Treatment Response In Multiple Myeloma Research Articles

Evaluating the HYDRASHIFT 2/4 Daratumumab assay: a powerful approach to assess treatment response in multiple myeloma

Evaluating the HYDRASHIFT 2/4 Daratumumab assay: a powerful approach to assess treatment response in multiple myeloma

Development of New CD38 Targeted Peptides for Cancer Imaging.

Multiple myeloma (MM) affects over 35,000 patients each year in the US. There remains a need for versatile Positron Emission Tomography (PET) tracers for the detection, accurate staging, and monitoring of treatment response of MM that have optimal specificity and translational attributes. CD38 is uniformly overexpressed in MM and thus represents an ideal target to develop CD38-targeted small molecule PET radiopharmaceuticals to address these challenges. Using phage display peptide libraries and pioneering algorithms, we identified novel CD38 specific peptides. Imaging bioconjugates were synthesized using solid phase peptide chemistry, and systematically analyzed in vitro and in vivo in relevant MM systems. The CD38-targetedbioconjugates were radiolabeled with copper-64 (64Cu) with100% radiochemical purity and an average specific activity of 3.3 - 6.6MBq/nmol. The analog NODAGA-PEG4-SL022-GGS (SL022: Thr-His-Tyr-Pro-Ile-Val-Ile) had a Kd of 7.55 ± 0.291nM and was chosen as the lead candidate. 64Cu-NODAGA-PEG4-SL022-GGS demonstrated high binding affinity to CD38 expressing human myeloma MM.1S-CBR-GFP-WT cells, which was blocked by the non-radiolabeled version of the peptide analog and anti-CD38 clinical antibodies, daratumumab and isatuximab, by 58%, 73%, and 78%, respectively. The CD38 positive MM.1S-CBR-GFP-WT cells had > 68% enhanced cellular binding when compared to MM.1S-CBR-GFP-KO cells devoid of CD38. Furthermore, our new CD38-targeted radiopharmaceutical allowed visualization of tumors located in marrow rich bones, remaining there for up to 4h. Clearance from non-target organs occurred within 60min. Quantitative PET data from a murine disseminated tumor model showed significantly higher accumulation in the bones of tumor-bearing animals compared to tumor-naïve animals (SUVmax 2.06 ± 0.4 versus 1.24 ± 0.4, P = 0.02). Independently, tumor uptake of the target compound was significantly higher (P = 0.003) compared to the scrambled peptide, 64Cu-NODAGA-PEG4-SL041-GGS (SL041: Thr-Tyr-His-Ile-Pro-Ile-Val). The subcutaneous MM model demonstrated significantly higher accumulation in tumors compared to muscle at 1 and 4h after tracer administration (SUVmax 0.8 ± 0.2 and 0.14 ± 0.04, P = 0.04 at 1h; SUVmax 0.89 ± 0.01 and 0.09 ± 0.01, P = 0.0002 at 4h). The novel CD38-targeted, radiolabeled bioconjugates were specific and allowed visualization of MM, providing a starting point for the clinical translation of such tracers for the detection of MM.

SRRM2 may be a potential biomarker and immunotherapy target for multiple myeloma: a real-world study based on flow cytometry detection

Serine/arginine repetitive matrix 2 (SRRM2) has been implicated in tumorigenesis, cancer development, and drug resistance through aberrant splicing; however, its correlation with multiple myeloma (MM) has not been reported. We investigated the potential of SRRM2 as a biomarker and immunotherapeutic target in MM by examining its expression in MM cells using flow cytometry. Our study included 95 patients with plasma cell disease, including 80 MM cases, and we detected SRRM2 expression on plasma cells and normal blood cells to analyze its relationship with clinical profiles. We found widespread positive expression of SRRM2 on plasma cells with little expression on normal blood cells, and its expression on abnormal plasma cells was higher than that on normal plasma cells. Comparative analysis with clinical data suggests that SRRM2 expression on plasma cells correlates with MM treatment response. MM patients with high SRRM2 expression had higher levels of serum β2-mg and LDH, ISS staging, and plasma cell infiltration, as well as high-risk mSMART 3.0 stratification and cytogenetic abnormalities, particularly 1q21 amplification. In patients with previous MM, high SRRM2 expression on plasma cells was associated with higher plasma cell infiltration, high-risk mSMART 3.0 risk stratification, cytogenetic abnormalities, more relapses, and fewer autologous stem cell transplant treatments. In summary, SRRM2 may serve as a novel biomarker and immunotherapeutic target for MM. Its expression level on plasma cells can help in risk stratification of MM and monitoring of treatment response.

Short-Chain Fatty Acid Production by Gut Microbiota Predicts Treatment Response in Multiple Myeloma.

