M-protein Levels Research Articles

ANALYSIS OF THE EFFECTIVENESS OF BORTEZOMIB-CONTAINING REGIMENS IN PATIENTS WITH MULTIPLE MYELOMA

Introduction. Multiple myeloma is a hematologic malignancy that affects the bone marrow, characterized by the abnormal proliferation of tumor plasma cells. This study aims to assess the effectiveness of a chemotherapy regimen consisting of bortezomib, lenalidomide, and dexamethasone in patients with progressive multiple myeloma, considering negative prognostic factors. Materials and Methods. Group I comprised 23 patients with progressive multiple myeloma who received chemotherapy with bortezomib, lenalidomide, and dexamethasone. The control group (Group II) consisted of 18 healthy individuals. Patients in Group I were examined twice: once before the initiation of treatment and again after completing three courses of chemotherapy. The evaluation included general and biochemical blood analyses, myelogram, immunofixation, and electrophoresis of blood serum and urine proteins, as well as the assessment of monoclonal paraprotein and the level of β2-microglobulin. Treatment response was evaluated according to the criteria set by the International Myeloma Working Group (2016). Results. Among patients receiving chemotherapy as first-line therapy, the overall response rate was 83.33% (15/18), of which a very good partial response was observed in 77.78% (14/18) of patients, a partial response in 5.55% (1/18), and disease progression in 16.67% (3/18) of patients. Specific treatment was associated with a decrease in the level of M-gradient in the blood of patients by 87.6% (p<0.01) and in urine by 96% (p<0.01). A direct correlation was found in Group I between the levels of M-gradient in blood and urine after treatment (r=+0.54; p<0.01 according to Spearman). After three courses of chemotherapy, the levels of total protein and creatinine in the blood serum decreased by 1.2 (p<0.01) and 1.3 times (p<0.05), respectively, compared to the initial examination data. The absence of response in one patient was characterized by an increase in urine M-protein level by 25.7% (0.44 vs. 0.35 g/L) and the presence of plasmacytoma; in the second patient, an increase in blood M-protein content was observed, doubling (11.28 g/L vs. 5.64 g/L). In the third patient, during the second examination, a tumor in the upper part of the sternum on the left with plasmacytic morphology was discovered, which had not been recorded before the start of specific treatment. Conclusion. The presence of plasmacytoma in patients with multiple myeloma may serve as a negative prognostic factor for achieving a response to chemotherapy with bortezomib, lenalidomide, and dexamethasone.

Isatuximab-dexamethasone-pomalidomide combination effects on serum M protein and PFS in myeloma: Development of a joint model using phase I/II data.

This study aimed at leveraging data from phase I/II clinical trials to build a nonlinear joint model of serum M-protein kinetics and progression-free survival (PFS) accounting for the effects of isatuximab (Isa), pomalidomide (Pom), and dexamethasone (Dex) in patients with relapsed and/or refractory multiple myeloma. Serum M-protein levels and PFS data from 203 evaluable patients, included either in a phase I/II study (n = 173) or in a phase I study (n = 30), were used to build the model. First, we independently developed a longitudinal model and a PFS model. Then, we linked them in a nonlinear joint model by selecting the link function that best captured the association between serum M-protein kinetics and PFS. A Claret tumor growth-inhibition model accounting for the additive effects of Isa, with an Emax function, Pom, and Dex on serum M-protein elimination was selected to describe serum M-protein kinetics. PFS was best described with a log-logistic model and associations with baseline beta-2 microglobulin level, age, and coadministration of Dex were identified. The instantaneous change in serum M-protein level was found to be associated with PFS in the final joint model. Using model simulations, we retrospectively supported the Isa 10 mg/kg weekly for 4 weeks, then biweekly (QW/Q2W) dosing regimen of the ICARIA-MM phase III pivotal study, and validated it using the same phase III pivotal study data.

Soluble B-cell maturation antigen levels for disease monitoring in oligo- and non-secretory relapsed multiple myeloma

Soluble B-cell maturation antigen (sBCMA) is overexpressed on multiple myeloma (MM) cells. We investigated whether sBCMA levels correlated with other myeloma tumor volume indicators and its utility in monitoring oligo-secretory/non-secretory (O-S/Non-S) MM. In 115 patients with newly diagnosed MM, sBCMA was compared with M-protein levels, bone marrow plasma cells (BMPCs), circulating tumor cells (CTCs), and total diffusion volume (tDV; estimated by whole-body diffusion-weighted magnetic resonance imaging) at diagnosis. sBCMA levels increased significantly with International Staging System stage, chromosome 1q21 gain/amplification and CTC levels. sBCMA also correlated strongly with %BMPC (r = 0.65), moderately with tDV (r = 0.55) and paraprotein levels (involved immunoglobulin in IgG and IgA subtypes, r = 0.44 and 0.4; involved free light-chain levels in light-chain-only MM, r = 0.61, all P < 0.05). Longitudinal changes in sBCMA were consistent with disease status in both 17 O-S/Non-S and other secretory MM cases. Furthermore, sBCMA levels increased as early as 6 months pre-relapse in almost all O-S/Non-S relapsed patients. Thus, sBCMA correlates strongly with total tumor volume in MM, as assessed using different modalities. We suggest that sBCMA is useful, not only for monitoring responses in patients with O-S/Non-S MM but also for early relapse detection and prediction.

Impact of chromosomal aberrations detected by chromosome banding analysis in symptomatic Waldenström's macroglobulinemia.

The clinicopathologic features and prognostic impact of MYD88 L265P (MYDL265P) and CXCR4 mutations (CXCR4Mut) have been well reported, although little is known regarding the impact of chromosomal aberrations (CA) detected by chromosome banding analysis (CBA) in symptomatic Waldenström's macroglobulinemia (sWM). Thus, we investigated the clinicopathologic features and prognostic impact in sWM with CAs identified by CBA. We retrospectively analyzed the clinicopathologic results and genomic alterations by droplet digital PCR, fluorescence in situ hybridization (FISH), and CBA using the G-banding method in bone marrow samples from sWM patients collected between April 2010 and March 2024 at our institute. The relationship between CAs and clinicopathologic features was evaluated, as well as the time to next treatment (TTNT). Thirty-five patients were enrolled. The median age was 71 years, and the median hemoglobin level was 10.1g/dL. The median serum IgM and M-protein levels were 3,009mg/dL and 2.95g/dL, respectively. MYDL265P was found in 30/35 patients (85.7%), whereas CXCR4Mut was found in 3/35 patients (8.6%). Deletion 6q identified by FISH in 5/18 patients (28%), and CAs using CBA in 9/34 patients (26%), including 4/34 (12%) complex karyotypes. sWM with CAs had more anemia (p = 0.04) and hypoalbuminemia (p = 0.007), in addition to higher serum M-protein and IgM levels (p = 0.03). With a median follow-up of 73 months, the median TTNT in patients with and without CAs was 27 and 68 months, respectively. CAs with CBA may be associated with clinical aggressiveness and shorter TTNT in sWM.

Population attributable fractions for risk factors for the progression of monoclonal gammopathy of undetermined significance to multiple myeloma in the Veteran population.

