Bone Marrow Plasma Cell Infiltration Research Articles

Artificial intelligence-based, volumetric assessment of the bone marrow metabolic activity in [18F]FDG PET/CT predicts survival in multiple myeloma.

Multiple myeloma (MM) is a highly heterogeneous disease with wide variations in patient outcome. [18F]FDG PET/CT can provide prognostic information in MM, but it is hampered by issues regarding standardization of scan interpretation. Our group has recently demonstrated the feasibility of automated, volumetric assessment of bone marrow (BM) metabolic activity on PET/CT using a novel artificial intelligence (AI)-based tool. Accordingly, the aim of the current study is to investigate the prognostic role of whole-body calculations of BM metabolism in patients with newly diagnosed MM using this AI tool. Forty-four, previously untreated MM patients underwent whole-body [18F]FDG PET/CT. Automated PET/CT image segmentation and volumetric quantification of BM metabolism were based on an initial CT-based segmentation of the skeleton, its transfer to the standardized uptake value (SUV) PET images, subsequent application of different SUV thresholds, and refinement of the resulting regions using postprocessing. In the present analysis, ten different uptake thresholds (AI approaches), based on reference organs or absolute SUV values, were applied for definition of pathological tracer uptake and subsequent calculation of the whole-body metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Correlation analysis was performed between the automated PET values and histopathological results of the BM as well as patients' progression-free survival (PFS) and overall survival (OS). Receiver operating characteristic (ROC) curve analysis was used to investigate the discrimination performance of MTV and TLG for prediction of 2-year PFS. The prognostic performance of the new Italian Myeloma criteria for PET Use (IMPeTUs) was also investigated. Median follow-up [95% CI] of the patient cohort was 110months [105-123months]. AI-based BM segmentation and calculation of MTV and TLG were feasible in all patients. A significant, positive, moderate correlation was observed between the automated quantitative whole-body PET/CT parameters, MTV and TLG, and BM plasma cell infiltration for all ten [18F]FDG uptake thresholds. With regard to PFS, univariable analysis for both MTV and TLG predicted patient outcome reasonably well for all AI approaches. Adjusting for cytogenetic abnormalities and BM plasma cell infiltration rate, multivariable analysis also showed prognostic significance for high MTV, which defined pathological [18F]FDG uptake in the BM via the liver. In terms of OS, univariable and multivariable analysis showed that whole-body MTV, again mainly using liver uptake as reference, was significantly associated with shorter survival. In line with these findings, ROC curve analysis showed that MTV and TLG, assessed using liver-based cut-offs, could predict 2-year PFS rates. The application of IMPeTUs showed that the number of focal hypermetabolic BM lesions and extramedullary disease had an adverse effect on PFS. The AI-based, whole-body calculations of BM metabolism via the parameters MTV and TLG not only correlate with the degree of BM plasma cell infiltration, but also predict patient survival in MM. In particular, the parameter MTV, using the liver uptake as reference for BM segmentation, provides solid prognostic information for disease progression. In addition to highlighting the prognostic significance of automated, global volumetric estimation of metabolic tumor burden, these data open up new perspectives towards solving the complex problem of interpreting PET scans in MM with a simple, fast, and robust method that is not affected by operator-dependent interventions.

Changes in RDW according to prognostic predictors in newly diagnosed multiple myeloma.

RDW is an erythrocyte index that increase in multiple myeloma, in which it appears to have an important role in predicting outcome. For this reason, we performed a retrospective analysis to evaluate the relationships of RDW with some important prognostic predictors. Specifically, in a cohort of 190 newly diagnosed multiple myeloma patients, we have examined the behaviour of RDW and its trend in relation to the ISS stage and other prognostic factors, such as albumin, beta-2 microglobulin, LDH and bone marrow plasma cell infiltration. We performed the analysis in the entire cohort of patients and in the three different disease isotypes (Light chain, IgA, and IgG multiple myeloma). The evaluation of RDW in the different isotypes was made with the Kruskal-Wallis test, integrated by the Dunn test. The comparison between the subgroups allocated above and below the median value of each prognostic factor, was made with the Mann-Whitney test. From our analysis, we observed that RDW is higher in the IgA multiple myeloma, and it increases significantly from ISS I to III. Moreover, RDW increases in the presence of lower albumin values, higher levels of beta2-microglobulin and LDH and in the presence of a greater bone marrow plasma cell infiltrate.

Ultra High-Risk Multiple Myeloma Patients with Multi-Hit Tumours and SKY92 High Risk Signature Are at Increased Risk of Early Relapse Even When Treated with Extended Intensified Induction and Consolidation - Results from the Optimum/Muknine Trial

