Fonder, Amie

Abstract Measurable residual disease (MRD) is a powerful prognostic tool in multiple myeloma, but predictors of achieving MRD negativity after autologous stem cell transplantation (ASCT) are not well defined. We studied 814 patients who achieved at least a very good partial response after ASCT between January 2016 and January 2023 and underwent MRD assessment by next-generation flow cytometry. Overall, 387 (48%) achieved MRD negativity after ASCT. The presence of t(11;14) (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.4–3.2; P< .01) and pretransplant response less than complete remission (OR, 2.1; 95% CI, 1.2-3.7; P< .01) independently predicted MRD positivity. Patients who were MRD positive had inferior progression-free survival (PFS; hazard ratio [HR], 1.99; 95% CI, 1.53-2.58; P< .001) and overall survival (HR, 1.62; 95% CI, 1.10-2.28; P = .009). Despite lower MRD-negative rate, 5-year PFS was similar among t(11;14) MRD positive (58%) and patients who were MRD negative (63%; P = .12). In patients who were MRD negative, the 5-year PFS was 73% in those without ≥2 HRCA compared with 55% in those with ≥2 HRCA (HR 1.9, 95% CI 1.2–3.3; P = .01). In the MRD-positive cohort, 5-year PFS was 53% in patients without ≥2 HRCA vs 17% in those with ≥2 HRCA (HR, 2.4; 95% CI, 1.6-3.6; P< .01). In addition, higher residual clonal plasma cell burden within MRD-positive disease was associated with inferior PFS (HR, 2.4; 95% CI, 1.2-6.9; P = .002). This study highlights that the presence of t(11;14) independently predicts MRD positivity after ASCT, although it does not significantly affect prognosis in this subgroup.

Abstract Solitary bone plasmacytoma (SBP) and SBP with minimal marrow involvement (SBPmm) are treated similarly with definitive radiation therapy (RT) followed by observation. However, differences in the natural disease course after RT between the two, are not well described. We performed a multicenter study assessing outcomes after RT in 141 patients with SBP and 102 with SBPmm diagnosed between January 2010 and December 2024. About 92% of patients with SBPmm progressed to multiple myeloma (MM) vs 76% of those with SBP (P = .01). Among patients with SBP, 21% progressed with a second solitary bone lesion vs 4% with SBPmm (P< .01). Patients with longer time to progression (TTP) after initial RT could achieve durable responses with RT to a second solitary plasmacytoma in the absence of other myeloma-defining events (MDE). Multifocal lytic bone lesions were the most common MDE, occurring in 89% and 81% of patients with SBPmm and SBP, respectively. Patients with SBPmm had a median TTP of 15 months (95% confidence interval [CI], 14-21) compared to 43 months (95% CI, 34-55) for those with SBP (P< .0001); 67% with SBPmm progressed within 2 years of diagnosis. Del(17p) and 1q+ (gain or amplification) were associated with shorter TTP to MM in SBPmm, with 2-year progression rates of 100% and 82%, respectively. We report significant differences in risk and modes of progression between SBP and SBPmm. Patients with SBPmm are at particularly high risk for early progression to MM, with most developing bone disease as the MDE. These findings support prospective studies incorporating frontline systemic therapy for SBPmm.

Abstract Gastrointestinal (GI) involvement is a clinically relevant but undercharacterized manifestation of systemic light chain amyloidosis (AL). We aimed to define the clinical spectrum, histologic patterns, and outcomes of symptomatic GI involvement in AL. We retrospectively analyzed 4396 patients with AL from 2010 to 2024, of whom 521 (11.9%) had provider-attributed symptomatic GI involvement; 66% had biopsy-proven GI AL. Symptoms most commonly included early satiety (61%), bowel irregularities (58%), nausea (35%), abdominal pain (28%), and dysphagia (23%). Autonomic neuropathy was frequent (43% clinician attributed; 23% via autonomic reflex testing) and contributed to dysmotility-related symptoms, often without GI biopsy positivity. Among 747 GI biopsies, mucosal infiltration predominated (71%) and was associated with bleeding (22% vs 9%), cachexia, and inferior survival, whereas vascular involvement was associated with lower bleeding risk. Combined involvement of mucosa, submucosa, and vessels conferred the worst prognosis (median overall survival [mOS], 2.4 vs 5.1 vs 7.8 years for 3 vs 2 vs 1 layer); mOS was 6.8 years and was primarily driven by cardiac stage and hematologic response (very good partial response [VGPR] or better: hazard ratio, 0.20; 95% CI 0.13-0.32), with more favorable outcomes in patients with isolated GI involvement. Cachexia and persistent diarrhea were the main drivers of morbidity, need for nutritional support, and GI-related mortality (odds ratio, 2.7 for the combined end point). GI bleeding rarely recurred after achieving VGPR or better. Overall, mucosal involvement, cachexia, and dysmotility define clinically meaningful GI AL and support systematic assessment of autonomic dysfunction as well as evaluation of the need for nutritional support as a GI-specific end point for AL trials.