The gut microbiota plays important roles in health and disease. We questioned whether the gut microbiota and related metabolites are altered in monoclonal gammopathies and evaluated their potential role in multiple myeloma and its response to treatment. We used 16S rRNA sequencing to characterize and compare the gut microbiota of patients with monoclonal gammopathy of undetermined significance (n = 11), smoldering multiple myeloma (n = 9), newly diagnosed multiple myeloma (n = 11), relapsed/refractory multiple myeloma (n = 6), or with complete remission (n = 9). Short-chain fatty acids (SCFA) were quantified in serum and tested in cell lines. Relevant metabolites were validated in a second cohort of 62 patients. Significant differences in alpha- and beta diversity were present across the groups and both were lower in patients with relapse/refractory disease and higher in patients with complete remission after treatment. Differences were found in the abundance of several microbiota taxa across disease progression and in response to treatment. Bacteria involved in SCFA production, including Prevotella, Blautia, Weissella, and Agathobacter, were more represented in the premalignant or complete remission samples, and patients with higher levels of Agathobacter showed better overall survival. Serum levels of butyrate and propionate decreased across disease progression and butyrate was positively associated with a better response. Both metabolites had antiproliferative effects in multiple myeloma cell lines. We demonstrate that SCFAs metabolites and the gut microbiota associated with their production might have beneficial effects in disease evolution and response to treatment, underscoring its therapeutic potential and value as a predictor.

Circulating serum microRNAs as biomarkers of drug resistance in multiple myeloma patients treated with bortezomib-based regimens – pilot study

Despite advances in multiple myeloma (MM) treatment, drug resistance remains a clinical challenge. We aimed to develop a prognostic model for bortezomib resistance based on miRNA expression profiling. The study included 40 previously untreated MM patients receiving bortezomib-based regimens (20 treatment-sensitive, 20 resistant). Pretreatment venous blood samples were analyzed for miRNA expression. Differential expression analysis revealed upregulated miR-27b-3p (FC 1.45, p = 0.017) and let-7b-5p (FC 1.44, p = 0.025) in the resistant group. Univariate analysis identified let-7b-5p (OR 3.17, 95%CI: 1.19–11.4, p = 0.04) and miR-27b-3p (OR 4.73, 95%CI: 1.4–26.6, p = 0.036) as risk factors for resistance. The final multivariate model included miR-27b-3p (OR 23.1, 95% CI: 2.8–452, p = 0.015), let-7b-5p (OR 4.38, 95% CI: 1.28–22.2, p = 0.038), and miR-103a-3p (OR 15.3, 95% CI: 1.33–351, p = 0.049). These miRNAs may serve as biomarkers of treatment response in MM. However, external validation is necessary to confirm the clinical utility of our model.

CircRNAs in diagnosis, prognosis, and clinicopathological features of multiple myeloma; a systematic review and meta-analysis.

Unlike improved treatment response in multiple myeloma (MM), the mortality rate in MM is still high. The study's aim is to investigate the potential role of circRNAs as a new biomarker for diagnosis, prognosis, and clinicopathological features of MM. We identified studies through Web of Science, Scopus, PubMed and ProQuest databases, and Google Scholar to August 2022. The SEN, SPE, PLR, NLR, DOR, and AUC were combined to investigate the diagnostic performance of circRNAs in MM. Also, HR and RR were used for prognostic and clinicopathological indicators, respectively. 12 studies for prognosis, 9 studies about diagnosis, and 13 studies regarding clinicopathological features. The pooled SEN, SPE, DOR, and AUC were 0.82, 0.76, 14.70, and 0.86, respectively for the diagnostic performance of circRNAs. For the prognostic performance, oncogene circRNAs showed a poor prognosis for the patients (HR = 3.71) and tumor suppressor circRNAs indicated a good prognosis (HR = 0.31). Finally, we discovered that dysregulation of circRNAs is associated with poor clinical outcomes in beta-2-microglobulin (RR = 1.56), Durie-Salmon stage (RR = 1.36), and ISS stage (RR = 1.79). Furthermore, the presence of del(17p) and t(4;14) is associated with circRNA dysregulation (RR = 1.44 and 1.44, respectively). Our meta-analysis demonstrates that the expression analysis of circRNAs is valuable for MM's diagnosis and prognosis determination. Also, dysregulation of circRNAs is associated with poor clinicopathological features and can be used as the applicable biomarkers for evaluating treatment effectiveness.