Background: We recently reported improved outcomes for patients with ultra-high risk (UHiR) newly diagnosed multiple myeloma (NDMM) by double hit/≥2 high-risk cytogenetic abnormalities (HRCA) and/or SKY92 risk signature or primary plasma cell leukemia (pPCL) in the OPTIMUM/MUKnine (NCT03188172; Kaiser et al, JCO 2023) trial. However, some participants still relapsed within the first 18 months of treatment despite stratified intensive therapy with Dara-CVRd, V-ASCT and extended Dara-VR(d) consolidation. In this analysis we characterise factors associated with early progression. Methods: In OPTIMUM, patients with UHiR NDMM (≥2 HRCA: t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p) or SKY92 high risk signature) or with pPCL received up to 6 cycles of Dara-CVRd induction, V-ASCT, 6 cycles Dara-VRd (Cons1) and 12 cycles Dara-VR (Cons2), before moving to monthly Dara-R maintenance until progression. OPTIMUM recruited 107 UHiR patients, including 9 pPCL. In this exploratory analysis, baseline clinical, laboratory and tumour molecular characteristics were compared between patients who experienced an Early Relapse, defined by MM relapse or MM-related death within 18 months from registration and those who did not, using descriptive statistics and hypothesis testing using two-sample t-tests or chi squared tests. Baseline characteristics were also compared by minimal residual disease (MRD; 10 -5 sensitivity by flow cytometry) status at the end of induction to elucidate whether baseline factors associated with early MRD negativity were overlapping with those associated with Early Relapse. Median follow-up was 51.5 months, and all patients had been on study for over 44 months. Results: Twenty-three (21%) of 107 UHiR patients experienced Early Relapse, versus 84 (79%) who did not. Patient age and gender were not different between groups. Platelet levels as a continuous variable were lower in the Early Relapse group vs those without (mean 179/nL, standard deviation (SD) 92/nL vs. mean 223/nL, SD 77/nL; P=0.0247), whereas haemoglobin, serum creatinine, calcium, presence of soft tissue plasmacytomas (PCM), bone lytic lesions or plasma cell bone marrow infiltration on diagnostic trephine were similar. ISS stage distribution differed between groups (P=0.0203): most Early Relapse participants were ISS stage 2 (13/23 (56.5%) vs 30/84 (35.7%) without Early Relapse), whereas ISS stage 3 was nominally similar (34.8% vs 31.0%). Most notably, only one of the 29 ISS stage 1 patients in OPTIMUM experienced Early Relapse. 57 of 107 (53.3%) patients entered OPTIMUM with ≥2 HRCA at diagnosis, and, of these, seven carried 3 HRCA. Five of seven participants (71.4%) with 3 HRCA experienced Early Relapse, opposed to only seven out of 50 (14%) with only 2 HRCA. 82 of 107 (76.6%) were SKY92 high risk at baseline. Only two of the 24 participants (8.3%) with SKY92 standard risk experienced Early Relapse, as opposed to 20 out of 82 (24.4%) with SKY92 high risk. Of individual HRCAs, only presence of del(17p) was associated with early relapse (P=0.002): 8 of 16 (50%) participants with del(17p) tumours experienced Early Relapse. However, seven of these 8 Early Relapse del(17p) tumours (88%) were also positive for SKY92 high risk signature. In contrast, the majority (62%) of del(17p) that did not relapse early were SKY92 standard risk. Of the 107 UHiR patients, 6 did not reach end of induction and 14 had no MRD result. Of 87 participants with interpretable MRD result at end of induction (EOI), 51% tested MRD-negative (44/87). Of clinical factors, only presence of PCM was associated with insufficient response (P=0.017, 5/5 MRD-positive), whereas ISS stage was not associated with MRD at EOI. Only one of four participants (25%) with 3 HRCA had MRD-negative status at EOI vs 66% of those with 2 HRCA. Also, the majority of patients (62%) identified by SKY92 high risk only were still MRD-positive. Conclusions: Our results suggest that presence of 3 or more HRCA, SKY92 high risk signature or del(17p) combined with SKY92 high risk are all associated with increased risk of Early Relapse despite intensified OPTIMUM treatment, and could help identify patients early who are candidates for novel, innovative first-line therapeutic approaches. Results also suggest utility of integrated molecular diagnostics, including gene expression risk profiling, to support clinical decision making in the era of advanced front-line combination therapies.

Bone Marrow Plasma Cell Infiltration Is a Prognostic Factor for Response to AL Amyloidosis Therapy

Background: In light-chain amyloidosis (AL), amyloid deposits cause disruption of organ function. High-dose chemotherapy with melphalan (HD) followed by autologous stem cell transplantation (ASCT) is considered the most effective therapy for AL, if tolerable. Recently, the Andromeda study demonstrated high response rates and long PFS without ASCT in AL. In AL, the biology of AL plasma cell dyscrasia varies widely. Both MM and MGUS, which can be biologically and genetically distinct, can be the cause of symptomatic AL and may warrant different therapeutic strategies. Only half of AL cases classify as myeloma with bone marrow plasma cells (BMPC) >10% and (SLiM-)CRAB criteria. Although high BMPC infiltration is associated with inferior therapy outcomes, clinical information are lacking whether patients with less than 10% BMPC equally benefit from ASCT or if less toxic approaches can be performed without decreasing efficacy. Methods: We retrospectively analyzed 150 patients from our institution with biopsy-proven systemic MGUS/MM derived AL amyloidosis diagnosed and treated between January 1, 2006 and June 30, 2023. 62 patients had BMPC >10% and 17 patients were excluded due to unknown bone marrow infiltration. Overall, we identified 71 patients with <10% BMPC and/or negative (SLiM-)CRAB criteria. To correlate therapy with clinical outcome, we divided this cohort based on treatment into two groups of patients that had received ASCT vs. patients treated without ASCT. All patients treated with ASCT had a cumulative melphalan dose of at least 140 mg/m². Non-HD therapies consisted of combinations with alkylators, CD38 moAbs, IMiDs, proteasome inhibitors and steroids. High-risk cytogenetics were assessed according to current IMWG criteria. Results: 21 (29.6 %) out of the 71 patients with <10% BMPCs received ASCT and 50 (70.4 %) were treated without ever receiving HD. 18 out of those received at least three cycles of Daratumumab containing regimen. Both groups were comparable with a medium BMPC infiltration of 5.4 and 4.7% and mainly exhibited lambda phenotype (81 and 70%, respectively). FISH analysis was available in 34 of them (47.9%) with t(11;14) in 80% of all cases and del13q14 in 40% as most common alterations. We identified a high-risk phenotype (del17p and gain1q) in 30% in patients receiving ASCT and in 19% of patients without. ECOG status at diagnosis was significantly lower (0.71 vs. 1.1) in the ASCT population compared to no ASCT and patients receiving HD were younger (mean age 57 vs. 66 years). Median PFS was 68 months for patients that received HD vs. 61 months for patients without HD and did not differ significantly between the two groups (p = 0.67) at a median follow- up of 33.5 months. Interestingly, the 18 patients treated with DaraVCd had a PFS of 100%, but at a comparably low median follow-up of 12.5 months, significantly surpassing ASCT in this population. However, the number of Daratumumab-based therapies in the ASCT population was low (n = 5). Conclusion: In a low risk population defined by <10% BMPC, patients treated with HD melphalan did not show a statistical PFS difference when compared to patients treated without ASCT. Acknowledging the fact that only a minor subset of our ASCT-treated patients received Dara, our data still provide evidence that less aggressive therapy omitting ASCT may be a resonable strategy for biologically low-risk AL.

