Kourelis, Taxiarchis

Background: Beside fibril-forming proteins, amyloid deposits contain other proteins which can influence organ toxicity, disease initiation and clearance. We investigated the association between the amyloid plaque proteomic signature of diagnostic renal biopsies from patients achieving deep and sustained hematologic remissions and renal organ response in AL amyloidosis. Methods: Retrospective study of newly diagnosed AL amyloidosis patients between 2010-2020. Patients were eligible if; (1) they had a baseline renal biopsy which had undergone laser micro-dissection and mass spectrometry, (2) were assessable for renal response [RenR, non-selective proteinuria ≥1g /24 hours, predominantly albumin], (3) were not on renal replacement therapy and did not experience renal progression within 3-months of diagnosis and (4) had RenR measurements, at least twice annually in the first year from treatment and annually thereafter. Patients who did not obtain a renal complete response (RenCR) required a hematologic very good partial response (VGPR) or better within 6 months of treatment initiation, sustained for a minimum of 6 months. Hematological and renal responses were graded according to consensus criteria. Overrepresentation analyses of differentially expressed proteins were performed using the WebGestalt 2019 and the reactome pathway database. A false detection rate corrected p value <0.05 was used to identify significantly overrepresented proteins and pathways. Results: We defined two organ response categories, to capture the extreme ends of the spectrum: renal suboptimal responders (n=24), patients for whom the best renal response was ≤partial response (RenPR), and renal complete responders (n=29), patients who obtained a RenCR at best response. Overall, the median follow-up was 6.7 years (IQR: 5.4-9.2), 6.6 years (IQR: 5.4-8.1) for complete responders, and 8.4 years (IQR: 6.1-11.3) for suboptimal responders. Between renal suboptimal responders and complete responders there was no significant difference in median age (63 vs 63 years, p=0.7), lambda light chain isotype (66% vs 79%, p=0.3), first-line therapy received and renal stage (Stage III: 14% vs 8%, p=0.9). The median time to RenCR was 52-months (IQR: 31-63). Protein pathways over-represented in renal complete responders included 14-3-3 proteins (YWHAG, YWHAH, YWHAQ, YWHAZ), early components of the complement cascade and complement regulatory proteins (C3, C4A, C4B, C8A, complement factor H), keratins, cytoskeletal proteins (tubulin, actin, filamen) and collagen IV. Protein pathways over-represented in renal suboptimal responders included terminal/effector components of the complement cascade (C5, C6, C8B, C9), amyloid signature proteins (ApoA1 and E, vitronectin, clusterin), proteoglycans (heparan sulfate proteoglycan), transgelin and metallopeptidase inhibitor 3. Proteins with the highest-fold increase in renal complete responders included serine protease inhibitor (SERPINA3) and F-box and leucine rich repeat protein (FBXL6), 9.0 x 106 & 7.7-fold, respectively. Proteins with the highest-fold increase in renal suboptimal responders included complement 6 and 8B, 3.5 & 3.6-fold, respectively. Conclusion: This is the first study to identify proteomic determinants of organ response in AL amyloidosis. Molecular chaperones involved in protein aggregate homeostasis, such as the 14-3-3 proteins are upregulated in renal complete responders, similar to what we have shown in our prior work. This suggests that organ responders may have a more favorable microenvironment which “primes” them for organ response after the amyloidogenic light chain has been cleared from the circulation. Renal suboptimal responders (≤RenPR) have elevated levels of terminal complement proteins including membrane attack complex proteins and reduced levels of early components or complement regulatory proteins, which may be responsible for reno-toxic and reno-protective effects, respectively.

