International Myeloma Working Group Guidelines Research Articles

Efficacy and safety of generic pomalidomide plus low-dose dexamethasone in relapsed or refractory multiple myeloma: a multicenter, open-label, single-arm trial

This multicenter, open-label, single-arm trial (ClinicalTrials.gov, NCT05236621) was conducted to confirm the efficacy and safety of generic pomalidomide plus dexamethasone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Total 79 eligible RRMM patients were planned to be included. Patients were treated with generic pomalidomide (4 mg daily on days 1–21, orally) and low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally; 20 mg for patients aged > 75 years) in 28-day cycles until disease progression with a maximum treatment duration of 2 years. The primary endpoint is the overall response rate (ORR) assessed by the independent review committee per the 2016 International Myeloma Working Group guidelines. A total of 85 eligible patients were included in this study from 32 centers in China, with a median age of 62.0 (range, 39–76) years, a median prior line of therapy of 4 (range, 1–16), and 41.2% patients with high-risk cytogenetics. The ORR was 38.8% (95% confidence interval (CI), 28.44–50.01). The disease control rate was 67.1% (95% CI, 56.02–76.87), meanwhile, the median progression-free survival was 5.55 months (95% CI, 3.68–7.52). Among the treatment-related adverse events (TRAEs), infective pneumonia (17.6%) was the most frequent non-hematologic adverse event, while a decrease in neutrophil count (52.9%) was the most common grade ≥ 3 TRAE. The study results indicated that the generic pomalidomide demonstrated consistent efficacy and a safety profile similar to the branded pomalidomide when combined with low-dose dexamethasone in Chinese RRMM patients.Registration number ClinicalTrials.gov NCT05236621, retrospectively registered on February 11, 2022.

Under-representation of black patients with multiple myeloma in studies supporting International Myeloma Working Group guidelines

IntroductionMultiple myeloma (MM) is more common in Black persons when compared to non-Hispanic White persons. The International Myeloma Working Group (IMWG) provides consensus for diagnosis and treatment of MM. Our study aimed to assess the racial composition of supporting studies used by IMWG to publish their guidelines MethodsWe performed a cross sectional study that included all IMWG publications up to July 2022. References cited in each publication were reviewed. Review articles, comments, editorials, case reports, and animal-based studies were excluded. ResultsA total of 59 IMWG publications with 3956 references were reviewed. Final analysis included 2047 references of which 39 % (n = 804) were clinical trials, 35 % (n = 712) were observational studies, 20 % (n = 401) were diagnostic and or genetic testing-based studies, 3 % (n = 65) were population-based analysis and 3 % (n = 65) classified as others. Only 10.4 % of included references (n = 213/2047) reported race/ethnicity of studied patients. The total number of patients in all referenced studies were 5,747,920, only 2.6 % (n = 150,790) black patients. Of the trials referenced and done exclusively in the US, 41 out of 282 (14.5 %) reported race/ethnicity with a total number of patients of 38,050 of which 2493 (6.5 %) were black patients. ConclusionIMWG guidelines were based mainly on studies that did not include enough Black patients. Guidelines should consider inclusion of observational, diagnostic and population-based studies with more black patients to allow for better reflection of disease prevalence, clinical characteristics and/or outcomes.

Comparison of three risk assessment models for thromboembolism in multiple myeloma patients receiving immunomodulators: a Brazilian historical cohort.

Venous thromboembolism (VTE) is among the complications of Multiple Myeloma (MM) and may occur in up to 10% of this patient population. However, medications used in MM therapy such as immunomodulators (IMID) may raise these rates. Thus, risk prediction models have been developed to quantify the risk of VTE in MM patients. The aim of this study is to compare the performance of three risk assessment models for VTE in newly diagnosed MM (NDMM) patients using immunomodulatory agents. A historical cohort study during a 10-year period in a Brazilian metropolis with NDMM treated with IMID. Data were collected from patient's medical charts for the period of one year to calculate the scores using IMPEDE VTE, SAVED, and International Myeloma Working Group (IMWG) guidelines. The area under the curve (AUC) of the Receiver Operating Characteristic curve analysis was calculated to assess the discriminative power of three risk assessment models. We included 131 patients (9 in the VTE group versus 122 in the non VTE group). According to IMPEDE, 19.1, 62.6, and 18.3% of patients were considered low, intermediate, and high risk, respectively. SAVED classified 32.1% as high risk and 64.9% had ≥2 risk factors based on IMWG guidelines. The AUC of the IMPEDE VTE score was 0.80 (95% CI 0.66-0.95, p = 0.002), of the SAVED score was 0.69 (95% CI 0.49-0.89, p = 0.057), and of the IMWG risk score was 0.68 (95% CI 0.48-0.88, p = 0.075). IMPEDE VTE was the most accurate in predicting the development of VTE in Brazilian patients on IMID therapy. The SAVED score and the IMWG guidelines did not show discriminative ability in predicting VTE based on the population involved in this study.

