ABSTRACT
Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade lymphoma with no standard therapy. Nine asymptomatic patients treated with a first-in-human, neoantigen DNA vaccine experienced no dose limiting toxicities (primary endpoint, NCT01209871). All patients achieve stable disease or better, with one minor response, and median time to progression of 72+ months. Post-vaccine single-cell transcriptomics reveal dichotomous antitumor responses, with reduced tumor B-cells (tracked by unique B cell receptor) and their survival pathways, but no change in clonal plasma cells. Downregulation of human leukocyte antigen (HLA) class II molecules and paradoxical upregulation of insulin-like growth factor (IGF) by the latter suggest resistance mechanisms. Vaccine therapy activates and expands bone marrow T-cell clonotypes, and functional neoantigen-specific responses (secondary endpoint), but not co-inhibitory pathways or Treg, and reduces protumoral signaling by myeloid cells, suggesting favorable perturbation of the tumor immune microenvironment. Future strategies may require combinations of vaccines with agents targeting plasma cell subpopulations, or blockade of IGF-1 signaling or myeloid cell checkpoints.
Subject(s)
Cancer Vaccines , Waldenstrom Macroglobulinemia , Humans , Male , Cancer Vaccines/immunology , Cancer Vaccines/therapeutic use , Cancer Vaccines/administration & dosage , Middle Aged , Female , Waldenstrom Macroglobulinemia/immunology , Waldenstrom Macroglobulinemia/therapy , Waldenstrom Macroglobulinemia/genetics , Aged , Tumor Microenvironment/immunology , Precision Medicine/methods , Vaccines, DNA/immunology , Vaccines, DNA/therapeutic use , Antigens, Neoplasm/immunology , B-Lymphocytes/immunologyABSTRACT
PURPOSE: Proteasome inhibitors (PIs), which cause cell death via tumor suppressor and pro-apoptotic proteins, are integral to treatment of many hematologic malignancies but are limited by their gastrointestinal adverse effects. Evidence regarding these PI-related adverse effects is scant. In this study, we evaluated gastrointestinal adverse events caused by PIs and compared gastrointestinal toxicities between bortezomib, carfilzomib, and ixazomib. METHODS: We conducted a retrospective study of cancer patients treated with PIs at a tertiary care cancer center to investigate the clinical characteristics of PI-related gastrointestinal adverse events. RESULTS: Our sample comprised 973 patients with PI exposure and stool studies ordered between January 2017 and December 2022. Of these, 193 patients (20%) had PI-related gastrointestinal toxicity based on clinical symptoms and stool study results. The most common symptom was diarrhea, present in 169 (88% of those with gastrointestinal toxicity). Twenty-two (11%) required hospitalization, and 71 (37%) developed recurrence of symptoms. Compared to bortezomib or carfilzomib, ixazomib had a longer interval from PI initiation to the onset of gastrointestinal symptoms (313 days vs 58 days vs 89 days, p = 0.002) and a significantly lower percentage of diarrhea-predominant presentation of gastrointestinal toxicity (71% vs 96% vs 91%, p = 0.048). CONCLUSION: While PI-related gastrointestinal toxicities have various presentations and courses based on different regimens, the vast majority of patients presented with milder disease behavior. Despite a considerably high rate of hospitalization and recurrence after treatment necessitating optimization of clinical management, our cohort demonstrates favorable outcomes without long-term consequences.