Introduction: Light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by tissue deposition of misfolded immunoglobulin light chains in the form of amyloid, leading to organ dysfunction. Halting the production of the amyloidogenic free light chains by achieving a deep hematologic response (HemR) is key to improving organ function, however, variation in organ responses exists. In this work, we investigated variables associated with liver response (LivR) in a large cohort of patients with AL amyloidosis. Methods: Retrospective study of newly diagnosed AL amyloidosis patients with liver involvement seen at Mayo Clinic within 90 days of diagnosis between January 2000 and December 2021. Patients were eligible if they (1) had liver involvement, defined as a baseline alkaline phosphatase (ALP) ≥ 1.5 x upper limit of normal (ULN) and (2) had LivR measurements at least twice annually in the first year from treatment and annually afterward. LivR was defined as a >50% reduction in alkaline phosphatase (ALP) from baseline value or normalization of ALP. LivR was recorded at 6, 12, and 24 months from treatment initiation and at the best LivR achieved. Patients who died prior to landmark assessment were considered non-responders at subsequent milestone assessments. Covariates associated with LivR were identified by univariate and multivariable logistic regression analyses and a proportional subdistribution hazard (Fine-Gray) model for competing risk (treating death as a competing event). Multivariable logistic regression models for LivR were created using best subset selection, with calculation of odds ratio (OR) and 95% confidence interval (CI). Results: A total of 130 patients were included, with a median age of 60 years (IQR 53-66), male predominance (69%), and a median follow-up of 8.8 years. Sixty percent of patients had lambda isotype, the median ALP was 368 IU/mL (IQR 279-589), with 48% of patients having ALP ≥3 fold the upper limit of normal (ULN). Median bilirubin was 0.7 mg/dL (IQR 0.5-1.1). Forty-three percent of patients received front-line autologous stem cell transplant (ASCT) with or without prior induction therapy, and 5% received daratumumab-based therapy as their front-line treatment. Liver response rate increased with time, with 36 patients (28%) achieving a LivR at 6 months, 47 (36%) at 12 months, 63 (48%) at 24 months, and 94 (72%) at best response. The median time to liver response was 14 months (7.22-32.67). At the 24-month landmark, age <60 years, ALP ≥3 fold ULN, and front-line ASCT were significantly associated with achieving a LivR on univariate logistic regression. On univariate logistic regression at best liver response, age <60 years, ALP ≥3 fold the ULN, kappa isotype, ≥HemVGPR within 6 months, and front-line ASCT were significantly associated with obtaining a LivR. On multivariable logistic regression, at 24 months, ALP ≥3 folds of ULN (OR=2.9, 95% CI 1.4-6.3, P=0.004) was significantly associated with an increased likelihood of LivR. Achieving ≥HemVGPR and front-line ASCT were also associated with increased LivR likelihood, although not statistically significant (p=0.094, p=0.078, respectively). At best liver response, achieving ≥HemVGPR within 6 months (OR=5.2, 95% CI 1.9-14.8), kappa isotype (OR=3.2, 95% CI 1.1-10.0), ALP ≥3 folds of ULN (OR=3.3, 95% CI 1.3-9.9), and front-line ASCT (OR=5.3, 95% CI 1.9-16.7) were factors significantly associated with LivR. The Fine-Gray model demonstrated kappa isotype (HR=1.7), baseline ALP ≥3 folds of ULN (HR=2.1), ≥HemVGPR within 6 months (HR=1.9), and age <60 years at diagnosis (HR=1.9) to be positively associated with achieving LivR (P<0.05). Conclusions: In this large cohort of liver AL amyloidosis, LivR was achieved in 72% of patients, and amongst responders, the median time to response was 14 months from therapy initiation. Predictors of LivR included kappa isotype, deep hematological response in the first 6 months of initial therapy, ASCT usage, and higher baseline ALP levels. These findings better inform clinicians on the likelihood of achievement of liver response and may enable ways to improve its achievement.

