Carfilzomib-based Therapy Research Articles

Carfilzomib-induced thrombotic microangiopathy (TMA) refractory to eculizumab: A case report and literature review.

This case report describes the clinical course of a patient with relapsed IgA kappa multiple myeloma with high-risk cytogenetics. Initially treated with daratumumab-bortezomib-lenalidomide-dexamethasone (Dara-VRD) then transitioned to lenalidomide maintenance. However, he experienced a relapse and was treated with carfilzomib-based therapy (CFZ) but developed drug-induced thrombotic microangiopathy (DI-TMA). Despite receiving eculizumab and supportive care, the patient's condition worsened, leading to encephalopathy and refractory gastrointestinal bleeding in the setting of persistent thrombocytopenia. Ultimately, the decision was made to transition to comfort-focused care. DI-TMA has been documented with various proteasome inhibitors such as ixazomib and bortezomib. Additionally, other medications such as cyclosporine, tacrolimus, clopidogrel, ticlopidine, and interferon have been associated with DI-TMA as well (Pisoni et al. (Drug Saf 24:491-501, 2001) [18]). Here we discuss a case of carfilzomib-induced TMA (CFZ-TMA) refractory to eculizumab as well as a review of the published literature.

Metabolomic signatures of carfilzomib-related cardiotoxicity in patients with multiple myeloma.

As a treatment for relapsed or refractory multiple myeloma (MM), carfilzomib has been associated with a significant risk of cardiovascular adverse events (CVAE). The goals of our study were to evaluate the metabolomic profile of MM patients to identify those at high risk prior to carfilzomib treatment and to explore the mechanisms of carfilzomib-CVAE to inform potential strategies to protect patients from this cardiotoxicity. Global metabolomic profiling was performed on the baseline and post-baseline plasma samples of 60 MM patients treated with carfilzomib-based therapy, including 31 who experienced CVAE, in a prospective cohort study. Baseline metabolites and post-baseline/baseline metabolite ratios that differ between the CVAE and no-CVAE patients were identified using unadjusted and adjusted methods. A baseline metabolomic risk score was created to stratify patients. We observed a lower abundance of tauroursodeoxycholic acid (T-UDCA) in CVAE patients at baseline (odds ratio [OR] = 0.47, 95% confidence interval [CI] = 0.21-0.94, p = 0.044) compared with the no-CVAE patients. A metabolite risk score was able to stratify patients into three risk groups. The area under the receiver-operating curve of the model with clinical predictors and metabolite risk score was 0.93. Glycochenodeoxycholic acid (OR = 0.56, 95% CI = 0.31-0.87, p = 0.023) was significantly lower in post-baseline/baseline ratios of CVAE patients compared with no-CVAE patients. Following metabolomic analysis, we created a baseline metabolite risk score that can stratify MM patients into different risk groups. The result also provided intriguing clues about the mechanism of carfilzomib-CVAE and potential cardioprotective strategies.

The Efficacy of Carfilzomib Treatment in Bortezomib-Refractory Patients-Real Life Experience in a Tertiary Romanian Hospital.

Background: Proteasome inhibitors (PIs) represent one of the most effective classes of therapy for patients with multiple myeloma (MM) and are incorporated in many of the current treatment regimens. The first-generation PI, bortezomib, has shown impressive results in patients with either newly diagnosed or relapsed/refractory MM, but once patients become resistant, treatment is increasingly challenging. Although the existing data show that the second-generation PI, carfilzomib, is highly efficient, there is still limited knowledge regarding the response to carfilzomib-based therapy in bortezomib-resistant patients. The aim of this study was to evaluate carfilzomib treatment performance in bortezomib-sensitive versus -refractory patients, in a real-life eastern European country setting. Methods: We retrospectively evaluated 127 adult patients exposed to bortezomib with relapsed or refractory MM, that subsequently received a carfilzomib-based therapy. We investigated the differences in the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) after carfilzomib-based therapy between the two patient groups. Results: The ORR in the bortezomib-sensitive group was significantly higher than that in the refractory group, leading to a superior PFS in this category of patients. For patients presenting with a high cytogenetic risk, we observed a significant difference in PFS between the bortezomib-sensitive and -refractory group, while standard cytogenetic risk patients presented a similar PFS regardless of the bortezomib sensitivity status. In addition, in patients with ISS (International Staging System) stage I or II, the previous sensitivity to bortezomib correlated with an improved PFS, while for patients with ISS stage III, both groups had a comparable PFS. No significant differences in OS were observed between the two groups. Conclusions: In countries where novel or experimental therapies are not readily available, carfilzomib-based therapy can still be a viable therapy option for patients presenting with bortezomib-refractory status, an ISS stage III, and standard cytogenetic risk.