Subject(s)
Boron Compounds , Bortezomib , Gastrointestinal Diseases , Glycine , Proteasome Inhibitors , Humans , Proteasome Inhibitors/adverse effects , Male , Female , Retrospective Studies , Middle Aged , Boron Compounds/adverse effects , Boron Compounds/therapeutic use , Aged , Glycine/analogs & derivatives , Glycine/adverse effects , Bortezomib/adverse effects , Bortezomib/administration & dosage , Gastrointestinal Diseases/chemically induced , Oligopeptides/adverse effects , Adult , Aged, 80 and overABSTRACT
BACKGROUND: Lenalidomide (R), bortezomib (V), and dexamethasone (d) is a standard-of-care regimen in newly diagnosed multiple myeloma (NDMM); however, characteristics and outcomes for nontransplanted patients receiving frontline RVd are not well understood. PATIENTS: The Connectâ MM Registry is a large, US, multicenter, prospective observational cohort study of NDMM patients. METHODS: This analysis investigated characteristics and outcomes of patients who received RVd alone or followed by Rd or R (RVd ± Rd/R) who did not undergo frontline autologous stem cell transplantation. RESULTS: As of August 2021, 314 of 1979 nontransplanted patients received RVd ± Rd/R as initial therapy. Of these, 135 were aged ≤ 65 years and 179 were > 65 years. 108 patients had time to relapse (TTR) of ≤ 12 months and 182 had TTR > 12 months. Baseline characteristics were comparable regardless of TTR and age group except renal function, which was more commonly impaired in older patients. Among patients aged ≤ 65 and > 65 years, median duration of first-line treatment was 6.3 and 9.0 months, median time to next line for those who received second-line therapy was 15.5 and 15.2 months, median progression-free survival (PFS) was 19.3 and 23.0 months, and median overall survival was 60.0 and 59.1 months, respectively. High-risk disease (per IMWG criteria) and high serum calcium were associated with higher hazard of progression or death; the adjusted PFS hazard ratio with respect to age (≤ 65 vs. > 65 years) based on multivariable analysis was 1.18 (0.89-1.57; P = .25). CONCLUSION: These results indicate RVd is active across age groups and provide a better understanding of outcomes with RVd in NDMM.
ABSTRACT
Upfront autologous stem cell transplantation (auto-SCT) remains standard of care for eligible patients with newly diagnosed multiple myeloma (NDMM), although recently its role has been questioned. The aim of the study was to evaluate trends in patient characteristics, treatment, and outcomes of NDMM who underwent upfront auto-SCT over three decades. We conducted a single-center retrospective analysis of patients with NDMM who underwent upfront auto-SCT at MD Anderson Cancer Center between 1988 to 2021. Primary end points were progression-free survival (PFS) and overall survival (OS). Patients were grouped by the year of auto-SCT: 1988-2000 (n = 249), 2001-2005 (n = 373), 2006-2010 (n = 568), 2011-2015 (n = 815) and 2016-2021 (n = 1036). High-risk cytogenetic abnormalities were defined as del (17p), t (4;14), t (14;16), and 1q21 gain or amplification by fluorescence in situ hybridization. We included 3041 MM patients in the analysis. Median age at auto-SCT increased from 52 years (1988-2000) to 62 years (2016-2021), as did the incidence of high-risk cytogenetics from 15% to 40% (P < .001). Comorbidity burden, as measured by a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) of >3, increased from 17% (1988-2000) to 28% (2016-2021) (P < .001). Induction regimens evolved from predominantly chemotherapy to immunomodulatory drug (IMiD) and proteasome inhibitor (PI) based regimens, with 74% of patients receiving IMiD-PI triplets in 2016-2021 (39% bortezomib, lenalidomide and dexamethasone (VRD) and 35% carfilzomib, lenalidomide and dexamethasone [KRD]). Response rates prior to auto-SCT steadily increased, with 4% and 10% achieving a ≥CR and ≥VGPR compared to 19% and 65% between 1988-2000 and 2016-2021, respectively. Day 100 response rates post auto-SCT improved from 24% and 49% achieving ≥CR and ≥VGPR between 1988-2000 to 41% and 81% between 2016-2021, respectively. Median PFS improved from 22.3 months between 1988-2000 to 58.6 months between 2016-2021 (HR 0.42, P < .001). Among patients with high-risk cytogenetics, median PFS increased from 13.7 months to 36.8 months (HR 0.32, P < .001). Patients aged ≥65 years also had an improvement in median PFS from 33.6 months between 2001 and 2005 to 52.8 months between 2016-2021 (HR 0.56, P = .001). Median OS improved from 55.1 months between 1988-2000 to not reached (HR 0.41, P < .001). Patients with high-risk cytogenetics had an improvement in median OS from 32.9 months to 66.5 months between 2016-2021 (HR 0.39, P < .001). Day 100 non-relapse mortality from 2001 onwards was ≤1%. Age-adjust rates of second primary malignancies were similar in patients transplanted in different time periods. Despite increasing patient age and comorbidity burden, this large real-world study demonstrated significant improvements in the depth of response and survival outcomes in patients with NDMM undergoing upfront auto-SCT over the past three decades, including those with high-risk disease.