Background: AL amyloidosis is a potentially fatal plasma cell dyscrasia. In a randomized phase 3 study (Kastritis E et al, NEJM 2021;385:46-58), the addition of daratumumab to cyclophosphamide, bortezomib and dexamethasone (Dara-CyBorD) significantly improved hematological and organ responses, and prolonged event-free survival (EFS). There was no overall survival (OS) difference at a median follow-up of 11.4 months. Methods: A retrospective study of AL amyloidosis patients seen at our institution between January 2018 and December 2022 who received upfront Dara-CyBorD or CyBorD. We excluded patients who received other forms of upfront therapy (including modifications of the above regimens, such as bortezomib-dexamethasone or daratumumab-dexamethasone). We compared the hematologic and organ responses, EFS and OS between the two treatment groups. Hematologic response was assessed at 2 and 6 months from therapy initiation, while cardiac and renal responses at 6- and 12-month landmarks. In all response evaluations, we included responses up to autologous stem cell transplantation (ASCT) if used or second-line therapy for any reason. For EFS analysis, an event was defined as death of any cause, hematological progression, end-stage cardiac or renal failure, or need for subsequent anti-plasma cell therapy in the absence of hematological progression. OS was calculated from the time of treatment initiation to death or last follow-up. Results: Among 641 newly diagnosed patients seen at our center between 2018 and 2022, 361 patients (56%) were included on intention-to-treat analysis [Dara-CyBorD =147 (41% of the cohort); CyBorD=214 (59%)]. There was no difference in the baseline characteristics between the treatment groups, including age, sex, difference between involved and uninvolved light chains, bone marrow plasma cells percentage, NT-proBNP and 24-hour proteinuria. The 2-month hematologic complete response (hemCR; 15.3% vs 4.4%, P<0.001) and very good partial response or better (≥hemVGPR; 62.2% vs 32.5%, respectively; P<0.001) were higher with Dara-CyBorD compared to CyBorD. At 6 months, the hemCR and ≥hemVGPR were again in favor of the Dara-CyBorD group compared to CyBorD (32.0% vs 13.7%, and 72.8% vs 46.7%, respectively; P≤0.002). The 6- and 12-month cardiac response rate in the Dara-CyBorD and CyBorD groups were 40.2% vs 22.6% (P=0.01) and 44.1% vs 23.2%, respectively (P=0.006). Cardiac ≥VGPR at the 6- and 12-month landmarks were statistically higher with Dara-CyBorD compared to CyBorD and increased in both arms between 6 and 12 months [20.5 % vs 9.3% (P=0.03) and 34.3 % vs 20.0% (P=0.04), respectively]. The 6-month and 12-month renal response to first-line therapy were numerically higher with Dara-CyBorD compared to CyBorD but were not statistically significant (48% vs 31.3%, P=0.10; 54.1% vs 30.1%, P=0.05). The 6 month and 12 months, renal ≥VGPR were numerically higher with Dara-CyBorD compared to CyBorD, again without statistical significance (26% vs 19.6%, P=0.63; 35.7% vs 17.2%, P=0.11, respectively). Treatment with Dara-CyBorD was significantly associated with lower 6-month mortality rate compared to CyBorD (8.8% vs 16.3%, P=0.04). With a median follow-up of 43.3 months (30 vs 59.4 months for Dara-CyBorD vs CyBorD, respectively; P<0.001), the two-year EFS was superior in the Dara-CyBorD group compared to CyBorD (69.1% vs 30.3%, hazard ratio (HR) 0.36, 95% confidence interval (CI), 0.26 to 0.48, P<0.001). The 2-year OS was also statistically higher in the Dara-CyBorD group compared to CyBorD (82.0% vs 69.6%, HR 0.53, 95% CI, 0.36 to 0.79, P=0.003). 148 patients (40.9%) proceeded to second-line therapy with a median of 5.1 months from first line therapy. To adjust for difference in follow-up time between the two treatment groups, we analyzed the second line therapy utilization at the 12-month mark which was statistically higher with CyBorD compared to Dara-CyBorD (42.9% vs 14.9%, P<0.001). Also, at 12 months, a higher proportion of patients treated with CyBorD received ASCT compared to Dara-CyBorD (24.3% vs 13.6%, P= 0.01). Conclusions: In this cohort of newly diagnosed AL amyloidosis patients in a large referral center, we confirmed higher hematological and organ response rates with Dara-CyBorD compared to CyBorD. We have also demonstrated that these higher response rates translate into a survival advantage of Dara-CyBorD over CyBorD.