Phase II Trial of Daratumumab, Bortezomib, Lenalidomide and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Background: Daratumumab, bortezomib, lenalidomide and dexamethasone (D-RVD) has shown high rates of minimal residual disease (MRD) negativity in newly-diagnosed multiple myeloma (MM) and is now a standard regimen in transplant-eligible patients. Lenalidomide has shown to delay progression in patients with high-risk smoldering multiple myeloma (HR-SMM) and curative intent trials with carfilzomib-based therapy and stem cell transplantation have been recently reported in HR-SMM leading to deep responses but with concern for treatment-related toxicities. Thus, we proposed to examine the activity and safety of fixed duration D-RVD in patients with HR-SMM, with MRD-adaptive duration of therapy. Methods: This is a phase II, open-label study evaluating D-RVD in HR-SMM. Eligibility criteria includes HR-SMM per Mayo 2018 “20-2-20” model and other previously established criteria including Mayo 2008 criteria, PETHEMA criteria, evolving type of SMM, and high-risk FISH. Treatment with D-RVD is 2 years (24 cycles) with daratumumab subcutaneous (SQ) per standard dose and schedule, bortezomib 1.3mg/m2 SQ on days 1, 8, 15 for cycles 1-6 then biweekly until completion of cycle 24, lenalidomide 25mg on days 1-21 for cycles 1-6 followed by 15mg d1-21 from cycles 7-24 with weekly low dose dexamethasone. All eligible patients undergo stem cell collection after 6 cycles of therapy. The primary objective is rate of MRD-negativity at 2 years. Secondary objectives include PFS, ORR, and safety. In part 2 of the study, patients that are MRD-positive after 2 years of treatment will be randomized to observation vs continued therapy with daratumumab and lenalidomide for an additional 24 months. The primary objective of part 2 is rate of MRD conversion from positive to negative. Results: At the time of data cut off in May 2023, 38 patients have been enrolled to part 1 with a median follow up of 18 months. The median age is 62 years old (range 36-77) with 23 females (61%) and 15 males (39%). The median plasmacytosis of enrolled patients was 20%, with median M-protein of 2.17 g/dL and median FLC ratio of 8.1. Twenty-four patients (62%) had at least one high-risk FISH abnormality (fifteen with 1q gain, four with t(4;14), one with t(14;16) and one with del 17p). Eight patients (21%) had more than one high-risk FISH abnormality. Most common grade 3 toxicities included neutropenia (13%), ALT increased (8%), and diarrhea (8%). Upper respiratory infections occurred in 61% of patients but were mostly low-grade (COVID-19 infection in 11 patients, 1 with grade 3). No patients discontinued therapy due to toxicity. Of the 35 patients that completed at least 2 cycles of therapy, the ORR is 100% with 43% CR, 34% VGPR and 17% PR with responses deepening over time. Seventy-seven percent of patients achieved VGPR or greater. MRD was evaluable in 22 patients at 6 months with MRD negativity rate of 59% and 14% at thresholds of 10 -5 and 10 -6, respectively. At 12 months, 20 patients were MRD-evaluable with 65% and 20% achieving MRD negativity at 10 -5and 10 -6, respectively. Of the 10 MRD-evaluable patients at 24 months, 60% were MRD negative at 10 -5 and 40% at 10 -6. No patients have progressed on treatment. Stem cell collection was successful in all eligible patients with average stem cell yield of 5.53 x 10 6 CD34+ cells/kg. Conclusions: D-RVD in HR-SMM demonstrates significant activity, including a 100% ORR and high rates of MRD-negative disease, preventing progression to overt myeloma.

Outcome of carfilzomib/pomalidomide-based regimens after daratumumab-based treatment in relapsed multiple myeloma: A Canadian Myeloma Research Group Database analysis.

