Quadruplet Regimen Research Articles

Contemporary Multiple Myeloma Treatment Patterns Among HCPs and Concordance with Expert Recommendations: Analysis of an Interactive Online Decision Support Tool

Background: The management of multiple myeloma (MM) continues to evolve with the emergence of new classes of therapy, most recently including BCMA-targeted therapies. Considering the expanding MM treatment armamentarium, we sought to identify contemporary practice patterns among healthcare professionals (HCPs) for MM and compare them with those of experts using an online decision support tool. Methods: An online decision support tool was developed with input from 5 experts providing therapy recommendations for 192 unique patient case scenarios based on considerations including disease setting, treatment history, access to therapy, and specific comorbidities. HCP tool users entered specific patient criteria to define a case along with their intended management for that case. The tool then showed the 5 expert recommendations for that same case scenario, and users were asked if the recommendations impacted their intended approach. An analysis of expert recommendations and user-selected therapy was performed. Results: Between April 2023 and July 2023, 207 patient cases were entered by 144 participating HCPs. HCP and expert treatment recommendations were frequently discordant, regardless of treatment setting (Table). The highest concordance between HCP and expert recommendations (47%; P <.0001) was in the induction setting (n = 111). In this setting, experts were more likely to recommend quadruplet regimens compared with HCPs (62% vs 27%, respectively; P <.0001). Treatment selection concordance was lower in the maintenance (n = 17; 24%; P <.0001) and relapsed/refractory settings (n = 79; 20%; P <.0001). The lowest concordance (10%; P <.0001) between HCP and expert treatment recommendations was noted in the relapsed/refractory setting specifically among patients who were refractory to earlier lines of therapy (n = 41; P <.0001). For patients who are refractory to earlier lines of therapy, experts were more likely to recommend an anti-CD38-based combination regimen compared with HCPs (81% vs 32; P <.0001). When recommending treatment for patients with triple- or penta-refractory disease, experts were significantly more likely to recommend BCMA-targeted agents (83% vs 39%; P <.0001). For HCPs whose treatment plan did not match expert recommendations in these scenarios, 53% of respondents indicated that expert recommendations confirmed or changed their intended therapy, but 31% indicated that there were barriers to implementing those recommendations. Conclusions: These data suggest ongoing challenges with incorporating the newest therapies and combinations across the spectrum of MM into patient care, particularly multidrug regimens in the induction and maintenance settings and BCMA-targeted therapies in those with triple- or penta-refractory disease. Continued education and development of resources for HCPs, including online decision support tools, may be increasingly important as the treatment of MM continues to grow in complexity.

Bleeding Diathesis Secondary to a Heparin-Like Anticoagulant in a Patient with Multiple Myeloma—A Case Report and Review of Literature

AbstractMultiple myeloma (MM) is a clonal plasma cell disorder that commonly presents with anemia, renal failure, hypercalcemia, and lytic bone lesions. MM is also frequently associated with thrombotic complications; however, it may rarely present with bleeding diathesis. We report a case of a 42-year-old gentleman with relapsed immunoglobulin G lambda MM who presented with epistaxis, gingival bleeding, and oozing at the venepuncture site. Routine tests of coagulation revealed a prolonged prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time. The PT and aPTT failed to correct with pooled normal plasma and the patient was thus diagnosed to have an acquired heparin-like anticoagulant (HLAC). The source of this HLAC has long been debated, but recent data have demonstrated that this HLAC may be the paraproteins produced by the malignant plasma cells. The patient was treated with intravenous protamine sulfate, repeated cycles of plasma exchange, and a daratumumab-based quadruplet regimen but eventually succumbed to an intracranial hemorrhage. HLAC is a rare but potentially fatal complication of MM that must be considered when patients with MM present with bleeding diathesis.

Clinical perspectives on the optimal use of lenalidomide plus bortezomib and dexamethasone for the treatment of newly diagnosed multiple myeloma.

To improve the outcomes of patients with the otherwise incurable hematologic malignancy of multiple myeloma (MM), a key paradigm includes initial treatment to establish disease control rapidly followed by maintenance therapy to ensure durability of response with manageable toxicity. However, patients' prognosis worsens after relapse, and the disease burden and drug toxicities are generally more challenging with subsequent lines of therapy. It is therefore particularly important that patients with newly diagnosed multiple myeloma (NDMM) receive optimal frontline therapy. The combination of lenalidomide, bortezomib, and dexamethasone (RVd) has consistently demonstrated a tolerable safety profile with significant and clinically relevant benefit, including deep and durable responses with improved survival in patients with NDMM regardless of their transplant eligibility. Furthermore, comparative studies evaluating this triplet regimen against both doublet and other triplet regimens have established RVd as a standard of care in this setting based upon its remarkable and concordant efficacy. Given the breadth of clinical data, physician familiarity, inclusion in treatment guidelines, and the emerging potential of RVd-containing quadruplet regimens, RVd will likely continue as a key cornerstone of the treatment of NDMM, and its role will therefore likely continue to grow as a therapeutic backbone in the initial treatment of MM.

Plasma cell leukemia: A multicenter retrospective study of 150 patients.

8014 Background: Despite the use of novel induction regimens, stem cell transplantation (SCT), and maintenance therapy, plasma cell leukemia (PCL) remains a challenging disease with a dismal prognosis. Currently, there is no agreed standard of care management for PCL. We conducted a multicenter retrospective analysis of the clinical presentation, treatment, and outcomes of 150 patients with PCL. Methods: Data of patients diagnosed with pPCL or sPCL between 01/2010 and 01/2021 were entered into a study-specific REDCap database from 7 different U.S. academic sites. PCL was defined as ≥ 5% circulating plasma cells. Clinical data included baseline patient characteristics, clinical presentation, treatment, therapeutic response, and survival outcomes. Overall survival (OS) curves were plotted using the Kaplan-Meier method. Cox proportional hazards regression tested associations between patient characteristics and OS, generating hazard ratios (HR) and 95% confidence intervals (CI), adjusted for PCL type (primary or secondary) and SCT. Results: The analytical cohort included 93 pPCL and 57 sPCL patients. Median age at diagnosis was 60 years. High-risk cytogenetics were found in 56.7% of the patients where it was documented. Of the 79 patients with a documented induction regimen, 58.2% received a proteasome inhibitor triplet, 22.8% received a VTD-Pace like conventional chemotherapy, and 3% received a daratumumab quadruplet regimen. SCT (autologous or allogeneic) was done in 56.1% of the patients. The median OS for all patients, those with pPCL, and those with sPCL was 20.3, 36.6, and 3.2 months, respectively. Secondary PCL was associated with worse survival outcomes compared with pPCL (HR, 2.46; 95% CI, 1.51-3.98; p<0.001) (Table). Median OS was better in patients treated with a proteasome inhibitor triplet regimen vs VTD PACE-like combination (28.2 versus 12.6 months). OS was prolonged among patients who underwent any type of SCT compared with those who did not undergo SCT (44.0 versus 5.7 months, p<0.001). Conclusions: This multicenter retrospective study is one of the largest PCL analyses performed to date and reveals the clinical practice patterns of treatment and survival of PCL patients across the U.S. in the novel treatment era. The survival analysis reinforces the poor prognosis in sPCL patients and the continued need for novel treatment approaches in this patient population. While limited by retrospective design, this analysis suggests prolonged survival with transplantation in both pPCL and sPCL. [Table: see text]

Advantage of achieving deep response following frontline daratumumab-VTd compared to VRd in transplant-eligible multiple myeloma: multicenter study.