Introduction: Ven is a BCL2 inhibitor that has shown clinical efficacy in RRMM patients (pts) particularly those that harbor t(11;14). Ven has been evaluated in clinical trials as a single agent, in combination with dexamethasone (dex), immunomodulatory drugs (IMiD), proteasome inhibitors (PI), and anti-CD38 monoclonal antibodies (MAb) yet its place in the therapeutic landscape remains in question. In this retrospective analysis, we aim to evaluate the real-world efficacy of Ven-based regimens in RRMM pts treated outside of a clinical trial across the 3-site MCCC. Methods: We retrospectively analyzed the medical records of pts with RRMM treated with Ven-based regimens between January 2015 and October 2023 at the MCCC. Refractoriness was defined by progression on or within 60 days of stopping treatment. Categorical variables were compared with Chi-square tests and continuous variables were compared with t-tests. Outcomes were estimated using the Kaplan-Meier method and curves were compared between the groups using log-rank tests. Results: 83 pts were included in the analysis. The median age was 71 (39-93), 63% were male, 93% were white, 27% had ISS III, 18% had high risk cytogenetics (HRCyto), 76% had t(11;14), the median prior lines of therapy (LOT) was 4 (1-15), 68% received ≥ 4 prior LOT, 87% received prior autologous transplant, 58% were triple-class refractory (TCR), 64%/23% were penta-drug exposed/refractory (PDE/R), 8% received prior BCMA-directed therapies (BDT), 58% received Ven+dex, 25% received Ven+PI +/-dex, 6 % received Ven+anti-CD38 MAb+/-dex and 11% received Ven+other. The median follow-up time from start of a Ven-based regimen was 29 months (mo). The median Ven dose was 800mg (20-1600) with 25% of pts receiving Ven ramp-up dosing. The overall response rate (ORR) to a Ven-based regimen was 58% and was 64% for pts with t(11;14) and 40% for pts without t(11;14); p=0.06. Ven-treated pts with HRCyto had inferior PFS (3mo) and OS (8mo) compared to patients who did not have HRCyto who had a PFS of 9mo (p=0.020) and OS of 80mo (p<0.001). The ORR for TCR and PDR pts were 52% and 42%, respectively. No significant ORR differences were noted across the different Ven-based regimens (p=0.32). The median PFS for pts with t(11;14) was 10mo compared to 2mo for pts w/o t(11;14); p=<0.001. The median OS for pts with t(11;14) was 80mo compared to 10mo for pts without t(11;14); p=0.001. Ven-treated pts who received 1-3 prior LOT has superior ORR, median PFS, and median OS; 89%, 25mo, and 99mo, respectively, compared to pts who received ≥4 prior LOT who achieved an ORR of 43% (p<0.001), median PFS of 5mo (p<0.001) and median OS of 25mo (p<0.001). Ven-treated pts that were TCR had inferior PFS (5mo) and OS (26mo) compared to pts who were not TCR who achieved a PFS of 12mo (p<0.001) and a median OS of 80mo (p=0.02).Ven-treated pts that were PDR had inferior PFS (4mo) and OS (22mo) compared to pts who were not PDR who achieved a PFS of 9mo (p<0.001) and a median OS of 80mo (p=0.02).Ven-treated pts who received prior BDT (n=7) achieved an ORR of 29% and had a median PFS and OS of 2mo and 6mo, respectively on a Ven-based therapy. 59 pts received additional therapy in the post Ven-progression setting. The ORR to post-Ven progression therapies was 53% (n=31/59), the median PFS was 9mo and median OS was 35mo. The most common post-Ven progression regimens used were PI-based (n=16; ORR=56%), anti-CD38 MAb-based (n=14; ORR=50%), BDT (n=12; ORR=83%), selinexor-based (n=3; ORR=0%) with BDT resulting in highest ORR (p=0.048) and PFS (p=0.005). Conclusions: Ven-based regimens are effective in heavily pre-treated pts with RRMM however they are more effective when used within 1-3 prior LOT, in pts with t(11;14), and in pts without HRCyto, TCR or PDR MM. BDT appear to be the most efficacious therapies in the post-Ven progression setting.

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 <.001). Serum FLC showed a comparable response rate of 98% (≥ PR) at the time of best electrophoretic response (p <.001). Ninety-nine percent of early FLC responders eventually achieved an overall response by sPEP/uPEP (p <.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 <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 < .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 < .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 <.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 (< 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.