Under-Representation of Black Patients with Multiple Myeloma in Studies Supporting International Myeloma Working Group Guidelines

Under-Representation of Black Patients with Multiple Myeloma in Studies Supporting International Myeloma Working Group Guidelines

MM-474 Minimal Residual Disease Perception and Utilization in Real-World Multiple Myeloma Treatment

Minimal residual disease (MRD) platforms carry prognostic and predictive value in hematologic malignancies. Yet, their role and adoption in the real world remains limited. Evaluate trends in self-reported perceptions and utilization of MRD in routine clinical care of multiple myeloma (MM) patients. U.S.-licensed oncologists and hematologists convened at a live meeting in January 2020 (cohort A) and April 2022 (cohort B) to review clinical updates presented at the 2019 and 2022 ASH annual meetings, respectively. Participant characteristics and demographics were collected via an online survey ahead of the meeting. During the meeting, participants responded to queries about their perceptions and use of MRD assessment in MM. In addition, both cohorts A and B were shown updated data on the role of MRD in routine MM care and were polled about MRD afterwards. Data were summarized using descriptive statistics. Cohort A and B were comprised of 58 and 51 participants, respectively; 60.3% and 60.8% identified their primary specialty as hematology/oncology; 60.4% and 84.3% practiced in a community-based setting. Myeloma was one of the top three hematologic malignancies treated by both cohorts. MRD status was not assessed in patients by 53.8% of cohort A (n=52) compared to 54.0% of participants in cohort B. Lack of evidence was a reported barrier in both cohorts (64.0% and 29.5% in cohorts A and B, respectively); additional lack of necessary guidelines for MRD utilization was a noted barrier in cohort B (30.8%). After reviewing new clinical data on MRD assessment in MM, 71.2% of cohort A participants requested more data and 78.0% of cohort requested guidelines to compel them to use or increase their use of MRD in MM. Over the past two years, community provider perception and utilization of MRD has not changed significantly, although providers demonstrated receptiveness to utilizing MRD if provided with adequate guidelines. It should be noted that current NCCN Guidelines and the International Myeloma Working Group guidelines provide guidance on the role of MRD during response assessment and surveillance periods. These findings suggest that further education on the role of MRD in routine care is needed.

PB1965: A META-ANALYSIS OF THE RATE OF MALIGNANT PROGRESSION OF MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE: PRELIMINARY FINDINGS FROM A SYSTEMATIC REVIEW

Background: Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant condition preceding multiple myeloma (MM) and other haematological malignancies (HM). Clinically the rate of progression from MGUS to HM is important; current guidelines from the International Myeloma Working Group (IMWG) report this rate as “around 1% per year”, however variation has been reported by ethnic groups, MGUS type, and clinical features. Aims: A systematic review of the published literature was conducted to investigate the rate of MGUS progression to support clinical practice. Methods: Four electronic databases (Embase, Medline, Pubmed and Web of Science) were searched from database inception to 11/12/2019 using key words and MeSH subject headings for “MGUS”, “haematological malignancy” and “progression”. Studies were reviewed against predefined eligibility criteria by two independent reviewers. For studies reporting progression events and person-years of follow-up, a random-effects meta-analysis model5 was used to produce a pooled rate of MGUS progression to HM and MM. Studies reporting on cumulative rates of progression at specified time-points (1, 5 and 10-year) were included in a narrative synthesis. Results: Overall, 36 papers met the inclusion criteria; 12 studies (sample size: 114-17,963; follow-up 3.3-42.1 years) were included in the meta-analysis. In preliminary analyses, the annual pooled rate of MGUS progression was 1.1% (95%CI 0.9-1.3) to HM and 0.9% (95%CI 0.7-1.1) to MM. In total, 18 studies contributed to the narrative synthesis on MGUS progression to HM (sample size: 52-17,963; follow-up 2.1-34.1 years) and 10 studies reported on MGUS progression to MM (sample size: 75-2046, follow-up: 2.1-17 years). These narrative syntheses highlighted the heterogeneity of research, which encompassed key traits like methods, sample sizes and follow-up duration. Studies were also mainly conducted in Europe, being particularly scarce in Asia. Between meta-analysis and narrative synthesis, only seven studies reported on IgM-MGUS progression to Waldenström’s macroglobinaemia or HM, which could not be clearly synthesised in either analysis due to differing reporting; these papers indicated higher progression rates in IgM-MGUS than non-IgM. Summary/Conclusion: Preliminary findings from this systematic review support current IMWG guidelines on the rate of MGUS progression to HM. However, as the majority of studies included were limited to geographic areas within Europe and USA, further research reflecting population and clinical diversity are needed.