The goal of induction therapy for multiple myeloma (MM) is to achieve adequate disease control. Current guidelines favor triplet (bortezomib-lenalidomide-dexamethasone; VRd) or quadruplet regimens (daratumumab, bortezomib-thalidomide-dexamethasone; D-VTd). In the absence of a direct comparison between two treatment regimens, we conducted this study to compare the outcomes and safety of VRd and D-VTd. Newly diagnosed MM patients aged ＞18 years who underwent induction therapy followed by autologous stem cell transplantation (ASCT) between November 2020 and December 2021 were identified. Finally, patients with VRd (N=37) and those with D-VTd (N=43) were enrolled. After induction, 10.8% of the VRd group showed stringent complete remission (sCR), 21.6% showed complete response (CR), 35.1% showed very good partial response (VGPR), and 32.4% showed partial response (PR). Of the D-VTd group, 9.3% showed sCR, 34.9% CR, 48.8% VGPR, and 4.2% PR (VGPR or better: 67.6% in VRd vs. 93% in D-VTd, P=0.004). After ASCT, 68.6% of the VRd group showed CR or sCR, while 90.5% of the D-VTd group showed CR or sCR (P=0.016). VRd was associated with an increased incidence of skin rash (P=0.044). Other than rashes, there were no significant differences in terms of adverse events between the two groups. Our study supports the use of a front-line quadruplet induction regimen containing a CD38 monoclonal antibody for transplant-eligible patients with newly diagnosed MM.

Thrombosis in multiple myeloma: Risk estimation by induction regimen and association with overall survival.

Lenalidomide-containing (R) triplet and quadruplet regimens are the standard of care for multiple myeloma (MM) and have been shown to increase the risk of thrombosis. The association between thromboembolism (TE) and survival in the novel multidrug era is not yet delineated. In this study, we evaluated the incidence of TE during the first year of MM diagnosis, its association with the type of induction regimen, and its impact on overall survival. We studied 672 newly diagnosed MM (NDMM) patients who received a triplet or quadruplet lenalidomide-based induction at the Mayo Clinic, Rochester. TE was diagnosed in 83 patients (12.4%). Of these, 56 (8.3%) had a deep venous thrombosis (DVT), 23 (3.4%) had a pulmonary embolism (PE) with or without the DVT, and 4 (0.6%) patients had a stroke. Carfilzomib-Rd (KRd) had the highest risk of TE (21.1%, 18/85), followed by quadruplets (11.1%, 5/45), bortezomib-Rd (9.6%, 51/531), and 0/11 (0%), treated with other lenalidomide-containing regimens. The difference in TE risk between KRd and the other regimens was statistically significant (OR=2.6, p < .01). Nine patients developed a TE before being exposed to any treatment. Survival was significantly lower among patients that developed a TE (66 vs. 133 months, p < .01). The association of TE with reduced survival demonstrated in univariate analysis (HR=2.2, 95% CI=1.6-3.3) was maintained in the multivariable analysis adjusted for high-risk interphase fluorescence in situ hybridization (FISH), sex, age, receipt of an upfront transplant, the response at induction, and the International Staging System (ISS) (HR=2.61, CI=1.74-3.9). We conclude that TE is an important aspect of MM management, and effective management is especially relevant in the novel treatment era.

Fixed Duration Daratumumab, Ixazomib, Lenalidomide, and Dexamethasone Quadruplet for Newly Diagnosed Multiple Myeloma - MRD Negativity and Survival Outcomes

Background: The combination of a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and dexamethasone is the current standard induction therapy for myeloma. Daratumumab (Dara), a monoclonal antibody directed against CD38, is highly effective in treating myeloma and improves response rates and progression free survival (PFS) when added to a PI or IMiD. Recent studies have shown high efficacy rates with quadruplet regimens that contain these three drug classes, potentially allowing for limited duration therapy as well as reduction in the steroid doses. We designed this trial to examine the efficacy of the quadruplet regimen containing daratumumab, ixazomib (an oral proteasome inhibitor), lenalidomide and dexamethasone (Dara-IRd) given for fixed duration, and to evaluate impact of early discontinuation of steroids. Patients and Methods: Patients with previously untreated MM who had measurable disease and adequate organ function were enrolled, irrespective of their autologous stem cell transplant eligibility (NCT03012880). The primary objective was to determine the rate of complete response to Dara-IRD combination. Treatment involved 28-day cycles consisting of ixazomib 4 mg days 1, 8, 15; lenalidomide 25 mg days 1-21, dexamethasone 40 mg, weekly and Dara 16 mg/kg, weekly for two cycles, every other week during cycles 3-6 and then every 4 weeks thereafter during induction (12-cycles) followed by Dara-ixazomib maintenance (maximum 24 cycles). Patients were enrolled into two sequential cohorts: Cohorts A (n=38) and B (N=40), with dexamethasone discontinued after two cycles in Cohort B. Transplant eligible patients were allowed to collect stem cells for future transplant anytime after 4 cycles. Serum immunofixation was assessed with mass spectrometry (MASS-FIX) and marrow MRD negativity by Euro flow (sensitivity of 1 in 105). Results: Seventy-eight patients were enrolled; median age was 63.5 (range 33, 81), 55% were male. A third of the patients were high risk by mSMART criteria and ISS stage 1, 2, and 3 had 41%, 35%, and 24% of patients respectively. All patients have completed the treatment phase and those who have not gone off study continue on observation. Among the 40 patients who have gone off study, the reasons for discontinuation among patients in Cohorts A and B, respectively were: progression, 9 and 12; alternate therapy (most often transplant), 11 and 8. The best overall response on therapy was 96% including 31% CR, 39% VGPR. For the entire cohort, time to response was fast, median time to VGPR, CR or minimal residual disease negative (MRD) negativity was 4 cycles. Responses deepened over the duration of treatment as shown in the figure; 31% of patients achieved a marrow MRD negative status (28% CR and MRDneg). After a median follow up was 37.8 months, median PFS or OS has not been reached. Five patients enrolled on the study have died. A grade 3 or higher adverse event at least possibly attributed to the study drugs was seen in 56% of patients. The most common toxicities included fatigue, neutropenia, lymphopenia, peripheral neuropathy, diarrhea, and nausea. Stem cells were collected in 60 patients; median (range) of CD34 cells/kg 7.8 (2.8, 15.9) x 106, with plerixafor used in 88% of patients as per our standard of care "on-demand” approach based on blood CD34 count. Conclusion: Dara-IRd is an active regimen in newly diagnosed MM, with high overall rates of response and deep and durable responses with nearly a third of the patients being MRDneg (Mass Spec based blood testing and flow based MRD), that improved over time with therapy. The toxicities were manageable, with dose modifications. All patients were able to collect stem cells when required, though the majority needed plerixafor. This study demonstrates excellent outcomes with limited duration quadruplet regimen without planned upfront autologous stem cell transplant and no maintenance till progression. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase II Study of the Combination of Daratumumab, Ixazomib, Pomalidomide, and Dexamethasone in Early Relapsed/Refractory Multiple Myeloma