Background Multiple myeloma (MM) is a hematological cancer characterized by the proliferation of plasma cells (PC). Progressive disease (PD) criteria are primarily characterized by an increase in (1) serum M-protein (SPEP), (2) urinary M-protein (UPEP), (3) serum free light chains (sFLC), or (4) PC percentage in the bone marrow. An essential aspect of the PD criteria is the requirement for confirmatory results from blood or urine analyses. However, in many cases, patients may be taken off treatment in favor of a new therapy after only one assessment. This can introduce clinical trial endpoint inaccuracies when confirmatory values are missing, resulting in increased censoring and underestimation of the progression rate (if the second assessment is not done). Moreover, in subjects with high tumor burden and rapidly progressing disease, it is often urgent to confirm PD before starting a subsequent line of treatment. This study assessed the necessity of repeating biomarkers to confirm PD if two biomarkers meet the progression criteria. Methods In this retrospective study, between 2002 and 2020, we assessed all consecutive patients with relapsed MM enrolled in any therapeutic clinical trial at Mayo Clinic. We included patients with measurable disease if SPEP and sFLC were available at the time of assessment. Patients required at least two consecutive assessments (by the same method) to be included in our study. PD was based on the IMWG criteria. Relapse characterized by the development of new bone lesions or extramedullary relapse without meeting biochemical progression criteria was an exclusion criterion. Patients starting a new line of treatment after non-confirmed PD were also excluded. Furthermore, patients who did not meet simultaneous progression criteria and had unconfirmed PD (did not meet IMWG criteria at the second assessment) were excluded from the analysis (n=15). The probability of meeting the progression threshold with 1 and 2 consecutive assessments was calculated. We then examined the proportions of patients meeting PD by 2 biomarkers simultaneously at the first assessment. Results We evaluated episodes of treatment among 434 patients enrolled in clinical trials, including 601 episodes: 593 episodes of biochemical confirmed PD and 8 episodes when patients did not progress but who met simultaneous progression criteria at the same time with two different biomarkers. Per measurable disease criteria, MM isotypes were 71.0% IgG, 16.8% IgA, 0.9% IgM, 1.2% IgD, 0.3% biclonal, and 9.8% light chain. According to the standard IMWG response criteria (sequential criteria), 78% and 9% of episodes reached the progression threshold with serum and urine M-components, respectively, with two consecutive assessments. For the FLC, 21% of episodes met the progression criteria. No patients had a second bone marrow examination for confirmation of PD. At the first available assessment, 82%, 19%, and 2% of episodes met progression threshold, respectively, with serum M-protein, urine M-protein, and both (serum + urine M-protein). Additionally, 58%, and 19%, episodes met the progression threshold at the first assessment with FLC and bone marrow examination, respectively. Moreover, 67% of patients with IgA myeloma meet the progression threshold with the total quantitative IgA. With the simultaneous criteria at time of first assessment, 403 episodes meet progression threshold: 45% with SPEP+sFLC (n=269/593), 4% with SPEP+UPEP (n=21/593), 9% with sFLC+UPEP (n=55/593), 11% with BME only (n=66/593), and 0.3% with qIgA +dFLC/UPEP (n=2/593). Thus, among these 413 episodes, which meet progression criteria by 2 simultaneous values at the time of the first assessment, 98% (n=413/(413+8)) of these patients (positive predictive value of the new criteria) subsequently had confirmed progression by sequential value. Conclusions In summary, we showed that the simultaneous criteria allow to identify patients with true progressive disease without overestimating the progression rate of myeloma. Therefore, confirmatory results of progression for relapsed MM patients having two biomarkers meeting criteria of progression at the same time is useless for determining disease progression.

Background and significance: Light chain (AL) amyloidosis is a plasma cell malignancy characterized by the production of amyloidgenic clonal light chains that deposit in various tissues. The addition of daratumumab to bortezomib, cyclophosphamide and dexamethasone (Dara-VCD) has improved the depth of hematologic and organ responses and is an approved induction therapy in newly diagnosed AL amyloid patients (DOI: 10.1056/NEJMoa2028631). However, this approach has not yet demonstrated an overall survival (OS) benefit and follow up remains short. With strict adherence to eligibility criteria, in particular severity of cardiac involvement, autologous stem cell transplantation (ASCT) as consolidative therapy is safe with transplant related mortality on par with multiple myeloma. This approach generates deep and sustained responses, but it is unclear if it offers an additional survival benefit following Dara-VCD induction. The only randomized trial evaluating the role of ASCT in AL amyloid is outdated (DOI: 10.1056/NEJMoa070484) and no randomized data exist to inform the optimal use of ASCT in the era of Dara-VCD induction. Furthermore, multi-organ involvement in AL amyloid drives morbidity and mortality thus the impact of any consolidative therapy on cardiac and renal involvement in addition to overall survival but must be defined. Finally, the approval of Dara-VCD therapy was based on complete hematologic response rates but there is increasing data demonstrating that achieving minimal residual disease (MRD) negativity by either bone marrow next generation flow cytometry (DOI: 10.1002/ajh.26562) or peripheral blood mass spectrometry (DOI: 10.1038/s41408-020-0291-8) generates improved organ response, hematologic progression free survival, and possibly OS. Methods: This randomized phase 3 SWOG led intergroup trial (S2213; NCT06022939) is being conducted within the United States and will accrue a total of 143 participants per arm. The primary endpoint will compare MOD-PFS (major organ deterioration progression free survival: defined as time from randomization to death, cardiac/renal progression, or hematologic progression) between participants receiving an ASCT with those receiving 3 cycles of Dara-VCD consolidation following 3 cycles of uniform Dara-VCD induction. Following the assigned consolidation, all patients will receive 18 months of daratumumab maintenance therapy. A median MOD-PFS of 31 months is anticipated in the non-ASCT arm. This study has 90% power and a two-sided significance level of 0.05 to detect a hazard ratio of 0.62 corresponding to a MOD-PFS of 50 months in the ASCT arm. Important additional endpoints include OS, hematologic PFS, cardiac and renal responses, MRD negativity both by peripheral blood mass spectrometry and bone marrow next generation flow cytometry, delayed utilization of ASCT, and quality of life. Key inclusion criteria include non-severe cardiac AL amyloid (NT-proBNP <5000; TnT < 0.06; NYHA I or II, EF ≥ 40%), CrCl ≥30 mL/min, serum dFLC > 2 mg/dL, and supine systolic BP ≥ 90 mmHg. Importantly, patients are permitted to have up to one full cycle or 28 days of any plasma cell directed therapy prior to enrollment. This trial was activated on 12/1/2023 with the first patient enrolled 07/01/2024. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819; and in part by Janssen Pharmaceuticals Inc. of Johnson & Johnson (now J&J Innovative Medicine).