Subject(s)
Hematopoietic Stem Cell Transplantation , Multiple Myeloma , Transplantation, Autologous , Humans , Multiple Myeloma/therapy , Multiple Myeloma/mortality , Middle Aged , Male , Female , Transplantation, Autologous/statistics & numerical data , Retrospective Studies , Aged , Treatment Outcome , AdultABSTRACT
PURPOSE: We present a phase I/II first-in-human trial evaluating the safety and efficacy of 50 mg and 200 mg doses of linvoseltamab, a B-cell maturation antigen × CD3 bispecific antibody in relapsed/refractory multiple myeloma (RRMM). METHODS: Phase II eligible patients had RRMM that either progressed on/after ≥three lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody or was triple-class (PI/IMiD/anti-CD38) refractory. Phase II treatment was once a week through week 14 and then once every 2 weeks. Phase II 200 mg patients who achieved a ≥very good partial response by week 24 received linvoseltamab once every 4 weeks. The primary end point in phase II was overall response rate (ORR). RESULTS: Among the 117 patients treated with 200 mg, the median age was 70 years, 39% had high-risk cytogenetics, and 28% had penta-refractory disease. At a median follow-up of 14.3 months, the ORR was 71%, with 50% achieving ≥complete response (CR). In 104 patients treated with 50 mg at a median follow-up of 7.4 months, the ORR was 48%, with 21% achieving ≥CR. The median duration of response (DOR) for 200 mg patients (n = 83) was 29.4 months (95% CI, 19.2 to not evaluable). Among 200 mg patients, the most common adverse events included cytokine release syndrome (35.0% Gr1, 10.3% Gr2, 0.9% Gr3), neutropenia (0.9% Gr2, 18.8% Gr3, 23.1% Gr4), and anemia (3.4% Gr1, 4.3% Gr2, 30.8% Gr3). Immune effector cell-associated neurotoxicity syndrome occurred in 7.7% of patients (2.6% each Gr1, Gr2, Gr3). Infections were reported in 74.4% of patients (33.3% Gr3, 2.6% Gr4); infection frequency and severity declined over time. CONCLUSION: Linvoseltamab 200 mg induced deep and durable responses, with a median DOR of 29.4 months, in patients with RRMM with an acceptable safety profile.
Subject(s)
Antibodies, Bispecific , Multiple Myeloma , Humans , Multiple Myeloma/drug therapy , Aged , Male , Female , Middle Aged , Aged, 80 and over , Antibodies, Bispecific/therapeutic use , Antibodies, Bispecific/adverse effects , Antibodies, Bispecific/administration & dosage , B-Cell Maturation Antigen/antagonists & inhibitors , B-Cell Maturation Antigen/immunology , Adult , Neoplasm Recurrence, Local/drug therapyABSTRACT
Autologous stem cell transplantation (autoHCT) is considered standard of care for newly diagnosed multiple myeloma (MM). Although most patients eventually progress after autoHCT, a small proportion achieve a durable response. In this retrospective study we included 1576 patients, 244 (15%) of whom were long-term responders (LTR), defined as having a progression-free survival (PFS) of ≥8 years after transplant. Patients in the LTR group were younger than the non-LTR group (median age 58.4 vs. 59.5 years; p = 0.012), less likely to have high-risk cytogenetics (4% vs. 14%; p < 0.001), more often had <50% bone marrow plasma cells (67% vs. 58%; p = 0.018) and R-ISS stage I disease (43% vs. 34%). More patients in the LTR group received post-transplant maintenance (63% vs. 52%; p = 0.002). Patients in the LTR group had higher rates of complete response (CR) at day100 (41% vs. 27%; p < 0.001) and at best post-transplant response (70% vs. 37%; p < 0.001), compared to the non-LTR group. Patients in the LTR groups had a median PFS of 169.3 months and the median overall survival (OS) had not been reached. The leading cause of death in the LTR was disease progression. In conclusion, 15% of patients in the cohort were LTR after upfront autoHCT, with distinct characteristics and a median PFS of more than 14 years.
