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Background: A deeper understanding of the cytogenetic features has enabled robust risk stratification for patients with newly diagnosed multiple myeloma (NDMM). However, heterogeneity persists in the currently available prognostic tools and there is further room for personalization. We assess the utility of PC-PRO, a test to measure the proportion of monotypic plasma cells in the synthetic phase (S-phase) of cell cycle, as a prognostic marker for NDMM. Methods: Patients with active MM diagnosed between January 2013 and January 2023 with a flow cytometry-based S-phase assessment at diagnosis were included. Flow cytometric immunophenotyping was performed using the following antibodies: CD19, CD38, CD45, CD138, cytoplasmic kappa and lambda immunoglobulin, and DAPI (4',6-diamidino-2-phenylindole). The percentage of plasma cells in S-phase was determined by measuring the proportion of cells with DNA content of the monotypic plasma cells between the G0/G1 and G2/M peaks. Plasma cell clonality was detected through demonstrating CD38 and CD138 positivity along with immunoglobulin light chain restriction, abnormality of CD19/ CD45 expression and/or ploidy difference by DAPI staining. High-risk cytogenetic abnormalities (HRCA) by FISH were defined as follows: presence of deletion 17p (del17p), t(4;14), t(14;16), t(14;20), 1q gain/amplification, 1p deletion (when available). Additionally, the second iteration of the revised ISS (R2-ISS), incorporating both laboratory and cytogenetic features as well an adaptation of the recently proposed International Myeloma Working Group (IMWG) Classification for high-risk disease, was utilized for risk stratification. All time-to-event analyses were performed using the Kaplan Meier method and compared using the log-rank test. Univariable and multivariable Cox proportional hazards analyses were performed to assess the independent prognostic impact of S-phase. Results: A total of 823 patients were included in the study. The median follow-up was 6 years [95% Confidence interval (CI): 5.5-6.3 years] and estimated median overall survival (OS) was 8.3 years. The median S-phase value for the cohort was 0.8 % (interquartile range: 0.5-1.4%), with 135 (16%) patients harboring an S-phase of ≥2% at diagnosis. Applying the R2-ISS prognostic model to our cohort, 11% (79/706) patients were stratified to the R2-ISS high-risk cohort; 93 patients (out of 788, 12%) had 2 or more HRCA at diagnosis. Patients with a S-phase ≥2% at diagnosis had a median OS of 3.9 years (95% CI: 2.9-5.7) vs. 9.2 years [95% CI: 7.9-not reached (NR)] for patients with a S-phase <2% [Hazard ratio (HR): 2.2 (95% CI: 1.7-2.8), p<0.0001]. The median OS was inferior for cohorts with an increasing S-phase value: S-phase of 0.1-1%: HR: 1 (standard), S-phase 1.1-3%: HR 1.7 (95% CI: 1.3-2.1), S-phase >3%: HR 3.0 (95% CI: 2.2-4.1)]. On a multivariable analysis including S-phase ≥2%, age at diagnosis of MM (>65 years) and R2-ISS high-risk status, S-phase ≥2% was an independent predictor of inferior OS [hazard ratio (HR) 1.9 (95% CI: 1.4-2.6), p<0.0001]. Age >65 years [HR 1.9 (95% CI: 1.5-2.5), p<0.0001] and R2-ISS high-risk status [HR 1.8 (1.3-2.6), p=0.001] were also independent predictors of OS. Within the sub cohort of patients with 2 or more of the listed high-risk cytogenetic features (n=93, 12%), a S-phase ≥2% (n=24) was associated with a worse median OS of 1.6 years (95% CI: 0.7-NR) vs. 6.2 years (95 % CI:3.3-NR) for S-phase <2% (p=0.002). Conclusion: Flow cytometry-based determination of the proportion of monotypic plasma cells in S-phase is an easy-to-study and powerful prognostic tool for NDMM. A S-phase of ≥2% at diagnosis is a predictor of OS independent of age and R2-ISS high-risk stage. An S-phase of ≥2% was able to identify a distinct group with markedly inferior outcomes even within the sub cohort of patients with 2 or more high-risk cytogenetic features.