Background: Light chain (AL) amyloidosis is a rare and understudied plasma cell disorder. It is caused by abnormal misfolding of monoclonal immunoglobulin light chains, leading to extracellular deposition of amyloid, ultimately resulting in organ dysfunction and death. Since AL amyloidosis is uncommon, therapies are adapted from the more common plasma cell disorders like multiple myeloma. Daratumumab, a monoclonal antibody targeting CD38, was first tested in several prospective and retrospective studies in AL patients with relapsed refractory disease. The ANDROMEDA study (Kastritis E et al, NEJM 2021) established daratumumab in combination with CyBorD (Cyclophosphamide-Bortezomib-Dexamethasone) followed by daratumumab maintenance as the new standard of care compared to CyBorD alone for newly diagnosed patients. Consequently, daratumumab maintenance has become universally offered to all newly diagnosed AL amyloidosis patients. Notably, there was no second randomization before the initiation of maintenance therapy in ANDROMEDA. Hence, a critical question that remains is whether the superior efficacy observed in the investigational arm of the ANDROMEDA trial is solely a result of the addition of daratumumab during the induction phase or if the maintenance phase contributed to the favorable outcomes in the investigational arm. We hypothesize that a shorter duration of maintenance would prove non-inferior to the standard duration of daratumumab maintenance in patients with AL amyloidosis that have responded to Daratumumab-CyBorD induction. To answer this question we are conducting a pragmatic phase 2 randomized trial assessing the optimal duration of daratumumab maintenance in patients with AL amyloidosis who have responded to Daratumumab-CyBorD induction. Study Design, Patients and Methods: We use broadened eligibility criteria consistent with pragmatic trial design. The estimated total enrollment is up to 96 patients. The main eligibility criteria are patients with biopsy-proven AL Amyloidosis who have completed 6 cycles of Dara-CyBorD-based induction treatment and achieved an adequate response to induction (defined as hematological complete response (CR), hematological very good partial response (VGPR), or hematological partial response (PR) with at least one organ response). Patients in whom bortezomib and/or cyclophosphamide were omitted from induction due to toxicity concerns or adverse effects are allowed. The major exclusion criteria are patients who were concomitantly diagnosed with multiple myeloma based on International Myeloma Working Group (IMWG) criteria. This phase II, open-label, multicenter trial (NCT05898646) randomizes patients who have attained an adequate response to 6 cycles of Dara-CyBorD-based induction in a 1:1 ratio, using a dynamic allocation procedure that balances the marginal distributions of the stratification factors (age, cardiac stage, and t(11;14) status). Randomization is to either single-agent daratumumab maintenance of 6 cycles duration (experimental arm) or 18 cycles of daratumumab maintenance (control arm) (cycle = 28 days). Treatment is allowed to be given at a local facility After completing maintenance treatment, patients will follow up every 3 months for up to 36 months from registration. The primary endpoint of the trial is to evaluate the non-inferiority of a shorter (6 cycles) daratumumab maintenance measured by event-free survival (EFS) compared to the standard maintenance of 18 cycles in newly diagnosed AL amyloidosis who receive 6 cycles of daratumumab-CyBorD based induction. EFS in this study is defined as time from registration to any of the following events: hematological progression, organ progression, subsequent anti-plasma cell therapy in the absence of hematological progression but with persistent organ dysfunction or death, whichever occurs first. Secondary endpoints are depth of hematological and organ response, bone marrow measurable residual disease negativity rate, duration of response, quality of life, and survival. By investigating whether a shorter duration of maintenance is non-inferior to the standard duration, we aim to inform clinical practice and potentially reduce the toxicities associated with prolonged maintenance therapy, including hypogammaglobulinemia, recurrent infections, the need for intravenous gammaglobulin replacement, and financial toxicity.