7552 Background: Multiple myeloma (MM) is the most common type of plasma cell cancer in the U.S. MM is consistently proceeded by monoclonal gammopathy of undetermined significance (MGUS). Studies have identified several risk factors for the progression of MGUS to MM. However, the contribution of each of these risk factors has not been quantified. We computed the population attributable fractions (PAFs) for selected risk factors in the U.S. Veterans Health Administration (VHA) health system. Methods: Veterans diagnosed with MGUS from 1999-2021 were identified and confirmed via a published natural language processing (NLP) model. We included Black and White patients whose immunoglobulin (Ig) subtype was IgA, IgG, or light chain. Patients who progressed to MM ≤6 months after MGUS diagnosis were excluded. We fit a multivariable time-to-event model controlling for sex, race (Black, White), Ig subtype (IgA, IgG, light chain), agent orange (AO) exposure, as well as M-protein level (≤, &gt;1.5 g/dL), Charlson Comorbidity Index (CCI), obesity status (underweight, normal weight, overweight, obese), and age, all at MGUS diagnosis. The outcome was progression of MGUS to MM, which was also confirmed by a published NLP model. PAF for a risk factor is the fraction of all MM cases in the veteran population that is attributable to this specific risk factor. It accounts for both the prevalence and relative risk of this factor in the population. We calculated PAF for black race, IgA, AO exposure, and overweight/obesity. Results: The analysis included 24,917 patients with MGUS. Among them, 7.8% (n=1,944) progressed to MM (follow-up median 5.6, IQR 3.3-8.8 years). In the veteran population with MGUS, 17.9% of all MM cases was attributable to overweight or obesity (PAF 17.9%, 95% confidence interval [CI] 11.0-24.3%); 7.6% was attributable to black race (PAF 7.6%, 95% CI 4.3-10.9%), 5.7% was attributable to IgA (PAF 5.7%, 95% CI 4.0-7.4%), and 2.4% was attributable to AO exposure (PAF 2.4%, 95% CI 1.0-3.9%). Conclusions: In the veteran population with MGUS, overweight/obesity, the only modifiable factor, is the top contributor to progression to MM cases. In veterans with MGUS, had the overweight or obese MGUS patients to be reversed to normal weight, an estimated 17.9% of the progression cases could have been avoided.Our findings highlight the importance of maintaining a normal weight for reducing the risk of progression of MGUS to MM. [Table: see text]

Hdp-101, an Anti-BCMA Antibody-Drug Conjugate with a Novel Payload Amanitin in Patients with Relapsed Multiple Myeloma, Initial Findings of the First in Human Study

Introduction Several antibody-drug conjugates (ADCs) are currently being evaluated in clinical trials in a variety of malignancies. The vast majority of these are based on a few toxic compounds, largely limited to microtubule- or DNA-targeting toxins which impact proliferating cells and have limited efficacy in diseases with a low proliferative fraction such as multiple myeloma. Thus, new compounds with alternative modes of action and the ability to actively induce cell death in non-proliferating tumor cells could enhance the therapeutic potential of ADCs. We are currently developing amanitin based ADCs. Amanitin specifically inhibits RNA polymerase II thereby inhibiting the cellular transcription process at very low concentrations irrespective of the proliferation status of the target cell. Subsequently tumor cells enter apoptosis and are eliminated. HDP-101 an Amanitin based antibody drug conjugate HDP-101 is a new ADC targeting BCMA carrying a synthetic version of amanitin as a payload. In vitro cytotoxic potency of HDP-101 was demonstrated on BCMA-positive myeloma cell lines, as well as on non-proliferating primary CD138+ cells isolated from patients with refractory myeloma The cytotoxic effects of HDP-101 were seen even in non-proliferating myeloma cells with low BCMA density. Toxicity was observed neither in non-BCMA expressing control cells nor in myeloma cells exposed to an amanitin-loaded non-target control antibody. In murine xenograft models of human myeloma, HDP-101 caused dose-dependent tumor regression including complete remissions after a single dose in subcutaneous and as well as in disseminated models. Safety profiling in Cynomolgus monkeys revealed a good therapeutic index after repeated dosing. Our non-clinical studies concluded that this amanitin-based ADC is a novel promising approach in the therapy of multiple myeloma to overcome drug resistance and improve patient outcome. HDP-101-01 Clinical study HDP-101-01 is a first-in-human, open label, non-randomized, multicenter, phase 1/2a trial with HDP-101 in patients with myeloma whose disease has progressed. The aim of the Phase 1 dose escalation part is to determine the Maximum Tolerated Dose and/or establish the Recommended Phase 2 Dose. The primary objective of the phase 2 dose expansion phase is to assess the preliminary anti-tumor activity of HDP-101. An adaptive Bayesian logistic regression model with overdose control principle is used to guide the dose escalation steps. An Interim Analysis is planned after each cohort is completed. The design of the study ensures a safe and adaptive dose escalation to reach a potential clinical benefit in a patient who have limited or no therapeutic options. HDP-101-01 Study progress The study started enrollment in February, 2022. As of 10th of July, 2023, eight (2 female and 6 male) patients were dosed in 3 consecutive dose cohorts. The median age of the patients was 70 years, ranging between 50 and 80. All 8 patients were heavily pre-treated and multidrug-resistant. The median previous lines of treatment were 7 (5 to 15). Table 1 HDP-101-01 Results Seven of 8 patients were evaluable for dose limiting toxicities (DLTs) in the first 3 treatment cohorts. The initial 3 cohorts were well tolerated, without any DLTs, there were no signs of liver and kidney toxicity, no infusion reaction was detected. No reports of keratopathy or visual acuity loss were observed. Free payload was not detected in any of the available pharmacokinetic samples. Based on the limited data, the PK of HDP-101 was in line with our expectation based on the preclinical observations, exposure to HDP-101 is dose proportional. Anti-drug antibody (ADA) was not detected and there's no sign of immunogenicity. Objective responses were not reported in these initial cohorts however in Cohort #3 (60μg/Kg) there was one patient ongoing after 8 cycles of treatment with SD. This patient had a slow decrease in M-protein levels. Image 1 The initial dose cohorts showed good tolerability in late stage relapsed and/or refractory multiple myeloma patients. The study continues to enroll patients to higher dose cohorts at selected sites in the US, Germany, Poland and Hungary. Currently the study is enrolling patients in Cohort #4 at the dose of 80μg/Kg. Additional updates will be provided at the 2023 ASH Annual Meeting.