Introduction: Light chain multiple myeloma (LCMM) is a distinct subtype of multiple myeloma (MM) characterized by the exclusive production of immunoglobulin light chains, unlike the common form of MM that produces the complete immunoglobulin. There is a paucity of literature on the specific tumor cell alterations leading to light chain-only disease as opposed to the typical presentation in MM. Additionally, data on treatment response and outcomes in this subgroup of patients is sparse. This study explores the differences in baseline characteristics, including cytogenetic abnormalities and treatment response between LCMM and multiple myeloma with heavy chain involvement. Materials and Methods: We reviewed patient charts to obtain clinical and laboratory information for individuals diagnosed with LCMM and those with heavy chain MM (comparison cohort) from 2004 to 2022. Patients were matched for age, sex, and year of diagnosis. Data collected included treatment assessment, overall survival, and progression-free survival (PFS). Associations between outcomes and categorical variables were analyzed using the chi-square test, while the Mann-Whitney U test was employed to compare medians. Progression-free survival following initiation of initial therapy and overall survival were assessed using Kaplan-Meier analysis. The Mayo Clinic Institutional Review Board (IRB) approved the study. Results: We identified 848 patients, representing 17.1% of newly diagnosed MM cases. The median age of the LCMM cohort was 63 years (range 16-92), with a female-to-male ratio of 1:5. The LCMM cohort had higher levels of lactate dehydrogenase (LDH), beta-2 microglobulin (p<0.0001), higher baseline creatinine (p<0.0001) and calcium (p<0.0001). The two cohorts had no significant difference in the International Staging System (ISS) or revised ISS (R2-ISS). Additionally, hemoglobin (Hb) and white blood cell count at presentation were higher in the LCMM cohort. Chromosome 1 abnormalities were lower in the LCMM cohort: 1q gain (OR-0.7; 95% CI: 0.6-0.9) and 1p deletion (OR-0.7; 95% CI: 0.6-0.9, p=0.02). Likewise, the frequencies of trisomies and hyperdiploidy were lower in the LCMM cohort, with odds ratios of 0.32 (p=0.012) and 0.37 (p<0.001), respectively. The frequencies of translocations t(4;14) (OR-0.35, p<0.001) and t(14;16) (OR-0.6, p=0.03) were lower in LCMM compared to heavy chain MM. In contrast, the frequencies of t(11;14) (OR-3.4) and t(6;14) (OR-4.9) and deletion of 13q(OR-1.3) was higher in the LCMM cohort. There was no significant difference in the occurrence of del(17p)/TP53 abnormalities. The median PFS after the first regimen was shorter in the LCMM cohort (23 months vs. 27 months, p=0.03), and this difference remained significant after adjusting for baseline adverse prognostic indices and treatment regimen. Median PFS in LCMM patients with monoclonal antibody (Mab) as part of their treatment was 37 months vs. 23 months (Proteasome Inhibitor or immunomodulator-based regimen without Mab), though this difference is not statistically significant p=0.87. No significant difference was found in overall survival between the two groups. Conclusion: This study highlights unique features of light chain multiple myeloma, including increased frequencies of specific cytogenetic abnormalities. Further evaluation of observed differences in cytogenetic abnormalities may enhance our understanding of LCMM and potentially guide baseline treatment choices to improve outcome.

Abstract Patient-reported outcomes (PROs) are associated with treatment outcomes in multiple myeloma (MM) in the clinical trial setting. However, most PRO tools are time consuming, which hinders use in routine practice. Our institution incorporated a “Hematology Patient-Reported Symptom Screen” (HPRSS), a 3-item questionnaire for fatigue, pain, and quality of life (QOL). The main objective of this study was to evaluate the impact of these symptoms on progression-free survival (PFS) and overall survival (OS) in a real-world cohort of patients with newly diagnosed MM. This retrospective study included patients with MM diagnosed between April 2011 and December 2017, seen at Mayo Clinic (Rochester, MN), who completed the HPRSS. Patients rated their symptoms on a scale from 0 to 10. Clinically relevant symptoms were defined as scores ≥5 for pain and fatigue, and ≤5 for QOL. At diagnosis, 735 patients had scores for all domains. The median follow-up was 8.1 years. Age was associated with increased odds of fatigue and decreased QOL. Female sex and comorbidities were associated with fatigue and pain. Higher disease stage, anemia, lytic lesions, and increased plasma cell burden were associated with fatigue, pain, and decreased QOL. Clinically relevant fatigue, pain, and decreased QOL were associated with decreased PFS and OS. On multivariate analysis including age, International Staging System III, high-risk cytogenetics, and postinduction transplantation, fatigue and decreased QOL were independently associated with decreased OS. A composite HPRSS score stratified patients into 3 groups with distinct OS. Patient-reported symptoms are prognostic in patients with newly diagnosed MM. The prognostic values of fatigue and decreased QOL are independent of age, disease stage, and transplant status.