Background: The combination of daratumumab (D), pomalidomide (P), and dexamethasone (d) has previously demonstrated high overall response rates in patients with relapsed/refractory (R/R) MM. Results of the phase 3 APOLLO study of DPd vs Pd in patients with R/R MM with at least 1 prior line of therapy showed 69% ORR with a median PFS of 12.4 months in those patients who received the triplet combination (Dimopoulos, et al. Lancet 2021). Quadruplet regimens may further improve results by providing deeper and more durable responses with more intensive regimens. We report interim findings from a phase 2 multicenter trial of the addition of ixazomib to DPd (DIPd) in patients with early R/R MM. Methods: This is a prospective, multi-center, open-label, single arm phase 2 study (NCT03590652) with a primary endpoint of overall response rate (ORR), safety, and efficacy of DIPd. Secondary endpoints include progression-free survival (PFS), overall survival (OS), and MRD-negativity rate. A Simon's optimal 2-stage design was used, with 14 subjects in stage 1 and 32 patients for stage 2. Eligible patients may not have had prior exposure to daratumumab or ixazomib, may not have progressed on prior pomalidomide, and must have received ≥1 or ≤3 prior lines of therapy including lenalidomide and a proteasome inhibitor. The first six patients in a safety run-in received daratumumab 16mg/kg IV weekly x 8 doses, biweekly x 8 doses, then monthly, pomalidomide 4mg orally on days 1-21, ixazomib 4mg orally on days 1, 8, 15, and dexamethasone 20-40mg weekly on a 28-day cycle. Grade 3-4 neutropenia was observed in 100% of patients in the safety run-in, prompting starting dose reductions to ixazomib 3 mg and pomalidomide 3 mg by the DSMB. An amendment allowed for subcutaneous daratumumab administration. MRD assessments are being performed by EuroFlow for patients in suspected CR. Pharmacodynamic changes in patients' tumor microenvironments were established by custom panel mass cytometry to include T-cell memory and activated subpopulations, B-cell content, NK-cell subpopulations as well as MDSCs, Tregs and T-exhaustive markers, monocytes and dendritic cells. Results: To date, 14 subjects were treated in stage 1, and 23 of 32 planned subjects in stage 2. Of the 30 evaluable patients to date, the median age was 62.5y (range 41-87), and were 50% female and 70% white. Patients had a median of 1 prior line of therapy (range 1-3), and 52% (12/23) had at least one high-risk FISH feature including -17p, +1q, t(14;16), t(14;20), or t(4;14) . Grade 3-4 treatment emergent adverse events include neutropenia (63%), lymphopenia (9%), non-specific leukopenia (3%), thrombocytopenia (9%), febrile neutropenia (13%), infection (22%), electrolyte disturbance (6%), respiratory condition (6%), infusion reaction (3%), thrombosis (3%), and psychiatric condition (3%). Median time on treatment (n=25) is 4.8 months (range: 0.4-30.8), with 15 patients currently remaining on DIPd therapy and 7 deaths (4 PD, 1 sepsis, 1 COVID, 1 surgical complication). ORR to date is 83% (25/30) in evaluable patients, and best responses include 8 (27%) sCR, 3 (10%) CR, 6 (20%) VGPR, 8 (27%) PR. After a median follow up of 15.1 months, the median PFS is 11.6 (95% lower bound: ≥ 7.4) months and median OS is 38.9 (95% lower bound: ≥ 18.8) months. Conclusion: The quadruplet regimen DIPd builds upon the successes of daratumumab-based triplet regimens showing that the addition of a 4th agent can result in improved overall response rates with manageable toxicity and the convenience of a nearly all-oral drug regimen in patients with early R/R MM. These data are particularly compelling for high risk disease as more than half of the patients treated to date had at least one high risk feature, offering a promising option for the management of early relapse in high risk patients.

Density of the Spleen in Low-Dose CT Scans Is Associated with High-Risk Disease Features and Shorter Survival in Newly Diagnosed Multiple Myeloma Patients

Introduction Whole body low-dose computed tomography (WBLDCT) is standard of care in the diagnostic work-up of suspected multiple myeloma. While the focus of clinical routine evaluation lies on the detection of osteolytic lesions or extramedullary myeloma manifestations, the entire informative capacity of WBLDCT scans seems underestimated. Here, the analysis of non-focal signal alterations might provide further diagnostic insights, and a recent study by Terao et al. described tumor-burden dependent loss of the splenic signal in diffusion-weighted MRI in newly diagnosed myeloma (NDMM) patients. However, due to limited availability of MRI, most NDMM patients receive WBLDCT at initial diagnostic work-up. Therefore, we asked if non-focal signal alterations of the spleen in WBLDCT scans (i.e., radiographic tissue density of the organ) in NDMM patients might correlate with disease characteristics, cytogenetics and clinical outcomes. Methods In this retrospective analysis, we screened clinical records of NDMM patients diagnosed and treated at our institution (LMU University Hospital Munich, Germany) between 01/2010 and 12/2020. Clinical and laboratory data from initial diagnosis until first relapse were integrated with segmentation analyses of WBLDCT scans taken within 90 days before diagnosis. Plasma cell dyscrasias others than MM as well as cases with CT scans taken >90 days before diagnosis or CT scans containing contrast media were excluded. Results A total of 231 consecutively treated NDMM patients were included with a median age of 66 years (range 25-89). Cytogenetic analyses were available in 177 (77%) patients of which 38 had high-risk (HR) aberrations including t(4;14), t(14;16) and del(17p). In 44 (19%) of patients a gain(1q) was found. Patients were classified according to ISS and R-ISS: ISS-1 84 (43%), ISS-2 56 (28%), ISS-3 57 (29%) and R-ISS-1 38 (22%), R-ISS-2 119 (70%), R-ISS-3 13 (8%). Induction therapy consisted of a doublet regimen in 61 (26%), a triplet regimen in 167 (72%) and a quadruplet regimen in 3 (1%) patients. From the entire cohort, 141 (61%) patients received high-dose melphalan and autologous stem cell transplantation (auto-SCT), and 46 (20%) patients underwent tandem auto-SCT. Maintenance therapy after auto-SCT was applied to 49 (35% of auto-SCT) patients. Spleen density gradually increased with ISS and R-ISS stages. Thus, ISS3 and R-ISS3 displayed a significantly increased spleen density compared to ISS1 and R-ISS1 patients (ISS3 40.7 HU vs. ISS1 35 HU, p=0.003; R-ISS3 45.4 vs. R-ISS1 32.5 HU, p=0.004, Fig. 1A). We further found spleen density to be significantly higher in patients with HR cytogenetics (HR vs SR HU, p=0.03), in particular with t(4;14) (p=0.04), but not with del(17p), t(14;16) or gain(1q). Moreover, it positively correlated with serum lambda light chain levels in patients with lambda paraproteinemia (r = 0.26, p = 0.02), but not with kappa light chain or immunoglobulin levels. Based on an optimal log-rank test separation algorithm, NDMM patients with a spleen density of > 53.5 HU (Spleenhigh) had a shorter survival compared to Spleenlow patients (median PFS: 18.9 vs 32.1 months, p=0.01, Fig. 1B; median OS: not reached, p=0.02). PFS and OS differences were similar in subgroup analysis of transplant-eligible (PFS: p=0.08; OS: p=0.04) and transplant-ineligible patients (PFS: p=0.02, OS: p=0.04). In multivariate cox regression analyses including Spleenhigh/low and R-ISS stages, spleen density remained an independent factor for shorter survival (HRPFS 2.45, 95%CI 1.21-4.49, p=0.007; HROS 3.24, 95%CI 1.06-8.23, p=0.02). Conclusion Our data suggest that high density of the splenic tissue in WBLDCT is associated with high-risk features and inferior survival of NDMM patients. Increased cell numbers or deposition of light chains within the spleen might represent modes of action. If validated in future prospective studies, spleen WBLDCT density may complement existing risk-stratification tools. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Interim Results of a Risk-Adaptive Phase II Study: Carfilzomib, Lenalidomide, Dexamethasone and Daratumumab (KRD-Dara) in Newly Diagnosed Multiple Myeloma (NDMM) at the Levine Cancer Institute (LCI)