Smoldering Multiple Myeloma Progressing to Active Multiple Myeloma Vs De-Novo Active Multiple Myeloma - a Comparison of Disease Characteristics, Organ Involvement and Outcomes in a Real-Life Multicenter Retrospective Cohort Study

Background Smoldering Multiple Myeloma (SMM) is an intermediate precursor phase in Multiple Myeloma (MM) evolution. SMM patients are monitored for progression to active disease, supposing such surveillance will identify myeloma-defining events (MDEs) early and consequently hasten treatment, prevent complications and improve outcomes. To what extent this approach is successful is not well established. We aimed to compare disease characteristics, end organ involvement and outcomes between SMM patients who progressed to active MM vs newly diagnosed MM (NDMM) patients. Methods We performed a two-center real-world case-control retrospective cohort study. Consecutive patients receiving first line treatment for MM after progressing from SMM were identified; each was matched by age and year of diagnosis (±2 years) to a patient first presenting as NDMM. SMM, MM, MDEs and response were defined by the International Myeloma Working Group (IMWG) criteria (2014, 2016); progression-free survival (PFS) and overall survival (OS) were calculated from active MM diagnosis. Data was extracted in 07/2023. Results We identified two cohorts of newly diagnosed MM patients, presented between 09/2008and 02/2023: Post SMM (P-SMM, N=57) and De novo MM patients (D-MM, N=57). Median follow up time was 38.6 months (IQR 23.3 - 72.7). There were no differences in baseline demographics between gender (p=.19), and median age: 73.4 (range 42 - 88) in the P-SMM group and 72.9 (range 42 - 92) in the D-MM (p=.75). Comparing MDEs using SLiM-CRAB criteria between groups, more patients in the D-MM group presented with hypercalcemia (p=.02) and lytic lesions (p=.03). Other domains were similar between groups: anemia (p=.68), renal failure (p=.59), FLC ≥100 (p=.76), % bone marrow plasma cells (BMPC) ≥ 60 (p=.11). D-MM patients had higher ISS/R-ISS at presentation: ISS ≥ II (30 vs 11, p=.004) and R-ISS ≥ II (31 vs 13, p=.002). Additional disease characteristics were balanced at diagnosis of active MM: heavy chain (p=.53), light chain type (p=.69), M-Protein level (p=.23), extra medullary disease (p=.14), Al amyloidosis (p=.13), and high-risk cytogenetics (p=.65). Bone involvement was more frequent in D-MM vs P-SMM patients, with significantly more pathological fractures (p=.006), bone pain (p=.001), and a detrimental bone disease (p=.001) (defined as combination of pathological fracture and/or ≥ 3 lytic lesions) (Figure 1B). Significantly higher rates of hospital admissions for upfront therapy initiation were seen in the D-MM group compared with P-SMM, 18 vs 7 (p=.008), as well as more potentially irreversible MDEs (pathological fractures and/or renal injury): 43 (p=.009) vs 31 (41.9%) respectively. Treatment patterns were balanced excluding bortezomib used more often in the D-MM (p=.009) and daratumumab in the P-SMM group (p=.03). Best response rates to upfront therapy were comparable between groups, (p=.71) as well as ≥ very good partial response (VGPR) rates (p=.88), 52.4% vs 47.6% in P-SMM and D-MM respectively. Frequency of skeletal imaging tests up-to 2-year period prior to active MM diagnosis were associated with lower rates of detrimental bone disease (p=.006). Despite the similar ≥ VGPR rates between cohorts, PFS was longer in the P-SMM group vs D-MM group, 39.6 vs 21.6 months, respectively (log-rank 0.01). A superior PFS in P-SMM group vs D-MM remained after correction for % BMPC at diagnosis (46.2% vs 58.8%, p=.03). OS was also longer, not reached vs 93.7 months (log-rank=.047) (Figure 1A). Conclusions Patients who develop active MM post SMM clinic surveillance presented with a lower disease burden, as well as reduced rates of detrimental bone disease and potentially irreversible MDEs. P-SMM patients had favorable PFS and OS rates. This may reflect effectiveness of SMM monitoring resulting in lower disease burden at time of treatment onset; favorable long-term outcomes may also be affected by variability in treatment patterns between groups. Another possible explanation is that patients with more indolent MM biology may have extended periods of precursor condition, hence increasing their likelihood to be diagnosed by incidental laboratory tests during their SMM phase.

Multicenter Descriptive Study of Monoclonal Gammopathy of Undetermined Significance in Patients with Heart Failure

Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is the presence of a monoclonal immunoglobulin without concurrent lymphoproliferative disease. It is found in about 5% of people aged 50 and older in the general population. Prevalence rates of MGUS increase with age, especially in men and individuals of Black ethnicity compared to women and White individuals, respectively. The diagnostic criteria for MGUS includes a serum M-protein level &amp;lt;3 g/dL, &amp;lt;10% clonal plasma cells in the bone marrow, and the absence of a myeloma-defining event. Though historically considered benign, emerging evidence suggests that MGUS patients, even without lymphoproliferative disorders, face increased risks of various diseases like bone diseases, recurrent infections, autoimmune disorders, peripheral neuropathy, renal complications, and cardiovascular disease (CVD). This study aims to investigate the prevalence and characteristics of individuals with both MGUS and heart failure (HF) and examine potential racial disparities between Black patients and non-Black patients with MGUS and HF. Methods: This is a retrospective multicenter study that includes patients diagnosed with both MGUS and New York Heart Association grade II or higher HF from January 2010 to January 2023. Patients with potential confounding conditions of MGUS were excluded, such as non-MGUS plasma cell dyscrasias, hematologic malignancies, autoimmune/inflammatory disorders, and viral illnesses. Laboratory data was recorded at the time of MGUS diagnosis, and HF data was derived from imaging studies performed closest to the time of MGUS diagnosis or at the initial diagnosis of HF if it was diagnosed after MGUS. Findings were summarized using descriptive statistics. Results: We analyzed a total of 128 patients with MGUS and HF, excluding 24 patients with potential MGUS confounders. Among the remaining 104 patients, 41 (39.4%) were female, and 63 (60.6%) were male. The cohort consisted of 80 (76.9%) Black patients and 24 patients of non-Black ethnicity. For the overall cohort, the mean age at MGUS diagnosis was 72, and the mean time from HF diagnosis to MGUS diagnosis was 22.5 months with a median of 9.1 months. In 24% of patients, HF and MGUS were diagnosed within less than 1 month of each other. The predominant monoclonal proteins observed were IgG Kappa, IgG Lambda, and IgA Kappa, found in 54 (51.9%), 30 (28.8%), and 13 (12.5%) patients, respectively. The average M spike was 0.7 +/- 0.6 (SD, standard deviation), and the average free light chain ratio was 2.3 +/- 2.3 (SD). The most common type of HF diagnosed was heart failure with reduced ejection fraction (HFrEF, EF &amp;lt;40%), occurring in 63.5% of the cohort. The etiology of HF in the cohort was attributed to ischemic cardiomyopathy in 43.3%, non-ischemic cardiomyopathy in 51%, and a combination of both in 5.7%. Table 1 presents the MGUS variables for the overall cohort and stratification by race. Table 2 displays the characteristics of study subjects based on the type of HF, including HFrEF, mid-range ejection fraction (HFmrEF, EF 40-49%), and preserved ejection fraction (HFpEF, EF &amp;gt;50%). Conclusion: This study did not find a significant association between MGUS variables and HF, likely due to the limited sample size. However, a larger study by Schwartz et al. using a Danish nationwide database with over 8,000 participants suggested that MGUS patients had a higher risk of incident CVD, even after adjusting for other comorbidities. They also noted a higher prevalence of CVD risk factors in patients with MGUS. These findings indicate a possible link between MGUS and CVD, though the true nature of this association remains uncertain - whether it's causal or coincidental. An interesting observation from our study is that MGUS is often incidentally detected in patients already diagnosed with HF. This suggests that physicians may come across MGUS while investigating the underlying causes of HF, raising the possibility of shared underlying factors or pathological processes between both conditions. Considering our findings, it's essential to recognize that MGUS patients may have a higher mortality risk independent of developing plasma cell disorders. Large-scale studies are needed to better understand the association between MGUS and CVD, potentially influencing monitoring and follow-up strategies for MGUS patients, especially concerning potential cardiovascular implications.