Abstract As patients with relapsed/refractory multiple myeloma (RRMM) continue to live longer, they might get exposed to most available drugs and drug classes during the disease course. For such late line RRMM or among patients without access to novel therapies, retreatment with a drug that the disease had previously been refractory to might be one option. In this retrospective study, we describe 315 patients with RRMM at our institution who were retreated with a drug that the disease had been previously refractory to. We found an overall response rate of 56.2% and a median progression-free survival (PFS) of 11 months with retreatment. Patients with a longer time on initial therapy with the index drug (>28.4 months) had a superior PFS with retreatment (median PFS, 16.9 vs 8.1 months; P < .001). Similarly, patients with a longer time gap between the initial line of therapy with index drug and retreatment with index drug (>46.1 months) had better PFS with retreatment (28.2 vs 8.9 months; P = .016). In conclusion, retreatment with a previously refractory drug is a viable therapeutic option for RRMM, with the most significant benefit derived in disease demonstrating sensitivity to initial drug exposure and among those with a longer gap between initial drug exposure and retreatment.

Abstract Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant disorder. The current standard of care is not to screen for MGUS, so it is often incidentally diagnosed in the clinic. It is unknown whether the outcomes of screened vs clinically detected MGUS differ. We compared the progression risk between screened vs clinical MGUS cohorts and assessed whether the MGUS detection method affected risk prediction of established clinical factors (score). We included 379 screened MGUS cases from the Olmsted County population-based study and 1384 patients with MGUS diagnosed during routine clinical evaluation at Mayo Clinic. Median follow-up time for the screened vs clinical cohort was 26.6 and 40.1 years, respectively. Accounting for death as a competing risk, the cumulative incidence of progression at 25 years was similar in the screened (11.1% [95% confidence interval [CI], 8.3-14.8]) vs clinical (10.1% [95% CI, 8.6-11.8]) MGUS cohorts, even when stratified by sex, age, or the baseline MGUS risk score. Overall, 0.9 (95% CI, 0.6-1.2) of patients with screened MGUS vs 1.0 (95% CI, 0.9-1.2) of those with clinically detected MGUS experienced disease progression for every 100 person-years of follow-up. MGUS detection method did not modify the association between MGUS risk score and progression risk (pinteraction = 0.217) and did not add to known risk factors for progression (likelihood ratio test; P = .839). Here, we show that progression risk among patients with screened vs clinically detected heavy-chain MGUS was similar. Future studies are needed to assess whether tailored follow-up of patients with screened MGUS affects clinical outcomes.

Abstract Despite the widespread use of carfilzomib (K) in relapsed/refractory multiple myeloma (RRMM), there is no consensus on optimal K dose in milligrams per square meter (mg/m2) or dosing schedule. We assessed three modern K prescribing patterns in RRMM using a large United States electronic health record-derived database. Our final cohort (n = 486) included 136 patients (28.0%) who received K 56 mg/m2 once weekly (K56-1x), 86 (17.7%) who received 56 mg/m2 twice weekly (K56-2x), and 264 (54.3%) who received 70 mg/m2 once weekly (K70-1x). Between 2016 and 2023, once-weekly dosing became more common: K70-1x proportions changed from 21.1% in 2016 to 50.6% in 2023, K56-1x from 15.8% to 37.0%, and K56-2x from 63.2% to 12.3%. Median real-world progression-free survival was 13.0 months [95% confidence interval (CI) 11.2-20.7] for K56-1x, 13.2 months (95% CI 9.0-28.1 months) for K56-2x, and 10.9 months (95% CI 9.9-15.3 months) for K70-1x; these differences were not statistically significant (log-rank p = 0.46). The prevalence of heart failure was comparable (<5% in all cohorts). In summary, our findings do not support improved outcomes with twice-weekly carfilzomib in RRMM. K56-1x may provide the best balance of efficacy, safety, and avoidance of time toxicity from frequent infusions.