Subject(s)
Hematopoietic Stem Cell Transplantation , Multiple Myeloma , Transplantation, Autologous , Humans , Multiple Myeloma/therapy , Multiple Myeloma/mortality , Middle Aged , Hematopoietic Stem Cell Transplantation/methods , Male , Female , Aged , Retrospective Studies , Adult , Remission Induction , Treatment OutcomeABSTRACT
OBJECTIVE: This study aimed to investigate the efficacy of Bacillus-based probiotics supplemented at two different levels to modulate the productive performance, egg quality, tibia traits, and specific cecal bacteria counts of Hy-Line Brown layers from 25 to 37 weeks of age. METHODS: A total of 216 twenty-five-week-old hens were randomly distributed into 3 experimental diets with 12 replicates of 6 birds per cage. Diets included basal diet supplemented with 0 (CON), 3×108 (PRO1), or 3×109 (PRO2) colony-forming unit (CFU) of the test probiotic containing Bacillus subtilis PB6, Bacillus subtilis FXA, and Bacillus licheniformis G3 per kilogram of feed. RESULTS: Improved egg weights and mass at 29 weeks; and feed intake at 31 weeks (p<0.10) were noticed with the probiotic-supplemented PRO1 and PRO2 diets. Considering egg quality, the shell thickness, Haugh units, and yolk color were improved; but yolk cholesterol was lowered (p<0.05) with PRO1 and PRO2 diets at 29 weeks. At both 33 and 37 weeks, the egg-breaking strength, shell color and thickness, albumen height, Haugh units, and yolk color were improved; but yolk cholesterol was similarly lowered (p<0.05) with the PRO1 and PRO2 diets. Improved tibia Ca, ash, weights, and density; and raised cecal counts of Bifidobacteria and Lactobacilli (p<0.05) were noticed with PRO1 and PRO2 diets. Improved tibia P but reduced Clostridia counts (p<0.10) were also observed with the PRO1 and PRO2 diets. CONCLUSION: Probiotic supplementation of Bacillus subtilis PB6, Bacillus subtilis FXA, and Bacillus licheniformis G3 at 3×108 CFU/kg of feed is adequate to significantly improve egg quality, lower yolk cholesterol, enhance several tibia traits, and raise the populations of beneficial cecal bacteria. Modest improvements in several productive parameters and tibia P but reduced Clostridia were also observed; and could warrant further investigation of probiotic effects beyond the current test period.
ABSTRACT
OBJECTIVES: To characterize the impact of prior exposure and refractoriness to lenalidomide or proteasome inhibitors (PIs) on the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma (RRMM). METHODS: INSURE is a pooled analysis of adult RRMM patients who had received IRd in ≥2 line of therapy from three studies: INSIGHT MM, UVEA-IXA, and REMIX. RESULTS: Overall, 391/100/68 were lenalidomide-naïve/-exposed/-refractory and 37/411/110 were PI-naïve/-exposed/-refractory. Median duration of therapy (DOT) was 15.3/15.6/4.7 months and median progression-free survival (PFS) was 21.6/25.8/5.6 months in lenalidomide-naïve/exposed/refractory patients. Median DOT and PFS in PI-naïve/exposed/refractory patients were 20.4/15.2/6.9 months and not reached/19.8/11.4 months, respectively. The proportion of lenalidomide-naïve/exposed/refractory patients in INSIGHT and UVEA-IXA who discontinued a study drug due to adverse events (AEs) was ixazomib, 31.6/28.2/28.0% and 18.6/6.7/10.5%; lenalidomide, 21.9/28.2/16.0% and 16.1/6.7/10.5%; dexamethasone, 18.4/20.5/16.0% and 10.6/0/10.5%, respectively. The proportion of PI-naïve/exposed/refractory patients in INSIGHT and UVEA-IXA who discontinued a study drug due to AEs was: ixazomib, 44.4/28.8/27.8% and 22.2/16.7/15.7%; lenalidomide, 33.3/22.0/19.4% and 16.7/15.9/11.8%; dexamethasone, 33.3/17.4/16.7% and 16.7/9.5/7.8%, respectively. REMIX AE discontinuation rates were unavailable. CONCLUSION: IRd appeared to be effective in RRMM patients in routine clinical practice regardless of prior lenalidomide or PI exposure, with better outcomes seen in lenalidomide- and/or PI-nonrefractory versus refractory patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Boron Compounds , Dexamethasone , Drug Resistance, Neoplasm , Glycine , Lenalidomide , Multiple Myeloma , Proteasome Inhibitors , Humans , Multiple Myeloma/drug therapy , Multiple Myeloma/mortality , Multiple Myeloma/diagnosis , Boron Compounds/administration & dosage , Boron Compounds/adverse effects , Boron Compounds/therapeutic use , Glycine/analogs & derivatives , Glycine/administration & dosage , Glycine/adverse effects , Glycine/therapeutic use , Lenalidomide/administration & dosage , Lenalidomide/adverse effects , Lenalidomide/therapeutic use , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Male , Proteasome Inhibitors/administration & dosage , Proteasome Inhibitors/therapeutic use , Proteasome Inhibitors/adverse effects , Aged , Female , Middle Aged , Treatment Outcome , Adult , Aged, 80 and over , Recurrence , RetreatmentABSTRACT
BACKGROUND: Endovascular techniques are advancing with the change of treatment paradigm for abdominal aortic aneurysms. Fenestrated EVAR (fEVAR) and branched EVAR (bEVAR) are used for complex aortic aneurysm repair. Both fEVAR and bEVAR have their own advantages and disadvantages. Semi-branches are a new feature that attempt to combine the advantages of both fEVAR and bEVAR. TECHNIQUE: We describe the use of a 4-vessel semi-branched EVAR in a failed EVAR case with a type 1a endoleak. CONCLUSION: The novel feature of semi-branches in custom-made EVAR devices in endovascular aortic treatment following failed EVAR appear to be a feasible option.
