Treatment in AL Amyloidosis: Moving towards Individualized and Clone-Directed Therapy

Systemic amyloid light chain (AL) amyloidosis is a rare protein deposition disease caused by a clonal B cell disorder of the bone marrow. The underlying diseases can be plasma cell disorders (monoclonal gammopathy of clinical significance, smoldering or symptomatic myeloma) or B cell non-Hodgkin’s lymphoma (e.g., Waldenstrom’s disease or marginal zone lymphoma) with secretory activity. It is crucial to characterize the underlying disease very precisely as the treatment of AL amyloidosis is directed against the (often small) B cell clone. Finally, the detection of cytogenetic aberrations of the plasma cell clone will likely play an important role for choosing an effective drug in the near future.

Diffusion-Weighted MRI—The Way Forward for MRI in Myeloma?

Multiple myeloma and other plasma cell disorders infiltrate the bone marrow in different patterns. While some patients show a homogeneous distribution of the clonal plasma cells others present with focal accumulations, commonly called focal lesions. Novel imaging techniques can provide information on these infiltration patterns and, due to their low invasiveness, can be performed repeatedly and therefore be used for monitoring. Conventional magnetic resonance imaging (MRI) has a high sensitivity for bone marrow assessment but cannot safely differentiate between active and inactive lesions. Therefore, positron emission tomography, especially combined with computed tomography (PET/CT), has been more widely used, at least for the monitoring of treatment response. Comparative, but mostly retrospective studies, have shown that functional MRI techniques, namely diffusion-weighted imaging (DWI), which assesses the movement of water molecules, can evaluate tissue cellularity with high sensitivity, which challenges the dominance of PET/CT in treatment response assessment. This review will discuss the benefits and challenges of DWI and compare it to other available imaging techniques used in patients with monoclonal plasma cell disorders.

Quantitative Cross-Sectional Analyses of Quality-of-Life Outcomes Related to Race, Sex, Age, and Clinical Stage Among Multiple Myeloma Patients at an Urban Center