Introduction: In myeloma, accurate risk stratification remains a challenge due to substantial biological heterogeneity and highly variable survival outcomes. Cross-sectional imaging is commonly obtained at the time of diagnosis, but imaging findings are not currently incorporated into risk stratification efforts in a standardized manner, despite their prognostic significance. Here, we investigate the use of novel image-based prognostic biomarkers obtained by automated image segmentation and radiomics feature extraction using machine learning methods. Methods: We obtained the pre-treatment 18F-FDG PET/CT scans of 443 patients with newly diagnosed myeloma and complete demographic and cytogenetic data (seen at Mayo Clinic between 2005 and 2019). The native DICOM images were pre-processed and subjected to automated image segmentation using nnU-Net (v1.0, inference using a pre-trained hematologic malignancies model). Limitations of this automated segmentation approach include heterogeneity introduced by varying image quality, technical differences related to PET reconstruction, and potential inclusion of non-neoplastic FDG-avid lesions in segmented regions. The quality of the automated image segmentation was evaluated by comparing the radiomics features obtained from ground-truth segmentation (manual lesion segmentation) and model segmentation in a separate cohort of patients with hematologic malignancies (n=72). We selected 42 radiomics features that moderately (r≥0.30, p<0.005, n=23) or strongly (r≥0.50, p<0.001, n=19) correlated between ground-truth (manual) and model (automated) segmentation for further evaluation in myeloma patients. PyRadiomics was used to extract discrete radiomics features for clinical prediction modeling. We evaluated the prognostic significance of tumor size-, shape-, and texture-related radiomics features and compared their predictive power to established prognostic factors (International Staging System [ISS], Revised ISS [R-ISS] stage and high-risk FISH cytogenetics). The outcome of interest was overall survival and the predictive power of competing proportional hazards regression models was assessed using Harrell's C-statistic. For modeling purposes, patients without measurable tumor volume were categorized as having undetectable radiomics features (0 for all features). All radiomics features were median dichotomized for downstream modeling. Forward feature selection and testing for multicollinearity were used to remove redundant features. Select radiomics features were divided into quintiles to generate an additive radiomics risk score and associated risk strata. Results: Median age at diagnosis of the 443 myeloma patients was 63 years (32-91) and 270 patients (62%) were men. After a median follow-up of 2.4 years (95% CI 0.1-7.4), median overall survival was 6.5 years (95% CI 5.5-NR). Most patients had detectable metabolic tumor volume (n=309, 70%) on their pre-treatment 18F-FDG PET/CT scan. Several of the 42 radiomics features were intercorrelated and two features were selected for further investigation based on their independent prognostic significance (forward feature selection). Higher maximum axial tumor diameter (HR 1.90, 95% CI 1.31-2.76, p=0.001) and a lower concentration of low gray-level values in the tumor (HR 1.73, 95% CI 1.20-2.49, p=0.004) were independently associated with overall survival in newly diagnosed myeloma. These associations were independent of age at diagnosis, sex, and R-ISS stage. We devised a simple additive risk score representing the sum of quintiles of the two radiomics features and divided the patients into three risk categories akin to the R-ISS. The predictive power of this radiomics risk score (Harrell's C=0.60) was comparable to the ISS (C=0.59) and the R-ISS (C=0.57). Conclusions: Automated image segmentation and radiomics feature extraction from 18F-FDG PET/CT scans is feasible. This approach yields image-based biomarkers that correlate with results obtained by manual imaging segmentation. Several radiomics features such as tumor size and heterogeneity have independent prognostic significance in newly diagnosed myeloma. These novel biomarkers rival the predictive power of the currently established risk stratification methods and may be used to improve risk stratification in myeloma.