Although daratumumab-containing regimens improve multiple myeloma (MM) outcomes, recurrence is inevitable. We performed a retrospective study using the Canadian Myeloma Research Group Database to benchmark the efficacy of carfilzomib- or pomalidomide-based therapies immediately following progression on daratumumab treatment. We identified 178 such patients; median number of prior lines of therapy was 3, 97% triple-class exposed, and 60% triple-class refractory. In our cohort, 75 received a subsequent carfilzomib-based therapy, 79 received a pomalidomide-based therapy, and 24 received a treatment with both immunomodulatory drug (IMiD) and proteasome inhibitor (PI) using carfilzomib and/or pomalidomide. The median progression-free survival (PFS) and overall survival (OS) for the entire cohort were 4.5 and 14.2 months, respectively. Carfilzomib-based therapy yielded a median PFS and OS of 4.5 and 10.2 months, respectively, compared to 5.2 and 21.7 months for pomalidomide-based therapy. Patients who received both IMiD and PI with carfilzomib and/or pomalidomide had a median PFS and OS of 4.1 and 14.5 months, respectively. Our observations demonstrate the poor outcome of MM patients when standard regimens based on carfilzomib and/or pomalidomide are utilized directly after daratumumab-based therapy given in the relapsed setting. Novel therapies, including immune therapies, are urgently needed to improve the outcomes of these daratumumab-exposed patients.

PB1996: TREATMENT PATHWAYS AT FIRST RELAPSE POST-ASCT IN MULTIPLE MYELOMA: IMPACT OF MAINTENANCE THERAPY ON TREATMENT OPTIONS

Background: The introduction of new agents and treatment combinations has led to significant improvements in outcomes for multiple myeloma (MM) patients. In particular, lenalidomide maintenance therapy (LenM) following autologous stem cell transplant (ASCT) in younger/fitter MM patients has now become standard given the survival benefits associated with it. However, most MM patients will relapse post-ASCT and many effective relapse regimens have a lenalidomide backbone (e.g. KRD: carfilzomib, lenalidomide, dexamethasone, DRD: daratumumab-RD, IRD: ixazomib-RD) making choice of regimen at first relapse increasingly difficult in patients progressing during LenM therapy. Real world data reflecting these choices is needed to inform treatment decisions and consensus guidelines. Aims: We carried out an audit with an aim to: 1. Evaluate treatment and outcomes in MM patients undergoing ASCT from 2010-2020 2. Assess the impact of LenM post-ASCT and therapy choice after relapse. Methods: We carried out a retrospective audit of all patients with MM attending an Irish hospital who underwent ASCT from 2010-2020. Data was collected by chart/electronic record review. Endpoints included no. of ASCT/year and type of induction/maintenance therapy, relapse rates post-ASCT and choice of post-relapse therapy. Results: 71 patients at our centre underwent ASCT for MM between 2010-2020 (24 female,47 male) with median age of 67 and most common isotype IgG Kappa (n=33). The most frequently used induction was cyclophosphamide(C), bortezomib(V) and dexamethasone(D) (>60%, VCD). Use of maintenance therapy increased markedly over this decade, with 0% receiving maintenance in 2010, 44% in 2014 and 83% in 2020. LenM was most common, >75% (n=28).Other maintenance therapies included bortezomib n=4, daratumumab (dara)n=3 and lenalidomide + bortezomib (RV) combination n=4. First relapse treatment data was available for 36 patients. Regimens included carfilzomib/dexamethasone (KD) n=16 +/- lenalidomide (KRD) n=1, pomalidomide (PD), n=1, ixazomib (ID) n=1, dara (n=3) and dara combinations, including daraVD, n=1, and daraPD, n=1. 26 patients did not receive maintenance containing lenalidomide and the majority of these patients received ASCT pre-2015. There were n=13 relapses in this group: n=4 received lenalidomide regimens (RVD/VCD) at relapse. KD n=4, dara n=1, and ID n=1 were also used. First relapse therapy for 17 patients who progressed during LenM included: KD(n=11) 64.7%, dara(n=2) 11.7%, pomalidomide(n=1) 5.8%, and RV(n=2) 11.7% and VCD(n=1) 5.8%. Overall, carfilzomib-based therapy (without lenalidomide) was the most commonly prescribed therapy on first relapse. We observed a clear increase in its use from 2015-2020, in parallel with increased use of LenM. We also noted reducing rates of lenalidomide-based relapse therapies in later years, correlating with increased LenM. Importantly, neither DRD or PVD combinations were reimbursed for prescription in Irish healthcare during the period of audit and are notable absences from the relapse treatment regimens used. Summary/Conclusion: This audit highlights the treatment pathway and outcomes for all patients with MM undergoing ASCT over 10 years in our centre. We have noted significant changes in choice of therapy upon relapse, with carfilzomib prescription rates increasing and lenalidomide-based regimen use decreasing. Our real world data provides direct insight into the effect of widespread LenM therapy on choice of agent upon relapse and highlights the need for consensus treatment guidelines to reflect this evolution in treatment for MM patients.