Background: The combination of carfilzomib, lenalidomide and dexamethasone (KRd) has previously demonstrated deep and durable responses in patients with NDMM. A quadruplet regimen incorporating daratumumab (KRd-Dara) may further improve results. We report an interim analysis from stage 1 (Simon's optimal 2-stage design) of an ongoing minimal residual disease (MRD)-driven, single center phase 2 trial of KRd-Dara. Methods: The study design has been previously published (Bhutani et al, Blood 2020 Abstr 1388). Briefly, patients with NDMM (both transplant eligible and ineligible) were allowed one cycle of non-protocol therapy (if deemed necessary) and then 7 or 8 cycles of induction therapy with KRd-Dara (total induction cycles: 8). MRD assessment was performed by both next generation sequencing (NGS) and next generation flow cytometry (NGF) at the end of 8 cycles of induction, post- autologous stem cell transplantation (ASCT), and every 4 cycles of consolidation (maximum of 12 cycles). Post-induction treatment was dictated by an MRD-driven algorithm, using MRD (NGS, 10-5) to assign patients to one of the 3 study groups. The primary endpoint is complete response (CR) + stringent CR (sCR) at the completion of KRd-Dara induction therapy. Group A (MRD negative post-induction) proceeded directly to lenalidomide maintenance therapy deferring ASCT, if transplant eligible. Group B (MRD positive, transplant eligible) received upfront ASCT, KRd consolidation (maximum 12 cycles), and then lenalidomide maintenance. Group C (MRD positive after 8 cycles of induction, transplant ineligible) received KRd consolidation (maximum 12 cycles) followed by lenalidomide maintenance. Conversion to MRD negative status at any protocol specified time point allowed the patients to proceed to lenalidomide maintenance. Results: Stage 1 futility analysis criteria were met in November 2021 and stage 2 enrollment is actively ongoing. As of a data cutoff of 4/8/22, 30/39 patients have been enrolled. Twenty-three patients were enrolled in Stage 1. The median age of stage I patients was 60 (range 34- 76) years, 74% were male and 35% were Black. R-ISS stage 3 was present in 2 (8.7%), high-risk cytogenetics in 1 (4.4%) and gain 1q21 in 7 (30.4%). Fifteen patients (65.2%) received one cycle of pre-study treatment. All patients completed 8 total cycles of induction therapy. At the end of induction, CR + sCR was achieved in 15/23 (65.2%) patients with sCR in 52.2%, and very good partial response (VGPR) in 7 (30.4%). The MRD negativity rate was 69.6% (NGS, 10-5) and 43.5% (NGS, 10-6). The MRD negativity rate by NGF was 82.6% at 10-5and 47.4% at 10-6 sensitivity level in 23 and 19 evaluable patients, respectively; 43% of bone marrow specimen tested by NGF were hemodiluted. Concordance of MRD by NGS/ NGF at 10-5 was 16/23 (69.6% in agreement and 30.4% disagreement, Cohen's kappa: 0.183). Concordance of MRD by NGS/ NGF at 10-6 was 12/19 (63.2% in agreement and 36.8% disagreement, Cohen's kappa: 0.257). Grade 3-4 treatment related adverse events (>10% of patients) included hypophosphatemia (30%), hypertension (13%), and neutropenia (13%). Covid infection occurred in 7 (30.4%) patients; only one needed hospitalization. Other Infections (any grade) were seen in 15 (65.2%) patients. At least one dose reduction of carfilzomib was required in 5 (21.7%) patients, dexamethasone in 3 patients, and lenalidomide in 4 patients. Systemic injection reactions to subcutaneous daratumumab occurred in 5 (21.7%). Thromboembolic events happened in 3 patients. No patient discontinued treatment because of toxicity. There was no treatment-related mortality during stage 1. Post-induction, 16 patients (MRD negative) transitioned to lenalidomide maintenance, 5 patients (MRD positive) underwent ASCT, and 2 patients (MRD positive) proceeded to consolidation phase. Stem cell collection for eligible patients (n=22) was performed upon completion of induction; 5 patients failed to collect optimal target (3 million CD34+ cells/kg) during their first mobilization attempt. Survival results will be updated after stage 2 enrollment is completed, but as of data cutoff, no subjects in the Stage 1 cohort have progressed. Conclusions: The quadruplet regimen KRd-Dara as induction in NDMM leads to deep responses reflected in high rates of sCR and MRD negativity with an acceptable and well-tolerated safety profile. The stage 2 enrollment is ongoing.

Demographic Patterns and Outcomes of Multiple Myeloma Patients Received Autologous Stem Cell Transplant: A Nationwide Analysis

Introduction: Triplet or quadruplet regimens with autologous stem cell transplant(ASCT) in eligible patients has become the standard of care for multiple myeloma(MM) in recent years due to improved outcomes. Significant racial and socioeconomic variations were observed in the past in regards to treatment utilization and outcomes. We aim to explore the demographic, racial distribution and inpatient mortality trends among MM patients receiving ASCT in recent years. Methods: Cases with a diagnosis of MM that received an ASCT were identified from the National Inpatient Sample database from 2016 to 2019 using the International Classification of Disease 10th Revision Diagnosis and Procedure Codes. Cochran Armitage test of trend, Chi-square tests and ANOVA tests were used to analyze trends, inpatient deaths (IPDs), and means between different groups of interest. The results are statistically weighted. Results: A total of 477,065 MM cases were identified from 2016-2019, out of which 25,145 received ASCT. The number of patients that received ASCT from 2016-2019 were 5925, 6185, 6625, and 6410 respectively. During the same time frame, the proportion of cases aged less than 65 were 3700 (62.4%), 3815 (61.7%), 3900 (58.9%), 3820 (59.6%), P<0.001. The number of cases in the age range 65-74 were 1840 (31.1%), 1920 (24%), 2155 (27%), 2075 (26%), P = 0.039 and the proportion of patients aged 75 and above were 135 (2.3%), 175 (2.8%), 240 (3.6%), 225 (3.5%), P <0.001. Females that received ASCT were 2660 (45%), 2585 (41.8%), 2805 (42.3%), 2690 (42%), P=0.003. The mean Charlson Comorbidity Index (Standard Deviation) from 2016 to 2019 was 4.36 (1.36), 4.37 (1.54), 4.48 (1.53), 4.53 (1.62), P <0.001. From 2016-19, the proportion of Caucasians, Blacks, Hispanics and Asian/Pacific Islanders are stated in Table 1. IPDs among ages less than 65, 65-74, and 75 and above from 2016-2019 were 125 (0.8%), 45 (0.6%) and 15 (1.9%) respectively. IPDs among Blacks was 10 (0.2%) when compared to Non-blacks 185 (0.9%), P<0.001. Caucasians noted to have an IPD of 125 (0.8%) compared to non-Caucasians 70 (0.7%), P=0.364, while Hispanics had IPDs in 20 (0.9%) compared to 175 (0.8%) in Non-hispanics, P=0.369. Conclusion: From 2016 to 2019, we observed an overall increase of MM patients receiving ASCT and continued to notice the similar trend among males. Hispanics and Asian/Pacific islanders were also noted to have an increasing trend of ASCT during the same time period. Conversely, there was a decrease in the proportion of MM patients receiving ASCT among the age group less than 65, 65-74, and females. IPD was noted to be lower in blacks; and also in the 65-74 years age group but higher among age 75 and above who received ASCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cyclophosphamide-Bortezomib-Dexamethasone (CyBorD) +/- Daratumumab Treatment Results in Sustained Hematologic Response in Patients with AL Amyloidosis: A Retrospective Analysis of Patients at Mayo Clinic