Introduction. Multiple myeloma (MM) patients suffer from disease symptoms and impact on quality of life (QoL) - a patient's sense of enjoyment, well-being, and ability to carry out activities of daily living. Reports on QoL in MM have focused on clinical trials that usually involve younger patients with adequate performance status (PS), mostly Caucasians. The median age of MM onset is 69 years; advanced age is associated with multiple comorbidities and deteriorating PS. Blacks have twice the incidence of MM compared to Caucasians; they also have a higher risk of dying due to poor healthcare utilization. Here, we explored the multifactorial nature of race, sex, age, and clinical stage in patient reported QoL outcomes using quantitative cross-sectional analyses from a single center in urban setting. Methods . Participants with a diagnosis of plasma cell disorders at various stages: MGUS, smoldering myeloma (SMM), or MM (newly diagnosed, maintenance, relapsed/refractory) were sequentially enrolled for a one-time measurement of QOL outcomes. Consent and study questionnaire were conducted verbally. Participants simply responded 'yes' or 'no' to nine question prompts outlined in Table 1, followed by verbal reasoning which was transcribed by the interviewer. The questionnaire included three main domains of QoL assessment based on existing literature review and feedback with our patient population. The first is physical symptoms and function (disease-related symptoms, treatment-related adverse events, sexual health and satisfaction with care), the second is mental health (depression, spirituality), and the third is social impact (financial burden, family support). Data were analyzed using chi-square test of independence. Participants will be re-approached for a second interview to determine changes to impact across the same QoL variables over time. The questionnaires validated within the current study will be used for a longitudinal cohort study to investigate whether a greater degradation is observed in one or more QoL domains during a specific time-point of MM disease course. Results. A total of 100 patients (males n=52) were enrolled. Median age was 64 years (IQR 55 - 68); 59 were Caucasian, 34 were Black, and 7 from other racial groups. At the time of interview: 7 were newly diagnosed or receiving induction therapy, 25 were undergoing stem cell transplant (SCT), 22 were on maintenance therapy, 33 were relapsed on salvage therapy, and 13 on no therapy (MGUS/SMM). Regardless of race, age, or sex, patients on therapy felt their QOL was impacted by fatigue (67%), and myeloma symptoms (65%). Black participants reported more fatigue as an impact on their QoL compared to other racial groups, p = .009. Women reported more impact from MM on sexual intimacy, p = .04, and impact from financial burden than male participants, p = .03. Younger patients <60 years old (n=38) reported more impact from treatment-related adverse events, p = .004, disease-related symptoms, p = .02, and dissatisfaction with information received about their disease and/or treatment, p = .004, compared to patients aged >60 years. Not surprisingly, patients with active MM (n=87); newly diagnosed on therapy, those undergoing SCT, or on maintenance, and relapsed disease) reported more MM symptoms p = <.001, and suffered from more fatigue, p = <.02, with higher impact on QoL compared to those with early-stage plasma cell disorders (MGUS, SMM). However, early-stage patients felt more dissatisfaction with information received and uncertainty about what to expect, p = <.001, compared to MM patients receiving therapy. Interestingly, there were no age, sex, race, or clinical stage dependent effects observed from SCT experience, spirituality or religion, and dissatisfaction with cancer care. Conclusions. Patients <60 years were impacted more by disease-related symptoms, treatment-related adverse events, in comparison to patients >60 years. Women felt their QoL was impacted by MM's affect on sexual intimacy and resulting financial burden in comparison to men. Black participants felt greater impact from fatigue in comparison to Caucasian and other races. Active MM patients on treatment were more impacted by disease-related symptoms and fatigue compared to early-stage patients. MGUS/SMM patients not on therapy were more impacted by dissatisfaction of information received compared to patients receiving treatment at time of data collection. Figure 1 Figure 1. Disclosures Badros: Janssen: Research Funding; J&J: Research Funding; BMS: Research Funding; GlaxoSmithKline: Research Funding.

Tracking Daratumumab Clearance Using Mass Spectrometric Approaches: Implications on M Protein Monitoring and Reusing Daratumumab

Background: MASS-FIX is a screening method for serum and urine monoclonal proteins in multiple myeloma and related plasma cell disorders, which uses immunoglobulin enrichment coupled with matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MALDI-TOF). In addition to superior sensitivity over conventional gel-based techniques, MASS-FIX can distinguish therapeutic monoclonal antibodies (MoAb) from patient's M protein. As the utilization of therapeutic MoAbs increases, it is essential to understand the persistence pattern of these therapeutic antibodies in the serum. We designed this study to evaluate the duration of daratumumab detection by MASS-FIX in the serum of treated patients. Methods: We used a prospectively maintained database at Mayo clinic to identify patients with multiple myeloma and related plasma cell disorders who were treated with a daratumumab-containing regimen anytime during their disease course and had serial MASS-FIX data available after discontinuation of daratumumab. A univariate analysis was performed to assess for factors that may impact the clearance of daratumumab. Results: We included 125 patients with plasma cell disorders who received daratumumab as first or subsequent line of treatment between March 15 th, 2016, and March 4 th, 2020. The median age was 60.2 years and 57% were male. The most common diagnoses were multiple myeloma (70%) and light chain amyloidosis (18%). Daratumumab-based treatments were initiated after a median of 28.8 (IQR: 6.4-76.3) months from initial diagnosis. The most common regimen used was daratumumab, bortezomib and dexamethasone (23%); 26% underwent transplant after daratumumab-based induction. The median duration of treatment with a daratumumab-based regimen was 208 (IQR: 99-479) days. The median follow-up from the time of daratumumab discontinuation was 457 (95% CI: 346-NR) days. By last follow up, daratumumab was not detected by MASS-FIX in 93 (74%) patients but remained detectable in 32 (26%) patients. The median time from daratumumab discontinuation to disappearance of daratumumab by MASS-FIX was 160 (IQR: 107-233) days. On univariate analysis, the presence of ≥0.5 grams of urine protein was associated with earlier disappearance of daratumumab on MASS-FIX [risk ratio (RR): 2.0, P=0.02). The median time from daratumumab discontinuation to disappearance of daratumumab on MASS-FIX was 116 (95%CI: 76-160) days in patients with urine protein ≥0.5 grams and 203 (95%CI: 162-216) days in patients with urine protein <0.5 grams (P=0.02). There was no association between the time to disappearance of daratumumab by MASS-FIX and old age ≥70 (RR: 0.9, P=0.81], male gender (RR: 0.9, P=0.60), eGFR <60 (RR: 1.0, P=0.98), daratumumab schedule (every 1/2 weeks vs >2weeks) (RR: 1.0, P=0.97), treatment duration (<200 days vs ≥200 days) ( RR: 1.0, P=0.95), or transplantation status (RR: 1.0, P=0.98). Conclusion: The therapeutic monoclonal antibody daratumumab remains detectable in the serum of treated patients by MASS-FIX for several months after discontinuation and the duration varies between individual patients. This data has implications for diagnostic and monitoring testing and may provide guidance for reuse of daratumumab in clinical trials and practice. Proteinuria is associated with earlier disappearance of daratumumab by MASS-FIX and may have implications in patients with amyloidosis and monoclonal immunoglobulin deposition disease (MIDD). Further studies are needed to identify additional factors associated with the timing of disappearance. Disclosures Murray: Mayo Clinic: Other: Has received patents for the Mass-Fix technology which has been licensed to the Binding Site with potential royalties.. Dispenzieri: Takeda: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Dingli: Alexion: Consultancy; Novartis: Research Funding; Apellis: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; GSK: Consultancy. Kumar: Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Carsgen: Research Funding; Tenebio: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