Abstract Dexamethasone is a key component of induction for newly diagnosed multiple myeloma (NDMM), despite common toxicities, including hyperglycemia and insomnia. In the randomized ECOG E4A03 trial, dexamethasone 40 mg once weekly was associated with lower mortality than higher doses. However, the performance of dexamethasone dose reductions below this threshold with regard to progression-free survival (PFS) and overall survival (OS) in NDMM has not been fully characterized. We conducted a secondary pooled analysis of the SWOG 0777 and SWOG 1211 studies of NDMM, which used lenalidomide and dexamethasone (Rd) alone, with or without bortezomib, and with or without elotuzumab. The planned dexamethasone intensity was 40 to 60 mg weekly in all arms. Patients were categorized into FD-DEX (full-dose dexamethasone maintained throughout induction) or LD-DEX (lowered-dose dexamethasone or discontinuation; only permitted for grade 3+ toxicities per both study protocols). Of the 541 evaluated patients, the LD-DEX group comprised 373 patients (69%). There were no differences in PFS or OS between the FD-DEX and LD-DEX groups, which were balanced in terms of age, stage, and performance status. Predictors of PFS and OS in the multivariate models were treatment arm, age ≥70 years, and thrombocytopenia. FD-DEX did not significantly improve either outcome. Our study suggests that dexamethasone dose reductions are common in multiple myeloma, even within clinical trials. Given the many toxicities and unclear benefits of dexamethasone in the era of modern treatment regimens, dexamethasone dose reduction during NDMM induction warrants further prospective studies. These trials were registered at www.clinicaltrials.gov as #NCT00644228 and NCT01668719.

Abstract Background New immunoglobulin free light chain (FLC) assays are available. Despite analytical differences, it seems possible to use free light chain ratios (FLCr) generated by different assays and apply similar cut-points for the diagnosis of multiple myeloma. It is still unknown if we can use different assays for risk stratification of patients with monoclonal gammopathy of undetermined significance (MGUS). Methods Patients diagnosed with MGUS (N = 923) had FLC tested using a nephelometric FreeLite (Binding Site) assay on BNII instruments (Siemens) and a Sebia FLC assay (Sebia) on a DS2 ELISA analyzer (Dynex). Patients were followed up for progression to any plasma cell dyscrasia (PCD) for several decades. The Mayo MGUS risk stratification model for progression was assessed with both assays (M-spike &gt;1.5 g/dL; non-IgG isotype and abnormal FLCr), using package insert reference intervals (RI) and a new metric called principal component 2 (PC2). Results There were 94 events of progression to PCD in the cohort during a median of 38 years of follow-up. Freelite and Sebia FLC showed similar hazard ratios in the risk models for elevated FLCr. An alternative clinical decision point lower than the package insert RI was evaluated for the Sebia assay, which improved risk stratification for patients with a low FLCr. The PC2 metric showed similar performance to the FLCr in models, without superior benefit. Conclusions The Sebia ELISA-based FLC assay can be employed in an MGUS risk stratification model with similar performance to the original 2005 risk stratification model using the FreeLite assay.

Abstract Disease overview Multiple myeloma accounts for approximately 10% of hematologic malignancies. Diagnosis The diagnosis requires ≥10% clonal bone marrow plasma cells or a biopsy proven plasmacytoma plus evidence of one or more multiple myeloma defining events (MDE): CRAB (hyper c alcemia, r enal failure, a nemia, or lytic b one lesions) attributable to the plasma cell disorder, bone marrow clonal plasmacytosis ≥60%, serum involved/uninvolved free light chain (FLC) ratio ≥100 (provided involved FLC is ≥100 mg/L and urine monoclonal protein is ≥200 mg/24 h), or >1 focal lesion on magnetic resonance imaging. Risk stratification The presence of del(17p), t(4;14), t(14;16), t(14;20), gain 1q, del 1p, or p53 mutation is considered high‐risk multiple myeloma. Presence of any two high risk factors is considered double‐hit myeloma; three or more high risk factors is triple‐hit myeloma. Risk‐adapted initial therapy In patients who are candidates for autologous stem cell transplantation, induction therapy consists of anti‐CD38 monoclonal antibody plus bortezomib, lenalidomide, dexamethasone (VRd) followed by autologous stem cell transplantation (ASCT). Selected standard risk patients can delay transplant until first relapse. Frail patients who not candidates for transplant are treated with VRd for approximately 8–12 cycles followed by maintenance or alternatively with daratumumab, lenalidomide, dexamethasone (DRd) until progression. Maintenance therapy Standard risk patients need lenalidomide maintenance, while bortezomib plus lenalidomide maintenance is needed for high‐risk myeloma. Management of relapsed disease A triplet regimen is usually needed at relapse, with the choice of regimen varying with each successive relapse. Chimeric antigen receptor T (CAR‐T) cell therapy and bispecific antibodies are additional options.