Imaging for Multiple Myeloma according to the Recent International Myeloma Working Group Guidelines: Analysis of Image Acquisition Techniques and Response Evaluation in Whole-Body MRI according to MY-RADS

Multiple myeloma (MM) is a malignant hematologic disease caused by the proliferation of clonal plasma cells in the bone marrow, and its incidence is increasing in Korea. With the development of treatments for MM, the need for early diagnosis and treatment has emerged. In recent years, the International Myeloma Working Group (IMWG) has been constantly revising the laboratory and radiological diagnostic criteria for MM. In addition, as whole-body MRI (WBMR) has been increasing used in the diagnosis and treatment response evaluation of patients with MM, the Myeloma Response Assessment and Diagnosis System (MY-RADS) was created to standardize WBMR image acquisition techniques, image interpretation, and response evaluation methods. Radiologists need to have a detailed knowledge of the features of MM for accurate diagnosis. Thus, in this review article, we describe the imaging method for MM according to the latest IMWG guidelines as well as the image acquisition and response evaluation technique for WBMR according to MY-RADS.

Development of New Scoring System for Whole Body Magnetic Resonance Imaging for Evaluation of Multiple Myeloma Lesions

Introduction: Advanced imaging with whole body MRI (WB-MRI) or positron-emission tomography (PET) is increasingly utilized in multiple myeloma (MM) as a diagnostic and prognostic modality. WB-MRI has become the standard of care for discerning active from asymptomatic multiple myeloma based on updated International Myeloma Working Group guidelines. WB-MRI is far superior to standard metastatic bone survey (MBS). It may outperform PET scan in some respects, namely in detection of the pattern and the extent of bone marrow infiltration, and its unique capability to quantify both burden of disease and response to treatment. We report on Yale method of WB-MRI protocol performed without gadolinium that differs from previously published methodology.Methods: WB-MRI imaging protocol was performed on a Siemens 3 Tesla magnet with a moving table, with the average imaging time of 60 minutes. It consisted of the following sequences: 1) Sagittal T1 of the total spine; 2) Coronal STIR (fluid sensitive) from the skull vertex through the ankles in 6 different stations, with merged images; 3) Coronal T1 (fat sensitive) from the neck through the feet in 5 stations, with merged images. We performed both baseline MBS and WB-MRI on 15 patients with newly diagnosed MM prior to initiation of therapy.Results: The WB-MRI imaging studies were reviewed and a standardized scoring system was designed to describe myeloma lesions based on the following parameters: 1) Size <1 cm, 1-3cm, >3cm: 1-3 points; 2) Endosteal scalloping: 1 point; 3) Associated marrow or periosteal edema: 1 point; 4) Cortical breakthrough: 1 point; 5) Associated soft tissue mass 1 point. This scoring system will be further validated in a larger prospective study of newly diagnosed patients with MM before and after induction. WB-MRI and MBS were evaluated for respective merits for disease staging and their impact on treatment decisions. Our WB-MRI protocol detected myeloma lesions in 33% of patients (5/15), whereas MBS identified lesions in only 6% (1/15). Overall, information obtained from WB-MRI significantly influenced the patient's staging in 73% of patients (11/15), and directly impacted treatment decisions in 46% of patients (7/15). WB-MRI identified myeloma bone lesions, which otherwise would have been missed by standard bone survey in 27% of patients (4/15). Myeloma related bone lesions occurred predominantly in the axial skeleton, most commonly seen in cervical, thoracic, lumbar spine and pelvis.Conclusion: Our method of WB-MRI protocol incorporates MM lesion scoring system, can be applied to patients regardless of renal impairment, provides valuable information on the extent and the stage of disease, and significantly influences treatment decisions. The proposed scoring system for myeloma lesions will be further validated in a larger prospective study for patients in newly diagnosed multiple myeloma. DisclosuresNo relevant conflicts of interest to declare.

Characterization of smoldering multiple myeloma: A population-based cohort study.