Telemedicine in Hematology: Tool to Improve Access and Patient Satisfaction

Introduction: Telemedicine can transform the future of medicine, especially in rural settings by improving access to medical care. Here were present the patient satisfaction data from both telemedicine and regular visits in our Hematology & Oncology clinics. In Hematology, we have used tele medicine for sickle cell disease, benign hematology cases like iron deficiency, thrombocytopenia, leukocytosis etc., and in malignant hematology for new patient consults, toxicity checks, follow up of plasma cell disorders, chronic leukemias and low intensity chemotherapies. Methods: We retrospectively collected patient satisfaction survey data from March 2020 to April 2021 for both telemedicine and regular visits. The patients were allowed to give a score from 1 to 99 regarding their experience at visit. We collected data on the following: likelihood of recommending, care provider, access and overall assessment. Results: A total of 53 patient satisfaction survey were available for telemedicine and 462 for regular visits. Over 60 % of tele visits were non cancer related and 40% were cancer related. The average score for likelihood of recommending, care provider, access, and overall assessment for tele visit were 73.5, 41.5, 73.5 and 62 respectively. The average score for likelihood of recommending, care provider, access, and overall assessment for regular visit were 13.75, 7.5, 26.5, and 11 respectively. Conclusion: The patient satisfaction scores for likelihood of recommending, care provider, access and overall assessment were significantly better for tele visits compared to regular visits. Disclosures Master: Blue Bird Bio: Current holder of individual stocks in a privately-held company.

Neutralizing Antibody Responses Against Sars-Cov-2 in Patients with Plasma Cell Disorders Who Are on Active Treatment after Two Doses of mRNA Vaccination