Application of an artificial intelligence-based tool in [18F]FDG PET/CT for the assessment of bone marrow involvement in multiple myeloma

Purpose[18F]FDG PET/CT is an imaging modality of high performance in multiple myeloma (MM). Nevertheless, the inter-observer reproducibility in PET/CT scan interpretation may be hampered by the different patterns of bone marrow (BM) infiltration in the disease. Although many approaches have been recently developed to address the issue of standardization, none can yet be considered a standard method in the interpretation of PET/CT. We herein aim to validate a novel three-dimensional deep learning-based tool on PET/CT images for automated assessment of the intensity of BM metabolism in MM patients.Materials and methodsWhole-body [18F]FDG PET/CT scans of 35 consecutive, previously untreated MM patients were studied. All patients were investigated in the context of an open-label, multicenter, randomized, active-controlled, phase 3 trial (GMMG-HD7). Qualitative (visual) analysis classified the PET/CT scans into three groups based on the presence and number of focal [18F]FDG-avid lesions as well as the degree of diffuse [18F]FDG uptake in the BM. The proposed automated method for BM metabolism assessment is based on an initial CT-based segmentation of the skeleton, its transfer to the SUV PET images, the subsequent application of different SUV thresholds, and refinement of the resulting regions using postprocessing. In the present analysis, six different SUV thresholds (Approaches 1–6) were applied for the definition of pathological tracer uptake in the skeleton [Approach 1: liver SUVmedian × 1.1 (axial skeleton), gluteal muscles SUVmedian × 4 (extremities). Approach 2: liver SUVmedian × 1.5 (axial skeleton), gluteal muscles SUVmedian × 4 (extremities). Approach 3: liver SUVmedian × 2 (axial skeleton), gluteal muscles SUVmedian × 4 (extremities). Approach 4: ≥ 2.5. Approach 5: ≥ 2.5 (axial skeleton), ≥ 2.0 (extremities). Approach 6: SUVmax liver]. Using the resulting masks, subsequent calculations of the whole-body metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in each patient were performed. A correlation analysis was performed between the automated PET values and the results of the visual PET/CT analysis as well as the histopathological, cytogenetical, and clinical data of the patients.ResultsBM segmentation and calculation of MTV and TLG after the application of the deep learning tool were feasible in all patients. A significant positive correlation (p < 0.05) was observed between the results of the visual analysis of the PET/CT scans for the three patient groups and the MTV and TLG values after the employment of all six [18F]FDG uptake thresholds. In addition, there were significant differences between the three patient groups with regard to their MTV and TLG values for all applied thresholds of pathological tracer uptake. Furthermore, we could demonstrate a significant, moderate, positive correlation of BM plasma cell infiltration and plasma levels of β2-microglobulin with the automated quantitative PET/CT parameters MTV and TLG after utilization of Approaches 1, 2, 4, and 5.ConclusionsThe automated, volumetric, whole-body PET/CT assessment of the BM metabolic activity in MM is feasible with the herein applied method and correlates with clinically relevant parameters in the disease. This methodology offers a potentially reliable tool in the direction of optimization and standardization of PET/CT interpretation in MM. Based on the present promising findings, the deep learning-based approach will be further evaluated in future prospective studies with larger patient cohorts.

RWD156 The Impact of the Sars-Cov-2 Pandemic (COVID-19) on the Incidence of Newly Diagnosed Multiple Myeloma Patients Using a Federated Network of Real-World Evidence in US and Germany

COVID-19 had an impact on health care, including diagnostics. Early diagnosis of MM is a critical factor for prognosis. We examined the impact of COVID-19 on incidence of NDMM patients and on characteristics in NDMM patients in US and in Germany. 44,164 NDMM patients were identified in TriNetX federated network across 55 healthcare organizations in US between January 2018 and December 2021. A bivariate analysis examined changes in patient characteristics in two cohorts before (Cohort 1; n=25513) and after (Cohort 2; n=18.651) the start of the COVID-19 pandemic in March 2020. 4172 NDMM patients were identified in the German database in a sample of across >100 healthcare organizations in the same time period. Similarly, bivariate analysis examined changes in patient characteristics before (Cohort 1; n=2252) and after (Cohort 2; n=1920) the start of pandemic. Analysis of US data showed a significant decrease in incidence of NDMM. Bivariate analysis revealed that NDMM patients in Cohort 2 have a significantly higher risk profile compared with patients in Cohort 1, higher incidence of renal failure (13.5% v. 15.43%), heart failure (10.3% v 11.26%), bone lesions (12.6% v. 13.05%) and anemia (26.8% v. 29.75%). The German data indicated an increased risk profile in Cohort 2, with higher reporting of renal impairment (12.3% v. 15.5%) and cardiac impairment (8.3% v. 10.9%). The higher risk profile was reflected in a significant increase of all SLiM-CRAB criteria, notably hypercalcemia (24.1 % v. 36.9%), bone marrow plasma cell infiltration (28.1% v. 36.8%) and free light chain involvement (27.3% v. 41.3%). The results provide real-world evidence of a change in risk profile for patients with NDMM during COVID-19. This higher risk profile is observed in both the US and Germany, and may negatively impact outcomes such as progression-free and five-year overall survival.

Soluble B-cell maturation antigen as a monitoring marker for multiple myeloma.

Objective: Response to treatment in multiple myeloma (MM) is routinely measured by serum and urine M-protein and free light chain (FLC), as described by the International Myeloma Working Group (IMWG) consensus statement. A non-negligible subgroup of patients however present without measurable biomarkers, others become oligo or non-secretory during recurrent relapses. The aim of our research was to evaluate soluble B-cell maturation antigen (sBCMA) as a monitoring marker measured concurrent with the standard monitoring in MM patients at diagnosis, at relapse and during follow up, in order to establish its potential usefulness in oligo and non-secretory disease. Method: sBCMA levels were measured in 149 patients treated for plasma cell dyscrasia (3 monoclonal gammopathy of unknown significance, 5 smoldering myeloma, 7 plasmacytoma, 8 AL amyloidosis and 126MM) and 16 control subjects using a commercial ELISA kit. In 43 newly diagnosed patients sBCMA levels were measured at multiple timepoints during treatment, and compared to conventional IMWG response and progression free survival (PFS). Results: sBCMA levels among control subjects were significantly lower than among newly diagnosed or relapsed MM patients [20.8 (14.7-38.7) ng/mL vs. 676 (89.5-1,650) and 264 (20.7-1,603) ng/mL, respectively]. Significant correlations were found between sBCMA and the degree of bone marrow plasma cell infiltration. Out of the 37 newly diagnosed patients who have reached partial response or better per IMWG criteria, 33 (89%) have had at least a 50% drop in sBCMA level by therapy week 4. Cohorts made similarly to IMWG response criteria-achieving a 50% or 90% drop in sBCMA levels compared to level at diagnosis-had statistically significant differences in PFS. Conclusion: Our results confirmed that sBCMA levels are prognostic at important decision points in myeloma, and the percentage of BCMA change is predictive for PFS. This highlights the great potential use of sBCMA in oligo- and non-secretory myeloma.