MiRNA-seq identification and clinical validation of CD138+ and circulating miR-25 in treatment response of multiple myeloma

BackgroundDespite significant advancements in multiple myeloma (MM) therapy, the highly heterogenous treatment response hinders reliable prognosis and tailored therapeutics. Herein, we have studied the clinical utility of miRNAs in ameliorating patients’ management.MethodsmiRNA-seq was performed in bone marrow CD138+ plasma cells (PCs) of 24 MM and smoldering MM (sMM) patients to analyze miRNAs profile. CD138+ and circulating miR-25 levels were quantified using in house RT-qPCR assays in our screening MM/sMM cohort (CD138+ plasma cells n = 167; subcohort of MM peripheral plasma samples n = 69). Two external datasets (Kryukov et al. cohort n = 149; MMRF CoMMpass study n = 760) served as institutional-independent validation cohorts. Patients’ mortality and disease progression were assessed as clinical endpoints. Internal validation was performed by bootstrap analysis. Clinical benefit was estimated by decision curve analysis.ResultsmiRNA-seq highlighted miR-25 of CD138+ plasma cells to be upregulated in MM vs. sMM, R-ISS II/III vs. R-ISS I, and in progressed compared to progression-free patients. The analysis of our screening cohort highlighted that CD138+ miR-25 levels were correlated with short-term progression (HR = 2.729; p = 0.009) and poor survival (HR = 4.581; p = 0.004) of the patients; which was confirmed by Kryukov et al. cohort (HR = 1.878; p = 0.005) and MMRF CoMMpass study (HR = 1.414; p = 0.039) validation cohorts. Moreover, multivariate miR-25-fitted models contributed to superior risk-stratification and clinical benefit in MM prognostication. Finally, elevated miR-25 circulating levels were correlated with poor survival of MM patients (HR = 5.435; p = 0.021), serving as a potent non-invasive molecular prognostic tool.ConclusionsOur study identified miR-25 overexpression as a powerful independent predictor of poor treatment outcome and post-treatment progression, aiding towards modern non-invasive disease prognosis and personalized treatment decisions.

Lumbar MR-based radiomics nomogram for detecting minimal residual disease in patients with multiple myeloma.

Minimal residual disease (MRD) is a standard for assessing treatment response in multiple myeloma (MM). MRD negativity is considered to be the most powerful predictor of long-term good outcomes. This study aimed to develop and validate a radiomics nomogram based on magnetic resonance imaging (MRI) of the lumbarspine to detect MRD after MM treatment. A total of 130 MM patients (55 MRD negative and 75 MRD positive) who had undergone MRD testing through next-generation flow cytometry were divided into a training set (n = 90) and a test set (n = 40). Radiomics features were extracted from lumbar spinal MRI (T1-weighted images and fat-suppressed T2-weighted images) by means of the minimum redundancy maximum relevance method and the least absolute shrinkage and selection operator algorithm. A radiomics signature model was constructed. A clinical model was established using demographic features. A radiomics nomogram incorporating the radiomics signature and independent clinical factor was developed using multivariate logistic regression analysis. Sixteen features were used to establish the radiomics signature. The radiomics nomogram included the radiomics signature and the independent clinical factor (free light chain ratio) and showed good performance in detecting the MRD status (area under the curve: 0.980 in the training set and 0.903 in the test set). The lumbar MRI-based radiomics nomogram showed good performance in detecting MRD status in MM patients after treatment, and it is helpful for clinical decision-making. • The presence or absence of minimal residual disease status has a strong predictive significance for the prognosis of patients with multiple myeloma. • A radiomics nomogram based on lumbar MRI is a potential and reliable tool for evaluating minimal residual disease status in MM.

Effects of teclistamab and talquetamab on soluble BCMA levels inpatients with relapsed/refractory multiple myeloma.

B-cell maturation antigen (BCMA) is selectively expressed as a surface protein on plasma cells and is a validated target for multiple myeloma (MM). A soluble form of BCMA (sBCMA) is elevated in the sera of patients with MM. The bispecific antibodies teclistamab (BCMA×CD3) and talquetamab (G protein-coupled receptor family C group 5 member D [GPRC5D]×CD3) are in clinical development as therapies for MM. Using data from patients with relapsed/refractory MM (N=300) who participated in phase 1 studies of teclistamab (NCT03145181) or talquetamab (NCT03399799), baseline serum sBCMA levels were quantitatively analyzed relative to response to treatment, percentage of bone marrow plasma cells (BMPCs), and cytogenetic risk. By cycle 3 day 1 of treatment, sBCMA levels declined from baseline in 50 (88%) of 57 responders and 49 (98%) of 50 responders to teclistamab and talquetamab, respectively. Depth of response correlated with the magnitude of sBCMA reduction. In contrast, sBCMA increased in 33 (80%) of 41 patients and 24 (49%) of 49 patients who did not respond to teclistamab or talquetamab, respectively. Baseline sBCMA levels correlated with the percentage of BMPC; patients with extramedullary plasmacytomas who had low levels of BMPC (≤10%) tended to have high baseline sBCMA levels (≥400 ng/mL), based on limited data. Baseline sBCMA levels and changes in sBCMA levels at cycle 3 day 1 were similar in patients with high- and standard-risk cytogenetics treated with teclistamab or talquetamab. These results support the use of sBCMA as a potential surrogate marker of tumor burden and treatment response in MM.