P25: CARFILZOMIB-BASED TREATMENTS COULD BE ADDED TO IMPEDE-VTE SCORE TO BETTER PREDICT VENOUS THROMBOEMBOLIC RISK IN MM PATIENTS

Introduction: Venous thromboembolic (VTE) risk in Multiple Myeloma (MM) patients treated with novel agents can be very high, particularly with lenalidomide combined with high dose steroid. Guidelines do not recommend a validated Risk Assessment Model (RAM) to precisely identify patients with high VTE risk, in order to personalize the thromboprophylactic strategy. The IMWG score, that is widely used, is not actually performing well, as VTE events continue to occur in about 15% of MM patients. We aim to test IMPEDE-VTE score, which seems to be the most effective RAM in MM, in our real life MM population, trying to eventually implement it with emergent new risk factors. Patients and methods: In our database, we prospectively collected data from 393 MM patients, treated from 2010 to 2021. One-hundred-thirteen (29%) patients were >75 years old, 45% were frail according to simplified Frailty Score, 17% had abnormal LDH level, 19% had renal failure and 4% had a BMI ≥35. ISS stage 3 was scored in 27% of patients and 31% of patients had high-risk cytogenetics. Sixty-six percent of patients received Immunomodulatory (IMIDs)-based therapy (lenalidomide in 32% of patients). Monoclonal antibodies (MoAbs) were used in 8% of patients (MoAbs associated to lenalidomide in 75%) and carfilzomib in 10% of patients (carfilzomib associated to lenalidomide in 51%). Patients were stratified per IMPEDE-VTE score: high, intermediate and low risk were formed by 10%, 41% and 49% of patients, respectively. Eleven percent of patients had a central venous catheter (CVC), and thromboprophylaxis was chosen according to the IMWG criteria (ASA or none 74%, anticoagulants 26%). We have finally analysed the impact of therapeutic risk factors on thromboembolic events’ incidence. Results: VTE events’ rate in our MM population was 16%, the majority of them occurring during the first three months from the starting of therapy. None of patient-related risk factors (age, CCI, Frailty Score, LDH value), nor disease-related risk factors (ISS, cytogenetics, renal failure), except for bone disease, was significant in univariate analysis for increasing VTE risk. On the contrary, CVC, IMPEDE-VTE score, lenalidomide and carfilzomib treatments retained statistical significance. Analysing therapy-related risk factors for VTE risk, we have found only a trend between the group treated with IMIDs-based (thalidomide, lenalidomide, pomalidomide) and that with non-IMIDs-based therapy (p=0.095). Nevertheless, patients treated with lenalidomide had higher VTE risk compared with patients treated without lenalidomide (13% vs 7% at 6 months; p<0.001). MoAbs-based therapy concurred to increase VTE risk, but only when associated to lenalidomide (p<0.001). On the contrary, carfilzomib monotherapy significantly increased VTE risk (p<0.001), regardless the association with lenalidomide. Stepwise Cox regression analysis selected IMPEDE-VTE score (LR-IR vs HR: 7% vs 16% at 6 months; p=0.032) and carfilzomib treatment (24% vs 7% at 6 months; p< 0.001) as independent significant risk factors for VTE. Conclusions: Despite our analysis being retrospective, we confirmed IMPEDE-VTE as a predictive score of VTE risk in a real life MM population. However, our analysis found carfilzomib-based therapy an independent risk factor from IMPEDE-VTE score. We attempt to prospectively study the “carfilzomib-based therapy” parameter in order to implement IMPEDE-VTE score, aiming to better stratify VTE risk in MM patients.

