Kyle, Robert A.

Summary Iron deficiency (ID) is often overlooked in patients with haematological malignancies due to other potential aetiologies. Daratumumab, an anti‐cluster of differentiation 38 (anti‐CD38) monoclonal antibody, is commonly used for treating multiple myeloma (MM) in the upfront and relapsed/refractory settings. Although anaemia is a common haematological toxicity associated with daratumumab, the contribution of ID in MM patients has not been systematically investigated. We conducted a retrospective case–control study to evaluate the prevalence of ID in newly diagnosed MM (NDMM) patients. Cases were patients receiving daratumumab, ixazomib, lenalidomide and dexamethasone (Dara‐IRD, n = 55). We compared this group with an age‐ and sex‐matched cohort of patients with NDMM who received bortezomib, lenalidomide and dexamethasone (VRD, n = 20) as induction therapy. At 1‐year, nearly 50% of Dara‐IRD‐treated patients met the criteria for ID (ferritin <30 mcg/L) compared with none of the VRD‐treated controls. All Dara‐IRD‐treated patients had a decrease in ferritin at 1‐year from baseline compared with only 45% of VRD‐treated patients. These findings identify a marked clinical signal of ID among NDMM patients receiving daratumumab‐based treatment. Although the study design does not establish causality or exclude regimen‐related confounding, it highlights the need for increased awareness of the importance of monitoring iron status in MM patients treated with daratumumab‐containing regimens.

Abstract Background: Waldenström Macroglobulinemia (WM) is an indolent B-cell lymphoplasmacytic lymphoma characterized by heterogeneous clinical behavior and variable progression patterns. While MYD88L265Pand CXCR4 mutations are frequently encountered, the broader genomic landscape underpinning disease evolution from smoldering WM (SWM) to active treatment naïve WM (TNWM), post-treatment remission WM (PTWM) and relapsed/refractory WM (RRWM) remains incompletely understood. To address this gap, we studied the mutational profile across the WM disease spectrum. Methods We performed whole exome sequencing (WES) on sorted (CD19 and/or CD138) bone marrow aspirates of patients across the spectrum of WM. Paired germline sequencing was performed using peripheral blood mononuclear cells (PBMCs). Unique molecular identifier-tagged reads were deduplicated using fgbio. WES data were processed through the Sarek pipeline. Any valid mutation from either caller, present on the index or in COSMIC was considered. Copy number variations (CNVs) were inferred via CNVkit and summarized at the gene and arm level (≥50% directional change). Mean tumor and germline coverages were 174X and 74X, respectively. Fisher's exact test was used for enrichment and hypergeometric test for overlap analyses. Results A total of 78 high-quality WM samples [15 SWM, 44 TNWM, 13 RRWM, 6 PTWM in remission (all with paired TNWM samples)] were sequenced. The mutational burden varied across disease states (median SWM=1.48 m/Mb, TNWM= 1.12 m/Mb, RRWM = 1.59 m/Mb; p=0.04). Density plots revealed bimodal VAF distributions, consistent with clonal and subclonal architectures in WM. Overall, 77% harbored a MYD88L265P mutation by WES. Among MYD88^WT^ patients, AS-PCR identified MYD88L265P in 4 (25%) not detected by WES, raising the overall mutation rate to 83%, plus one with a non-L265P variant. Low VAF (&lt;10%) MYD88L265P mutations were seen in 6% of matched PBMCs. MYD88 copy number gain was seen in 2 (17%) MYD88WT TNWM patients. CXCR4 mutations were detected in 38% by WES (18% each frameshift and nonsense). Two (4%) CXCR4WT samples were positive by PCR, giving an overall rate of 40%. CXCR4 mutations were more frequent in RRWM (54%) vs TNWM (41%) and SWM (27%), though not statistically significant. Del(6q) and Del(17p) were noted in 16% (n=12) and 7% (n=5) of patient samples. All del(17p) events were noted in TNWM samples and in one paired post-treatment sample. Overall rate of del(17p) and TP53 mutation was 