ABSTRACT
The second revision of the International Staging System (R2-ISS) is a simple tool to risk-stratify newly diagnosed multiple myeloma (NDMM) patients. Here, we completed a retrospective analysis to evaluate the utility of R2-ISS in NDMM patients who underwent up-front autologous haematopoietic stem cell transplantation (auto-HCT). A total of 1291 patients were included, with a median age of 62 years (range 29-83). The distribution of R2-ISS stages was: 123 (10%) stage I, 471 (36%) stage II, 566 (44%) stage III and 131 (10%) stage IV. With a median follow-up of 42.2 months (range 0.3-181.0), the median PFS was 73.0, 65.2, 44.0 and 24.8 months, (p < 0.001) and the median OS was 130.8, 128.5, 94.2 and 61.4 months (p < 0.001) for patients with R2-ISS stages I, II, III and IV respectively. On multivariable analysis (MVA) for PFS, using R2-ISS stage I as reference, R2-ISS stages III (hazard ratio [95% confidence interval], 1.55 [1.05-2.29]; p = 0.028) and IV (2.04 [1.24-3.36]; p = 0.005) were associated with significantly inferior PFS. In the MVA of OS, using R2-ISS stage I as reference, only R2-ISS stage IV was associated with significantly inferior OS (2.43 [1.18-5.01]; p = 0.017). Overall, we found that R2-ISS is a reliable prognostic tool for NDMM patients undergoing up-front auto-HCT.
Subject(s)
Hematopoietic Stem Cell Transplantation , Multiple Myeloma , Neoplasm Staging , Transplantation, Autologous , Humans , Multiple Myeloma/therapy , Multiple Myeloma/mortality , Multiple Myeloma/pathology , Middle Aged , Aged , Female , Male , Adult , Retrospective Studies , Aged, 80 and over , Risk Assessment/methods , Treatment OutcomeABSTRACT
The prognostic impact of additional copies of chromosome 1q (1q + ) on outcomes of newly-diagnosed multiple myeloma (NDMM) patients undergoing autologous transplantation (autoSCT) is unclear. We conducted a retrospective single-center analysis of NDMM patients with 1q21 gain/amplification (3 or ≥4 copies of 1q, respectively) that received autoSCT between 2008-2018. 213 patients were included (79% 1q gain; 21% 1q amplification). The most commonly used induction regimen was bortezomib, lenalidomide, and dexamethasone (41%). At day100 post-autoSCT and at best post-transplant response, 78% and 87% of patients achieved ≥VGPR, and 38% and 50% achieved MRD-negative ≥VGPR, respectively. Median PFS and OS for the entire cohort were 35.5 months and 81.4 months, respectively. On multivariable assessment for PFS, MRD negative ≥VGPR before autoSCT (HR 0.52, p = 0.013) was associated with superior PFS, whereas 1q amplification was associated with inferior PFS (2.03, p = 0.003). On multivariate analysis for OS, achieving MRD negative ≥VGPR at best post-transplant response was associated with superior survival (0.29, p < 0.001), whereas R-ISS III and concomitant del17p or t(4:14) were associated with inferior survival (6.95, p = 0.030, 2.33, p = 0.023 and 3.00, p = 0.047, respectively). In conclusion, patients with 1q+ NDMM, especially 1q amplification, have inferior survival outcomes compared to standard-risk disease after upfront autoSCT, though outcomes are better than other high-risk cytogenetic abnormalities.