Introduction: Measurable residual disease (MRD) is a well-validated prognostic marker and interim outcomes measure in patients with multiple myeloma (MM). Despite its broad acceptance as a robust prognostic marker, the MRD status is only available down the treatment line, and there is limited information on the markers at diagnosis that can predict achievement of MRD negativity post-transplant. This study explored the relationship between baseline risk factors and post-autologous stem cell transplantation (post-ASCT) MRD status, as well as the combined impact of these baseline factors and post-ASCT MRD status on progression-free survival (PFS) and overall survival (OS). Patients and Methods: We conducted a retrospective, single-center study of patients achieving at least VGPR after ASCT between 01/01/2016 and 12/30/2023, majority (n=814, 98%) received ASCT in the frontline setting. MRD testing was performed between days 60-100 post-transplant using next-generation flow cytometry with a sensitivity of at least 1x10^5 nucleated cells (minimum 2x10^6 cells assessed). Treatment response and disease progression were determined by IMWG criteria. High-risk disease (HRD) was defined as presence of International Staging System ISS stage 3, high lactate dehydrogenase, 1q gain, 17p deletion, or t(4;14) chromosomal abnormalities. We calculated PFS/OS from transplant day 0 to first documented event (progression or death). Categorical variables were compared using chi-square and Fisher's exact tests. Non-parametric tests compared continuous variables, and logistic regression analyses tested associations between clinical/lab variables and MRD status post-ASCT. Time-to-event analyses were performed using Kaplan-Meier and compared using log-rank test. Multivariable analyses were conducted using the Cox regression model. Result: The study cohort included 831 newly diagnosed MM patients. The median follow-up for the cohort was 50 months (95% CI: 48-51). 48% (n=402) achieved MRD negativity (MRD-neg) post-ASCT. Univariate analysis demonstrated that R2-ISS stage, depth of response pre-ASCT, and presence of t(11;14) to be associated with worse MRD-negativity rates. Multivariate analysis revealed that t(11;14) significantly decreased the odds of MRD-negativity (p<0.0001, OR=0.4, 95% CI: 0.3-0.6) and a deeper pre-ASCT response was associated with increase odd of MRD-negativity OR-4.7 (95%CI 3.2-7.4) p<0.0001. Patients with MRD-positive disease post-transplant had an inferior estimated median PFS of 57.6 months (95% CI: 49-69) with a 5-year PFS of 49% (95% CI: 43-56), compared to an estimated median PFS of 83.3 months (95% CI: NA) and a 5-year PFS of 66% in MRD-negative patients (p<0.0001, HR=1.9, 95% CI: 1.5-2.5). Similarly, MRD positivity was associated with an inferior OS [estimated median of 92.6 months (95% CI NA) ,5-year OS 76% (95%CI 72-82) for MRD-pos vs. Median OS NR, 5-year OS 85%(95%CI NA) in MRD-neg; p=0.003, HR=1.69, 95% CI: 1.2-2.38)]. In MRD-neg patients, a baseline bone marrow plasma cells BMPC% >60% was significantly associated with worse PFS (HR=1.9, 95% CI: 1.26-2.99; p<0.01). High-risk disease was not associated with an inferior PFS or OS in patients with MRD-negativity. For MRD-neg patients, estimated median PFS was not reached for those without HRD, 5-year PFS was 66% (95%CI 51-85), compared to 83 months(95%CI 65-NA) for those with HRD, 5-year PFS was 65%(95%CI57-74), p=0.6441. The median OS was not reached in either group (p=0.07). Five-year OS was 94% (95%CI 86-100) in MRD-neg without HRD vs. 81%(95%CI 75-87) with HRD (p=0.07). In MRD-pos patients, median PFS was 81 months (95%CI 58-NA) for those without HRD, 5-year PFS of 59% (95%CI 46-77), compared to PFS of 41 months(95%CI 36-52) for those with HRD ,5-year PFS of 39% (95%CI 31.3-47) , p=0.003. Median OS was not reached in MRD-pos patients without HRD, but it was 59.8 months ( for those with HRD (p=0.0012). Five-year OS was 94% (95%CI 89-99) in MRD-pos without HRD vs. 67%(95%CI 60-74) with HRD (p<0.0001). For every 1 log increase in the residual cell % on MRD testing in MRD-pos patients, the hazard ratio for PFS increased by 42% (p=0.0002, HR=1.42, 95% CI: 1.2-1.7). Conclusion: Patients with t(11;14) have a reduced likelihood of achieving MRD negativity post-ASCT, whereas high-risk cytogenetics did not impact MRD-negativity rates. Achievement of MRD negativity post-ASCT mitigates the impact of high-risk characteristics.