14% (n=11). RRWM was enriched in ARID1A alterations, a gene implicated in chromatin remodeling and plasma cell identity formation [38% (n=5) in RRWM vs. 11% (n=6) in TNWM and SWM], compared to TNWM and SWM p=0.03]. Alterations in NF-kB signaling gene MAP3K14 were more frequent in RRWM (31%, n=4) compared to the SWM/TNWM cohort [(7%), n=4; p=0.036). We noted an enrichment in the TP53 mutation rate in RRMW [n=3, 23%, OR 7.7] compared to TNWM and SWM cohorts [n=2, 4%), p=0.04]. Mutations in FUBP1 (p=0.03), an upstream regulator of MYC, and CARD11 (p=.043), a B-cell signaling scaffold protein were also more frequent in RRWM. Notably, none of the SWM patients harbored an ARID1A alteration (p=0.057), suggesting acquisition during progression. CNV analysis revealed that MAP3K14 amplifications were frequent in RRWM (n=3, 23%) compared to SWM/TNWM [n=2 (4%), p=0.043]. RRWM samples showed increased CD79B mutations (15%) and significant overlap with the C5/ABC diffuse large B-cell lymphoma (DLBCL) genomic cluster (Chapuy et al., Nat. Med. 2018; p=0.007). This overlap remained significant after excluding MYD88L265P (p=0.019), driven by CARD11, CD79B, and IGLL5, suggesting that a subset of RRWM may acquire an ABC DLBCL-like mutational profile. These findings warrant further investigation using transcriptional profiling. Conclusions This study provides a genomic map of WM evolution from precursor to relapse. Increasing somatic mutations and CNVs support stepwise progression. Enrichment of genes involved in chromatin remodeling and plasma cell identity formation (ARID1A), NF-kB or BCR signaling (CARD11, MAP3K14), and DNA damage repair (TP53) were noted at relapse, all of which have been shown to drive aggressive disease biology. Emergence of an ABC-like genotype in a proportion of RRWM indicates convergent evolution with aggressive lymphomas. Transcriptional studies are warranted to explore this further.

Abstract Background Central nervous system involvement in multiple myeloma (CNS-MM) is a rare but highly aggressive manifestation. Limited data exists regarding its incidence, biology, treatment patterns, and outcomes. A deeper understanding of the features unique to CNS-MM will help inform risk stratification and management strategies. Methods We conducted a retrospective study of CNS-MM patients at our institution between January 2000 and December 2023. We identified 305 MM patients with pathology-proven extramedullary disease (EMD). CNS involvement was defined as the presence of parenchymal (brain or spine) or leptomeningeal involvement by MM. Univariate analysis was performed to compare the clinical characteristics between EMD patients with and without CNS-MM. Results Out of 305 patients with EMD, we identified 22 patients with CNS-MM. Common symptoms prompting evaluation of CNS-MM were headaches (32%), numbness or tingling (32%), weakness (27%), confusion (23%), falls (23%), and visual disturbances (14%). Among these patients, 17 (77%) had detectable disease in cerebrospinal fluid (CSF), 12 (55%) in the brain parenchyma, 4 (18%) in the spinal cord parenchyma and 6 (27%) in the leptomeninges. Of the CNS-MM patients, the median age at diagnosis of MM was 58.3 years and the median time to CNS-MM involvement was 16.2 months, with 3 (14%) patients having CNS involvement at diagnosis. The predictors of CNS-MM development were high-risk cytogenetics (OR 2.9, p=0.04) and presence of additional visceral organ involvement outside of the CNS (OR 3.4, p=0.03). EMD was multifocal in 20 CNS-MM patients (83%) and visceral organ involvement [most commonly lymphadenopathy (27%), solid organ (18%) and pleural fluid (14%)] was present in 14 (64%) of these patients, compared to 54% in EMD patients without CNS-MM. High-risk cytogenetics [del(17p), 1q gain/amplification, t(4;14), t(14;16), t(14;20)] were seen in 16 (73%) patients, most commonly 1q gain or amplification (40%), t(4;14) (23%), and del(17p) (18%). Five (23%) exhibited a double-hit profile. In comparison, 113 (40%) EMD patients without