Subject(s)
Hematopoietic Stem Cell Transplantation , Multiple Myeloma , Humans , Multiple Myeloma/genetics , Multiple Myeloma/therapy , Retrospective Studies , Transplantation, Autologous , Chromosome AberrationsABSTRACT
B-cell maturation antigen (BCMA) plays a pathobiologic role in myeloma and is a validated target with five BCMA-specific therapeutics having been approved for relapsed/refractory disease. However, these drugs are not curative, and responses are inferior in patients with molecularly-defined high-risk disease, including those with deletion 17p (del17p) involving the tumor suppressor TP53, supporting the need for further drug development. Del17p has been associated with reduced copy number and gene expression of RNA polymerase II subunit alpha (POLR2A) in other tumor types. We therefore studied the possibility that HDP-101, an anti-BCMA antibody drug conjugate (ADC) with the POLR2A poison α-amanitin could be an attractive agent in myeloma, especially with del17p. HDP-101 reduced viability in myeloma cell lines representing different molecular disease subtypes, and overcame adhesion-mediated and both conventional and novel drug resistance. After confirming that del17p is associated with reduced POLR2A levels in publicly available myeloma patient databases, we engineered TP53 wild-type cells with a TP53 knockout (KO), POLR2A knockdown (KD), or both, the latter to mimic del17p. HDP-101 showed potent anti-myeloma activity against all tested cell lines, and exerted enhanced efficacy against POLR2A KD and dual TP53 KO/POLR2A KD cells. Mechanistic studies showed HDP-101 up-regulated the unfolded protein response, activated apoptosis, and induced immunogenic cell death. Notably, HDP-101 impacted CD138-positive but not-negative primary cells, showed potent efficacy against aldehyde dehydrogenase-positive clonogenic cells, and eradicated myeloma in an in vivo cell line-derived xenograft (CDX). Interestingly, in the CDX model, prior treatment with HDP-101 precluded subsequent engraftment on tumor cell line rechallenge in a manner that appeared to be dependent in part on natural killer cells and macrophages. Finally, HDP-101 was superior to the BCMA-targeted ADC belantamab mafodotin against cell lines and primary myeloma cells in vitro, and in an in vivo CDX. Together, the data support the rationale for translation of HDP-101 to the clinic, where it is now undergoing Phase I trials, and suggest that it could emerge as a more potent ADC for myeloma with especially interesting activity against the high-risk del17p myeloma subtype.
ABSTRACT
Aim: We pooled data from three observational studies (INSIGHT MM, UVEA-IXA and REMIX) to investigate the real-world effectiveness of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory myeloma. Materials & methods: INSIGHT MM was a prospective study conducted in countries across Europe, Asia and North/Latin America while UVEA-IXA and REMIX were multicenter, retrospective/prospective studies conducted in Europe. Patients who had received IRd as ≥2nd line of therapy were analyzed. Primary outcomes were time-to-next treatment (TTNT) and progression-free survival (PFS). Results: Overall, 564 patients were included (median follow-up: 18.5 months). Median TTNT and PFS were 18.4 and 19.9 months; both outcomes were numerically longer for earlier versus later lines. Median treatment duration was 14.0 months. Overall response rate was 64.6%. No new safety concerns were noted. Conclusion: The effectiveness of IRd in routine practice appears similar to the efficacy observed in TOURMALINE-MM1. IRd benefit in earlier versus later lines was consistent with previous reports.
Subject(s)
Glycine , Multiple Myeloma , Humans , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Boron Compounds/therapeutic use , Dexamethasone/therapeutic use , Glycine/analogs & derivatives , Lenalidomide/therapeutic use , Multicenter Studies as Topic , Multiple Myeloma/drug therapy , Prospective Studies , Retrospective StudiesABSTRACT
The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.
Subject(s)
Lymphoma, B-Cell , Waldenstrom Macroglobulinemia , Humans , Waldenstrom Macroglobulinemia/therapy , Waldenstrom Macroglobulinemia/drug therapyABSTRACT
Aim: To compare the effectiveness of in-class transition to all-oral ixazomib-lenalidomide-dexamethasone (IRd) following parenteral bortezomib (V)-based induction versus continued V-based therapy in US oncology clinics. Patients & methods: Non-transplant eligible patients with newly diagnosed multiple myeloma (MM) receiving in-class transition to IRd (N = 100; US MM-6), or V-based therapy (N = 111; INSIGHT MM). Results: Following inverse probability of treatment weighting, overall response rate was 73.2% with IRd versus 57.5% with V-based therapy (p < 0.0001). Median duration of treatment was 10.8 versus 5.3 months (p < 0.0001). Overall, 18/24% of patients discontinued IRd/V-based therapy due to adverse events. Conclusion: IRd after V-based induction was associated with significantly improved overall response rate and duration of treatment than continued V-based combination therapy. Clinical Trial Registration: US MM-6: NCT03173092; INSIGHT MM: NCT02761187 (ClinicalTrials.gov).