A sensitive high-resolution mass spectrometry method for quantifying intact M-protein light chains in patients with multiple myeloma

To determine the disease status and the response to treatment for patients with multiple myeloma, measuring serum M-protein levels is a widely used alternative to invasive punctures to count malignant plasma cells in the bone marrow. However, the quantification of this monoclonal antibody, which varies from patient to patient, poses significant analytical challenges. This paper describes a sensitive and specific mass spectrometry assay that addresses two objectives: to overcome the potential interference of biotherapeutics in the measurement of M-proteins, and to determine the depth of response to treatment by assessing minimal residual disease. After immunocapture of immunoglobulins and free light chains in serum, heavy and light chains were dissociated by chemical reduction and separated by liquid chromatography. M-proteins were analyzed by high-resolution mass spectrometry using a method combining a full MS scan for isotyping and identification and a targeted single ion monitoring scan for quantification. This method was able to discriminate M-protein from the therapeutic antibody in all patient samples analyzed and allowed quantification of M-protein with a LLOQ of 2.0 to 3.5 µg/ml in 5 out of 6 patients. This methodology appears to be promising for assessing minimal residual disease with sufficient sensitivity, specificity, and throughput.

Monoclonal Protein Concentration and Risk of Multiple Myeloma: Is 0.5 g/DL the New 1.5?

Introduction : Monoclonal Gammopathy of Undetermined Significance (MGUS) is an asymptomatic clonal plasma cell disorder with a risk of progression to multiple myeloma (MM). To provide an accurate prognosis, monoclonal protein (M-protein) concentration has been used to assess risk of progression to myeloma. Current risk models developed from stored serum samples in a predominately white population of patients indicated a low risk of progression (less than 1% per year) in patients with M-protein of &amp;lt;1.5 g/dL. Little is known about M-protein concentration and risk of progression in patients tested during routine clinical care in a more diverse population. We assessed the outcomes of MGUS five years after diagnosis, and determined the association between baseline characteristics and the rate of progression to MM. Methods: We used data from national Veterans Health Administration system to identify patients diagnosed with MGUS from 1999-2021 and were followed from MGUS diagnosis until progression, death, or the date 7/11/2023 was reached. MGUS diagnosis and progression to MM was confirmed utilizing a natural language processing algorithm. We included patients of black and white race and those with IgG, IgA, or light chain MGUS. The exposure was M-protein concentration at MGUS diagnosis, stratified by ≤0.5, &amp;gt;0.5-≤1.0, &amp;gt;1.0-≤1.5, &amp;gt;1.5 g/dL. We plotted the cumulative incidence function curve and used a multivariable Fine-Gray sub distribution hazard model with progression at 5 years as the event of interest, and death as a competing event. Covariates included sex, race, MGUS type, age, body mass index (BMI), diabetes, renal disease, and other comorbidities summarized by Charlson Comorbidity Index at MGUS diagnosis. Results: We included 15,520 patients with MGUS. The mean age at the diagnosis was 71.1. IgG subtype was more common (83.2%) than IgA (12.7%), and light chain (4.1%). 19.6% and 39.5% of patients had renal disease and diabetes, respectively. Black veterans represented 5600 (36.1%) of the cohort. At 5 years, 26.6% of veterans with an M-protein of &amp;gt;1.5 g/dL were diagnosed with myeloma, compared to 11.7% with 1.1-1.5 g/dL, 6.9% with 0.6-1.0 g/dL, and 3.3% with ≤0.5 g/dL. In multivariable models an M-protein &amp;gt;1.5 was associated with a greater risk of progression compared to ≤0.5 (multivariable-adjusted Hazard Ratio [aHR] 9.76, 95% Confidence Interval [CI] 8.37-11.40). Overall, increasing age was shown to have lower risk of transitioning to MM at 5 years with aHR of 0.983 (95% CI 0.978-0.988). Conclusion: In this modern cohort, only an M-protein of ≤0.5 g/dL was associated with a less 1% per year risk of developing MM. Conversely, 26.6% of veterans with an M-protein level &amp;gt;1.5 g/dL developed MM at 5 years. Risk of MM in patients clinically evaluated for MGUS may be higher than previously thought and new models of MM progression should be developed.

Evaluating the Effect of Evolving Changes in Serum Biomarkers on the Risk of Progression in Smoldering Multiple Myeloma

Introduction Smoldering multiple myeloma (SMM) is a heterogeneous condition which includes patients with varying risk of progression to active multiple myeloma (MM). The current risk stratification model is based on biomarkers reflecting disease burden at the time of diagnosis, without regard to evolution of biomarkers over time. In this study, we evaluated the dynamic changes in the monoclonal protein (MP) concentration and the free light chain ratio (FLCr), and their relation to risk of progression from SMM to MM. Methods We included all SMM patients managed at Memorial Sloan Kettering Cancer Center between 2002 and 2019, with follow up until end of 2022. Date of diagnosis and progression, as well as baseline laboratory, pathology and imaging data were manually reviewed. Serial FLC and MP were obtained through computerized data extraction. Diagnoses of SMM and MM were defined according to IMWG 2014 criteria and/or starting MM directed therapy. Time to progression (TTP) was assessed using the Kaplan-Meier method, with log-rank tests for comparison between groups. We used multivariate Cox regression to estimate the risk of progression with hazard ratios (HRs) and 95% confidence intervals (CIs). Results A total of 398 patients were included in the study; the median age was 64 years and 55% were men. At baseline, the median M-protein was 1.3 g/dL, and the median FLCr was 9.8. The overall median TTP for the cohort was 94 months during a median follow up time of 65 months. First, we stratified patients into quintiles (Q1-Q5) based on baseline M-protein and FLCr, with the highest risk of progression seen in Q5 for M-protein (defined as MP ≥2.2 g/dL, median TTP 29 months [95% CI: 24-64]) and Q5 FLCr (defined as FLCr ≥26, median TTP 36 months [29-62]), respectively (p&amp;lt;0.001). We compared patient trajectories during the first year of follow up based on the baseline quintiles. Interestingly, among patients who progressed from SMM to MM during the first year (11%, n=42/369), only 43% had a baseline M-protein ≥2.2 g/dL (Q5) and 43% had a FLCr ≥26 (Q5). In fact, among those who progressed, 29% had a baseline M-protein &amp;lt;1.6 g/dL (Q1-Q3), and 26% had baseline FLCr &amp;lt;11.3 (Q1-Q3). The patient trajectories during the first year of follow up based on the M-protein level are characterized in Figure 1. We then analyzed changes in M-protein and FLCr during the first year, and stratified patients into quintiles based on the rate of change. We defined evolving M-protein (eMP) and evolving FLCr (eFLCr) based on the levels of the top quintile for each group, which was an increase in ≥0.3 g/dL for eMP and ≥50% increase for eFCLr. Patients with eMP had an increased risk of progression with a median TTP of 22 months (17-not reached [NR]) after the first year (p&amp;lt;0.001). Patients with eFLCr had a median TTP of 48 months (21-116) after the first year (p&amp;lt;0.001). Recognizing that patients with high baseline M-protein level and FLCr also may have a greater increase, we developed a multivariate model adjusting for baseline levels of M-protein and FLCr. In the multivariate model, we included age, gender, and baseline M-protein ≥2g/dL and FLCr ≥20 from the Mayo 2018 risk score, as well as eMP and eFLCr. Adjusting for baseline risk, patients with eMP (Q5) had a HR of 1.8 (0.98-3.16) of progression and patients with eFLCr (Q5) had a HR of 2.9 (1.4-6) of progression using patients with little to no change in M-protein or FLCr as reference (Table 1). Finally, we did a subgroup analysis evaluating eMP and eFLCr in each baseline risk group separately. Patients with no serum risk markers per Mayo-2018 at baseline (i.e. MP &amp;lt;2g/dL, FLCr &amp;lt;20, n=127) who had both eMP (≥0.3 g/dL increase) and eFLCr (≥50% increase), had a median TTP of 25 months (0.42-NR), patients who had either eMP or eFLCr had a median TTP of 100 months (42-NR), whilst patients with neither eMP nor eFLCr had a median TTP of 201 months (130-NR), (p&amp;lt;0.001). Conclusion In summary, we found that when adjusting for baseline M-protein level and FLCr, evolving changes in M-protein and FLCr were associated with a higher risk of progression from SMM to MM. Interestingly, for patients with low risk by baseline stratification (M-protein &amp;lt;2g/dL and FLCr &amp;lt;20), the presence of eMP (≥0.3 g/dL increase) and eFLCr (≥50% increase) was associated with a median TTP of 25 months, similar to those with a baseline high risk. Thus, in addition to baseline disease burden, dynamic disease evolution should be considered in the risk stratification for patients with SMM.

