.2021.03.031DOI Listing
July 2021

Oral ixazomib, lenalidomide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma.

Blood 2021 07;137(26):3616-3628

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN; and.

Continuous lenalidomide-dexamethasone (Rd)-based regimens are among the standards of care in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. The oral proteasome inhibitor ixazomib is suitable for continuous dosing, with predictable, manageable toxicities. In the double-blind, placebo-controlled TOURMALINE-MM2 trial, transplant-ineligible NDMM patients were randomized to ixazomib 4 mg (n = 351) or placebo (n = 354) plus Rd. After 18 cycles, dexamethasone was discontinued and treatment was continued using reduced-dose ixazomib (3 mg) and lenalidomide (10 mg) until progression/toxicity. The primary endpoint was progression-free survival (PFS). Median PFS was 35.3 vs 21.8 months with ixazomib-Rd vs placebo-Rd, respectively (hazard ratio [HR], 0.830; 95% confidence interval, 0.676-1.018; P = .073; median follow-up, 53.3 and 55.8 months). Complete (26% vs 14%; odds ratio [OR], 2.10; P < .001) and ≥ very good partial response (63% vs 48%; OR, 1.87; P < .001) rates were higher with ixazomib-Rd vs placebo-Rd. In a prespecified high-risk cytogenetics subgroup, median PFS was 23.8 vs 18.0 months (HR, 0.690; P = .019). Overall, treatment-emergent adverse events (TEAEs) were mostly grade 1/2. With ixazomib-Rd vs placebo-Rd, 88% vs 81% of patients experienced grade ≥3 TEAEs, 66% vs 62% serious TEAEs, and 35% vs 27% TEAEs resulting in regimen discontinuation; 8% vs 6% died on study. Addition of ixazomib to Rd was tolerable with no new safety signals and led to a clinically meaningful PFS benefit of 13.5 months. Ixazomib-Rd is a feasible option for certain patients who can benefit from an all-oral triplet combination. This trial was registered at www.clinicaltrials.gov as #NCT01850524.
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http://dx.doi.org/10.1182/blood.2020008787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8462404PMC
July 2021

Paving the way to precision medicine in multiple myeloma.

Expert Rev Hematol 2021 Apr 12;14(4):323-327. Epub 2021 Apr 12.

Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.

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http://dx.doi.org/10.1080/17474086.2021.1905515DOI Listing
April 2021

Current approaches to management of high-risk multiple myeloma.

Am J Hematol 2021 07 13;96(7):854-871. Epub 2021 Apr 13.

Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.

The median overall survival in multiple myeloma is rapidly approaching 10 years; however, in nearly a fifth of patients the prognosis remains poor. Therefore, the modern-day management of myeloma patients should be individualized, with a more intense and continuous approach in these high-risk patients. This includes first-line treatment based on multi-drug combinations employing the most effective drug combinations, upfront autologous stem cell transplantation (in eligible patients with tandem transplantation being a consideration), and maintenance based on proteasome inhibitor-based combinations. This paper reviews the results of recent retrospective analyses and clinical trials, but also gives a glance into the future by presenting the ongoing trials.
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http://dx.doi.org/10.1002/ajh.26161DOI Listing
July 2021

Clinical Characteristics and Outcomes of Patients With Primary Plasma Cell Leukemia in the Era of Novel Agent Therapy.

Mayo Clin Proc 2021 03;96(3):677-687

Division of Hematology, Mayo Clinic, Rochester, MN. Electronic address:

Objective: To evaluate the clinical outcomes of patients with primary plasma cell leukemia (pPCL) defined by 5% or greater clonal circulating plasma cells on peripheral blood smear and treated with novel agent induction therapies.

Patients And Methods: A cohort of 68 patients with pPCL diagnosed at the Mayo Clinic in Rochester, Minnesota, from January 1, 2000, to December 31, 2019, and treated with novel agent induction therapies was evaluated.

Results: The median follow-up was 46 (95% CI, 41 to 90) months. The median bone marrow plasma cell content was 85% (range, 10% to 100%) and median clonal circulaitng plasma cell percentage on the peripheral blood smear was 26% (range, 5% to 93%). There was a preponderance of t(11;14) primary cytogenetic abnormality in this cohort. The median time to next therapy (TTNT) and overall survival (OS) for all patients with pPCL patients in this cohort was 13 (95% CI, 9 to 17) and 23 (95% CI, 19 to 38) months, respectively. However, when stratified by cytogenetic risk, the median TTNT and OS were 16 and 51 months for standard risk vs 9 and 19 months for high risk (P=.01 for OS).

Conclusion: Primary plasma cell leukemia remains an aggressive disease with poor prognosis despite novel agent-based therapies. Some patients have better than expected survival and this phenomenon may be influenced by the absence of high-risk cytogenetics. Newer treatment regimens are needed to improve the prognosis of this devastating disease.
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http://dx.doi.org/10.1016/j.mayocp.2020.06.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7939118PMC
March 2021

MASS-FIX for the detection of monoclonal proteins and light chain N-glycosylation in routine clinical practice: a cross-sectional study of 6315 patients.

Blood Cancer J 2021 03 4;11(3):50. Epub 2021 Mar 4.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Immunoenrichment-based matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), termed MASS-FIX, offers several advantages over immunofixation for the detection and isotyping of serum monoclonal protein, including superior sensitivity and specificity, the ability to differentiate therapeutic monoclonal antibodies, and the rapid identification of light chain (LC) N-glycosylation. We identified 6315 patients with MASS-FIX performed at our institution since 2018. Of these, 4118 patients (65%) with a wide array of plasma cell disorders (PCD), including rare monoclonal gammopathies of clinical significance, had a positive MASS-FIX. Two-hundred twenty-one (5%) of the MASS-FIX positive patients had evidence of LC N-glycosylation, which was more commonly identified in IgM heavy chain isotype, kappa LC isotype, and in diagnoses of immunoglobulin light chain (AL) amyloidosis and cold agglutinin disease (CAD) compared to other PCD. This cross-sectional study describes the largest cohort of patients to undergo MASS-FIX in routine clinical practice. Our findings demonstrate the widespread utility of this assay, and confirm that LC N-glycosylation should prompt suspicion for AL amyloidosis and CAD in the appropriate clinical context.
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http://dx.doi.org/10.1038/s41408-021-00444-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933343PMC
March 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
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