e20028 Background: There is increasing interest in characterizing Smoldering Multiple Myeloma (SMM) due to the availability of novel therapies shown to delay symptomatic progression to Multiple Myeloma (MM) with considerably less toxicity. The lack of population-based disease registries has made epidemiologic data on SMM difficult to acquire. Existing cohort studies of SMM patients have largely been conducted in specialized referral centers. This surveillance study characterizes the epidemiology of SMM in a real-world, clinical population using data from a large, integrated healthcare delivery system. Methods: We performed a retrospective study of all new SMM cases identified in Kaiser Permanente Northern California (KPNC) during 2010-2017, based on either (or (2) a new MM diagnosis in the KPNC Cancer Registry without initiation of plasma cell-directed therapy within 1 year of diagnosis. Those without KPNC membership for at least 1 year after diagnosis were excluded. Age at diagnosis, sex, race/ethnicity, and Charlson Comorbidity Index (CCI) at diagnosis were examined. The incidence of SMM was calculated using KPNC membership denominators, and a 2-sided Cochran-Armitage test was used to test for trend. Among the SMM cohort, characteristics were examined using the chi-squared test, including data before/after the Nov 2014 International Myeloma Working Group (IMWG) diagnostic criteria update. Results: A total of 251 new SMM cases were identified from 2010-2017. The average annual incidence of SMM was 1.2 per 100,000, increasing from 1.0 per 100,000 in 2010 to 1.5 per 100,000 in 2017 (p&lt;0.05 for trend). The demographic characteristics of the SMM cohort were notable for mean age 70.0 ± 11.7 years, 63.8% male, and 61.0% non-Hispanic White, 17.1% Black, 10.0% Hispanic, and 11.6% Asian. Overall, 73.7% had at least 1 comorbidity, based on CCI. When comparing 116 SMM cases diagnosed after the IMWG update to 135 cases diagnosed before the IMWG update, those diagnosed after the revised IMWG guidelines were significantly more likely to have at least 1 existing comorbidity (80.2% vs 68.2%, p=0.03). Conclusion We identified a contemporary cohort of patients with SMM from a large, integrated healthcare system. During our 8-year study period, the annual incidence of SMM increased slightly, including after 2014 when the IMWG criteria for SMM were refined. We observed that patients diagnosed after the 2014 IMWG update were more likely to have at least 1 comorbidity. Whether these trends relate to background population characteristics or are specific to recognized SMM cases bears further study. Follow-up analyses will examine the rate of progression from SMM to MM and the presence or absence of severe, irreversible, end-organ damage at the time of progression.

Involved free light chain: an early independent predictor of response and progression in multiple myeloma

Serum and urine protein electrophoresis (sPEP/uPEP) are the standard methods for monitoring of multiple myeloma (MM). However, a method of detection with shorter half-life, such as serum-free light chain (FLC), could detect the response or progression earlier. In total, 450 MM patients were assessed in first, second, and third line. Response and progression were classified according to International myeloma working group guidelines. The overall median time to partial response or better was detectable significantly earlier with involved free light chain (iFLC) 1.94 months (IQR: 1.61–2.23) compared to sPEP 5.39 months (IQR: 3.88–7.00). In first line, iFLC detected progression earlier compared to sPEP, particularly in patients with progression more than 18 months after best response. In conclusion, a response observed by iFLC occurs at least a median of 3 months before response is detected by sPEP/uPEP.

Serum free light chain reference intervals in an Optilite and their influence on clinical guidelines

BackgroundSerum free light chain (FLC) analysis has been incorporated into the International Myeloma Working Group guidelines for the diagnosis and management of all monoclonal gammopathies. These recommendations were solely based on a single assay method (Freelite assay) and instrument. Here, we establish new reference intervals (RIs) for kappa and lambda FLC and the kappa-lambda difference and sum and a new diagnostic range for kappa/lambda FLC ratio (K/L-FLC) in an Optilite turbidimeter (The Binding Site) with the Freelite assay. MethodsTo establish new RIs, the CLSI EP28-A3C protocol was applied to 249 sample blood donors from Fuenlabrada, Spain, and the central 95% and total range were estimated. Samples from patients with polyclonal hypo- and hypergammaglobulinemia were used for the evaluation of K/L-FLC as a monoclonal proliferation index. ResultsThe new RIs and the new K/L-FLC diagnostic range for the Optilite (0.65–2.56 mg/L) are very different from those in on the guidelines (0.26–1.65 mg/L). We propose new RIs for the K − L difference and the K + L sum. Diagnostic range validation as a monoclonal proliferation index with samples with hypo- and hypergammaglobulinemia confirms this new range. ConclusionsIn this study, we present the FLC RI for Freelite reagents measured on an Optilite turbidimeter. These ranges are different from those provided by the manufacturer and from those used in most studies in the literature, which may lead to patient misclassification. Manufacturers and clinical laboratories must strive to provide RIs for the technology they are using and for their population.

Comprehensive Updates in the Role of Imaging for Multiple Myeloma Management Based on Recent International Guidelines.

The diagnostic and treatment methods of multiple myeloma (MM) have been rapidly evolving owing to advances in imaging techniques and new therapeutic agents. Imaging has begun to play an important role in the management of MM, and international guidelines are frequently updated. Since the publication of 2015 International Myeloma Working Group (IMWG) criteria for the diagnosis of MM, whole-body magnetic resonance imaging (MRI) or low-dose whole-body computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography/CT have entered the mainstream as diagnostic and treatment response assessment tools. The 2019 IMWG guidelines also provide imaging recommendations for various clinical settings. Accordingly, radiologists have become a key component of MM management. In this review, we provide an overview of updates in the MM field with an emphasis on imaging modalities.