Blood-Based Mass Spectrometry MRD Tracking (M-InSight) in Multiple Myeloma Patients from Clinical Trial NCT02513186

Multiple Myeloma (MM) is a type of cancer of the bone marrow characterized by an anormal growth of the number of plasma cells, which produce a monoclonal antibody (M-protein). Measurable residual disease (MRD) is an important prognostic factor in multiple myeloma to evaluate the depth of treatment response which is widely used in clinical trials. MRD is therefore monitored using techniques that measure the number of tumor cells in the bone marrow (BM). On top of being invasive for the patient, BM-MRD might not represent accurately the disease burden because of the heterogeneous nature of a single area measure in the BM. With new drugs and treatment regimen guided by MRD soon, collecting samples at more frequent timepoints is critical to evaluate the depth of response, thus the need of less invasive sampling becomes evident. To overcome all these difficulties, M-InSight (Sebia), a cutting-edge mass spectrometry (MS) technique that allows quantitation of the M-protein in blood has been developed. MS is used to sequence the M-protein then select and quantifies clonotypic peptides from the variable (CDR) region which are used to track the M-protein level of MM patients. The high sensitivity of M-InSight enables the quantification of M-protein at much lower concentrations than current blood techniques used for diagnostic, which makes it possible to track low level M-protein and potentially detect a relapse before the apparition of new symptoms. The main objective of this study was to show that M-insight can monitor MRD in blood samples of MM patients treated by isatuximab during the maintenance phase. Samples from 15 newly diagnosed non eligible for transplantation MM patients from a Sanofi clinical trial (NCT02513186) were chosen to monitor MRD by M-InSight. All patients were selected from the VRDI Part B (bortezomib, lenalidomide, dexamethasone) consisting of evaluating the preliminary efficacy (complete response [CR] rate) of isatuximab administered at the selected dose in combination with bortezomib based regimen. The treatment period included 4 induction cycles (24-week duration), followed by a maintenance period consisting of 4 weeks cycles until progression, unacceptable AE, or patient willingness to discontinue. M-InSight was used to sequence the M-protein (collected predose at Day 1 of Cycle 1) and to measure M-protein concentration in the serum samples collected during the maintenance phase. Results were compared to SPEP, IFE and MRD at 10-6 sensitivity by clonoSEQ®️ (Adaptive Biotechnologies). After 4 cycles of induction, all patients had Very Good Partial Response. Rate of 9/15 CR, 5/15 VGPR and 1 sCR was observed as the best overall response. NGS MRD data were obtained for 14 patients of which 8 reached MRD negativity at 10 -6 sensitivity. 4 of the remaining 6 patients relapsed during maintenance. Clonotypic peptides were identified in all 15 patients from the baseline sample. A total of 302 serum samples collected during maintenance were analyzed. M-protein quantification was highly concordant with the one obtained by SPEP when available (Pearson R=0.78, p&amp;lt;0.01). 100% of patients that were MRD positive by NGS 10 -6 were MS-MRD positive and could be quantified by M-InSight. 60% of patients that were MRD negative by NGS 10 -6 were still positive and quantifiable by M-InSight, suggesting higher sensitivity. The remaining 40% was negative by both NGS and MS. M-insight was able to monitor the disease on 5 patients that had sustained MRD (consecutive MRD negativity) and stable M-protein levels (no increase or decrease of M-protein by 2-fold for 2 consecutive time points). All 4 patients that developed PD had an increase of M-protein of at least 2-fold in 2 consecutive time points showing that M-InSight was able to provide an earlier detection of relapse, when SPEP was still negative for 3 of these. Only one patient had unmeasurable M-protein concentration, staying unmeasurable for 1 year and negative by NGS MRD. The lowest M-protein concentration measured by M-InSight was 0.01 mg/dL (10 mg/dL). This study shows that MRD monitoring on blood is feasible using an ultra-sensitive technique, avoiding invasive bone-marrow aspiration. M-InSight shows accurate monitoring of the depth and kinetics of response to treatment thanks to frequent timepoints. M-InSight can track low level of M-protein in CR patients and detect early relapse.

Risk Factors of Smoldering Multiple Myeloma: Results from the Screened Istopmm Study