Can urine studies be replaced by serum free light chains measurements to assign responses in multiple myeloma patients?

Serum and urine protein electrophoresis and immunofixation are the preferred techniques for monitoring monoclonal proteins and evaluating treatment response in multiple myeloma (MM) patients with measurable disease. However, urine studies are subjected to limitations that may lead to inaccuracies or prevent guidelines compliance. We retrospectively studied if the substitution of urine studies by measuring serum free light chains (sFLCs) results in a comparable disease monitoring, both in intact immunoglobulin (II) and light chain (LC) MM patients. In our cohort, equal or higher percentages of disease were identified by sFLCs at baseline and maximum response as compared to urine studies. Achieving very good partial response or better (≥VGPR) according to the response criteria proposed by the French group (evaluating sFLCs instead of urine) and the IMWG response criteria were associated to a 62% and 63% reduced risk of progression, respectively. A similar prognostic value for reaching ≥VGPR was also observed among LCMM patients when the French group and the IMWG response criteria were applied. Overall, these results support the replacement of urine studies by the sFLCs assay in IIMM. In LCMM, sFLCs could be used for monitoring and urine studies could be performed only to confirm complete remissions and progressions.

Functional Imaging in the Evaluation of Treatment Response in Multiple Myeloma: The Role of PET-CT and MRI.

Bone disease is among the defining characteristics of symptomatic Multiple Myeloma (MM). Imaging techniques such as fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET/CT) and magnetic resonance imaging (MRI) can identify plasma cell proliferation and quantify disease activity. This function renders these imaging tools as suitable not only for diagnosis, but also for the assessment of bone disease after treatment of MM patients. The aim of this article is to review FDG PET/CT and MRI and their applications, with a focus on their role in treatment response evaluation. MRI emerges as the technique with the highest sensitivity in lesions' detection and PET/CT as the technique with a major impact on prognosis. Their comparison yields different results concerning the best tool to evaluate treatment response. The inhomogeneity of the data suggests the need to address limitations related to these tools with the employment of new techniques and the potential for a complementary use of both PET/CT and MRI to refine the sensitivity and achieve the standards for minimal residual disease (MRD) evaluation.

Detection of Measurable Residual Disease Biomarkers in Extracellular Vesicles from Liquid Biopsies of Multiple Myeloma Patients-A Proof of Concept.

Monitoring measurable residual disease (MRD) is crucial to assess treatment response in Multiple Myeloma (MM). Detection of MRD in peripheral blood (PB) by exploring Extracellular Vesicles (EVs), and their cargo, would allow frequent and minimally invasive monitoring of MM. This work aims to detect biomarkers of MRD in EVs isolated from MM patient samples at diagnosis and remission and compare the MRD-associated content between BM and PB EVs. EVs were isolated by size-exclusion chromatography, concentrated by ultrafiltration, and characterized according to their size and concentration, morphology, protein concentration, and the presence of EV-associated protein markers. EVs from healthy blood donors were used as controls. It was possible to isolate EVs from PB and BM carrying MM markers. Diagnostic samples had different levels of MM markers between PB and BM paired samples, but no differences between PB and BM were found at remission. EVs concentration was lower in the PB of healthy controls than of patients, and MM markers were mostly not detected in EVs from controls. This study pinpoints the potential of PB EVs from MM remission patients as a source of MM biomarkers and as a non-invasive approach for monitoring MRD.

Spinal MRI-Based Radiomics Analysis to Predict Treatment Response in Multiple Myeloma.

The aim of this study was to explore the clinical utility of spinal magnetic resonance imaging-based radiomics to predict treatment response (TR) in patients with multiple myeloma (MM). A total of 123 MM patients (85 in the training cohort and 38 in the test cohort) with complete response (CR) (n = 40) or non-CR (n = 83) were retrospectively enrolled in the study. Key feature selection and data dimension reduction were performed using the least absolute shrinkage and selection operator regression. A nomogram was built by combining radiomic signatures and independent clinical risk factors. The prediction performance of the nomogram was assessed using the area under the receiver operating characteristic curve (AUC), calibration curves, and decision curve analysis. Treatment response was assessed by determining the serum and urinary levels of M-proteins, serum-free light chain ratio, and the percentage of bone marrow plasma cells. Thirteen features were selected to build a radiomic signature. The International Staging System (ISS) stage was selected as an independent clinical factor. The radiomic signature and nomogram showed better calibration and higher discriminatory capacity (AUC of 0.929 and 0.917 for the radiomics and nomogram in the training cohort, respectively, and 0.862 and 0.874 for the radiomics and nomogram in the test cohort, respectively) than the clinical model (AUC of 0.661 and 0.674 in the training and test cohort, respectively). Decision curve analysis confirmed the clinical utility of the radiomics model. Nomograms incorporating a magnetic resonance imaging-based radiomic signature and ISS stage help predict the response to chemotherapy for MM and can be useful in clinical decision-making.