Daratumumab Dose Analysis Among Patients with Multiple Myeloma in a US Community Oncology Setting: A Retrospective Observational Study in Integra Connect Network

BACKGROUND Since the FDA's initial indication for the use of daratumumab in relapsed/refractory multiple myeloma (RRMM) in November 2015, usage has been expanded by subsequent approvals in newly diagnosed, transplant-ineligible MM patients, and more recently in newly diagnosed transplant-eligible patients. Real World Data (RWD) has been published demonstrating daratumumab's efficacy in RRMM settings[1]and its utility of split dosing for the initial dose[2]. However, no study has been published to examine the real-world dosing patterns of daratumumab compared to the FDA standard dosing schedule. While there are minimal variations in the approved dosing schedule of daratumumab, generally accepted dosing is weekly in week 1 through week 8, q 2 Wks in week 9 through week 24, and q 4 Wks after week 24, all at the standard 16 mg/kg dosage[3]. In its approved dosing schedule, adjustments are made in the frequency of administration, but not in the standard weight-based dosing. METHODS Utilizing the Integra Connect database which contains 17 community oncology network accounts and over 1,900 providers in US, we collected all MM patients treated with daratumumab between January 1, 2016 and March 31, 2020. We then excluded any patient whose first line of therapy (LOT) was ambiguous, in order to correctly identify the daratumumab-containing LOTs. We also excluded LOT 1 daratumumab transplant induction due to the wide variation in daratumumab dosing schedules in clinical trials in the transplant eligible patient[4]. LOTs were determined based on International Myeloma Working Group guidelines[5]. Data were collected on the date of each individual daratumumab administration, counting initial split dose, if utilized, as 1 dose. The duration of daratumumab and number of doses administered were calculated and corrected for any time on treatment breaks. The study was conducted per individual patient by LOT cohorts, and for the entire cohort of patients. We utilized the standard dose schedule for daratumumab noted above to establish the expected doses of daratumumab and calculated the compliance dose ratio (ratio of actual doses to expected doses per time on therapy) to evaluate how closely real-world treatment adhered to the standard dosing schedule. RESULTS 1037 MM patients were included with at least 6 doses of daratumumab administration and without stem cell transplant or uncertain LOT. Across all LOTs, the mean duration of daratumumab treatment was 5.6 months with a median duration of 9.8 months. After week twenty-four, 671 (65%) patients remained on daratumumab-containing regimens, with 330 patients continuing q 1 Wk or q 2 Wks dosing, whereas the standard would employ a switch to q 4 Wks dosing (Figure 1). Overall compliance dose ratio was consistently above 100%, implying a significant proportion of patients were receiving more frequent dosing than expected under the standard dosing schedule (Figure 2). We carefully evaluated patients in various LOTs and combination therapies. Drug combination was not found to exert a significant impact on the daratumumab dosing pattern. Compliance dose ratio of daratumumab is slightly higher in RRMM compared to the dose ratio in LOT 1 newly diagnosed MM, but even LOT 1 has a ratio greater than 1 (Figure 3). It should be noted that this increased compliance dose ratio is present in all LOT cohorts despite 25% of patients being started on doses less frequent than weekly (Figure 1). CONCLUSIONS In real-world community oncology practices, daratumumab is utilized in a more frequent dosing schedule than the FDA approved standard dosing. With standard dosing there are 23 daratumumab doses in the first 52 weeks. The compliance dose ratio found in our RWD implies 27.3 doses in the first year for the entire cohort and 26.9 and 28.3 doses in LOTs 2 and 3 respectively. Thus, significantly increased drug and administrative costs are incurred over those anticipated in respect to daratumumab dosing utilization. This study is limited to the EMR and administrative claims data of those individuals who are being treated in a community oncology setting. Residual confounding and bias may exist due to entry error and unobserved patient characteristics.

Efficacy and Safety of Idecabtagene Vicleucel (ide-cel, bb2121) in Elderly Patients with Relapsed and Refractory Multiple Myeloma: KarMMa Subgroup Analysis

Efficacy and Safety of Idecabtagene Vicleucel (ide-cel, bb2121) in Elderly Patients with Relapsed and Refractory Multiple Myeloma: KarMMa Subgroup Analysis

Serum markers alone can define high-risk smouldering multiple myeloma: new insights from the Czech Myeloma Group model.