Subject(s)
Multiple Myeloma , Humans , Multiple Myeloma/diagnosis , Multiple Myeloma/drug therapy , Bortezomib/adverse effects , Lenalidomide/therapeutic use , Dexamethasone , Glycine , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Boron Compounds/adverse effectsABSTRACT
PURPOSE: Radiation therapy (RT) is an important treatment modality for patients with multiple myeloma (MM). Although patients are living longer with MM, they are more likely to have comorbidities related to treatment, such as bone pain; however, RT can provide symptom relief. To date, the characterization of patients who have received RT in the real-world setting has been limited. METHODS AND MATERIALS: The Connect® MM Registry is a large, US multicenter, prospective observational cohort study of adult patients with newly diagnosed MM from mostly community sites. RT utilization and outcomes were analyzed quarterly throughout treatment. Factors associated with RT use were identified via multivariable analysis. RESULTS: A total of 3011 patients were enrolled in the Connect MM Registry with 903 patients (30%) having received RT at any time. There was a significant difference (P < .05) in overall RT use among patients with an Eastern Cooperative Oncology Group performance status of 0 to 1 versus ≥2, International Staging System disease stage I/II versus III, a history of plasmacytoma or a novel agent in their first regimen, and any number of bone lesions or severe osteoporosis/fracture. RT use was associated with having bone lesions or severe osteoporosis (vs not having bone lesions). Additionally, RT use was associated with ethnicity (Hispanic vs not) and Connect MM Registry cohort (cohort 1 [enrolled 2009-2011] vs 2 [enrolled 2012-2016]). In the 6 months before death, increased RT use was associated with increasing number of treatment lines (P < .0001) and high- versus standard-risk disease (per International Myeloma Working Group criteria; P = .0028). CONCLUSIONS: Real-world results from the Connect MM Registry show RT is frequently used and is associated with clinical factors, including performance status and disease stage. Earlier in MM diagnosis, RT may be used as an adjunct to palliate symptoms or delay systemic therapy. Toward the end of life, RT is more frequently used for palliation when treatment options are often limited.
Subject(s)
Multiple Myeloma , Osteoporosis , Adult , Humans , Multiple Myeloma/radiotherapy , Prospective Studies , Ethnicity , RegistriesABSTRACT
PURPOSE: Radiation therapy (RT) is the standard treatment for solitary plasmacytoma (SP); however, the optimal management of RT-refractory SPs is unknown. We examined outcomes after early systemic therapy, surgical resection, or observation for patients with RT-refractory disease and assessed the potential impact of treatment selection on disease outcomes. METHODS AND MATERIALS: We retrospectively reviewed patients with SP treated with definitive radiation and evaluated at a single institution with persistent disease on imaging or biopsy. Descriptive statistics were used to characterize patient and disease characteristics and treatment outcomes. RESULTS: Of 102 total SP patients, 17 (17%) were RT-refractory. The median RT dose was 45 Gy, and median follow-up was 71 months from end of RT. Fifteen patients had additional treatment for refractory disease at a median time of 9.5 months after RT, with the following subsequent interventions: surgical resection (n = 4), additional RT (n = 2), systemic therapy without evidence of multiple myeloma (MM; n = 4), systemic therapy for progression to MM (n = 5), and observation (n = 2). Of 4 patients treated with surgical resection, 3 progressed to MM 22 to 43 months after diagnosis. Of 2 patients treated with additional RT, neither responded, and both had pathologic confirmation of residual disease after the second course. Four patients treated with systemic therapy without MM all had complete responses on positron emission tomography and no subsequent MM progression. Eight patients were initially observed after RT for ≥12 months (n = 8) or ≥24 months (n = 6). Of the 2 patients in continued observation, both had stable/unchanged avidity after radiation treatment for 12 and 22 months and ultimately had a slow decrease of disease avidity over multiple years. CONCLUSIONS: Patients with RT-refractory SPs can achieve good local control with alternative therapies, such as surgery or systemic therapy, if needed. Additional RT does not seem to be effective. Given the known high rates of progression from SP to MM, close observation of asymptomatic persistent disease until disease progression is likely sufficient in most cases.