Serum Abnormal Metabolites for Evaluating Therapeutic Response and Prognosis of Patients With Multiple Myeloma.

AimsTo evaluate abnormal metabolites related to treatment response and prognosis of multiple myeloma (MM) patients through ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS).MethodsForty-six symptomatic MM patients were included in this study who had a prior high level of positive monoclonal proteins before receiving targeted therapy with bortezomib-based regimens. UPLC-MS along with traditional immunofixation was performed on MM diagnostic samples and effective serum samples, and UPLC-MS was used to target valuable metabolic markers related to M protein.MM patients were segregated into pre-therapy (pre-T) and post-therapy (post-T) groups according to the response after chemotherapy. A monoclonal protein could be detected at baseline in 33 newly diagnosed MM (NDMM), 13 refractory and relapsed MM (RRMM) patients and 20 healthy controls (HC) by immunofixation.ResultsBetween pre-T and post-T patients, the data showed that 32, 28 and 3 different metabolites were significantly correlated with M protein in IgG, IgA and light chain-type MM, respectively. These identified metabolites were significantly enriched in arginine and proline metabolism as well as glycerophospholipid metabolism pathways. Among them, PC (19:0/22:2) was displayed to increase significantly and consistently with M protein in each subtype of MM after treatment, which obviously indicated that it was related to the treatment response of MM. Further survival analysis of metabolic markers found that aspartic acid, LysoPE (16:0), SM (d18:1/17:0), PC (18:0/24:1), PC (16:0/16:0), TG (18:1/18:1/22:5) and LysoPE (18:2) reaching a certain cutoff value may be associated with shorter progression free survival (PFS). Finally, Cox multivariate regression analysis identified three factors were independent prognostic factors of MM. Moreover, there were significantly different in PC (19:0/22:2) and in aspartic acid between MM patients and healthy people.ConclusionThis work identified significant metabolic disorders in 46 pairs off pre- and post-therapy MM patients, specifically in arginine, proline and glycerophospholipid pathways. The abnormal metabolites have the potential to serve as new biomarkers for evaluating treatment response and prognosis, as well as early monitoring of disease activity. Therefore, these systematic studies on abnormal metabolites as biomarkers for diagnosis and treatment will provide the evidence for future precise treatment of MM.

Comparative Performance of Whole-Body MRI and FDG PET/CT in Evaluation of Multiple Myeloma Treatment Response: Systematic Review and Meta-Analysis.

BACKGROUND. Traditional approaches for evaluating multiple myeloma (MM) treatment response have low sensitivity for residual disease. Recent studies highlight the utility of whole-body MRI or FDG PET/CT in evaluating treatment response, with increasing emphasis on DWI. OBJECTIVE. This systematic review was conducted to assess the diagnostic accuracy of whole-body MRI and FDG PET/CT for MM treatment response assessment. EVIDENCE ACQUISITION. Studies in which whole-body MRI or FDG PET/CT was used to evaluate MM treatment response were identified through search of the PubMed and EMBASE databases through June 30, 2021. Pooled sensitivity and specificity for detecting response were calculated by bivariate modeling. The diagnostic performances of whole-body MRI and FDG PET/CT were compared. Subgroup analyses were conducted to assess studies comparing the modalities and studies in which whole-body MRI included DWI. EVIDENCE SYNTHESIS. Twelve studies comprising 373 patients were included: six evaluated both modalities, four evaluated whole-body MRI only, and two evaluated FDG PET/CT only. Of studies of MRI, five included DWI. Pooled sensitivity and specificity were 87% (95% CI, 75-93%) and 57% (95% CI, 37-76%) for whole-body MRI versus 64% (95% CI, 45-79%) and 82% (95% CI, 75-88%) for FDG PET/CT (sensitivity, p = .29; specificity, p = .01). For studies directly comparing the modalities, pooled sensitivity and specificity were 90% (95% CI, 80-100%) and 56% (95% CI, 44-68%) for whole-body MRI versus 66% (95% CI, 47-85%) and 81% (95% CI, 72-90%) for FDG PET/CT (sensitivity, p = .18; specificity, p < .001). Sensitivity and specificity were 93% (95% CI, 75-98%) and 57% (95% CI, 21-87%) for DWI versus 74% (95% CI, 60-85%) and 56% (95% CI, 38-73%) for whole-body MRI without DWI (sensitivity, p = .27; specificity, p = .99). The AUC values were 0.84 for whole-body MRI, 0.83 for FDG PET/CT, and 0.92 for DWI. CONCLUSION. FDG PET/CT had significantly higher specificity, and whole-body MRI had higher sensitivity (though nonsignificant). DWI may contribute to the high sensitivity of whole-body MRI. CLINICAL IMPACT. The results of this meta-analysis suggest potential complementary roles of whole-body MRI and FDG PET/CT in assessment of MM treatment response. Future studies should explore their combination through PET/MRI.