Introduction Smoldering multiple myeloma (SMM) is an asymptomatic precursor condition to multiple myeloma (MM) that carries a higher risk of progression to MM than monoclonal gammopathy of undetermined significance (MGUS). This study aimed to identify potential risk factors of SMM by analyzing the association of baseline characteristics, body mass index, smoking, alcohol consumption, prior diagnoses of autoimmune diseases and prior chronic infections and SMM in the screened Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study cohort. Methods The iStopMM study is a screening study for MM precursors where 75,422 individuals over 40 years old in Iceland were screened with serum protein electrophoresis (SPEP) and free light chain (FLC) analysis. Those with a positive screening result were randomized to one of the three study arms, with clinical evaluation at the study center, including bone marrow sampling, performed in two of them. MGUS was defined by the presence of a serum M-protein concentration less than 30 g/L and less than 10% clonal plasma cells in the bone marrow, and SMM was defined as 10-60% bone marrow plasma cells and/or M-protein concentration over 30 g/L, both in the absence of MM defining events. IgM MGUS was excluded in this analysis. Height and weight were measured at the first visit to the study center, alcohol and smoking habits were evaluated with questionnaires. Information on previous diagnoses (ICD codes) was obtained from central health registries with almost 100% completeness. Logistic regression models were used to calculate odds ratio (OR) with 95% confidence interval (CI) to compare risk factors in SMM vs. MGUS and SMM vs. controls. All analyses were adjusted for age and sex. Results At the first study center evaluation, 210 individuals were diagnosed with SMM and 1,456 with MGUS. Data from 70,627 controls with negative SPEP and normal FLC analysis were included. Individuals with SMM were older and more frequently male than controls, however there was no statistically significant difference between the sex and age distribution of individuals with SMM and MGUS (Figure). Immunoparesis (OR 3.98; 95% CI: 2.74-5.76), abnormal FLC ratio (OR 3.61; 95% CI: 2.59-5.02), IgA isotype (OR 2.64; 95% CI: 1.83-3.83) and increasing M-protein levels (OR per g/L 1.33; 95% CI: 1.27-1.39) were all associated with increased odds of SMM compared to MGUS. BMI measured at the first study visit was not significantly different between individuals with MGUS and SMM (overweight vs. normal weight OR 1.08; 95% CI: 0.74-1.56). Neither current or previous smoking nor alcohol consumption more than once per week (vs. less) was associated with increased risk of SMM compared to MGUS (OR 0.88; 95% CI: 0.60-1.31, and OR 0.97; 95% CI: 0.62-1.53, respectively) or controls (OR 0.92; 95% CI: 0.64-1.33, and OR 0.85; 95% CI: 0.57-1.27, respectively). Prior diagnosis of autoimmune disease was not associated with SMM as compared to MGUS (OR 1.19; 95% CI: 0.81-1.74) or controls (OR 1.21; 95% CI: 0.85-1.73). A previous diagnosis of a chronic infection was not statistically significantly associated with increased risk of being diagnosed with SMM as compared to MGUS (OR 1.53; 95% CI: 1.00-2.34) but an association was seen when compared to controls (OR 1.54; 95% CI: 1.05-2.28). In individuals with SMM, the most common chronic infections were varicella zoster virus and herpes simplex virus, no diagnoses of hepatitis virus or chronic bacterial infections were observed. Conclusion In this large population-based screening study we did not find an association of smoking, alcohol consumption, BMI, or a prior diagnosis of autoimmune disease and SMM compared to MGUS. We found an association between a previous diagnosis of a chronic infection and SMM which could be explained by reverse causality, i.e., that SMM leads to immune impairment which increases the risk of viral infections. We found no significant age or sex difference between individuals with MGUS and SMM, but results from blood tests, including immunoparesis, abnormal FLC ratio, IgA-isotype, and higher levels of M-protein were all associated with SMM compared to MGUS. Our results indicate that neither lifestyle factors nor chronic inflammatory conditions increase the risk of SMM, and that the differences between individuals with MGUS and SMM can be detected in blood assessments associated with the plasma cell clone, but not in demographic or behavior related factors.

Expanded natural killer cells potentiate the antimyeloma activity of daratumumab, lenalidomide, and dexamethasone in a myeloma xenograft model

The development of new treatment agents in recent decades has significantly improved the survival of patients with multiple myeloma (MM). Nonetheless, MM remains an incurable disease; therefore, novel combination therapies are required. Natural killer (NK) cells are one of the safest immunotherapeutic options. In this study, we found that the anti-myeloma activity of expanded NK cells (eNKs) was improved by daratumumab, lenalidomide, and dexamethasone (DRd) in an MM xenograft mouse model. NK cells expanded from peripheral blood mononuclear cells collected from MM patients were highly cytotoxic against DRd pretreated tumor cells in vitro. To mimic the clinical protocol, a human MM xenograft model was developed using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγnull (NSG) mice. MM bearing mice were randomly divided into six groups: no treatment, eNK, Rd, Rd + eNKs, DRd, and DRd + eNKs. DRd significantly enhanced the cytotoxicity of eNKs by upregulating NK cell activation ligands and effector function. DRd in combination with eNKs significantly reduced the serum M-protein level and prolonged mouse survival. In addition, DRd significantly increased the persistence of eNK and homing to MM sites. These results show that the anti-myeloma activity of ex vivo-expanded and activated NK cells is augmented by the immunomodulatory effect of DRd in MM-bearing mice, suggesting the therapeutic potential of this combination for MM patients.

The Association between Body Mass Index Trajectory and the Progression of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma

Background: Obesity is a known risk factor for multiple myeloma (MM), as prior studies have shown that body mass index (BMI) greater than 25 kg/m2 (at a fixed time point) increases the risk for MM and its premalignant condition, monoclonal gammopathy of undetermined significance (MGUS). However, to date, no studies have evaluated whether changes in BMI over time affect the progression of MGUS to MM. We aimed to assess the association between changes in BMI following a diagnosis of MGUS and the progression of MGUS. Methods: Patients with MGUS from 1999-2021 in the Veterans Health Administration were identified. We used a natural language processing (NLP) based algorithm to confirm MGUS diagnosis and progression, including smoldering MM and MM. Only patients with IgG, IgA, or light chain MGUS and black and white patients were included in the analyses. Patients with Diabetes Mellitus (DM) were excluded from analysis due to potential confounding bias. Patients who progressed within 5 years of MGUS diagnosis were also excluded. Excess BMI was defined as BMI over 25 kg/m2. To capture the trajectory of excess BMI, the area under the curve (AUC) of excess BMI during the 5 years following MGUS diagnosis was calculated. A multivariable time-to-competing-event analysis was performed to estimate the multivariable-adjusted association of AUC of excess BMI with progression with death as the competing event. The covariates included BMI at MGUS diagnosis, M-protein level (>= 1.5g/dL), age at MGUS diagnosis, sex, race, MGUS heavy chain subtype, light-chain MGUS. Results: After applying our inclusion and exclusion criteria, our analytic cohort included 7,739 MGUS patients. Our multivariable time-to-competing-event analysis revealed a positive association between excess BMI trajectory and MM progression (multivariable-adjusted hazard ratio, aHR, 1.02, 95% confidence interval, CI, 1.01-1.03) - a 2% increase in risk of progression per 1 kg/m2 increase in excess BMI per year following MGUS diagnosis. Conclusion: In patients diagnosed with MGUS, increases in excess BMI by 1 kg/m2 per year were associated with 2% increased risk of progression to MM. This finding suggests that maintaining a healthy weight in patients with MGUS may reduce the risk of progression. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Tool to Longitudinally Assess the Secretory Capacity of Myeloma Cells throughout the Course of Disease