Introduction Light chain (AL) amyloidosis is a rare plasma cell disorder characterized by amyloid fibril deposition in various organs leading to progressive organ damage. The standard of care therapy has been cyclophosphamide-bortezomib-dexamethasone (CyBorD) until January 2021 when daratumumab was approved by the FDA for use after data from the Phase 3 ANDROMEDA trial revealed improved outcomes with the quadruplet regimen. Here, we retrospectively evaluated the outcomes of patients with newly diagnosed AL amyloidosis treated with CyBorD +/- daratumumab as first line therapy at the Mayo Clinic from 2009 to 2022. Methods The study was approved by the Mayo Clinic Institutional Review Board. We performed a retrospective analysis of patients diagnosed with AL amyloidosis between 2009 and 2022 who received CyBorD +/- daratumumab as first line therapy. The regimen consisted of subcutaneous bortezomib (1.3 mg/m2 or 1.5mg/m2 on days 1, 4, 8, and 11 every 28 days), cyclophosphamide (300mg/m2 orally or IV weekly), and dexamethasone (20-40mg orally or IV weekly). In patients who also received daratumumab, dosing was 1,800 mg weekly for cycles 1 and 2, every 2 weeks for cycles 3-6, followed by weekly for any additional cycles. Data extracted from the medical record included patient characteristics, subsequent therapies, labs, rates of relapse, and outcomes. Results There were 164 patients available who met criteria for inclusion of newly diagnosed AL amyloidosis. Of the 164, 30 (18.3%) received CyBorD with daratumumab. Mean age at diagnosis was 63.8 years (range, 35-81 years). Most frequent organ involvement included cardiac in 73.8% and kidney in 61.0% patients. Eighty-one percent of patients achieved a hematologic response (defined as complete response in 38% or very good partial response, VGPR, in 43%). No patients were considered eligible for transplant at diagnosis, however after CyBorD +/- daratumumab therapy, 62 (37.8%) received an autologous stem cell transplant (ASCT). Over half of patients received maintenance therapy after initial treatment (53.7%), with daratumumab being the most common maintenance therapy prescribed (62.5%). The most frequent treatment related adverse event included peripheral neuropathy (40.7%), although no patients experienced grade 4 peripheral neuropathy. Forty-five percent of patients experienced cytopenias during treatment, however only <1% required transfusions. There was no difference in treatment related adverse effects with the addition of daratumumab. At 1-year, overall survival was 94% (95% CI 0.90-0.98) and at 5 years, overall survival was 77% (95% CI 0.67-0.87). Conclusions In our retrospective analysis, CyBorD +/- daratumumab produced a durable hematologic response in newly diagnosed patients with AL amyloidosis. Although 18% of patients received daratumumab, outcomes were still excellent, with nearly 40% of patients eligible for ASCT after treatment and 5-year overall survival of 77%.

Stem Cell Mobilization Characteristics for Transplant Eligible Patients with Newly Diagnosed Multiple Myeloma (NDMM) Treated with Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab (KRd-Dara)

Introduction: CD38 monoclonal antibody (mAb)-containing quadruplet regimens have been shown to improve depth and duration of response in patients with NDMM eligible for autologous stem cell transplant (ASCT). However, some studies have raised concerns about the detrimental effect of combined lenalidomide and CD38 mAbs on stem cell mobilization. As an exploratory endpoint, we evaluated the effect of KRd-Dara on stem cell mobilization and collection in the Levine Cancer Institute (LCI) KRd-Dara study (NCT04113018) that permits up to 8 cycles of induction with KRd-Dara followed by an MRD-directed treatment algorithm for transplant-eligible and transplant-noneligible patients (Bhutani et al, Blood 2020 Abstr 1388). We provide a table summarizing our results from stage 1, along with two other phase II studies, the MANHATTAN (Landgren et al, JAMA Oncol 2021) and the MASTER (Costa et al, JCO 2021) studies that used variable numbers of KRd-Dara induction cycles prior to stem cell apheresis. Patients and study design: Eligible patients had NDMM and an ECOG performance status score of 0-2. Induction treatment consisted of 28-day cycles of KRd-Dara with intravenous carfilzomib, 20/56 mg/m2 (days 1, 8, and 15); lenalidomide orally, 25 mg (days 1-21); dexamethasone weekly; daratumumab (subcutaneous) per standard approved dosing schedule. One pre-study cycle with non-protocol therapy was allowed. During stage I of the study, stem cell collection for transplant-eligible patients was performed after 8 cycles of induction. All patients were mobilized with granulocyte-colony stimulating factor (G-CSF, 10 µg/kg) daily for 5 days. Preemptive Plerixafor was administered in the evening of Day 4 if the blood CD34+ cell count was <50/µl. Collection was done over 2 days in some patients who failed to collect sufficient CD34+ cells during the first day. A second mobilization attempt after a few weeks of additional wash-out was allowed. Our center-specific minimum required collection target is 3 x 106 CD34+ cells/kg, below which the stem cell dose is considered inadequate to perform a single ASCT. Physicians requested collection for potentially 2 or 3 transplants per patient, with a collection goal of 8 -12 x 106 CD34+ cells/kg. Mobilization failure was defined as the proportion of patients with Day 4 CD34 count <1/µl or collection of <3 x 106 CD34+ cells/kg (considered inadequate for even one ASCT) during the first mobilization attempt. Results: Among the 22 mobilized patients during stage 1 analysis, the median age was 60 years (range, 34 to 72) and 32% were African Americans. Eighteen patients received plerixafor, 3 did not based on futility as their Day 4 blood CD34 count was zero, and only one patient met the threshold of not receiving Plerixafor. The median total CD34+ cells collected were 7.73 x 106/kg (range, 0.00-19.18). Six (27%) patients had mobilization failure after their first attempt. Four of these patients underwent a second attempt after a median of 56 days (range, 36-98 days), with only one patient collecting enough CD34+ cells for one ASCT. Of the 10 patients whose collection goal was 2 transplants (8 million CD34 cells/kg), 9 patients did not meet the goal. Of the 12 patients whose collection goal was 3 transplants (12 million CD34 cells/kg), 8 patients did not meet the goal. Conclusions: The stem cell mobilization failure rate was high in patients collecting after 7 or 8 cycles KRd-Dara. Second remobilization with G-CSF and plerixafor was successful in only 1 of the 4 patients. We have modified stage 2 of the protocol to allow stem cell collection after cycle 3 of KRd-Dara induction. We plan to do combined analyses of LCI, MANHATTAN and MASTER to determine predictive factors associated with poor stem cell mobilization after KRd-Dara induction. Based on our results, we recommend stem cell collection after 3-4 cycles of KRd-Dara regimen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Investigating Differences in Treatment (Tx) Patterns and Clinical Characteristics Among Patients (Pts) Diagnosed with Multiple Myeloma (MM) Across Racial Groups