Mass spectrometry vs immunofixation for treatment monitoring in multiple myeloma

AbstractMonitoring of the monoclonal protein (M-protein) by electrophoresis and/or immunofixation (IFE) has long been used to assess treatment response in multiple myeloma (MM). However, with the use of highly effective therapies, the M-protein becomes frequently undetectable, and more sensitive methods had to be explored. We applied IFE and mass spectrometry (EXENT&FLC-MS) in serum samples from newly diagnosed MM patients enrolled in the PETHEMA/GEM2012MENOS65 obtained at baseline (n = 223), and after induction (n = 183), autologous stem cell transplantation (n = 173), and consolidation (n = 173). At baseline, the isotypes identified with both methods fully matched in 82.1% of samples; in the rest but 2 cases, EXENT&FLC-MS provided additional information to IFE with regards to the M-protein(s). Overall, the results of EXENT&FLC-MS and IFE were concordant in >80% of cases, being most discordances due to EXENT&FLC-MS+ but IFE− cases. After consolidation, IFE was not able to discriminate 2 cohorts with different median progression-free survival (PFS), but EXENT&FLC-MS did so; furthermore, among IFE− patients, EXENT&FLC-MS identified 2 groups with significantly different median PFS (P = .0008). In conclusion, compared with IFE, EXENT&FLC-MS is more sensitive to detect the M-protein of patients with MM, both at baseline and during treatment, and provides a more accurate prediction of patients' outcome. This trial was registered at www.clinicaltrials.gov as #NCT01916252.

Prediction of Early Treatment Response in Multiple Myeloma Using MY-RADS Total Burden Score, ADC, and Fat Fraction From Whole-Body MRI: Impact of Anemia on Predictive Performance.

BACKGROUND. The recently released Myeloma Response Assessment and Diagnosis System (MY-RADS) for multiple myeloma (MM) evaluation using whole-body MRI (WB-MRI) describes the total burden score. However, assessment is confounded by red bone marrow hyperplasia in anemia. OBJECTIVE. The purpose of this study is to assess the utility of the MY-RADS total burden score, ADC, and fat fraction (FF) from WB-MRI in predicting early treatment response in patients with newly diagnosed MM and to compare the utility of these measures between patients with and without anemia. METHODS. This retrospective study included 56 patients (40 men, 16 women; mean age, 57.4 ± 9.6 [SD] years) with newly diagnosed MM who underwent baseline WB-MRI including DWI and modified Dixon sequences. Two radiologists recorded total burden score using MY-RADS and measured the ADC and FF of diffuse and focal disease sites. Mean values across sites were derived. Interobserver agreement was evaluated, and the mean assessments of the readers were used for further analyses. Presence of deep response after four cycles of induction chemotherapy was recorded. Patients were classified as having anemia if their hemoglobin level was less than 100 g/L. The utility of WBMRI parameters in predicting deep response was assessed. RESULTS. A total of 24 of 56 patients showed deep response, and 25 of 56 patients had anemia. Interobserver agreement, which was expressed using intraclass correlation coefficients, ranged from 0.95 to 0.99. Among patients without anemia, those with deep response compared with those without deep response had a lower total burden score (9.0 vs 18.0), a lower ADC (0.79 × 10-3 mm2/s vs 1.08 × 10-3 mm2/s), and a higher FF (0.21 vs 0.10) (all p < .001). The combination of these three parameters (optimal cutoffs: ≤ 15 for total burden score, ≤ 0.84 × 10-3 mm2/s for ADC, and > 0.16 for FF) achieved sensitivity of 93.8%, specificity of 93.3%, and accuracy of 93.5% for predicting deep response. In patients with anemia, none of the three parameters were significantly different between patients with and without deep response (all p > .05), and the combination of parameters achieved sensitivity of 56.3%, specificity of 100.0%, and accuracy of 72.0%. CONCLUSION. Low total burden score, low ADC, and high FF from WB-MRI may predict deep response in patients with MM, although only among those without anemia. CLINICAL IMPACT. WB-MRI findings may help guide determination of prognosis and initial treatment selection in MM.