CNS-MM had high risk cytogenetics. The median overall survival (OS) from diagnosis of CNS-MM was 6 months (95%CI:1.26-36) compared to 15.6 months (95%CI: 12-18) from diagnosis of EMD in EMD patients without CNS-MM (p=0.05). Median OS from diagnosis of MM in the CNS-MM cohort was 36 months (95%CI: 22.8-NA) compared to 55.2 months (95%CI: 45.6-68.4) in EMD patients without CNS-MM (P=0.11). When excluding CAR-T or bispecific therapy recipients, median OS from diagnosis of MM for CNS-MM was 22 months versus 48 months in EMD patients without CNS-MM (P=0.02). Overall response rate in our CNS-MM cohort with first treatment for EMD was 32% compared to 48% in EMD patients without CNS-MM (p=0.04). In patients with CNS-MM, median progression-free survival (PFS) from CNS-MM diagnosis was 3.3 months (95%CI: 0.8-12) versus 3.9 months (95%CI: 3-5.1) in EMD patients without CNS involvement (p=0.2). Six (27%) CNS-MM patients received CAR-T; 3 received cilta-cel, 2 received ide-cel and one received a BCMA CAR-T on trial. Bispecific therapy was used in 4 (18%) patients, with 2 receiving Teclistamab and 2 Talquetamab. Three (14%) CNS-MM patients received both CAR-T and bispecific therapy. The median PFS on CAR-T therapy was 10.5 (95%CI: 5.6-NA) months and 12.7 (95%CI: 10.2-NA) months on bispecific therapy. The median OS from diagnosis of CNS-MM for patients who received CAR-T or bispecific therapy was 36 months (95%CI: 14.0-NA), compared to 1.2 months (95%CI: 0-14.4) for those who did not (p=0.002). Six (27%) patients with CNS-MM, all of whom had CSF involvement of disease, received intrathecal therapy; methotrexate in 3, cytarabine in 2, and one receiving both. Two of these patients demonstrated improvement in cerebrospinal fluid findings following intrathecal chemotherapy, in conjunction with other therapies. Patients who received intrathecal chemotherapy had a median OS measured from development of EMD of 10.8 (95%CI: 3.6-NA) months, compared to 15 months (95%CI: 4.8-NA) in those without IT chemotherapy (p=0.59). Conclusion Central nervous system involvement in MM is relatively uncommon and associated with dismal outcomes. High-risk cytogenetics and involvement of other visceral sites are associated with a higher risk of CNS involvement. Intrathecal therapy offers limited value and immune effector therapies represent efficacious options for treatment.

Abstract Background Measurable residual disease (MRD) negativity post- autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM) is associated with favorable outcomes and may overcome the adverse impact of high-risk cytogenetic abnormalities (HRCAs). However, as the definition of high risk evolves and MRD emerges as a key endpoint, understanding its prognostic value within individual HRCAs is critical for treatment guidance. Methods We retrospectively included patients with NDMM that underwent an ASCT between September 19, 2016, and October 19, 2023, and achieved MRD negativity on Day 100 post ASCT. The MRD testing was conducted using multiparameter flow cytometry with a sensitivity of 2x10. HRCAs were defined as del(17p), 1q21+ gain or amplification (1q21+), t(4;14), t(14;16), t(14;20) and del(1p) and rest were considered standard risk (SRCA). Patients were grouped by the number of HRCAs (0, 1, ≥2). An adaptation of the recently proposed International Myeloma Society (IMS)/International Myeloma Working Group (IMWG) classification for high-risk disease (TP53 mutation unavailable) was also used. Progression-free survival (PFS), measured from stem-cell infusion to progression or death, was estimated using Kaplan–Meier methodology and compared using log-rank test. Results We identified 386 patients with MRD negativity post ASCT, of which 381 had cytogenetic data available for analysis. The median follow-up for the study cohort was 47.3 months (95% CI: 43.2-50). The median age at the time of ASCT was 65.7 (25.4-79.2) years and 58.3% patients were males. A total of 49% (n=189) patients had standard-risk cytogenetics, 31.4 % (n=121) harbored 