The overall risk of developing symptomatic multiple myeloma (MM) from the asymtomatic precursor state, smoldering multiple myeloma (SMM), is 10% per year, but varies greatly with the presence of certain risk factors.1 The heterogeneous clinical course of SMM has led the International Myeloma Working Group (IMWG) to propose that patients with an 80% risk of progression at two years after an SMM diagnosis should be regarded as symptomatic MM patients and offered treatment.2 Therefore, the updated diagnostic MM criteria included three biomarker sassociated with a very high risk of progression; BMPC% ≥60, sFLCr ≥100 and/or more than one focal lesion on MRI.2 Within the last decades, several variables have been identified as associated with an increased risk of SMM progression to MM. Most risk-models are composed of a combination of serum markers3, 4 or a combination of serum markers along with bone marrow biopsy5, 6 flow-cytometry,7 imaging8 or molecular markers.9, 10 However, there is still no international consensus on which factors should be used as the standard risk stratification. Furthermore, one study found poor consistency between two widely used risk-models (PETHEMA and Mayo Clinic) when applied to the same patient cohort.11 Also, in the Danish study we found that the two-year progression-risk of having an abnormal FLC ratio ≥100 was only 30% and thus nowhere near the >80% risk as shown in the two studies which formed the basis of the IMWG guidelines.4 There are two important problems with the different SMM risk-models published so far: (i) the models are usually based on single-centre observations, and (ii) not all models consist of easily accessible markers for risk stratification. Together, this increases the risk of bias and to a certain degree compromises the ability of the risk-models to be used in the broader SMM population. It seems reasonable to assume that the lack of reproducibility of SMM high-risk models is also influenced by the biological heterogeneity of precursor diseases. A study analysing the whole genome sequence of pared tumour samples from 10 patients progressing from SMM to MM showed that the complexity of the genomic profile is generally not associated with a shorter time-to-progression (TTP) and that both a static and spontaneous sub-clonal evolution was found among the tested patients.12 How conventional serum and/or bone marrow markers serve as the correct proxy for the underlying genomic profile of the individual SMM patient is unknown. In this issue of the journal, Hájek et al. presents a new risk-model based on the data from the Czech Myeloma Group (CMG) and Heidelberg group. Based on data from the nationwide CMG registry, the authors first identified a high-risk subpopulation of SMM patients with a 78·7% two-year progression risk using immunoparesis, M-protein level ≥2·3 g/l and a FLC ratio >30 risk factors only. The risk-model was subsequently tested externally in the Heidelberg cohort, which arguably represents a specialised MM centre. Interestingly, the authors found a remarkably similar two-year progression risk (81·3%) when the model was tested in the Heidelberg population. Furthermore, Hájek et al. used the same data for a post-hoc comparison with other published risk-models and found that the CMG data did not meet the 80% progression rate threshold, indicating that the CMG model is more robust than previously proposed risk-models. Do we need more risk-models for SMM? With the QuiRedex study we saw that upfront treatment with lenalidomide-dexamethasone of high-risk patients does prolong TTP and overall survival (OS).13 Side effects were fairly modest with few grade 3 events.13 Arguably, if patients have a better OS and side effects are manageable, then the risk of doing more harm than good when starting anti-MM treatment is low. However, if high-risk SMM patients with high-risk features are to be considered as symptomatic MM patients, standard treatment should arguably involve three-drug induction treatment followed by ASCT for younger as well as fit elderly patients. Recently, daratumumab monotherapy for high-risk SMM patients was evaluated in the phase 2 Centaurus trial.14 The study did not meet the co-primary endpoint of CR >15%, thus indicating that a more aggressive multi-drug regimen is probably needed for disease eradication. Several clinical trials using different risk-models are underway to evaluate intensive treatment approaches in SMM. A real strength with the new CMG model is the external validation and use of accessible serum risk factors which makes this model practical for inclusion in future clinical trials or for the evaluation of SMM patients in everyday clinical practice.

Imaging of Monoclonal Gammapathy of Undetermined Significance and Smoldering Multiple Myeloma.

Multiple myeloma (MM) is always preceded by an initial monoclonal gammopathy of undetermined significance (MGUS) that then develops into asymptomatic or smoldering multiple myeloma (SMM), which constitutes an intermediate clinical stage between MGUS and MM. According to a recent study, risk factors for faster MGUS to MM progression include an M protein of 1.5 g/dL or more and an abnormal free light chain ratio in patients with non-IgM MGUS. Therefore, the International Myeloma Working Group (IMWG) decided to recommend whole-body computed tomography (WBCT) for patients with high-risk MGUS in order to exclude early bone destruction. Studies evaluating magnetic resonance imaging (MRI) in SMM found an optimal cutoff of two or more focal lesions to be of prognostic significance for fast progression into symptomatic disease and considered this biomarker as a myeloma-defining event (MDE) needing to start therapy with the aim to avoid progression to harmful bone lesions. Moreover, studies assessing positron emission tomography (PET) with computed tomography (CT) using 18F-deoxyglucose (FDG) (FDG-PET/CT) in SMM showed that presence of focal bone lesion without underlying osteolysis is associated with a rapid progression to symptomatic MM. Latest IMWG guidelines recommended to perform WBCT (either CT alone or as part of an FDG-PET/CT protocol) as the first imaging technique at suspected SMM and, if these images are negative or inconclusive, to perform whole-body MRI. The goal of this paper is to clarify the role of different imaging modalities in MGUS and SMM workups.