Calculated Whole Blood Viscosity and Albumin/Fibrinogen Ratio in Patients with a New Diagnosis of Multiple Myeloma: Relationships with Some Prognostic Predictors.

In this single center study, we retrospectively evaluated the calculated hemorheological profile in patients with a new diagnosis of multiple myeloma, with the aim to evaluate possible relationships with some prognostic predictors, such as ISS, albumin levels, beta2-microglobulin, red cell distribution width, and bone marrow plasma cell infiltration. In a cohort of 190 patients, we examined the calculated blood viscosity using the de Simone formula, and the albumin/fibrinogen ratio as a surrogate of erythrocyte aggregation, and then we related these parameters to prognostic factors, using the Kruskal-Wallis and the Mann-Whitney tests, respectively. From our analysis, it emerged that the evaluated hemorheological pattern differed in the three isotypes of multiple myeloma, and the whole blood viscosity was higher in IgA and IgG isotypes with respect to the light chain multiple myeloma (p < 0.001). Moreover, we observed that, as the ISS stage progressed, the albumin/fibrinogen ratio was reduced, and the same hemorheological trend was traced in subgroups with lower albumin levels, higher beta2-microglobulin and red cell distribution width RDW values, and in the presence of a greater bone marrow plasma cell infiltrate. Through the changes in blood viscosity in relation to different prognostic factors, this analysis might underline the role of the hemorheological pattern in multiple myeloma.

Prevalence of smoldering multiple myeloma based on nationwide screening.

Smoldering multiple myeloma (SMM) is an asymptomatic precursor to multiple myeloma. Here we define the epidemiological characteristics of SMM in the general population in Iceland. The iStopMM study (ClinicalTrials.gov ID: NCT03327597 ) is a nationwide screening study for multiple myeloma precursors where all residents in Iceland 40 years or older were invited to participate. SMM was defined as 10-60% bone marrow plasma cells and/or monoclonal (M) protein concentration ≥3 g dl-1, in the absence of myeloma-defining events. Of the 80,759 who gave informed consent to participate, 75,422 (93%) were screened. The prevalence of SMM in the total population was 0.53% (95% confidence interval (CI) = 0.49-0.57%) in individuals 40 years or older. In men and women, the prevalence of SMM was 0.67% (95% CI = 0.62-0.73%) and 0.39% (95% CI = 0.35-0.43%), respectively; it increased with age in both sexes. For the 193 individuals with SMM, median age was 70 years (range 44-92 years) and 60% were males. The mean M protein concentration of individuals with SMM was 0.62 g dl-1 (range 0.01-3.5 g dl-1) and 73% had 11-20% bone marrow plasma cell infiltration. The high prevalence of SMM has implications for future treatment policies in multiple myeloma as the evidence supporting treatment initiation at the SMM stage is emerging.

593 PRESENTATION AND OUTCOME OF PATIENTS WITH COEXISTING CARDIAC AL AND ATTR AMYLOIDOSIS

Abstract Background Incidence of ATTRwt amyloidosis increased in the last years, especially thanks to the possibility of a non-bioptic diagnosis. However, if a monoclonal component (MC) is detected, amyloid typing is mandatory to rule out AL amyloidosis. Differential diagnosis is even more important now that we have labelled treatment for both types of amyloidosis. In some cases, typing on endomyocardial biopsy (EMB) revealed the presence of both light chains (LC) and transthyretin (TTR) in the heart of the same patient (Sidiqi, et al, Blood Cancer J. 2019). We present a series of patients with coexisting AL and ATTR in the heart. In these cases, we elected to administer treatment for AL amyloidosis due to the more rapid course of this disease and because in Italy and in Germany tafamidis is not prescribable for patients with coexisting AL amyloidosis. Objective: To evaluate the outcome of patients with coexisting AL and ATTR amyloidosis in the heart after treatment for AL amyloidosis. Material &amp; Methods: We identified 17 patients with coexisting AL and ATTR amyloidosis evaluated in a German (n=5) or Italian (n=12) referral center. Typing was performed by immunohistochemistry with custom made antibodies (IHC; N=5) and immunoelectron microscopy (IEM; N=8). In 4 cases, EBM samples were subjected to protein extraction following a new procedure (patent n EP3417295). SDS-PAGE/Western Blot analysis was performed for the main amyloidogenic proteins and its results were validated by mass spectrometry. Cardiac responses and progression were assessed according to AL amyloidosis criteria. Results 3 patients were excluded because of post-mortem diagnosis and 1 because amyloid deposits were characterized on bone marrow biopsy and it was not possible to unequivocally conclude for the coexistence of LC and TTR in the heart. Thirteen patients were included in the analysis. Four had a positive abdominal fat pad (AFP). Three underwent EMB because typing by IHC was not possible on AFP by IHC. In 1 IEM was positive for TTR only, but given the presence of an abnormal free LC ratio and albuminuria, the patient underwent EBM that was positive both for LC and TTR at IEM. Perugini score 1 was observed in 3 patients, of whom 1 was positive for a TTR mutation (Val40Ile). In 1 case, bone marrow plasma cell infiltrate was ≥60%, in absence of other multiple myeloma defining events. All patients received treatment for AL amyloidosis and 10 had response data. None was treated for ATTR. At 6 months 9 achieved a hematologic response (HR) and 3 a cardiac response. Six patients had a cardiac progression, despite 5 had achieved a HR (complete response [CR] in 2, very good partial response [VGPR] in 2 and partial response in 1 case). After a median follow-up of 33.8 months, 2 patients died of worsening of heart failure after 15 and 48 months from diagnosis, despite the maintenance of CR and VGPR. Both had AL cardiac progression at 6 months. Summary &amp; Conclusion This is the largest series of patients with coexisting AL and ATTR amyloid deposits in the heart and the first reporting outcome to AL treatment. The AFP was commonly negative and when positive typing was not possible by IHC. Moreover, IEM did not find AL deposits in 1 case. This was unexpected and may reflect a selection bias: patients with a MC and AL amyloidosis in the AFP are unlikely to be further tested for ATTR. This finding warrants further studies and a possible revision of diagnostic algorithms. Treatment for AL amyloidosis may not be able to stop progression in these patients, who should be granted access to anti-ATTR therapies.