1 HRCA, 15.3% (n=59) patients had two HRCAs and 3.1% (n=12) had 3 HRCAs. The individual HRCA by their prevalence were: 1q21+ in 35.5%(n=137), del(17p) in 14.3% (n=55), t(4;14) in 10.9% (n=42), t(14;16) in 5.4% (n=21), del(1p) in 4.2% (n=16), and t(14;20) in 1.04% (n=4) of patients. The most common double-hit lesions were1q21+ gain and/or amplification co-occurring with t(4;14) (33.9%, n=20) and del(17p) with 1q21+ (18.6%, n=11). Despite universal MRD negativity at Day 100, several HRCAs remained prognostically significant for PFS. Patients with del(17p) had worse 3-year PFS (71%) than those without (81%) [hazard ratio (HR)=1.85, 95% CI 1.11–3.07, p = 0.0172], though 3-year OS did not significantly differ at data cutoff (80% vs. 92%, p=0.1176). Presence of 1q21+ was associated with an inferior 3-year PFS (73%) compared to those without [84%, HR: 1.96 (95% CI: 1.25–3.06), p=0.0026], while 3-year OS was similar (88% vs. 91%, HR:1.33 p=0.36). Isolated 1q21+ had inferior PFS with comparable OS when compared to SRCA [3-year PFS of 82% vs. 88% respectively (HR:1.97, p=0.0177)]; 3-year OS was 91% vs. 94% (HR:1.38, p=0.44)]. Among 1q21+ patients, those with co-occurring HRCAs had a 3-year PFS of 66% vs. 81% for isolated 1q21+ (HR: 1.47, p=0.21). Patients with t(4;14) had worse 3-year PFS (64%) vs. 82% in non t(4;14) [HR 2.11(95% CI: 1.21-3.67) p=0.0064], and 3-year OS of 82% compared to 91% [HR 2.14 (95% CI: 1.02–4.49), p=0.038]. Isolated t(4;14) showed a 3-year PFS of 59% vs. 87% in standard-risk (p=0.06), and 3-year OS of 90% vs. 93% [HR 3.29, 95% CI 0.95–11.33, p = 0.06]. The presence of t(14;16), t(14;20), and del(1p) did not significantly affect 3-year PFS (all p&gt;0.1), likely due to small subsets. When patients were grouped by the number of HRCAs, PFS declined with increasing cytogenetic complexity. Compared to standard risk, the 3-year PFS was 77% for 1 HRCA vs [HR = 2.11 (95% CI: 1.29–3.46), p = 0.0027], 67% for ≥2 HRCA [HR = 2.64 (95% CI: 1.53–4.57), p = 0.0005]. Maintenance therapy was used in 98% of patients. Patients with HRCAs received a doublet maintenance compared to SRCA (p&lt;0.0001), even in MRD negative disease post ASCT. Conclusion In patients with certain HRCA, achievement of MRD negativity post-ASCT does not overcome the adverse impact of HRCA on PFS. In our cohort, patients with del(17p), t(4;14), or 1q21+ continued to exhibit significantly shorter PFS despite achieving MRD-negative status. These findings underscore the need for ongoing risk-adapted strategies even in patients with MM who attain MRD-negative state. The OS estimates are immature at this time.

Disease response and progression assessment in multiple myeloma (MM) is based on various measurements of monoclonal protein (serum and urine protein electrophoresis, serum free light chain (FLC, and or quantitative immunoglobulins). Currently, the IMWG consensus response criteria require two sequential assessments of any one marker made at any time before confirmation of disease progression and the institution of any new therapy. However, this can be cumbersome in clinical trials. Herein, we hypothesized that if two markers meet the progression criteria simultaneously, a repeat of either will not be necessary for confirmation. We retrospectively studied all sequential patients with myeloma enrolled in clinical trials at Mayo Clinic. We identified 583 episodes of confirmed progression in our study. Among the 583 progression episodes, nearly 70% (sensitivity of the simultaneous criteria) met the two simultaneous variable criteria at the first testing, indicating progression. Conversely, among 413 patients who met progression criteria by two simultaneous values, 98% (specificity of the simultaneous criteria) of patients subsequently had confirmed progression by sequential values. In summary, for patients with two disease burden markers meeting the simultaneous progression criteria, sequential assessment either one for confirmation may not be necessary to determine disease progression.