Composition of the Immune Environment at Baseline Correlates with Time to Response and Treatment Outcome in Newly Diagnosed Transplant-Ineligible Multiple Myeloma (MM) Patients Randomized to Krd or Ktd Followed By Carfilzomib Maintenance or Observation (AGMT_MM 02 Study)

Composition of the Immune Environment at Baseline Correlates with Time to Response and Treatment Outcome in Newly Diagnosed Transplant-Ineligible Multiple Myeloma (MM) Patients Randomized to Krd or Ktd Followed By Carfilzomib Maintenance or Observation (AGMT_MM 02 Study)

S100 Calcium Binding Protein Family Members Associate With Poor Patient Outcome and Response to Proteasome Inhibition in Multiple Myeloma.

Despite several new therapeutic options, multiple myeloma (MM) patients experience multiple relapses and inevitably become refractory to treatment. Insights into drug resistance mechanisms may lead to the development of novel treatment strategies. The S100 family is comprised of 21 calcium binding protein members with 17 S100 genes located in the 1q21 region, which is commonly amplified in MM. Dysregulated expression of S100 family members is associated with tumor initiation, progression and inflammation. However, the relationship between the S100 family and MM pathogenesis and drug response is unknown. In this study, the roles of S100 members were systematically studied at the copy number, transcriptional and protein level with patients’ survival and drug response. Copy number analysis revealed a predominant pattern of gains occurring in S100 genes clustering in the 1q21 locus. In general, gains of genes encoding S100 family members associated with worse patient survival. However, S100 gene copy number and S100 gene expression did not necessarily correlate, and high expression of S100A4 associated with poor patient survival. Furthermore, integrated analysis of S100 gene expression and ex vivo drug sensitivity data showed significant negative correlation between expression of S100 family members (S100A8, S100A9, and S100A12) and sensitivity to some drugs used in current MM treatment, including proteasome inhibitors (bortezomib, carfilzomib, and ixazomib) and histone deacetylase inhibitor panobinostat. Combined proteomic and pharmacological data exhibited significant negative association of S100 members (S100A4, S100A8, and S100A9) with proteasome inhibitors and panobinostat. Clinically, the higher expression of S100A4 and S100A10 were significantly linked to shorter progression free survival in patients receiving carfilzomib-based therapy. The results indicate an association and highlight the potential functional importance of S100 members on chromosome 1q21 in the development of MM and resistance to established myeloma drugs, including proteasome inhibitors.

Carfilzomib in Relapsed or Refractory Multiple Myeloma Patients with Early or Late Relapse Following Prior Therapy: A Subgroup Analysis of the Randomized Phase 3 Aspire and Endeavor Trials

Carfilzomib in Relapsed or Refractory Multiple Myeloma Patients with Early or Late Relapse Following Prior Therapy: A Subgroup Analysis of the Randomized Phase 3 Aspire and Endeavor Trials

Immunophenotyping of Baseline Bone Marrow Reveals a Specific Pattern of Immune Cells Associated with Greater Depth and Sustained Response in Newly Diagnosed Patients Randomized to Krd or Ktd Followed By Carfilzomib Maintenance or Control (AGMT MM 02 Study)

Immunophenotyping of Baseline Bone Marrow Reveals a Specific Pattern of Immune Cells Associated with Greater Depth and Sustained Response in Newly Diagnosed Patients Randomized to Krd or Ktd Followed By Carfilzomib Maintenance or Control (AGMT MM 02 Study)

Efficacy and safety profile of deep responders to carfilzomib-based therapy: a subgroup analysis from ASPIRE and ENDEAVOR