Application of risk factors for venous thromboembolism in patients with multiple myeloma starting chemotherapy, a real-world evaluation.

IntroductionWithin the first year of diagnosis, up to 1 in 3 multiple myeloma (MM) patients will experience a venous thromboembolism (VTE). The International Myeloma Working Group (IMWG) has thromboprophylaxis guidelines that stratify patients into low or high risk for thrombosis and subsequently recommend thromboprophylaxis, but it is unknown if these recommendations are being followed or if they are effective. The purpose of this study was to assess efficacy of the IMWG guidelines and investigate other potential VTE risk factors.MethodsStudy participants were treated at the University of Kansas Medical Center between 2007 and 2013, and charts were reviewed to extract data. Cases (MM and VTE) were matched to controls (MM and no VTE) at approximately 1:3 ratio based on gender, age (±5 years), and time of MM diagnosis (±5 years).ResultsA total of 80 cases and 211 controls were matched. Most patients (82%) were considered high risk for experiencing a VTE at the time of their MM diagnosis and 18% were considered low risk. Neither risk category (P = 0.16) nor thromboprophylaxis at baseline (P = 0.37) predicted VTE, though cases were more likely than controls to have an increased risk of thrombosis at the time of clot compared to their baseline risk (P = 0.09).ConclusionOur results suggest that IMWG guidelines are not being consistently followed and therefore could not be validated. Additional risk factors were not identified, but risk for VTE may change over time suggesting patients may require ongoing assessment of VTE risk and thromboprophylaxis throughout the disease course.

The Real-World Frequency of 24-Hour Urine Protein Electrophoresis (UPEP), Serum Free Light Chain (SFLC), and Serum Protein Electrophoresis (SPEP) Testing in Patients with Multiple Myeloma (MM)

IntroductionUp to 20% of MM patients present with light-chain-only multiple myeloma (LCMM), which is not detectable using serum protein electrophoresis testing. 24-hour urinalysis may be the guideline-endorsed method for monitoring LCMM, but impracticalities can limit its use. We sought to assess how patients with MM and LCMM were followed for progression in the community setting by specimen type using real-world data, analyzing the frequency of testing for patients with MM (based on SPEP) or LCMM (based on UPEP or SFLC).MethodsThis retrospective cohort study used information from the Flatiron Health database, which is derived from electronic health record data; Institutional Review Board approval with a waiver of informed consent was obtained. The cohort included 4591 patients followed for MM and LCMM from 01/01/2011 to 06/30/2018 at community oncology clinics across the United States. The cohort was limited to patients with a confirmed diagnosis of MM on or after 01/01/2011, who received at least one line of therapy and did not receive a stem cell transplant. Patients whose start of MM treatment (captured through chart review) was > 30 days before the start of structured activity in the database were excluded as this may indicate missing therapy data. The specimen type was the test used to follow patients for progression throughout their disease course. Tests were eligible to define the specimen type if they occurred ≤ 90 days before or any time after an initial MM diagnosis. If a patient had multiple test types within this timeframe, the specimen type was determined using a hierarchy (at least one detectable SPEP [≥ 1 g/dL] > at least one detectable 24-hour UPEP [≥ 200 mg] > SFLC [any numeric value]), consistent with International Myeloma Working Group (IMWG) criteria. A LCMM diagnosis was assumed when a detectable M spike (≥1 g/dL) via SPEP could not be found 90 days before or any time after the initial MM diagnosis date, but a detectable lab value was found within that timeframe via 24-hour UPEP (≥ 200mg) or a SFLC (any numeric value).ResultsAmong all patients in the cohort with MM (N=4591), 27.7% (N=1272) received a UPEP test, 58.1% (N=2666) received a SFLC test, and 79.2% (N=3635) received a SPEP test at baseline, defined as occurring within 90 days on either side of the MM diagnosis date. Patients with a UPEP specimen type had less frequent testing than patients with a SPEP or SFLC specimen type. For patients with a UPEP specimen type (N=229), the median of the median time between two tests was 95 days, compared to 42 days for patients with a SFLC specimen type (N=1274) and 35 days for patients with a SPEP specimen type (N=2536). 32.7% (N=1503) of the cohort had LCMM; of those patients, 84.8% were followed by SFLC while only 15.2% were followed by UPEP.Conclusions24-hour urine tests for UPEP are not used often in routine clinical practice despite IMWG guidelines: the guidelines may not reflect a realistic standard of care in the real-world setting. While performing UPEP in addition to SFLC regularly may be the ideal practice for monitoring LCMM, impracticalities such as issues with collection technique and proper storage of urine samples may be hindering its regular use in the real world. The SFLC test may present a more realistic alternative for evaluation of disease status in patients with LCMM, and its ease of use could facilitate more frequent serial testing. This in turn could improve the measurement of progression at more regular intervals, potentially reducing patient exposure to therapies that are no longer effective. To our knowledge, this is the first study to investigate the differences in utilization of UPEP, SFLC, and SPEP testing conducted to follow MM and LCMM progression in the real world. [Display omitted] DisclosuresFoster:Flatiron Health: Employment. Lipitz:Flatiron Health: Employment. Torres:Flatiron Health: Employment. Carson:Roche: Consultancy; Flatiron Health: Employment; Washington University in St. Louis: Employment.