Introduction: Published studies have shown significant racial disparities in MM incidence, Tx patterns, and outcomes. Black/African American (AA) pts have both higher MM incidence and corresponding mortality than White (W) pts. AA pts present at younger median age yet are less likely to be enrolled in clinical trials of novel therapeutic agents or undergo stem cell transplant (SCT). However, in studies performed in equal access situations, AA have comparable or better overall survival, highlighting the importance of improved access to healthcare. Using a large, real-world database we explored how tx patterns and clinical characteristics differ between racial groups and have evolved over a 10-y period. Methods: This retrospective observational study examined MM pts identified in the Flatiron Health from 1 Jan 2011 to 31 Jan 2022. This US-based real-world database collects electronic health records data from community practices (~80%) and academic centers (~20%). Pts aged ≥ 18 y, with a documented MM diagnosis (first diagnosis = index date) between 1 Jan 2011 and 31 Oct 2021 who received at least first-line (1L) systemic therapy and had ≥ 3 mo of follow-up were included. Descriptive statistics were used for all continuous, categorical, and binary study variables. Results: A total of 9083 pts were analyzed: 65% (n = 5904) were W; 20% (n = 1810) were AA; 15% (n = 1369) were 'Other race' (O). These proportions did not vary by year of diagnosis. Before 2015, 33% (n = 3036) of all pts were diagnosed with MM, 52% (n = 4700) diagnosed by 2015-2019, and 15% (n = 1347) diagnosed ≥ 2020. Median age at index was 70, 66, and 68 y in W, AA, and O pts, respectively. A Charlson Comorbidity Index (CCI) score ≥ 1 at index was reported in 9.3% of pts overall; the proportion of pts with CCI ≥ 1 increased over time: W 4.8% (< 2015), 10.2% (2015-2019), and 14.2% (≥ 2020); AA 5.3% (< 2015), 12.4% (2015-2019), and 16.7% (≥ 2020); and O 4.7% (< 2015), 11.3% (2015-2019), and 10.3% (≥ 2020). At diagnosis hypercalcemia was rare (4.2% overall), without appreciable differences by race. Renal insufficiency (creatinine clearance > 2 µmol/L) was seen in 15.9% of pts overall and differed by race: W 15.1%, AA 19.2%, and O 15.2%; this was stable across study periods. Overall 37.9% of pts had anemia; W 35.5%, AA 44.9%, and O 39.8%. Bone lesions, identified using International Classification of Diseases codes, were rare (1.1% overall). Overall, 30.4% of pts received SCT and median time from index date to SCT was 8 mo (232 d). Across race cohorts, 31.8%, 28.7%, and 26.8% of W, AA, and O pts, respectively, received SCT and median time to SCT was 7.4, 8.4, and 8.0 mo for W, AA, and O pts, respectively. The proportion of pts who had triplet or quadruplet 1L regimens was similar across race cohorts (W 58.1%; AA 58.0%; and O 60.3%). While the percentage of pts receiving triplet or quadruplet regimens increased over time for all races and were similar, W pts generally received quadruplet therapy more often than AA and O pts (Figure 1). Before 2015, the most common 1L regimen was lenalidomide + dexamethasone (Rd) across all races (W 23.8%; AA 26.2%; and O 19.4%), and Rd + bortezomib was the most common 1L regimen from 2015 to Jan 31, 2022. The average time from index date to start of 1L therapy was 153, 173, and 170 d for W, AA, and O pts, respectively, indicating a longer time to tx for AA and O pts. Time from diagnosis to 1L tx shortened over time for all races. In ≥ 2020 the percentages of pts treated within 1 mo of diagnosis were W 45.7%; AA 43.0%; and O 49.1% (Figure 2). Average duration of 1L therapy was 13, 13, and 12 mo for W, AA, and O pts, respectively. Conclusion: This real-world study presents pt characteristics and tx patterns using the Flatiron database. Compared with W pts, AA pts were more likely to present with anemia and renal insufficiency, and experienced higher CCI scores over time, possibly indicating later diagnosis. By including pts who received at least 1L therapy, this group of pts analyzed likely represents an equal access setting, despite lower rates of private insurance and delayed tx onset among AA. Thus, in contrast to prior studies, AA and W pts were found to have similar tx patterns, including access to highly active combination therapy and SCT use. This indicates that prior disparities in the availability of novel agents can be overcome with appropriate resourcing, and although limited differences in tx were identified by race, further analysis exploring disparities in access to 1L therapy are needed. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone (Isa-KRd) in Patients with High-Risk Newly Diagnosed Multiple Myeloma: Planned Interim Analysis of the GMMG-Concept Trial