Multiple myeloma (MM) remains an incurable clonal plasma cell malignancy characterized by the production of monoclonal protein (M-protein). However, MM presents with variable M-protein secretory status. Plasma cells are professional antibody factories that secrete vast amounts of immunoglobulins (Igs) and myeloma cells are exquisitely sensitive to disruption of protein homeostasis. Proteasome inhibitors (PI) target the unfolded protein response by inhibiting degradation of ubiquitinated proteins (and paraproteins), leading to protein accumulation within the endoplasmic reticulum that culminates in cell death. International Myeloma Working Group (IMWG) criteria to assess tumor volume rely on the secretory function of MM cells determined by the concentration of the circulating monoclonal protein to infer tumor burden. Hence, changes in M-protein levels may be indicative of therapeutic response or disease progression. PIs can selectively target the most highly secretory MM, while residual cells, the source of relapse, are less secretory. Circulating M-protein levels are a product of the number of MM cells and the amount of M-protein secreted by each individual cell. IMWG criteria assumes that the secretory power of an individual myeloma cell remains constant throughout the course of treatment. However, this assumption has not been tested, due to the inability to accurately measure MM cell numbers. Since Next Generation Sequencing (NGS) allows for direct measurement of tumor cell number, we developed a method to define a "Secretory Power Index” (SPI) as a longitudinal tool to assess tumor burden. Methods: NGS on patient BM samples was checked while disease level was below VGPR throughout the disease course as standard-of-care. Patients with IgA and light chain MM were excluded due to different half-life of circulating M-protein. The ratio between IgG monoclonal proteins in mg/L to number of tumor cells measured by NGS was defined as SPI. The SPEP value 4 weeks before and after NGS was utilized to calculate SPI. If NGS could not count any myeloma cells (negative test) but there was circulating M-protein, the SPI was replaced with highest value was detected among the patient population. If NGS test was positive but there was no circulating protein the SPI was counted as zero. Mann-Kendall's non-parametric statistical test was used to assess the significance of SPI trend over the time. The comparison was performed intra-patient and not inter-patient. Results: 47 patients with >2 MRD assessment were included and 5 patients were excluded due to SPEP unavailability. Median age was 70 years (range 53-78), 25 patients were male (60%), 15 of patients were African-American (36%), and 27 patients were Caucasian (64%). 30 patients were IgG Kappa (71%) and the rest were IgG lambda (Table 1). Median total nucleated cells evaluated was 1.3x106 (range 0.5-3.2x106). Median number of dominant sequence identified was 2 sequences. All patients had first SPI after first line of therapy, 26 (62%) second SPIs were measured after second line of therapy and the rest in later lines. 8 (19%) patients had extramedullary disease with attachment to the bony compartment and none had known visceral disease at diagnosis. Median first SPI was 75 (range 0-1040). Mann-Kendall trend tests showed a statistically significant decrease in SPI over time (S = 2460.0, p < 0.001) which was significant after entering factors, e.g., age, race, light chain type, triple vs. quadruple induction. Conclusions and Limitations: Here, we developed a method to assess secretory power of myeloma cells. The results suggest that the SPI decreases over the time as patients go through different lines of therapy. The spatial heterogeneity of disease in BM may interfere with NGS sampling, however high predictability of long remission based on NGS negative BM highlights the high validity of this method. We will validate this tool in a larger prospective cohorts to demonstrates that IMWG criteria could under-estimate the response measured by global secretory function. This phenomenon is observed in light chain escape when MM progression presents as slight or no increase in monoclonal MM antibody with rapid rise in light chains. Also, non-secretory escape is not uncommon at very late stages of MM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Lava-051, a Novel Bispecific Gamma-Delta T-Cell Engager (Gammabody), in Relapsed/Refractory MM and CLL: Pharmacodynamic and Early Clinical Data

Background: LAVA-051 is a Vγ9Vδ2-T cell engaging bispecific antibody of 27 kDa that directly engages tumor expressed CD1d and the Vδ2-TCR chain of Vγ9Vδ2-T cells to kill tumor cells in a tumor target-dependent manner. Binding between LAVA-051 and CD1d also causes the activation of a second effector cell type: invariant natural killer T (iNKT) (Nature Cancer 2020;1:1054-1065). By dual engagement of these unique innate-like T cell subsets with inherent antitumor activity, LAVA-051 has the potential to exhibit high potency antitumor activity. Based on clinical experience with systemic activation of Vγ9Vδ2-T cells through aminobisphosphonates and in vivo studies in non-human primates (NHP) with a surrogate CD1d-γδ T cell engager, a low risk for cytokine release syndrome (CRS) is expected. CD1d is expressed by tumor cells in the majority of patients with CLL (chronic lymphocytic leukemia) and MM (multiple myeloma), while expression in AML (acute myeloid leukemia) is most pronounced on (myelo)monocytic subtypes. The local tolerance of subcutaneous (SC) administration of LAVA-051 was studied in a NHP model with no signs of local intolerance or histopathological abnormalities observed. Methods: An open label, accelerated titration design, phase 1/2a study in patients with relapsed/ refractory CLL and MM (NCT04887259) is ongoing to determine the safety of LAVA-051 and its recommended Phase 2a dose (RP2D). Adverse Events (AEs) are graded per CTCAE V5.0 criteria and CRS is graded per ASTCT criteria. IMWG criteria (MM) and iwCLL guidelines (CLL) are used for disease evaluation. The RP2D will be the optimal biological active dose, supported by a panel of specific pharmacodynamic assays to determine the pattern of change in the binding of LAVA-051 to peripheral blood Vγ9Vδ2-T cells (i.e. Vγ9Vδ2-TCR occupancy), and in the frequency and activation status of Vγ9Vδ2-T and iNKT cells in circulation. LAVA-051 is administered by IV infusion over 2 hours twice a week or by SC administration; observation of changes in PD parameters following SC administration as compared to IV infusion will enhance selection of RP2D administration and schedule. Results: As of July 25, 2022, a dose level of 100 µg has been reached (starting dose 0.45 µg) with no reports of CRS or dose limiting toxicities (DLTs). Eight patients in total have been treated with LAVA-051; 4 patients with MM and 4 patients with CLL with treatment duration range of 1.6 to 18.1 weeks. Treatment emergent AEs (TEAEs) were predominantly of grade 1 and 2 severity, with a minority of AEs observed across more than one dose level: lymphadenopathy, pyrexia (underlying causes different from CRS), epistaxis, dyspnea, and leukopenia. Severity of TEAEs did not increase with escalating doses and no patient discontinued treatment due to an AE. Disease stabilization has been observed in two patients. Despite no observation of formal response, lymph node shrinkage was observed in one CLL patient and decreasing M-protein levels in one MM patient. Pharmacodynamic data reflect changes as expected per LAVA-051 mechanism of action (MoA): Vγ9Vδ2-T cell activation markers (CD25 and CD69) were consistently upregulated in each dose cohort where this could be assessed, maximum measured Vγ9Vδ2-T cell receptor occupancy increased with higher dose cohorts, and iNKT cell activation was observed. Furthermore, no significant increases in IL-6 or other CRS-related cytokines have been observed. Pharmacokinetic data indicate predictable and linear pharmacokinetics. Updated safety, PD, and PK results following IV and SC administration will be presented at the congress. Conclusions: LAVA-051 has been well tolerated early in dose escalation with pharmacodynamics and early clinical signs reflective of its intended MoA. The differentiating importance of these pharmacodynamic parameters with any correlating preliminary antitumor activity will be further elucidated with continued dose escalation by the IV and SC route and in the determination of the RP2D and schedule.