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.

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 < .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 >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.

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 Patients with multiple myeloma (MM) who do not respond to initial therapy have worse outcomes than primary responders, and effective treatments are lacking in this population. However, the outcomes of primary refractory disease in the modern treatment era have not yet been studied. We reviewed patients with MM treated with triplet/quadruplet therapy at our institution to assess the incidence of primary refractory disease and the impact of salvage therapies in this population. We identified 1127 patients, of whom 1086 were evaluated for hematologic responses after 4 to 6 cycles. Of these, 93.3% (1013) had evidence of response, whereas 6.7% (73) had primary refractory disease. With a median overall survival (OS) of 51.3 months, patients with primary refractory disease had an increased risk of shorter survival in univariable and multivariable analyses (hazard ratio [HR], 3.5 [95% confidence interval (CI), 2.5-4.9]; HR, 4.3 [95% CI, 2.6-6.9], respectively). In the subgroup analysis of patients with primary refractory disease, those who received second-line autologous stem cell transplantation (ASCT) had increased second progression-free survival (20.9 vs 8.1 months; P < .01) and second OS (74.7 vs 31.3 months; P = .02) compared with patients who did not. We conclude that early progression remains a significant factor for shorter OS in the current era, and salvage ASCT could be the most beneficial option for this population.

Two Letters to Blood address the risks of COVID-19 in populations with precursors of hematological disease. In the first article, Miller and colleagues report on whether clonal hematopoiesis of intermediate potential (CHIP) is associated with adverse outcomes with COVID-19, finding no association between CHIP and 28-day mortality while providing data indirectly linking IL-6 signaling and patient outcomes. In the second article, Ho and colleagues investigate the outcomes of patients with monoclonal gammopathy of undetermined significance (MGUS) with COVID-19, reporting that one-fourth had a severe infection and that on multivariable analysis, adverse outcomes are more likely if immunoparesis is present.

Abstract Almost all patients with multiple myeloma (MM) eventually relapse, either asymptomatically or with end-organ damage. However, it remains unclear whether initiating therapy at the time of biochemical progression (BP) improves the outcomes compared with initiating therapy at the clinical progression (CP) stage. Here, we retrospectively assessed 1347 patients with relapsed MM. Most progressions were BP (60.4%); 39.6% had CP. The most prevalent symptoms at relapse were new or evolving bone disease (80.9%), anemia (38.0%), and renal failure (12.7%). Patients with BP had longer median time from second-line treatment to the next treatment compared with patients who had CP (17.0 vs 9.6 months; P < .001) as well as longer median overall survival from first relapse (59.4 vs 26.2 months; P < .001). Male sex (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.02-2.18; P = .04), plasma cell labeling index ≥2% (OR, 1.58; 95% CI, 1.02-2.45; P = .04), and extramedullary disease at diagnosis (OR, 1.84; 95% CI, 1.08-3.13; P = .03) were associated with higher risk of CP, whereas very good partial remission or better had decreased risk of CP (OR, 0.62; 95% CI, 0.43-0.91; P = .02). To conclude, patients with CP have inferior postprogression outcomes compared with patients who have BP. Patients with deeper response to first-line therapy are less likely to develop CP. The presence of a specific CRAB (C, hypercalcemia; R, renal failure; A, anemia; B, bone disease) symptom at diagnosis predicts for the development of similar CRAB symptoms at relapse.

Abstract Multiple myeloma (MM) is a plasma cell malignancy that is characterized by diverse clinical presentations. Although biochemical assessment of disease activity is commonly used to monitor treatment response, findings on magnetic resonance imaging and positron emission tomography (PET)/computed tomography (CT), among other imaging modalities, have proven to harbor prognostic value. We sought to corroborate these findings by examining the prognostic significance of fluorodeoxyglucose PET/CT scanning in the setting of newly diagnosed MM. We retrospectively analyzed 195 patients with a PET/CT available at diagnosis and at 6 months posttreatment to examine their value as an adjuvant metric to conventional hematologic responses in terms of time to next treatment (TTNT) and overall survival (OS). The median TTNT and OS for the entire cohort were 24.6 months (95% confidence interval [CI], 20.4-29.1) and 79 months (95% CI, 63.1-119.1), respectively. When comparing PET/CT negative (−) with PET/CT positive (+) patients, we found significantly prolonged median TTNT (55.2 vs 17.8 months, P < .0001) and OS (unreached vs 60.8 months, P < .0001) in the former group. We then examined the additive value of PET/CT on the hematologic response achieved at 6 months and found that PET/CT (−) is associated with significantly increased median TTNT and OS for the very good partial response (VGPR) group and the less than VGPR group. Importantly, PET/CT retained prognostic significance after adjusting for multiple other predictive variables. We conclude that a PET/CT (−) at 6 months confers a significant prognostic advantage for patients with newly diagnosed MM and adds significant value to the hematologic response assessment.