Subject(s)
Bone Neoplasms , Multiple Myeloma , Plasmacytoma , Humans , Plasmacytoma/pathology , Retrospective Studies , Multiple Myeloma/diagnosis , Treatment Outcome , Bone Neoplasms/radiotherapy , Positron-Emission TomographyABSTRACT
BACKGROUND: The prognostic significance of minimal residual disease (MRD) status before autologous hematopoietic stem cell transplantation (autoHCT) in patients with multiple myeloma (MM) has not been clearly elucidated. METHODS: Retrospective single-center study of adult MM patients who achieved ≥very good partial response (VGPR) after induction therapy from 2015 to 2021 received upfront autoHCT and had available pretransplant MRD status by next-generation flow cytometry. The cohort was divided into pretransplant MRD-negative (MRDneg) and MRD-positive (MRDpos) groups. RESULTS: A total of 733 patients were included in our analysis; 425 were MRDneg and 308 MRDpos at autoHCT. In the MRDpos group, more patients had high-risk cytogenetic abnormalities (48% vs. 38%, respectively; p = .025), whereas fewer patients achieved ≥CR before autoHCT (14% vs. 40%; p < .001). At day 100 after autoHCT, 37% of the MRDpos versus 71% of the MRDneg achieved ≥CR, and at best posttransplant response 65% versus 88% achieved ≥CR, respectively. After a median follow-up of 27.6 months (range, 0.7-82.3), the median PFS was significantly shorter for patients in the MRDpos group compared to the MRDneg group: 48.2 months (95% confidence interval [CI], 0.3-80.5) versus 80.1 months (95% CI, 0.5-80.1), respectively (p < .001). There was no significant difference in overall survival between the two groups (p = .41). Pretransplant MRDpos status was predictive of shorter PFS in multivariate analysis (hazard ratio, 1.80; 95% CI, 1.31-2.46; p < .001). The impact of pretransplant MRD status was retained in most of the examined subgroups. CONCLUSIONS: In patients achieving ≥VGPR to induction, pretransplant MRDpos status was associated with a lower CR rate after autoHCT and a shorter PFS.
Subject(s)
Hematopoietic Stem Cell Transplantation , Multiple Myeloma , Adult , Humans , Multiple Myeloma/therapy , Treatment Outcome , Neoplasm, Residual/therapy , Retrospective Studies , Transplantation, AutologousABSTRACT
The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.
Subject(s)
Multiple Myeloma , Humans , Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Medical Oncology , Multiple Myeloma/therapy , Multiple Myeloma/drug therapy , Neoplasm Recurrence, Local/drug therapyABSTRACT
Lymphoplasmacytic lymphoma (LPL) is an incurable low-grade B-cell lymphoma of the bone marrow. Despite a cumulative risk of progression, there is no approved therapy for patients in the asymptomatic phase. We conducted a first-in-human clinical trial of a novel therapeutic DNA idiotype neoantigen vaccine in nine patients with asymptomatic LPL. Treatment was well tolerated with no dose limiting toxicities. One patient achieved a minor response, and all remaining patients experienced stable disease, with median time to disease progression of 61+ months. Direct interrogation of the tumor microenvironment by single-cell transcriptome analysis revealed an unexpected dichotomous antitumor response, with significantly reduced numbers of clonal tumor mature B-cells, tracked by their unique BCR, and downregulation of genes involved in signaling pathways critical for B-cell survival post-vaccine, but no change in clonal plasma cell subpopulations. Downregulation of HLA class II molecule expression suggested intrinsic resistance by tumor plasma cell subpopulations and cell-cell interaction analyses predicted paradoxical upregulation of IGF signaling post vaccine by plasma cell, but not mature B-cell subpopulations, suggesting a potential mechanism of acquired resistance. Vaccine therapy induced dynamic changes in bone marrow T-cells, including upregulation of signaling pathways involved in T-cell activation, expansion of T-cell clonotypes, increased T-cell clonal diversity, and functional tumor antigen-specific cytokine production, with little change in co-inhibitory pathways or Treg. Vaccine therapy also globally altered cell-cell communication networks across various bone marrow cell types and was associated with reduction of protumoral signaling by myeloid cells, principally non-classical monocytes. These results suggest that this prototype neoantigen vaccine favorably perturbed the tumor immune microenvironment, resulting in reduction of clonal tumor mature B-cell, but not plasma cell subpopulations. Future strategies to improve clinical efficacy may require combinations of neoantigen vaccines with agents which specifically target LPL plasma cell subpopulations, or enable blockade of IGF-1 signaling or myeloid cell checkpoints.