The Gamma Gap: A Point-of-Care Test That Correlates with Disease Burden and Treatment Response in Multiple Myeloma

Introduction:Multiple Myeloma (MM) is the malignant neoplasm of plasma cells and is often characterized by the production of large amounts of non-functional, monoclonal immunoglobulins (M spike) that serve as a surrogate for tumor burden and treatment response. Currently, the gold standard for monitoring response status is serum and urine protein electrophoresis (SPEP and UPEP, respectively), which quantify the M spike. Unfortunately, the turnaround time for these tests is not immediate; SPEP is ~3 days and UPEP ~7 days. Waiting for news on chemotherapeutic response is a significant psychological stressor for cancer patients and their families, and moreover leads to uncertainty when a clinician is face-to-face with a patient and PEP data are not yet available. Currently the lack of a validated, inexpensive, same-day point-of-care response assessment represents an unmet need. One such test may be the gamma gap (GG). The GG is the calculated difference between a patient's total serum protein and albumin. In patients with a substantial serum M-spike, the GG is typically elevated since excess myeloma-derived immunoglobulins elevate total protein but not albumin. Measurements of both total protein and albumin can be can be obtained from a standard comprehensive metabolic profile (CMP) or equivalent within 1 hour after blood draw. We hypothesized that the GG is a reliable indicator of disease burden and therapeutic response, and can be used as a surrogate point-of-care test for assessing response status in myeloma patients while awaiting SPEP results.Methods: A retrospective chart review study was performed. Patients were included in the study if they met the following criteria: diagnosed between 2000 and 2015 at the Duke Healthcare system, had MM with detectable M spike either undergoing treatment (including relapsed bone marrow transplant patients) or surveillance only, and had both an SPEP and a complete metabolic panel (CMP, including albumin and total protein drawn within 2 weeks of each other) . Patients were excluded if they had a concurrent second malignancy, did not have SPEP and/or CMP for specific timepoints, had light chain disease (because these will not produce an M spike), or were diagnosed before 2000. The sample size was calculated at 200 patients.We assessed patient data at three timepoints: at the beginning of treatment, midway (halfway through the total number of cycles received for a given treatment strategy), and at the end of a given line of treatment. Treatment responses were defined using standard IMWG response criteria. To assess the relationship between the GG and M-spike, formulas were extracted using a linear regression model and Pearson's correlation coefficients were calculated. To evaluate the relationship between GG and treatment response, an ordinal logit regression model was employed.Results: A total of 693 patients were screened. Manual chart review was performed on 349 patients: 200 patients were included in the final analysis and 149 were excluded based on the exclusion criteria. We found that the GG is highly correlated with the serum M-spike at the beginning of treatment, with a correlation coefficient of 0.87 (fitted linear model: M-spike=-2.50+0.95GG) (Figure 1). Similarly, at the midpoint of therapy, GG and M-spike are highly correlated, with a correlation coefficient of 0.84 (fitted linear model: M-spike=-2.33+0.88GG). Importantly, by fitting the logit model, GG is also a significant predictor of treatment response at midpoint, with a p-value of <0.00001. Finally, the GG and M-spike are highly correlated at the end of therapy, with a correlation coefficient of 0.88 (fitted linear model: M-spike=-2.38+0.90GG). Again, GG is also a significant predictor of treatment response at the end of treatment with a p-value of <0.00001.Conclusion: These data suggest that the GG is an accurate predictor of both disease burden as well as treatment responses in patients with a detectable M spike. Importantly, this demonstrates that the GG may be comfortably used by physicians at the bedside as an indicator of treatment response, which can lighten a patient's burden when waiting for SPEP/UPEP. Furthermore, our formulas may be used at the bedside for the calculation of M spike. Our study has important implications in our care of patients with MM. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prospective Comparison of 18-FDG PET/CT and Whole-Body MRI with Diffusion-Weighted Imaging in the Evaluation of Treatment Response of Multiple Myeloma Patients Eligible for Autologous Stem Cell Transplant.