Examining the Clinical Heterogeneity of Smoldering Multiple Myeloma

Examining the Clinical Heterogeneity of Smoldering Multiple Myeloma

Cost Effectiveness in Low Risk MGUS Patients

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant disorder characterized by the asymptomatic presence of a monoclonal protein. It is defined by an M protein < 3 gm/dl, less than 10% clonal plasma cells in the bone marrow, and the absence of anemia, hypercalcemia, renal insufficiency and bone lesions. In 2010 the International Myeloma Working Group (IMWG) advocated for MGUS patients to be stratified into low risk disease, which carries a 5% risk of progression to multiple myeloma at 20 years, and high risk disease, which represents a 20% risk at 20 years. This stratification model categorizes patients as low risk if they have an IgG paraprotein with an M-component < 1.5 g/dl and a normal free light chain (FLC) ratio. As such, it is suggested that the initial workup be comprised of a serum protein electrophoresis (SPEP), an immunofixation (IFE), and a FLC ratio. A bone marrow biopsy (BM) and bone survey should only be performed if anemia, hypercalcemia or an elevated creatinine of unclear etiology is noted. If these studies place a patient into the low risk, it is suggested the patient follow up at 6-months with only an SPEP. If the SPEP is stable, the next follow-up is recommended to occur at 2 to 3 year intervals unless symptoms arise suggestive of a plasma cell dyscrasia.The risk stratification of MGUS patients was validated in 2013 by Turesson et al. in a Swedish cohort (Blood, 2014; 123:338-345). Nevertheless, the risk model is not universally accepted and unnecessary office visits along with laboratory studies are performed on low risk patients.The purpose of this study was to perform an internal retrospective review of our patients diagnosed with low risk MGUS, evaluating excess medical costs incurred when patients were not risk stratified by the IMWG recommendations.Methods:MGUS patients seen in the Hematology Oncology Division of Drexel University between 2014 and 2016 were retrospectively categorized into high and low risk based on the IMWG criteria. Those determined to be low risk were evaluated over two years for extra costs incurred outside the IMWG recommendations. Extra cost was tallied based on initial workup and surveillance studies performed up to two years from diagnosis.Costs per test and follow up visits were based on our office appointment pricing and BM biopsy charges. Laboratory costs were obtained based on pricing from ACCU reference lab.Cost per test (varies by lab/provider)SPEP $67UPEP $130Serum IFE $200Urine IFE $72IgA $27IgG $27IgM $27K/L ratio $120B2 microglobulin $42Office Visit $40 - $100Bone Survey $500 - $1200BM biopsy $500- $1000Results:Sixty patients seen between 2014 and 2016 met the criteria for MGUS. Twenty-eight patients were determined to have low risk disease. Of the 28 patients, five were diagnosed prior to 2010 and were excluded. In the remaining 23 patients, four followed up at exactly six months from diagnosis and only one had an SPEP. The most common test ordered was quantitative immunoglobulins (QI) aside from a CBC and CMP. The total number of excess office visits was 49. Three patients had unnecessary BM biopsies (total cost $1,000 - $2,000), and 11 had unnecessary bone surveys (Total $5,500 - $13,200). The total cost of unnecessary lab tests within 2 years was $6,024 and the total cost of unnecessary office visits within 2 years was $1960 - $4900. Thus, the average excess spent per patient was $630 - $1135, for a total excess cost for the 23 patients of $14,484 - $26,124.Conclusion:This internal review highlights the excess medical costs incurred when patients are not risk stratified by the IMWG recommendations. Ideally, no further health care dollars should be spent for low risk MGUS patients who have a stable SPEP at the 6-month visit until the 2 or 3 year follow up visit. The actual excess amount spent in our office in 2 years for these patients was $14,484 - $26,124 beyond the cost of the standard of care recommended by the IMWG guidelines. Additionally, these values did not include excess basic labs such as a CBC or CMP and it did not include extension of our investigation out to three years which would result in further unnecessary costs. One patient was noted to accumulate excess cost due to his co-morbid condition of prostate cancer, which led to increased surveillance for his low risk MGUS. The risk stratification model allows physicians to offer patients a better understanding of their disease, decrease the patient's burden and reduce the cost on healthcare. DisclosuresNo relevant conflicts of interest to declare.