Background Patients (Pts) with multiple myeloma (MM) experience prolonged immunosuppression due to the incurable nature of the disease and corresponding treatment modalities. Due to this many MM pts with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) require hospitalization, with an increased mortality rate over healthy adults. Two mRNA vaccines against (SARS-CoV-2): BNT162b2 & mRNA-1273 were approved under an emergency use authorization (EUA) by the Food and Drug Administration (FDA) due to the high efficacy in preventing SARS-CoV-2. The aim of this study was to analyze the antibody (Abs) response in all pts with plasma cell disorders (PCD) including MM, AL-Amyloidosis, and smoldering myeloma (SMM) who are on active treatment. Patients & Methods All pts (MM, AL-Amyloidosis, and SMM) on active treatment who received SARS-CoV-2 mRNA vaccine were identified at the University of Kansas Health System between January 2021 to July 2021and reviewed retrospectively. Descriptive analyses were performed on available data for patient characteristics. Abs against SARS-CoV-2 were measured using methodology approved by the FDA (enzyme-linked immunosorbent assay; cPass SARS-CoV-2 Neutralizing Antibody Detection Kit; GenScript, Piscataway, NJ). We stratified pts into clinically relevant responders (>250 IU/mL), partial responders (50-250 IU/mL), and non-responders (<50 IU/mL) Results A total of 118 pts were identified in our analysis and are described in Table 1. Of the total pts, 102 (86%) had MM, 13 (11%) pts had AL-Amyloidosis, and 3 (3%) pts had SMM. Median age was 69 years (45-95), 96 pts (81%) were Caucasian, and 57 (48%) were male. Median lines of prior treatment was 2 (1-13). Active PCD patients were treated with single-agent therapy in 60 pts (51%), doublet-based therapy in 5 pts (4%), and triplet-based therapy in 51 pts (43%). Daratumumab based therapy was utilized in 59 pts (50%). All pts included received two doses of either BNT162b2 or mRNA-1273. At the time of abs testing 82 patients (69%) were in a very good partial response (VGPR) or better, 29 pts (25%) were in partial response, while 7 pts (6%) had stable disease. Five pts (4%) had COVID-19 infection prior to the vaccine. The median time between thesecond dose of the vaccine and testing for Abs was 100 days (34-190). Only 46 pts (39%) developed an adequate response, 36 pts (30.5%) had a partial response, while 36 (30.5%) did not respond to the vaccine. Low Ab levels were seen in all PCD subtypes with the following mean levels: SMM :25.4 (5.4- 36.9) IU/mL, MM 148 (0- >250) IU/mL, and AL- Amyloidosis 92.35 (range 0- >250) IU/mL. Among the 5 pts with COVID-19 infection prior to the vaccination, full Abs response was observed in 4 pts, and 1 patient had no Abs response. Type of treatment did not affect the response to treatment in any clinically meaningful way. The odds ratio of achieving a clinically relevant Abs response was higher in pts with absolute lymphocyte counts>0.5 K/uL (p=0.01) and IgG levels> 400 mg/dL (p=0.04) and lower in pts receiving treatments with daratumumab combinations or anti-BCMA therapy (p<0.0001). Higher levels of anti-SARS-CoV-2 Abs were observed in pts with ≥ VGPR (mean≈147 IU/mL) compared to <VGPR (mean≈ 119 IU/mL). However, in this dataset, this difference was not statistically significant (p=0.17). Conclusion mRNA vaccine Ab response is lower in PCD pts getting active treatment compared with the general population. For PCD patients on active treatment, mRNA vaccine produced full antibody responses and partial responses in 39% and 30.5% of pts, respectively. anti-SARS-CoV-2 abs are especially low for patients on daratumumab combinations or anti-BCMA therapy, low lymphocytes, and low IgG levels at the time of vaccination. Some PCD may not develop anti-SARS-CoV-2 abs despite vaccination and/or previous COVID-19 infection. Therefore, checking anti-SARS-CoV-2 abs may be clinically useful in identifying patient's response. Further prospective studies should ascertain the value of a 3 rd vaccine dose in this population. Figure 1 Figure 1. Disclosures Mahmoudjafari: Omeros: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. McGuirk: Astelllas Pharma: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Gamida Cell: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Fresenius Biotech: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; Pluristem Therapeutics: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Novartis: Research Funding. Atrash: Jansen: Research Funding, Speakers Bureau; AMGEN: Research Funding; GSK: Research Funding.