Bone Marrow-Free Sequencing of M Protein Genes in Monoclonal Gammopathies

Introduction In patients with monoclonal gammopathies, M proteins are patient-unique, can cause potentially fatal organ damage and can be used to track the B cell/plasma cell tumor after therapy. The presence of circulating tumor cells and the possibility to analyze the antibody repertoire through NGS and proteomics approaches may provide a window of opportunity to identify patients' specific M protein genes in the peripheral blood, without invasive bone marrow investigations. Methods Mononuclear cells from peripheral blood were subjected to single-molecule real-time sequencing of the M protein (SMaRT M-Seq)1 to obtain the circulating repertoire of the affected light chain isotype in a cohort of patients with MGUS (n=3), MM (n=8) and AL amyloidosis (n=36) at diagnosis. Tryptic digestion peptides from urinary proteins were subjected to mass spectrometry analysis to identify or validate the clonal light chain sequence from the obtained circulating repertoire2. SMaRT M-Seq on matched bone marrow samples to identify the bona fide clonal light chain sequence was performed for confirmatory purposes. Results Reads with 100% identity to the bona fide clonal light chain sequences were identified in the peripheral blood of 44 patients (94%) and were the dominant clonal sequence in 35 cases (75%). In all cases where the most abundant, discrete clonal sequence represented at least 15% of all reads detected within the peripheral blood (n=26, 55%), such sequence invariably coincided with the bona fide clonal light chain sequence as defined by bone marrow sequencing studies (Figure 1A). In a subset of cases (n=21), we also analyzed the urinary proteome and mapped tryptic digestion peptides against each patient's peripheral blood antibody repertoire. In all cases, peptide mapping correctly identified the bona fide clonal light chain sequence as the light chain sequence with the highest relative abundance, sequence coverage, and number of unique peptides among all light chain sequences identified in the patient's peripheral blood (Figure 1B). The percentage of peripheral blood sequences corresponding to the bona fide clonal light chain sequence significantly, but modestly correlated with bone marrow plasma cell infiltration (R2 0.30). Conclusion Sequencing of the circulating light chain repertoire through SMaRT M-Seq, eventually coupled with mass spectrometry-based analysis of the urinary proteome, enables the identification of the full-length clonal light chain sequence in most patients with a monoclonal gammopathy. The possibility of reliably determining disease-related immunoglobulin gene sequences even from the peripheral blood from large cohorts of patients has the potential to uncover molecular mechanisms of M protein-related clinical manifestations which have remained largely unexplored so far2. It could also facilitate approaches to personalized medicine, including the implementation of sequence-based predictive models for the identification of potentially pathogenic M proteins3,4, and the sensitive detection of patients' specific M proteins at diagnosis and MRD after anti-clonal therapy5.

Acquired Loss of a Sex Chromosome Is a Positive Prognostic Factor for Patients with Multiple Myeloma Undergoing ASCT

Introduction: In patients with multiple myeloma (MM), small somatic genetic lesions in non-malignant blood cells, i.e. clonal hematopoiesis, has been found to be associated with inferior survival and other adverse outcomes (Mouheddine T.H. et al. - Nature Comm. 2020). However, large-scale alterations on a chromosomal level are also acquired in ageing blood cells and may impact patient outcomes. Methods: Using a novel bioinformatic approach, we performed a genome-wide analyses of chromosomal aberrations in 998 patients with multiple myeloma before undergoing autologous stem cell transplant (ASCT) in a national population-based cohort. Post-induction harvest samples were analyzed with a custom Illumina deCODE Genetics SNP array and further processed using MoChA bioinformatic pipeline (Loh P., Genovese G. et al. - Nature 2020) to identify acquired mosaic chromosomal alterations (mCAs). Comprehensive clinical data was collected from nationwide registries with long-term follow-up (the Danish Multiple Myeloma Registry and the Danish Civil Registration System). Data included information on diagnostic criteria, peripheral blood counts, M protein, β-2 microglobulin, albumin, genetic myeloma aberrations by FISH, treatment, response to ASCT, progression, and death. Results: We identified 178 patients (17.8%) with acquired chromosomal alterations before undergoing ASCT. Autosomal mCAs were identified in 77 patients (7.7%), while 109 patients (10.9%) had loss of sex chromosomes (X or Y). Alterations were found on all chromosomes. Median cell fraction of autosomal mCA clones was 6.6% (IQR 2.7-20.4) in the analyzed harvest samples. Loss of sex chromosome was strongly associated with higher age (Wilcoxon P < 0.0001), while the age association was less robust for autosomal mCAs (Wilcoxon P = 0.094). There was no impact of type of induction regimen on frequency of mCAs. Full clinical annotation was available for 799 patients. Median follow-up was 6.4 years. Interestingly, at MM diagnosis, bone marrow plasma cell infiltration was significantly lower in patients with loss of chromosome X or Y (β coefficient -9.1%, P = 0.003). In accordance, hemoglobin level at diagnosis was also significantly higher in patients with sex chromosome loss (P = 0.027), despite these patients being older. In addition, the response to ASCT was superior in patients with loss of a sex chromosome. In patients that obtained at least a very good partial response after ASCT, 12.9% had sex chromosome loss, while only 4.7% of patients with poorer responses had sex chromosome loss (chi-square test P = 0.0017). In relation to these findings, overall survival was found to be superior in patients with loss of chromosome X, also when adjusted for age and sex (adj.P = 0.02). This survival difference was however only observed for long-term survivors (after more than four years of follow-up), indicating a possible interaction with later treatments. On the contrary, detection of multiple autosomal mCAs (n=14 patients) was associated with early age-independent inferior survival (adj.P = 0.005). A single autosomal mCA did not affect overall survival. To identify possible infiltration of malignant cells in the stem cell harvest, in a subset of patients (n=360) we were able to cross-check mCAs with FISH data on chromosomal variants identified in CD138+ sorted myeloma cells. We found no overlap between common myeloma chromosomal aberrations by FISH and identified mCAs. This indicates that the identified mCAs are from cells of the non-malignant hematopoietic system and not from myeloma plasma cells. Conclusion: In a longitudinal nationwide cohort of MM patients we examined the impact of acquired hematopoietic chromosomal alterations. Somatic mCAs or loss of sex chromosome was detected in stem cell harvest material in almost one fifth of patients undergoing ASCT. Sex chromosome loss was significantly associated with higher age, but surprisingly, it was also significantly associated with better response to ASCT and longer overall survival. The underlying biological causes of these findings remain to be elucidated. With regards to clonal origins, we did not identify any chromosomal variants to be present in both the myeloma clone (by diagnostic CD138+ FISH) and in the harvest product (by mCA analysis) in the same patient.