e19545 Background: Cytogenetic abnormalities (CA) at diagnosis are important prognostic factors in multiple myeloma (MM), but there is limited information on how these abnormalities evolve at first relapse and their significance. Methods: This retrospective study included patients aged ≥18 years, with a confirmed diagnosis of MM who experienced at least one disease relapse and had fluorescence in situ hybridization analysis within six months of both diagnosis and relapse. Data on CA and clinical outcomes were collected. High-risk (HR) secondary CA were defined as the presence of deletion of chromosome 17p (del17p) or gain or amplification of chromosome 1q. The primary objective was to evaluate changes in HR secondary CA at first relapse, while the secondary objective was to assess the impact of the cytogenetic changes on overall survival (OS) from diagnosis. Based on the presence or absence of HR secondary CA, patients who were tested for HR secondary CA at both time points were classified into four groups: 1) persistent absence of HR secondary CA, 2) emergence of HR secondary CA at relapse, 3) persistent presence of HR secondary CA, and 4) loss of HR secondary CA at relapse. Results: A total of 233 patients diagnosed between 2004 and 2023 were included. HR secondary CA were tested in 98.7% (n= 230) of patients at diagnosis, with 24.8% (n=57) testing positive. At first relapse, testing for HR secondary CA was performed in 97.4% (n=227) of patients, of whom 23.8% (n=54) tested positive. Del17p was evaluated in 98.3% (n=229) of patients at baseline and 95.7% (n=223) at relapse, with positivity increasing from 10.9% (n=25) to 15.3% (n=34). Gain or amplification of chromosome 1q was evaluated in 49.4% (n=115) at baseline and 25.5% (n=60) at relapse, with positivity rate rising from 28.7% (n=33) to 38.3% (n=23). There were no differences in overall response rate or very-good-partial-response-or-better rates to the initial therapy at diagnosis between the groups. (Table) Emergence/persistence of HR CA were associated with lower OS from diagnosis. Conclusions: Emergence of HR secondary CA at first relapse in MM has prognostic significance. These findings highlight the importance of serial cytogenetic testing for risk stratification. Response rate to initial line of therapy and overall survival from diagnosis among patients tested for HR secondary CA both at diagnosis and first relapse (n=224). Outcome Persistent absence of HR secondary CA(n=142) Emergence of HR secondary CA at relapse (n=25) Persistent presence of HR secondary CA (n=27) Loss of HR secondary CA at relapse(n=30) p-value Overall response rate a 75% (106) 76% (19) 63% (17) 67% (20) 0.5 b Very-good-partial response or better response rate 43% (61) 36% (9) 44% (12) 40% (12) >0.9 b Median (95% CI) OS from diagnosis in years 11.3 (9.7-13.4) 7.5 (5.1-12.1) 6.1 (4.2-9.4) 10.1 (6.5-14.1) <0.0001 c a Partial response or better; b Chi-square test; c Log-rank test.

ABSTRACT As the treatment paradigm for Waldenström macroglobulinemia (WM) continues to evolve, the debate surrounding the prioritization of depth of response versus disease control as therapeutic goals gains significant relevance. However, the impact of depth of response from fixed‐duration therapy on overall survival (OS) was unclear. This multicenter study evaluated the prognostic impact of depth of response using a landmark survival analysis. A total of 440 patients with WM treated with frontline fixed‐duration regimens were included. Attaining a major response (MaR) was associated with superior outcomes, including significantly longer OS. The estimated 5‐year PFS rates for patients with MaR at 6 months versus not were 50% versus 32%, respectively, p < 0.001, and the estimated 5‐year OS rates for patients with MaR at 6 months versus not were 89% versus 70%, respectively, p < 0.001. In a multivariable analysis, MaR at 6 months was independently associated with superior PFS (HR 0.66, p = 0.007) and OS (HR 0.28, p < 0.001). Similar results were seen when considering deeper responses (CR + VGPR vs. PR). Depth of response at 6 months is an important prognostic marker in WM and an independent predictor of PFS and OS. These results support its utilization as a suitable endpoint in clinical studies in WM.

Abstract In this study, we first analyzed data from 147 patients with solitary plasmacytomas treated at the Mayo Clinic between 2005 and 2022 and then expanded our investigation through a systematic review and meta-analysis of 62 studies, encompassing 3487 patients from the years 1960 to 2022. Our findings reveal that patients with up to 10% clonal plasma cells in their bone marrow (BM), denoted as plasmacytoma +, had a significantly reduced median disease-free survival (DFS) of 15.7 months vs 79 months, P &lt; .05, observed in patients with true solitary plasmacytomas, with no clonal cells in the BM. Risk factors identified for shorter DFS included the presence of clonal plasma cells in the marrow and a difference between involved and uninvolved free light chains of &gt;5 mg/dL. The meta-analysis portion of our study highlighted a male predominance among patients, with a median age of 58 years, and confirmed radiation therapy as the predominant treatment modality. We also found that DFS rates at 3, 5, and 10 years were 66.9%, 55%, and 42.1%, respectively, and noted a significant difference in outcomes between patients with bone and extramedullary plasmacytomas, with the latter group exhibiting better survival rates. This dual-faceted approach provides a thorough overview of survival rates and critical risk factors for patients with plasmacytoma, underscoring the vital role of accurate disease staging at diagnosis and the impact of tumor location on patient prognosis.