Background: High-risk (HR) multiple myeloma (MM) patients (pts) have a significantly disadvantageous prognosis. Emerging data show that achievement of minimal residual disease (MRD) negativity is associated with better outcome in HR pts. Most recently, several clinical trials demonstrated that addition of monoclonal anti CD38 antibodies (i.e. isatuximab) significantly improve MRD negativity, response rate and survival when added to standard of care regimens. Carfilzomib (K), lenalidomide (R) and dexamethasone (d) is one of the most effective and tolerable regimens in newly diagnosed multiple myeloma (NDMM). The phase II CONCEPT trial (NCT03104842) investigates the quadruplet regimen isatuximab plus KRd (Isa-KRd) in HR NDMM in induction and consolidation including high-dose melphalan (HDM) for pts being transplant-eligible (TE). Here, we report for the first time the planned interim analysis (IA) of the primary endpoint MRD negativity after consolidation for TE-patients and the corresponding final analysis of transplant non-eligible (TNE) pts. Methods: 153 pts with HR NDMM were included into the open-label, academic, multicentre phase II clinical trial, an extension cohort of TE pts is currently recruiting. According to the trial design, 99 of 127 TE pts in study arm A (TE-ITT) were included in the intention-to-treat population (ITT) of the planned IA (TE-ITT-IA); results of the 26 TNE pts in study arm B (TNE-ITT) are finally reported. HR MM was defined by the presence of del17p or t(4;14) or t(14;16) or > 3 copies 1q21 in combination with ISS 2 or 3 stage disease. Pts could be included after a maximum of 1 cycle of MM treatment. Pts received 6 cycles of Isa-KRd induction, followed by HDM for TE pts or 2 Isa-KRd cycles for TNE pts, 4 cycles Isa-KRd consolidation and Isa-KR maintenance. Primary endpoint is MRD negativity at end of consolidation measured by next-generation flow at the minimum sensitivity threshold of 10-5 (H0: MRD-neg-rate ≤ 50% (TE) and ≤ 30% (TNE), tested by one-sided binomial test), this planned IA reports on. Secondary endpoint is progression-free survival (PFS), tertiary endpoints include overall response rate (ORR) and safety. Results: 125 pts (99 TE-ITT-IA, 26 TNE-ITT) were included from August 2017 to April 2020 in the IA population in 17 German Centres. No bias arose in the reduction of the TE-ITT population to the TE-ITT-IA population. Based on inclusion criteria, all pts had cytogenetic HR disease including del17p in 55 pts (44.0%), t(4;14) in 48 (38.4%), t(14;16) in 19 (15.2%) and > 3 copies 1q21 in 45 pts (36.0%). 38 pts (30.4%) had ≥ 2 HR aberrations. 66 pts (52.8%) had ISS 2 and 58 (46.4%) ISS 3 disease. Median age (range) was 58 (35-73) years in the TE-ITT-IA and 74 (64-87) years in the TNE-ITT. The design of the study provides for the MRD-analysis to be performed on 93 patients in the TE-ITT-IA and 24 patients in the TNE-IA. At the end of consolidation, in the TE-ITT-IA population 67.7% (n=63) of pts were MRD negative, 3.2% (n=3) MRD positive, 24.7% (n=23) timepoint not reached, 4.3% (n=4) missing (4 pts not assessable, 2 did not start). In the TNE-ITT population 54.2% (n=13) of pts were MRD negative, 0% MRD positive, 45.8% (n=11) timepoint not reached. The primary endpoint was significantly reached in both study arms (p = 0.0004 for TE-ITT-IA and p=0.012 for TNE-ITT). ORR (best response to treatment) in the TE-ITT-IA was 94.9% (n=94) with 72.7% showing complete remission (CR) or better (n=72), 18.2% (n=18) very good partial remission (VGPR), 4% (n=4) partial remission (PR), 1% (n=1) progressive disease (PD) and 4% (n=4) timepoint not reached. In the TNE-ITT, 57.7% (n=15) showed CR or better 30.8% (n=8) VGPR, 3.8% (n=1) were unknown and 7.7% (n=2) timepoint not reached. Updated PFS data will be shown. Safety-population consists of 122 pts. In total, 85.2% (n=104) developed ≥ grade 3 treatment-emergent adverse events (TEAEs). Serious TEAEs occurred in 64.8% (n=79) of pts. TEAEs leading to discontinuation of study treatment occurred in 5 pts. Conclusions: The CONCEPT trial is the first trial investigating Isa-KRd for HR NDMM in TE and TNE patients. Isa-KRd in induction and consolidation leads to high MRD negativity rates after consolidation in this difficult-to-treat population. Toxicity was consistent with expectations and no new safety signals occurred in this IA. In our view, our data underline the importance of optimized quadruplet treatment in NDMM, especially in HR disease.

A single arm phase Ib/II trial of first-line pembrolizumab, trastuzumab and chemotherapy for advanced HER2-positive gastric cancer

In this multi-center phase II trial, we evaluated the efficacy and safety of a quadruplet regimen (pembrolizumab, trastuzumab, and doublet chemotherapy) as first-line therapy for unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC) (NCT02901301). The primary endpoints were recommended phase 2 dose (RP2D) for phase Ib and objective response rate (ORR) for phase II. The secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, time to response and safety. Without dose-limiting or unexpected toxicities, the starting dose in the phase Ib trial was selected as RP2D. In 43 patients, the primary endpoint was achieved: the objective response rate was 76.7% (95% confidence interval [CI]: 61.4–88.2), with complete and partial responses in 14% and 62.8% of patients, respectively. The median progression-free survival, overall survival, and duration of response were 8.6 months, 19.3 months, and 10.8 months, respectively. No patients discontinued pembrolizumab because of immune-related adverse events. Programmed death ligand-1 status was not related to survival. Post hoc analyses of pretreatment tumor specimens via targeted sequencing indicated that ERBB2 amplification, RTK/RAS pathway alterations, and high neoantigen load corrected by HLA-B were positively related to survival. The current quadruplet regimen shows durable efficacy and safety for patients with HER2-positive AGC.

Elotuzumab and Weekly Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Without Transplant Intent

Treatment of newly diagnosed multiple myeloma (NDMM) with a quadruplet regimen consisting of a monoclonal antibody, proteasome inhibitor, immunomodulatory imide, and corticosteroid has been associated with improved progression-free survival (PFS) compared with triplet regimens. The optimal quadruplet combination, and whether this obviates the need for frontline autologous stem cell transplant (ASCT), remains unknown. We evaluated elotuzumab and weekly carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) without ASCT in NDMM. To investigate the efficacy of Elo-KRd using a measurable residual disease (MRD)-adapted design in NDMM regardless of ASCT eligibility. This multicenter, single-arm, phase 2 study enrolled patients between July 2017 and February 2021. Median follow-up was 29 months. Twelve to 24 cycles of Elo-KRd; consecutive MRD-negative results at 10-6 by next-generation sequencing (NGS) after cycles 8 (C8) and 12 determined the duration of Elo-KRd. This was followed by Elo-Rd (no carfilzomib) maintenance therapy until disease progression. The primary end point was the rate of stringent complete response (sCR) and/or MRD-negativity (10-5) after C8 Elo-KRd. Secondary end points included safety, rate of response, MRD status, PFS, and overall survival (OS). As an exploratory analysis, MRD was assessed using liquid chromatography mass spectrometry (MS) on peripheral blood samples. Forty-six patients were enrolled (median age 62 years, 11 [24%] aged >70 years). Overall, 32 (70%) were White, 6 (13%) were Black, 3 (6%) were more than 1 race, and 5 (11%) were of unknown race. Thirty-three (72%) were men and 13 (28%) were women. High-risk cytogenetic abnormalities were present in 22 (48%) patients. The rate of sCR and/or MRD-negativity after C8 was 26 of 45 (58%), meeting the predefined statistical threshold for efficacy. Responses deepened over time, with the MRD-negativity (10-5) rate increasing to 70% and MS-negativity rate increasing to 65%; concordance between MRD by NGS and MS increased over time. The most common (>10%) grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively). There was 1 grade 5 myocardial infarction. The estimated 3-year PFS was 72% overall and 92% for patients with MRD-negativity (10-5) at C8. An MRD-adapted design using elotuzumab and weekly KRd without ASCT showed a high rate of sCR and/or MRD-negativity and durable responses. This approach provides support for further evaluation of MRD-guided deescalation of therapy to decrease treatment exposure while sustaining deep responses. ClinicalTrials.gov Identifier: NCT02969837.

HTA53 Combination Therapies: Two Is Company but Is Three (OR MORE) a Concern?

Combination therapies are becoming increasingly common, including triplet and quadruplet regimens, which can increase potential efficacy, but also raise toxicity concerns. The objective of this analysis is to understand how safety criteria is weighted throughout the HTA assessment process and determine whether payers and HTA bodies believe the added clinical benefits of combination regimens outweigh the risks, using Non-Small Cell Lung Cancer (NSCLC) and Multiple Myeloma (MM) as case studies.