The CAR-Hematotox Score As a Prognostic Model of Toxicity and Response in Patients Receiving BCMA-Directed CAR-T for Relapsed/Refractory Multiple Myeloma

Introduction: Hematological toxicity and infectious complications are both common and substantially contribute to non-relapse mortality of CAR T-cell therapy. The recently developed CAR-HEMATOTOX (HT) score represents a validated risk-stratification system of hematotoxicity, infections, and clinical outcomes for R/R LBCL (Rejeski et al. Blood 2021/JITC 2022). The score integrates parameters of pre-CAR-T hematopoietic reserve (e.g. ANC, hemoglobin, platelet count) and inflammation (e.g. CRP, ferritin). Whether the HT score is of diagnostic utility in relapsed/refractory multiple myeloma (R/R MM) remains unclear. Methods: In this multicenter retrospective study, we characterized the influence of the HT score on toxicity and clinical outcomes in 102 patients receiving BCMA CAR-T with ciltacabtagene autoleucel (n=7) or idecabtagene vicleucel (n=95) in a standard-of-care setting across five international CAR-T centers. CRS and ICANS were graded according to ASTCT criteria. Neutrophil recovery phenotypes were defined as quick recovery vs. intermittent recovery vs. aplastic as previously described (Rejeski et al. Blood 2021). Early infection events (day 0-90) were defined as bacterial, viral or fungal based on microbiologic data or as a clinical syndrome of infection (e.g. pneumonia, cellulitis, cystitis) based on retrospective chart review. Severe (grade ≥3) infections were defined as requiring intravenous anti-infective agents and/or hospitalization. Kaplan-Meier estimates of progression-free (PFS) and overall survival (OS) were compared using the log-rank test. Results: The baseline patient features were representative of R/R MM patients receiving BCMA CAR-T in a real-world setting: median age was 65 (range 39-81), median ECOG was 1 (interquartile range 0-1), median LDH was 200 U/L (IQR 173-240 U/L), and patients had received a median of 6 prior treatment lines (IQR 5-7). A total of 28% had high-risk genetic abnormalities (del17p, t(4;14), t(14;16)). Notably, the large majority of patients had received a prior autologous stem cell transplant (88.2%). On the last bone marrow (BM) assessment prior to CAR-T, greater than 5% clonal plasma cells were detected in 52% of patients. In terms of toxicity, the rate of severe (grade ≥3) CRS and ICANS was 4% and 8%, respectively. Tocilizumab was applied in 79/102 patients (77%); glucocorticoids were used in 43/102 patients (42%). The median CAR-HEMATOTOX score was 1 (IQR 1-3), including 46 HThigh and 56 HTlow patients. When comparing the risk groups, we found that HThigh patients more frequently exhibited BM plasma cell infiltration (59% vs. 34%, p=0.05). Serum LDH levels did not significantly differ by HT score (median 215 vs. 193 U/L, n.s.). The duration of severe neutropenia (ANC<500/µL) was significantly increased in HThigh patients compared to their HTlow counterparts (9 vs. 3 days, p<0.0001). The proportion of patients displaying aplastic neutrophil recovery was markedly increased in the HThigh group (Fig. 1A: 30 vs. 3%, p<0.001). The rate of severe CRS (9% vs. 0%, p=0.038) and severe ICANS (17% vs. 0%, p=0.001) was higher in HThigh patients, likely resulting in the increased use of glucocorticoids (57% vs. 30%, p=0.009). When studying infectious complications, we found that infections of any-grade were more common in the HThigh cohort (61% vs. 25%, p=0.0003). This was particularly evident for severe infections (39% vs. 3.6%, p<0.0001), including 2 fatal bacterial infections in HThigh patients. Overall, the increased toxicity burden observed in the HThigh cohort translated into a longer median duration of hospitalization (12 vs. 8 days, p<0.0001). Finally, a high HT score was associated with inferior PFS (Fig. 1B: 1-year PFS 80% vs. 27%, p<0.0001) and OS (1-yr OS 93% vs. 62%, p<0.0001). Conclusions: These findings emphasize the importance of baseline inflammatory state and hematopoietic function for the subsequent development of toxicity and early progression in patients receiving BCMA-directed CAR-T. The easy-to-use CAR-HEMATOTOX score enables early risk-stratification prior to lymphodepletion. Considering their overall low risk of severe toxicity, HTlow patients represent an attractive population to explore outpatient CAR-T application. On the other hand, patients with a high HT score likely benefit from intensified monitoring, anti-infective prophylaxis, early G-CSF, and awareness for a potential stem cell boost. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Responders After Autologous Stem Cell Transplantation in Multiple Myeloma

IntroductionMultiple myeloma (MM) is considered an incurable hematological neoplasm. For transplant-eligible patients, initial treatment includes an induction phase followed by an autologous stem cell transplantation (ASCT). Despite the introduction of several drugs in the past years, relapses still occur. Nevertheless, some patients achieve sustained responses after successful induction treatment and ASCT.MethodsWe retrospectively evaluated all patients diagnosed with MM in our institution who underwent induction treatment and ASCT between 1990 and 2015. The subset of patients who achieved a sustained response (any degree) for 5 or more years after ASCT without further treatment or signs of progression were distinguished as “long-term responders” (LTRs). In the non-LTR group, a cohort referred to as “prolonged responders” (PLRs) showed sustained response of at least 5 years after ASCT but eventually relapsed. We collected and analyzed clinical and laboratory data.ResultsTwo hundred and fifty patients were diagnosed with MM and received induction treatment and ASCT at our institution in the study period. Among them, 54 (21.6%) patients met the criteria for LTR. Some diagnostic features such as a younger age, female gender, ECOG performance status of 0, lower International Staging System (ISS) stage, lower bone marrow plasma cell infiltration, and lower serum levels of calcium, C-reactive protein, and lactate dehydrogenase (LDH) were found to be more prevalent in LTR. Female gender, an ECOG performance status of 0, a localized Durie-Salmon stage, an ISS of I–II, the absence of bone disease, and an LDH within normal range were also predictive of longer progression-free survival (PFS) and overall survival (OS) in the whole cohort. The depth of the response achieved after induction and ASCT as well as the administration of an IMID-based maintenance regimen may play a role in the differences observed on PFS between cohorts. A detectable M-protein with a monoclonal gammopathy of undetermined significance (MGUS)-like behavior was detected in one-third of LTR after ASCT. Although relapses continue to occur in patients who achieve a 5-year treatment-free period after ASCT, a plateau is observed in the survival curves at approximately 21 years of follow-up.