To understand the profile of best responders (complete response or better [≥CR]) to carfilzomib, we described the characteristics, progression-free survival (PFS), overall survival (OS) data, and the safety of patients who achieved ≥CR to carfilzomib-based treatment in ASPIRE and ENDEAVOR. In post hoc analyses from ASPIRE and ENDEAVOR, median PFS and OS were longer for ≥CR patients versus those who achieved a very good partial response or partial response (VGPR/PR). In the carfilzomib arm of ASPIRE, median PFS was 50.4 months for ≥CR versus 22.1 months for VGPR/PR; median OS was 67.0 versus 44.2 months, respectively. In the carfilzomib arm of ENDEAVOR, median PFS was 34.0 for ≥CR versus 20.4 months for VGPR/PR; median OS was non-estimable. Despite the longer treatment duration, fewer patients with ≥CR versus VGPR/PR experienced treatment-emergent adverse events that led to discontinuation of carfilzomib-based treatment in ASPIRE or ENDEAVOR. Low serum lactate dehydrogenase was the only factor associated with achieving ≥CR vs patients not achieving CR in ASPIRE in multivariate regression analyses. No association was found between cytogenetic risk status and reaching ≥CR. Carfilzomib treatment may lead to rapid and deep responses, irrespective of most patient characteristics.

An Observational, Retrospective Analysis of Retreatment with Carfilzomib in the Management of Patients with Multiple Myeloma

An Observational, Retrospective Analysis of Retreatment with Carfilzomib in the Management of Patients with Multiple Myeloma

Health-related quality of life of carfilzomib- and daratumumab-based therapies in patients with relapsed/refractory multiple myeloma, based on German benefit assessment data

BackgroundCarfilzomib and daratumumab are licensed in relapsed/refractory multiple myeloma (RRMM), but no head-to-head trials have been conducted.MethodsWe used data from dossiers prepared for the German Federal Joint Committee based on two phase III randomized trials of carfilzomib-based therapies (ASPIRE, ENDEAVOR) and two of daratumumab-based therapies (POLLUX, CASTOR) to conduct a descriptive assessment of health-related quality of life (HRQoL). HRQoL was assessed using the European Organisation for Research and Treatment of Cancer 30-item HRQoL Questionnaire, with hazard ratios calculated for carfilzomib- and daratumumab-based therapy versus comparators for time to HRQoL deterioration of ≥ 10 points. Analyses were also conducted on data from the EORTC 20-item myeloma-specific questionnaire, the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity scale, and the visual analog scale of the EuroQoL 5-dimension, 5-level questionnaire, where results for these instruments were available. As the designs and patient population of the four trials were similar but not identical, the analysis included only indirect, descriptive comparisons.ResultsCompared with lenalidomide/dexamethasone, median time to deterioration in global health status/QoL was longer for carfilzomib-based therapy versus control, but similar for daratumumab-based therapy and control. Compared with bortezomib/dexamethasone, time to deterioration was significantly longer for carfilzomib-based therapy versus control for global health status/QoL and numerous functional and symptom subscales. HRQoL measurement is feasible in large RRMM populations.ConclusionDescriptive assessment of HRQoL data suggests potential benefits for carfilzomib-based over daratumumab-based therapy.

Prospective Study of Cardiac Events During Proteasome Inhibitor Therapy for Relapsed Multiple Myeloma.

Cardiovascular adverse events (CVAEs) can occur during proteasome inhibitor (PI) therapy. We conducted a prospective, observational, multi-institutional study to define risk factors and outcomes in patients with multiple myeloma (MM) receiving PIs. Patients with relapsed MM initiating carfilzomib- or bortezomib-based therapy underwent baseline assessments and repeated assessments at regular intervals over 6 months, including cardiac biomarkers (troponin I or T, brain natriuretic peptide [BNP], and N-terminal proBNP), ECG, and echocardiography. Monitoring occurred over 18 months for development of CVAEs. Of 95 patients enrolled, 65 received carfilzomib and 30 received bortezomib, with median 25 months of follow-up. Sixty-four CVAEs occurred, with 55% grade 3 or greater in severity. CVAEs occurred in 51% of patients treated with carfilzomib and 17% of those treated with bortezomib (P = .002). Median time to first CVAE from treatment start was 31 days, and 86% occurred within the first 3 months. Patients receiving carfilzomib-based therapy with a baseline elevated BNP level higher than 100 pg/mL or N-terminal proBNP level higher than 125 pg/mL had increased risk for CVAE (odds ratio, 10.8; P < .001). Elevated natriuretic peptides occurring mid-first cycle of treatment with carfilzomib were associated with a substantially higher risk of CVAEs (odds ratio, 36.0; P < .001). Patients who experienced a CVAE had inferior progression-free survival (log-rank P = .01) and overall survival (log-rank P < .001). PI therapy was safely resumed in 89% of patients, although 41% required chemotherapy modifications. CVAEs are common during PI therapy for relapsed MM, especially with carfilzomib, particularly within the first 3 months of therapy. CVAEs were associated with worse overall outcomes, but usually, discontinuation of therapy was not required. Natriuretic peptides were highly predictive of CVAEs; however, validation of this finding is necessary before uniform incorporation into the routine management of patients receiving carfilzomib.