Simple SummaryOver the past decade, the imaging of multiple myeloma has evolved with the increasing use of modern imaging techniques such as 18-FDG PET/CT and MRI. Both imaging modalities have high sensitivity for the detection of bone involvement. 18-FDG PET/CT may help assess treatment response, but conventional MRI lacks prognostic value. Diffusion-Weighted is a newer MRI technique that could improve the assessment of tumor response. The aim of this prospective study was to compare the prognostic value of 18-FDG PET/CT and whole-body diffusion-weighted MRI in the evaluation of the treatment response of multiple myeloma after induction chemotherapy and after transplant. After a median follow-up of 32 months in 30 patients, we found that only 18-FDG PET/CT had significant prognostic value at two important time points of patients’ treatment. Integrating PET/CT metabolic response to the overall monitoring of disease activity might be of value in further improving patient’s management in multiple myeloma.To compare the prognostic values of 18-FDG PET/CT (FDG-PET) and Whole-Body MRI with Diffusion-Weighted Imaging (WB-DW-MRI) in the evaluation of treatment response of Multiple Myeloma (MM) patients eligible for ASCT. Thirty patients with newly diagnosed MM prospectively underwent FDG-PET and WB-DW-MRI at baseline, after induction chemotherapy and after ASCT. Response on WB-DW-MRI was evaluated with the MY-RADS criteria. FDG-PET was considered positive if residual uptake was superior to liver uptake. Imaging results were not used for treatment modification. The impact of imaging results on PFS was analyzed. After a median follow-up of 32 months, 10 patients relapsed. With WB-DW-MRI, post-induction examination was positive in 3/25 and post-ASCT examination was positive in 3/27 patients. However, neither study showed prognostic impact on PFS. FDG-PET was positive in 5/22 post-induction and 3/26 patients post-ASCT, respectively. Positivity of FDG-PET, post-induction or post-ASCT, was associated with a shorter PFS (post-induction: median PFS 19 months vs. not reached, log-rank p = 0.0089; post-ASCT: median PFS 18 months vs. not reached, log-rank p = 0.0005). Preliminary results from this small, single-center, prospective study show that, whether performed post-induction or post-ASCT, FDG-PET has a higher prognostic value than WB-DW-MRI for treatment response evaluation of newly diagnosed MM.

Total Diffusion Volume Estimated By Whole-Body Diffusion Magnetic Resonance Imaging for the Assessment of Tumor Burden in Multiple Myeloma

Introduction: Whole-body diffusion-weighted magnetic resonance imaging (wbDWI) is an emerging imaging technique for assessing the tumor burden of patients with multiple myeloma (MM). Total diffusion volume (tDV) is a potential parameter to quantify the tumor volume of bone marrow (BM) images obtained by wbDWI. The apparent diffusion coefficient (ADC) value, also calculated with wbDWI, has the potential to accurately evaluate the treatment response of MM; however, correlation between tDV and the treatment response of MM remains poorly studied. Methods: We retrospectively selected patients with newly-diagnosed, symptomatic MM who were treated at Kameda Medical Center, Japan, from January 2016 to November 2019; we analyzed the tDV obtained by wbDWI before and after treatment. We used the BD score software (PixSpace, Japan) to analyze tDV. Briefly, the regions of interest, including areas with abnormally high signal intensity of diffusion weighted imaging considered to contain myeloma lesions in the BM or extramedullary tissue, were automatically obtained with a b-value of 900 s/mm2. Physiological areas with high signal intensity were removed manually. Threshold values for distinguishing diseased areas from the background were manually adjusted to cover all bone lesions. Diagnosis and response were assessed using the International Myeloma Working Group criteria. We compared tDV before and after treatment, and in each response category. Comparison of continuous variables between the two categories and between three or more sets were analyzed using Wilcoxon test and Kruskal-Wallis test, respectively. All statistical analyses were performed using R (version 4.0.2; R Foundation, Vienna, Austria). Results: We analyzed 42 patients (18 men; median age, 71.5 years; interquartile range [IQR]: 65.0-77.0) whose pre- and post-treatment tDV values were available. The type of myeloma at diagnosis included immunoglobulin G (IgG) (n=21, 50%), immunoglobulin A (IgA) (n=12, 28%), and light chain alone (n=9, 21.4%). Three patients (7.1%) underwent wbDWI when they achieved partial response (PR); 6 patients (14.2%) achieved very good partial response (VGPR), 3 patients (7.1%) achieved complete response (CR), and 30 patients (71.4%) achieved stringent complete response (sCR). In all patients, median tDV decreased significantly before and after the treatment (median, 464.24 mL [IQR: 152.99-929.23] and 108.2 mL [IQR: 27.76-368.85], respectively; p&amp;lt;0.001) (Figure 1). Median tDV after treatment trended to be progressively low for patients who achieved PR, VGPR, CR, and sCR (tDV: 381.33 mL, 218.85 mL, 19.26 mL, and 63.97 mL, respectively; p=0.12). However, these values were not statistically significant. We also compared the tDV before and after treatment for patients who achieved less than CR (PR and VGPR) and those who achieved CR or better (≥CR). The median tDV of the patients who achieved less than CR was 298.24 mL [IQR: 147.88-381.33] and for those who achieved ≥CR was 62.65 mL [IQR: 19.26-279.79] (p=0.02) (Figure 2). We also compared the decreasing rate of tDV before and after treatment between patients who achieved less than CR and those who achieved ≥CR. The median decreasing rate of tDV was 61.0% 72.0% for patients who achieved less than CR and ≥CR, respectively. Although this result was not statistically significant, the data suggests that patients who achieved a deeper response tended to have a larger decreasing rate of tDV. Conclusions: Our data shows that tDV correlates with the depth of treatment response, and thus, is a potentially useful marker for evaluating the treatment response in patients with MM. Disclosures No relevant conflicts of interest to declare.