INTRODUCTION Primary plasma cell leukemia (pPCL) is a rare and aggressive form of multiple myeloma (MM) with poor survival outcomes. Fluorescence in situ hybridization (FISH) evaluation is essential for the initial risk stratification in MM, and the presence of multiple high-risk (HR) cytogenetic abnormalities by FISH portends a worse prognosis in MM. We have previously observed that the presence of HR cytogenetic abnormalities by FISH at diagnosis is known to confer a poor overall survival (OS) in patients with pPCL. However, less is known about the cumulative effect of multiple HR cytogenetics abnormalities compared to a single HR cytogenetic abnormality on the OS outcomes of patients with pPCL. AIM To evaluate the prognostic implications of additive HR cytogenetics abnormalities by FISH in patients with pPCL treated with novel agents. METHODS We evaluated patients with newly diagnosed pPCL at the Mayo Clinic Comprehensive Cancer Center from 2014 - 2023 that received induction with novel agent combinations. pPCL was defined as patients meeting the diagnostic criteria for MM with 5% or more circulating plasma cells (cPCs) present on morphologic evaluation of their peripheral blood smear. HR cytogenetics abnormalities by FISH was defined by the presence of any one of the following: 1q gain/amplification, t(4;14), t(14;16), t(14;20), and del(17p). Time to next treatment (TTNT) and OS analysis were performed using the Kaplan-Meier method, and differences were assessed using the log-rank test. Statistical analyses were performed using the SAS biostatistical software JMP 17.0.1 (SAS Institute Inc). RESULTS We included 89 patients with newly diagnosed pPCL who received novel agents as first-line therapy between 2014 to 2023. The median follow-up was 45 months (95% CI: 35 - 65). At diagnosis, the median bone marrow plasma cell content was 80% (Range: 10 - 100), and the median cPC% on the peripheral smear was 21% (range: 5 - 85). There were 51 patients (59%) who had 20% or more cPCs on their peripheral smear. There was a preponderance of pPCL patients who had t(11; 14) as their primary cytogenetic abnormality (43%). The median lines of therapy received were 2 (Range: 1 - 9). There were 12 (13%) patients who received intensive induction therapy containing continuous infusional chemotherapy regimens at the onset of their diagnosis. Of the remaining patients, 35 (45%) were treated with a quadruplet (anti-CD38 antibody, proteasome inhibitor and immunomodulator), 24 (31%) with a triplet (proteasome inhibitor and immunomodulator) and 18 (23%) with a doublet (proteasome inhibitor only). The median OS for all pPCL patients in this cohort was 47 months (95% CI: 37 - 100). However, when stratified by cytogenetic risk, the median OS was 101 months (95% CI: 57 - NR) for those patients without any HR cytogenetic abnormalities (N = 24, 27%) vs. 37 months (95% CI: 22 - 63) for those with one or more HR cytogenetic abnormalities (N = 65, 73%) (P = 0.006). Of the patients with any HR cytogenetic abnormalities, 33 (36%) had one HR cytogenetic abnormalities and 32 (34%) had two or more HR cytogenetic abnormalities. The median OS for patients with one compared to two or more HR cytogenetic abnormalities were 47 (95% CI: 38 - 111), and 22 (95% CI: 17 - 37) months, respectively (P = 0.031). The median TTNT was 22 months (95% CI: 16 - 58) for those patients without any HR cytogenetic abnormalities vs. 16 months (95% CI: 9 - 21) for those with one or more HR cytogenetic abnormalities (P = 0.09). The median TTNT from the time of diagnosis for pPCL patients with one compared to two or more HR cytogenetic abnormalities were 18 (95% CI: 6 - 41) and 16 (95% CI: 10 - 19) months, respectively (p = 0.247). CONCLUSION Patients with pPCL with more than one HR cytogenetic abnormality had an inferior OS compared to those with only one HR cytogenetic abnormality, implicating the additive adverse effects of multiple HR cytogenetics abnormalities. In contrast, patients with pPCL without any HR cytogenetic abnormalities had a relatively long median OS (over 100 months).