Early cardiac response is possible in stage IIIb cardiac AL amyloidosis and is associated with prolonged survival

AbstractPatients with immunoglobulin light chain (AL) amyloidosis and stage IIIb cardiac involvement have a dismal outcome despite the introduction of novel treatments. However, a rapid hematologic response translates in better survival. We evaluated the impact of early cardiac response and its depth on outcome in 249 patients with newly diagnosed stage IIIb cardiac AL amyloidosis. Hematologic and cardiac responses were evaluated by intent to treat. After a median follow-up of 52 months, 219 (84%) patients died, and median survival was 4.2 months. The 30- and 90-day hematologic response rates were 22% (at least very good partial response [VGPR] in 9%) and 24% (at least VGPR in 15%), respectively. Early hematologic response resulted in better survival. At 90 days, 21 (8%) patients achieved a cardiac response (cardiac very good partial response [cardiac VGPR] in 12 cases and cardiac partial response [cardiac PR] in 9). At the 90-day landmark analysis, cardiac response resulted in longer survival (median, 54 months), also in those patients who have achieved at least VGPR (median, 62 vs 26 months, P = .011). Patients with cardiac VGPR had a longer survival than those with cardiac PR (median, 92 vs 24 months; P = .027), whereas patients without cardiac response had a poor survival (median, 6 months). A baseline difference of involved/uninvolved free light chains > 50 mg/L (odds ratio [OR], 0.21, P = .024) and a bone marrow plasma cell infiltrate > 10% (OR, 0.23, P = .040) were negative predictors of 90-day cardiac response. Early cardiac responses are rare but possible in stage IIIb AL amyloidosis and translate to longer survival.

Survival in patients with multiple myeloma: a real-life single-center study

Introduction: The development of novel drugs with a different mechanism of action has led to considerable progress in multiple myeloma (MM) treatment. However, the exact associations between overall survival (OS) and different treatment types, response to treatment, as well as clinical and laboratory parameters, have not been fully elucidated. We aimed to determine the effect of clinical and laboratory parameters, type of induction therapy, and high-dose chemotherapy with autologous hematopoietic stem-cell transplant (auto-HSCT) on OS in patients with MM. Material and methods: This retrospective study included 413 patients with MM treated between 2006 to 2017. Correlations between selected clinical and laboratory parameters and OS were assessed. The severity of MM was evaluated using the Durie-Salmon classification. Results : The median OS was 4.08 years. The overall response rate to chemotherapy was 76%. The complete remission (CR) rates were higher in patients receiving bortezomib-based therapy than in those receiving thalidomide-based therapy or standard chemotherapy ( p &lt; 0.001). The CR rate was positively correlated with OS. The use of auto-HSCT with bortezomib-based therapy was associated with longer OS. Renal failure and elevated urinary protein levels were inversely correlated with OS. The severity of MM at diagnosis was also associated with OS. The percentage of bone marrow plasma cell infiltration did not correlate with OS. Conclusions: MM is still diagnosed too late, by which time patients have developed almost irreversible complications. However, we confirmed that novel treatments improve OS in these patients, especially when used in addition to auto-HSCT. These findings may facilitate clinical therapeutic decision making.

P967: TUMOR BURDEN AS A CRITICAL PROGNOSTIC FACTOR OF PRIMARY EXTRAMEDULLARY DISEASE

Background: Multiple myeloma (MM) is the second most common hematological malignancy characterized by malignant plasma cell (PC) infiltration of the bone marrow (BM). In the case of extramedullary MM (EMD), plasma cells survive and proliferate outside of the bone marrow microenvironment. Primary EMD is found in newly diagnosed MM (NDMM) patients. Aims: The aim of this study was to describe clinical features and treatment outcomes of primary EMD patients and to define possible risk factors. Methods: In total, 724 primary EMD patients were diagnosed in the Czech Republic between 2004 and 2021 by using modern imaging methods. As a reference group, 2440 MM patients without any evidence of EMD were used. All patients enrolled into the analysis were treated by novel agents. Patients’ data were analyzed from the Registry of Monoclonal Gammopathies of the Czech Myeloma Group (RMG). Results: Primary EMD patients had less frequently advanced ISS (ISS 3) (OR 0.51 [95% CI: 0.42–0.63], p<0.001), high paraprotein levels (>20g/l) (OR 0.64 [95% CI: 0.54–0.76], p<0.001) and high PC infiltration of bone marrow (>10%) (OR 0.35 [95% CI: 0.30–0.42], p<0.001) when compared to reference MM patients. Median PFS in newly diagnosed primary EMD patients was comparable to reference MM patients (23.2 months [95% CI: 21.2–26.2] vs. 23.3 months [95% CI: 22.5–24.8], p=0.800). Median OS was comparable to reference patients (52.6 months [95% CI: 46.3–62.0] vs. 55.0 months [95% CI: 51.6–58.9], p=0.504). By multivariate analysis, adjusted for ISS, we found high levels of BM PCs (>10%) together with 3 and more EMD lesions as an independent risk factor for inferior survival in primary EMD patients (PFS: HR 1.92 [95 % CI: 1.28–2.87]; OS: HR 2.06 [95 % CI: 1.35–3.14], both p=0.001). Summary/Conclusion: We found primary EMD patients distinct from reference MM patients. Survival intervals of both groups of patients were comparable. We found that the intra- and extramedullary tumor burden is an independent key factor influencing primary EMD prognosis. This work was supported by grant AZV NU21-03-00076.