Minimal Residual Disease Monitoring By Targeted Mass Spectrometry Allows Early Relapse Detection in Multiple Myeloma

Background Multiple myeloma (MM) is a clonal plasma cell disorder found in the bone marrow that produces a monoclonal immunoglobulin (M-protein). With blood based electrophoretic assays such as serum protein electrophoresis (SPEP) the M-protein is monitored, but with limited sensitivity. Minimal residual disease (MRD) negativity during remission correlates with prolonged progression free survival. Lack of sensitivity prevents MRD detection by conventional blood based assays. Bone marrow based assays such as next-generation sequencing (NGS) are highly sensitive in measuring MRD. However, bone marrow biopsies introduce a risk of non-representative sampling and are invasive, which limits repeated testing. Frequent MM monitoring during remission could provide actionable information on disease activity and treatment response. Earlier detection of disease progression could lead to early intervention and, potentially, patient survival benefits. Aim The aim of this study was to perform M-protein monitoring on blood samples of MM patients with sensitive targeted mass spectrometry (MS-MRD), to show the capabilities of this MRD-approach. Methods Forty-one MM patients were selected from the IFM 2009 study (ClinicalTrials.gov number: NCT01191060) with 13-31 serum samples per patient collected longitudinally over 29-60 months follow-up. RNA sequences, NGS-MRD, and SPEP data were available to us. All patients were treated with lenalidomide, bortezomib, and dexamethasone, but only treatment arm B received autologous stem-cell transplantation (ASCT). For each patient, 2 unique tryptic peptides from the M-protein were selected, 1 peptide was selected for patients with only light chain M-protein. For early increases in disease activity, absolute M-protein quantification (g/dL) was performed based on tryptic peptides and stable isotope-labeled peptide as an internal standard. Results Out of a total of 929 measured samples, M-protein was detected in 879 samples by MS-MRD and only in 195 samples by SPEP. Furthermore, MS-MRD showed a 78% concordance with NGS-MRD with 14 samples being MS-MRD positive but NGS-MRD negative. Sensitivity can vary per patient and was estimated between 0.03-0.57 mg/dL in this cohort. Based on the M-protein profiles obtained with MS-MRD, during the maintenance treatment, increase of disease activity was observed in a subset of patients from arm A whereas all patients from arm B, who received ASCT, showed a persistent M-protein decrease. An increase of MM disease activity was observed earlier with MS-MRD in 13 out of 14 patients known to progress during the serum collection period, with a median of 455 days gained compared to the original trial data (p<0.0001). Figure 1 shows MS-MRD data showing disease activity 16 months prior to the known progression. Conclusion A non-invasive and sensitive MS-MRD assay for frequent MM monitoring was implemented on clinical trial samples. MS-MRD showed that patients who received ASCT had a more durable response with decreasing M-protein levels. Moreover, in 93% of the cases an increase of disease activity was detected earlier than with conventional blood tests by more than a year. Future perspective The dynamic information on disease activity that is provided by the MS-MRD can provide patients with feedback on their disease status after each checkup, and can provide clinicians options for evidence based treatment escalation or de-escalation. While the overall patient benefit of such personalized treatment still needs to be assessed in clinical trials, we expect that this can improve patient quality of life and allow for more efficient use of pharmacotherapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ACQUIRED VON WILLEBRAND SYNDROME SECONDARY TO MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE: LONG-TERM REMISSION AFTER TREATMENT WITH BORTEZOMIB

To describe a case report of a patient with monoclonal gammopathy of undetermined significance (MGUS) who progressed to Acquired von Willebrand syndrome (AVWS) and was successfully treated with bortezomib. Case report with literature review. A 54-years-old woman presented at our center to investigate an M-spike. She had been treated for chronic kidney disease due to glomerulonephritis for eight years and was on peritoneal dialysis waiting for a kidney transplant. During laboratory workup, a serum M-protein (0.3 g/dL) was detected by protein electrophoresis and a monoclonal IgG kappa was identified. After one year of follow-up, and with stable M-protein levels, the patient started complaining of increased bleeding from minor wounds, bruises in inferior limbs and repeated episodes of epistaxis. The patient had no personal or family history of bleeding disorders. Laboratory testing included normal blood and platelet counts, normal prothrombin and thrombin time but increased activated partial thromboplastin time (APTT ratio 1.62). Mixing study results showed APTT correction. Factor VIII coagulant activity (FVIII:C) was 12% but no inhibitor was detected. Von Willebrand factor antigen (vWF:Ag) was 10% and ristocetin cofactor activity (vWF:RCo) was 3%, with a vWF:RCo/vWF:Ag ratio of 0.3. Given the absence of previous personal and family history of bleeding and the diagnosis of MGUS, the diagnostic hypothesis of AWVS was made. To confirm this hypothesis, we performed a recovery test after infusion of von Willebrand factor (vWF 50 UI/kg), which results were suggestive of increased vWF clearance. The patient required treatment only after three years of AVWS diagnosis due to severe lingual hematoma. She was treated with two units of packed red blood and immunoglobulin (0.4g per kg for five days), with successful bleeding control. vWF:Ag, vWF:RCo and FVIII:C levels were also increased but returned to baseline values after three weeks. Because the patient was scheduled to undergo a kidney transplantation and the high risk of bleeding could lead to graft loss, it was decided to treat the MGUS-associated AVWS. She was treated with three cycles of dexamethasone 20 mg and cyclophosphamide 300 mg with no response. A second line treatment was started with dexamethasone 12 mg and bortezomib 1.5mg/m2 for a total of five cycles. After the end of the treatment, APTT, vWF:Ag, vWF:RCo results normalized and monoclonal paraprotein was eradicated. The patient was submitted to a kidney transplantation without bleeding complications. Two years after the end of the treatment, she remains in remission, with undetectable monoclonal paraprotein and normal coagulation and VWF tests. MGUS-associated AWVS is a rare bleeding disorder, and few data is available on the best treatment approach. We reported a case that transiently responded to immunoglobulin. This response, however, was not sufficient to warrant hemostatic levels of vWF required for kidney transplantation. Treatment of MGUS with bortezomib and dexamethasone led to eradication of the M-spike and normalization of the coagulation parameters. This response was durable, as the patient remains in remission of both MGUS and AWVS two years after the end of the treatment. This particular case highlights the importance of treating the underlying cause of the coagulopathy once the remission of AVWS only occurred after monoclonal gammopathy was controlled.

Combined Therapy with Ixazomib, Lenalidomide, and Dexamethasone for Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Changes Syndrome.

Objective Immunomodulatory drugs and proteasome inhibitors are therapeutic options for polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. This study aimed to evaluate the efficacy and safety of the combination of ixazomib, lenalidomide, and dexamethasone (IRd) for POEMS syndrome. Methods Six consecutive patients with POEMS syndrome who were treated with the IRd regimen at Chiba University Hospital between April 2018 and August 2021 were included. Serum M-protein and serum vascular endothelial growth factor (sVEGF) levels, overall neuropathy limitation scales (ONLS), clinical symptoms, and adverse events were assessed. Results Of the six patients, five had received prior treatments. Patients received a median of 5 cycles (range, 3-28 cycles) of IRd. Following treatment, serum M-protein disappeared in two patients, sVEGF levels returned to normal in two patients, two patients showed a reduction in the ONLS of 1, and clinical symptoms improved in four patients. The median level of sVEGF decreased from 2,395 pg/mL (range, 802-6,120 pg/mL) to 1,428 pg/mL (range, 183-3,680 pg/mL) in three months. Adverse events, including rash, neutropenia, sensory peripheral neuropathy, and nausea, were observed in three patients, which necessitated dose reduction or discontinuation of treatment. Conclusion IRd can be a therapeutic option for POEMS syndrome, albeit with careful monitoring of adverse events.