Introduction: Uniform assessment of response to treatment is crucial to managing myeloma and developing new therapies. Measurement of the monoclonal protein (s) secreted by the myeloma cells forms the cornerstone of disease assessment in MM and has primarily been performed by electrophoretic methods in the serum and urine, as well as assessment of free light chains in the serum. According to international myeloma working group (IMWG) guidelines, serial serum-free light chain (sFLC) is included in MM response assessment to define stringent complete response and for evaluating partial response (PR) or progressive disease (PD) in non/oligo-secretory MM. This study aims to determine the added value of serial sFLC measurements in monitoring response and progression in MM with measurable disease by comparing the kinetics of FLC with M spike measured by electrophoresis in serum or urine. Methods: This retrospective observational study included newly diagnosed MM patients evaluated at Mayo Clinic in Rochester between 2011-2021. All patients had measurable sFLC (involved FLC level ≥ 10mg/dL, with abnormal sFLC ratio) along with measurable M-protein by serum or urine protein electrophoresis at diagnosis. Serial measurements of sFLC and M-protein by electrophoresis (sPEP/uPEP) were prospectively collected from the electronic medical records at different time points. FLC-response and FLC-PD were evaluated based on IMWG criteria. Results: The study cohort included 839 patients, 52% with measurable M protein by electrophoresis in serum, 27% in both serum and urine, and 21% in urine-only. A significant association was observed between sFLC and electrophoretic response during the induction and at the time of best response (p &lt;.001). Serum FLC showed a comparable response rate of 98% (≥ PR) at the time of best electrophoretic response (p &lt;.001). Ninety-nine percent of early FLC responders eventually achieved an overall response by sPEP/uPEP (p &lt;.001). In the urine-only group, 99% achieved at least a PR by uPEP, and all showed at least a PR based on sFLC. We observed comparable median percentage changes in serial dFLC and urine M-protein, with parallel trends (p &lt;0.001). The correlation coefficients between the change of sFLC and urine M-protein showed a moderate/strong correlation with coefficients (r) of 0.791, 0.597, 0598, 0.545, after cycles 1, 2, 3, 4, respectively, (p &lt; .001). The response for all cohorts was detected earlier by dFLC (median time 1.1 months, 95% CI: 1.06-1.17), in comparison with serum M-protein (1.5 months, 95% CI: 1.40-1.62) and urine M-protein (2.8 months, 95% CI: 2.42-3.10) with p &lt; .001. In the urine-only group, earlier detection of response by dFLC (1.1 months, 95% CI: 1.00-1.2) was observed, compared to urine M-protein (2.4 months, 95% CI: 2.00-2.7) (p &lt;.001). After a median follow-up of 52 (IQR 27.6, 72.3) months, 56% had PD: 62% by s-FLC, 56% by serum M-protein, and 24% by urine M-protein. Among patients with PD by uPEP, all except one patient met sFLC-PD. Within patients with PD, sFLC was the only detectable tumor marker in 12% of cases at the time of the second line of treatment. After four cycles of induction, there was no difference in PFS between VGPR response determined by sFLC, sPEP, and uPEP (p =0.538). The median second-PFS for patients with onlysFLC-PD was similar to those with urine M-protein PD with or without sFLC-PD (HR 1.28, 95% CI =0.77-2.13. p 0.334). However, the median overall survival (OS) from the first relapse was significantly better for patients with onlysFLC-PD than those with urine M-protein PD (HR 1.87, 95% CI =1.07-3.27. p 0.026). Conclusions: In this study, achieving sFLC-VGPR has a similar impact on PFS as electrophoretic-VGPR after induction, indicating that serial sFLC can potentially replace the requirement for urine M-protein response (&lt; 100mg in 24-hours urine) as part of the electrophoretic-VGPR criteria, as required by IMWG. A similar response rate between sFLC and urine paraprotein confirms the current cutoffs (90% for urine and 50% for dFLC for VGPR) used for response categories for s-FLC. We also observed that in 12% of patients with PD, sFLC was the only marker of progression, highlighting the value of serial s-FLC in monitoring relapse. In conclusion, our study supports the integration of serial sFLC measurements for monitoring response and progression in MM, even with electrophoretic measurable disease.