Subsequent Treatment Outcomes of Multiple Myeloma Refractory to CD38-Monoclonal Antibody Therapy

Subsequent Treatment Outcomes of Multiple Myeloma Refractory to CD38-Monoclonal Antibody Therapy

Carfilzomib in Relapsed or Refractory Multiple Myeloma Patients with Early or Late Relapse Following Prior Therapy: An Analysis of Overall Survival in Subgroups from the Randomized Phase 3 Aspire and Endeavor Trials

Carfilzomib in Relapsed or Refractory Multiple Myeloma Patients with Early or Late Relapse Following Prior Therapy: An Analysis of Overall Survival in Subgroups from the Randomized Phase 3 Aspire and Endeavor Trials

Association between Patient Profile and Outcomes of Best Responders to Carfilzomib: A Post-Hoc Sub-Group Analysis of Aspire and Endeavor

Association between Patient Profile and Outcomes of Best Responders to Carfilzomib: A Post-Hoc Sub-Group Analysis of Aspire and Endeavor

Differential response to carfilzomib based on initial therapy with bortezomib in multiple myeloma.

e19515 Background: Proteasome inhibitors (PIs) are efficacious in multiple myeloma (MM). In randomized phase 3 studies Carfilzomib doubled the progression free survival (PFS) compared to Bortezomib from 9.4 mo to 18.7 mo (ENDEAVOR study) in relapsed and refractory MM. However concern for suboptimal Carfilzomib based therapy (CBT) response in patients (pt) progressing on Bortezomib based therapy (BBT) suggests “cross-resistance”. Methods: AfterIRB approval, all pt with symptomatic MM over the last 10 years at the Michael E. DeBakey VA Medical Center with initial BBT followed by salvage CBT at progression were included. The primary aim was to evaluate ORR (PR + VGPR+CR) and and PFS by the IMWG criteria, among relapsed/refractory pt treated with salvage CBT whether or not they had an initial BBT response (i.e., primary refractory+stable vs CR+PR+VGPR). Results: In this cohort, the median overall survival was 45 mo. Pt initially treated with BBT had an ORR of 17/19 (89.4%) and median PFS of 7.7 mo. For 12 pt attaining PR, PFS was 4.3 mo, whereas for those achieving CR/VGPR was 9.1 mo, p= 0.03. Two pt were primary refractory to BBT and also to CBT. For initially treated BBT responders the ORR with CBT was 68.4% (13/19), median PFS was 5.26 mo. 6/19 pt (32%) were CBT refractory. PFS during BBT for CBT responders versus CBT refractory patients was not statistically different. Among those who responded to both CBT and BBT there was no significant correlation between the PFS or depth of response (CR vs VGPR vs PR) with initial BBT and PFS with CBT. Conclusions: In our retrospective analysis, pt who exhibited primary resistance to initial BBT did not benefit from salvage therapy with CBT, raising the possibility that hard-wired PI-resistance mechanisms exist. Among BBT responders, CBT ORR was 68%. However the PFS with CBT was significantly shorter than the published literature of CBT in RRMM naïve to PI leading us to hypothesize that uncharacterized resistance mechanisms from “priming” bortezomib leads to inferior outcome with salvage CBT. We conclude that CBT can be attempted in those who respond to BBT independent of depth of response or PFS duration. However, alternative therapies should be considered in pt with primary refractoriness to BBT.

(482) - Treatment of Antibody Mediated Rejection of the Lung Allograft with Carfilzomib-Based Therapy

(482) - Treatment of Antibody Mediated Rejection of the Lung Allograft with Carfilzomib-Based Therapy