P592: GILTERITINIB IN COMBINATION WITH VENETOCLAX, LOW DOSE CYTARABINE AND ACTINOMYCIN D FOR FLT3 MUTATED RELAPSED OR REFRACTORY ACUTE MYELOID LEUKEMIA

Background: A second generation FLT3 inhibitor Gilteritinib has become a standard of care for FLT3 mutated relapsed or refractory acute myeloid leukemia (FLT3m R/R AML). However, remission duration and overall survival remain unsatisfactory. Preliminary results of doublet Gilteritinib + Venetoclax and triplet Gilteritinib + Venetoclax + Hypomethylator regimens are encouraging. Herein, we report the quadruplet regimen consisting of Gilteritinib, Venetoclax, Low Dose Cytarabine and Actinomycin D (ACTIVE + G) for the treatment of FLT3m R/R AML in the clinical practice setting. Aims: To evaluate the efficacy and safety of the ACTIVE + G regimen. Methods: This was an observational, retrospective study. The patients were at least 18 years of age and had FLT3m R/R AML. All patients provided informed consent for treatment and data collection. The ACTIVE + G regimen consisted of Venetoclax 600mg/d p/o from day 1 up to day 28, Cytarabine 20mg/m2 s/c on days 1-10, Actinomycin D 12.5 µg/kg i/v on days 1-3 (on days 1-2 for patients ≥65 years) and Gilteritinib 120mg/d p/o starting from either day 4 or day 10 and continued up to day 28. Indications for stopping Venetoclax and Gilteritinib before day 28 were life-threatening infections or faster hematological recovery in responding patients. A second ACTIVE + G cycle was administered in non-responders without evidence of progressive disease after Cycle 1 or in responders with positive measurable residual disease (MRD). Responders after ACTIVE + G could proceed to either allogeneic stem cell transplantation (alloSCT) or maintenance therapy with Venetoclax, Low Dose Cytarabine and Gilteritinib. We evaluated baseline characteristics, composite CR (CRc = CR + CRi + CRp), overall response (ORR = CRc + MLFS), MRD negativity rates (<0.1% by multiparameter flow cytometry), overall survival (OS), relapse-free survival (RFS), grade 3-5 non-hematological toxicities and day 30 and day 60 mortality rates. Results: Fifteen patients had been treated with ACTIVE + G, of whom 8 (53%) were female. The median age was 66 years (34-87), median ECOG was 2 (0-3). FLT3-ITD mutation was confirmed in 80% (12/15) of cases and 20% (3/15) had FLT3-TKD. The most common co-mutations were NPM1 (53%, 8/15), DNMT3A (27%, 4/15), IDH1 (20%, 3/15) and IDH2 (20%, 3/15). Three patients (20%) had adverse cytogenetics. The median number of previous treatment lines was 2 (1-5). Twelve patients (80%) had received prior intensive chemotherapy, 3 patients (20%) had prior Venetoclax exposure and 9 patients (60%) had been previously treated with FLT3 inhibitors (Midostaurin – 7, Sorafenib – 1, Gilteritinib – 1). Three patients (20%) had relapsed after alloSCT. The majority of patients (80%, 12/15) had received 1 cycle of ACTIVE + G, 3 patients (20%) had been treated with 2 cycles. The CRc and the ORR were 67% (10/15) and 93% (14/15), respectively. MRD negativity was confirmed in 50% (5/10) of CRc cases. The median OS and RFS were 8.6 and 12.9 months, respectively. The most common non-hematological grade 3-5 adverse events were febrile neutropenia (73%, 11/15), sepsis/bacteremia (53%, 8/15), pneumonia (33%, 5/15) and secondary hemophagocytosis (13%, 2/15). Day 30 and day 60 mortality rates were 13% (2/15) and 20% (3/15), respectively. Image:Summary/Conclusion: A quadruplet regimen ACTIVE + G demonstrated high efficacy in this small group of R/R FLT3m AML patients irrespective of their prior exposure to FLT3 inhibitors or Venetoclax. The main toxicities were infectious complications attributable to prolonged myelosuppression. Prospective clinical trials are needed to verify our results.

PB2011: CHIDAMIDE COMBINED WITH THALIDOMIDE, CYCLOPHOSPHAMIDE AND DEXAMETHASONE (TC2D) AS AN ORAL QUADRUPLET REGIMEN FOR RELAPSED/REFRACTORY MYELOMA PATIENTS: INITIAL RESULTS OF A PHASE IIA, MULTICENTER TRIAL

Background: Research has showed histone deacetylase (HDAC) is overexpressed in plasma cells. Panobinostat was the first HDAC inhibitor (HDACi) approved by FDA for patients with relapse and refractory multiple myeloma (RRMM) in 2015. Chidamide is an oral subtype-selective HDACi, independently developed in China and approved for peripheral T-cell lymphoma. Preclinical findings have demonstrated the anti-myeloma activities of chidamide in vitro and in vivo. Aims: Here we report the initial efficacy and safety of this prospective, phase IIa, multicenter clinical trial with the chidamide based oral quadruplet regimen in patients with RRMM (ChiCTR2000035100). Methods: The TC2D regimen (thalidomide 100mg on days 1-28, chidamide 5mg on days 1-24, cyclophosphamide 50mg on days 1-24, dexamethasone 20mg on days 1,8,15,22) was administered to patients with RRMM of a 28-day cycle. Overall response rate (ORR) was based on patients whose response ≥MR and clinical beneficial rate (CBR) was calculated in patients completed at least 3 cycles and reached ≥SD. Results: A total of 32 patients were enrolled as of June 30, 2021, with a median age of 63.5 years (range 49–74). 82% (19/23) of which had unfavorable cytogenetics (defined by the presence of del (17p) or p53 mutation, t (4:14), t (14:16), t (14:20), amp (1q)). 75% were double refractory to bortezomib and lenalidomide. 43% (14/32) were heavily pre-treated (>3 lines). 59% (19/32) of patients completed ≥ 3cycles at the cut-off date (Table 1). With the median follow-up of 6 months (range 0.7–19.5), the median progression free survival (PFS) was 3.3 months and the 6-mon PFS rate was 27.5% (Fig 1a). Median overall survival (OS) has not reached yet, 6-mon survival rate was 82%, and the estimated 12-month survival rate was 65% (Fig 1b). Study end points were death (8 cases, 25%) and disease progression (24 cases, 75%). Patients who received ≥3 cycles of treatment had a superior median PFS (3.8 vs 1.4 months, P=0.01) than < 3 cycles. Of the 28 patients whose follow-up time more than 3 months, ORR was 25% and CBR was 46.4%, respectively. Better CBR (56.3% vs. 33.3%) and ORR (31.3% vs. 16.7%) were observed in patients received less than 3 prior lines, although with no significant statistical difference. Stratified analysis of PFS and OS showed no significant differences in sex, age, clinical classification, cytogenetic risk, prognosis score (DS and ISS staging system), and the status of ASCT. Grade 3/4 adverse events were mainly hematological toxicity (neutropenia 28%, anemia 34%, thrombocytopenia 15.6%), which could be tolerated. Fatigue was reported in 68.8% (22/32) of the patients. The incidence of all-cause infection was 37.5% (12/32). There were no treatment related deaths observed. Image:Summary/Conclusion: To our knowledge, this is the first report of chidamide-based oral quadruplet regimen for patients with RRMM. Preliminary results suggested efficacy and relatively high safety, and different groups of patients could benefit from this regimen. A longer treatment period may strengthen this effect. The most common adverse events were hematological toxicity which could be controlled. Choices of treatment are also influenced by physical and emotional impact of hospitalization or frequent hospital visits, which reflects the patient’s ability to continue their treatment and quality of life. Hospitalization and intravenous fluids are not involved in this regimen, which bring far more convenience and could be a cost-effective alternative for patients. Updated results will be presented at the following trial.