P932: ON-DEMAND PLERIXAFOR WITH CYCLOPHOSPHAMIDE AND G-CSF FOR HEMATOPOIETIC STEM-CELL MOBILIZATION IN MULTIPLE MYELOMA PATIENTS: FINAL RESULTS OF THE MOZOBL06877 STUDY

Background: High-dose melphalan and autologous stem-cell transplant (ASCT) are pillars for the upfront treatment of ASCT-eligible newly diagnosed multiple myeloma (ND)MM patients (pts) or as salvage strategy at relapse. Failure to collect an adequate number of hematopoietic stem cells (HSC) to receive ASCT (<2×106 CD34+ cells/kg) occurs in 5%-15% of MM pts undergoing HSC mobilization with granulocyte colony-stimulating factor (G-CSF) or G-CSF+cyclophosphamide (G-CSF/CY). Aims: We report the final results of the observational MOZOBL06877 study (NCT03406091; partially supported by Sanofi investigation funds) to prospectively assess the performance of HSC mobilization with G-CSF/CY plus on-demand CXCR4 inhibitor plerixafor (PLX) in NDMM pts treated with novel agents. Methods: NDMM pts undergoing HSC mobilization with CY (2-4 g/m2) and G-CSF (5-10 mcg/kg/day) were enrolled and observed up to 30 days after mobilization. According to its label, “on-demand” PLX was administered in pts with <20 CD34+ cells/ul after ≥4 days of G-CSF or in case <1×106 CD34+ cells/kg were collected on the first apheresis day. Pts gave written informed consent. The primary endpoint was the poor mobilizer rate, defined as the rate of pts collecting <2×106 CD34+ cells/kg or requiring PLX. Secondary endpoints were the identification of predictive factors for PLX use and safety during mobilization. Results: 301 NDMM pts were enrolled and analyzed; 72% received induction with bortezomib-thalidomide-dexamethasone, 9% a lenalidomide (Len)-based and 3% a daratumumab (Dara)-based regimen. Overall, 48 pts (16%) were poor mobilizers: 14 (5%) failed to yield ≥2×106/Kg CD34+, while 34 (11%) required rescue with PLX. Among pts yielding <2×106/Kg CD34+ cells, 4 received PLX, while 10 did not. Among pts who successfully collected ≥2×106/Kg CD34+ (n=287, 95%), 34 (12%) required PLX: 23 (68%) due to a CD34+/uL count ≤20 after ≥4 days of G-CSF and 11 (32%) to a collection <1×106/Kg after the first apheresis day. In pts mobilized with PLX, median number of CD34+×106/L cells increased from 17.5 (IQR 10.8-25.6) before PLX to 58.3 (IQR 34.2-100.2) after PLX. Median number of CD34+/Kg collected in pts who did not require PLX was 10.2×106 (IQR 8.3-13.2). In pts who required PLX, a median of 6.5×106 CD34+/Kg (IQR 4.6-9.6) was collected. An adequate HSC yield for ≥2 ASCTs (≥4×106/Kg) was obtained in 96% and 85% of pts not receiving or receiving PLX, respectively. Median number of apheresis days was 1 (IQR 1-2) in pts not requiring PLX and 2 (IQR 1-2) in pts requiring PLX. In a multivariate analysis (Table), factors predicting PLX use were advanced disease stage (R-ISS 3 vs 1-2, OR 5.5, P=0.01), bone marrow (BM) plasma cell (PC) infiltration at diagnosis (PC>60% vs ≤60%, OR 4.2, P<0.001), pre-mobilization absolute neutrophil count (ANC, < vs >2500/mmc, OR 2.8, P=0.01), and the use of Len-based (Yes vs No, OR 3.4, P=0.02) or Dara-based induction regimens (Yes vs No, OR 5.3; P=0.04). Grade 3 infections occurred in 3 pts (1%), with no grade 4-5 reported. Image:Summary/Conclusion: Among NDMM pts treated with novel-agent-based induction and undergoing HSC mobilization with CY/GCSF, “on-demand” PLX in case of low CD34+ cell count or insufficient HSC yield was a safe and effective rescue strategy, reducing mobilization failure from 16% to 5%. Predictive factors for PLX use were advanced disease stage, high BM plasmacytosis, low ANC values before mobilization and the use of Len/Dara during induction. Preemptive PLX in pts with ≥1 risk factors should be investigated to further reduce the risk of mobilization failure.

Correlation between whole skeleton dual energy CT calcium-subtracted attenuation and bone marrow infiltration in multiple myeloma

ObjectivesObjective evaluation of the extent of skeletal marrow involvement in multiple myeloma remains a clinical gap for CT. We aimed to develop a quantitative segmentation pipeline for dual energy CT and to assess whether quantified whole skeleton calcium-subtracted attenuation values correlate with biopsy-derived bone marrow infiltration in multiple myeloma. MethodsConsecutive prospective patients with suspected/established myeloma underwent dual source CT from the skull vertex to proximal tibia. Whole skeleton segmentation was performed for 120 kVp-equivalent images as follows: following Hounsfield unit (HU) thresholding, a Chan-Vese morphological operation was implemented to generate a whole skeleton segmentation mask. This mask was then applied to corresponding whole skeleton material decomposition calcium-subtracted maps, generating whole skeleton HU values. Associations with biopsy-derived bone marrow plasma cell infiltration percentage were assessed with Spearman’s rank correlation; significance was at 5%. Results21 patients (12 females; median (IQR) 67 (61, 73) years) were included; 16 patients had osteolytic bone lesions; 15 patients underwent bone marrow biopsy. Segmentation and quantification were feasible in all patients. Median (IQR) of the average skeletal calcium-subtracted attenuation was −59.9 HU (-66.3, −51.8HU). There was a positive correlation with bone marrow plasma cell infiltration percentage (Spearman’s rho: + 0.79, p < 0.001). ConclusionWhole skeleton calcium-subtracted attenuation is associated with the degree of bone marrow infiltration by plasma cells, providing an objective measure of marrow involvement with the potential to allow earlier detection of disease.

Differences and Similarities in Treatment Paradigms and Goals between AL Amyloidosis and Multiple Myeloma

Although there are similarities in the treatment paradigms between AL amyloidosis and multiple myeloma, there are also fundamental differences. A similarity is of course the use of anti-plasma cell drugs in both diseases; however, the most serious mistake a hemato-oncologist can make is to use the same treatment schedule in dosing and frequency in AL amyloidosis patients as in multiple myeloma patients. AL amyloidosis patients with &gt;10% bone marrow plasma cell infiltration in particular are at risk of receiving a more intensive treatment than they can tolerate. This difference in dosing and frequency is true for many anti-clonal drugs, but it is most apparent in the use of high-dose melphalan and autologous stem cell transplantation. While in multiple myeloma in the age group of ≤70 years, more than 80% of patients are fit enough to receive this intensive treatment, this is the case in less than 20% of AL amyloidosis patients. A similarity is the alignment in the goal of treatment. Although in AL amyloidosis has long been recognized that the goal should be complete hematological remission, this has become more apparent in multiple myeloma in recent years. A common goal in the coming years will be to evaluate the role of minimal residual disease to improve survival in both diseases.