Very Good Partial Response Rate Research Articles

Daratumumab-Based Therapeutic Approaches and Clinical Outcomes in Multiple Myeloma and other Plasma Cell Dyscrasias: Insights from a Nationwide Real-World Chart Review Study.

Singapore leads Southeast Asia in the routine use of daratumumab for multiple myeloma and other plasma cell dyscrasias. This retrospective review analyzed 112 patients who received daratumumab between 2012 and 2020. Tolerability, and efficacy based on prior lines (PL) of therapy, cytogenetic risk group, and the presence of renal impairment were presented. Infusion-related reactions occurred in 26.8% of patients. Grades 1 and 2 hematological and non-hematological adverse events were observed in 14.3% and 33.9% of patients, respectively. After a median follow-up of 16.9 months, there was no significant difference in overall response rates (ORR) (86% versus 76.3%, p = 0.082) or depth of response (≥ complete response (CR), 35.1% versus 28.9%, p = 0.469) between myeloma patients with and without renal dysfunction. Newly diagnosed and relapsed/refractory patients had an ORR of 92% and 76.3%, and a ≥ VGPR (very good partial response) rate of 80% and 55.3%, respectively. Median progression-free survival (PFS) was better for patients with 0/1 PL compared to ≥ 2 PLs (19.8 versus 6.2 months, p < 0.001), with a deeper response (≥ CR, 38.5% versus 16.7%, p = 0.033). Forty-six and a half percentage of patients had high-risk FISH abnormalities, and those with 0/1 PL had a significantly better ORR than those with ≥ 2 PLs (83.3% vsersus 47.1%, p = 0.022), achieving an ORR similar to that of the general cohort (80.2%, p = 0.905). In conclusion, positioning daratumumab in earlier lines of therapy leads to better outcomes and may mitigate the impact of high-risk FISH abnormalities.

Prognostic impact of cytogenetic abnormalities detected by FISH in AL amyloidosis with daratumumab-based frontline therapy

AbstractWe performed an international retrospective study on 283 patients with light chain (AL) amyloidosis to investigate the prognostic impact of cytogenetic abnormalities by fluorescence in situ hybridization, when treated with frontline daratumumab–based therapy. The cytogenetic subgroups of interest were t(11;14), gain/amp(1q) (hereafter, +1q), hyperdiploidy, deletion(13q), del(17p), and myeloma high-risk (HR) translocations (t[4;14], t[14;16], or t[14;20]). The end points of interest were rate of hematologic complete response (heme-CR), very good partial response (VGPR) or better, and hematologic event-free survival (heme-EFS). The incidence of abnormalities was as follows: t(11;14), 53.4%; deletion (13q), 28.9%; +1q, 22.3%; hyperdiploidy, 19.4%; HR translocations, 6.6%; and deletion(17p), 4.5%. The heme-CR rate by cytogenetic subgroups were as follows: t(11;14) vs no t(11;14), 45.2% vs 41.8% (P=0.597); del(13q) vs no del(13q), 46.8% vs 42.8% (P=0.594); +1q vs no +1q, 30.2% vs 47.9% (P=0.022); hyperdiploidy vs no hyperdiploidy, 39.5% vs 44.9% (P=0.541); HR translocations vs none, 45.5% vs 43.1% (P=0.877); and del(17p) vs no del(17p), 50.0% vs 42.9% (P=0.658), respectively. Similarly, +1q was the only subgroup with a significantly lower VGPR or better rate (64.2% vs 79.0%; P=0.033). At a median follow-up of 19.8 months, the median heme-EFS was 49.6 months (95% CI, 24.7-not reached [NR]), and the 2-year overall survival (OS) was 80.98% (95% CI, 75.6-85.4). The presence of +1q was significantly associated with worse heme-EFS on multivariate analysis (HR 2.06, 95% CI, 1.14-3.71; P=0.017). Notably, there was no adverse prognostic impact of t(11;14) on heme-EFS or OS. In conclusion, +1q is associated with worse outcome in the daratumumab-era. Clinical trials testing novel frontline immunotherapies should be enriched in +1q to further improve outcomes in this subgroup.

Smoldering Multiple Myeloma Progressing to Active Multiple Myeloma Vs De-Novo Active Multiple Myeloma - a Comparison of Disease Characteristics, Organ Involvement and Outcomes in a Real-Life Multicenter Retrospective Cohort Study

Background Smoldering Multiple Myeloma (SMM) is an intermediate precursor phase in Multiple Myeloma (MM) evolution. SMM patients are monitored for progression to active disease, supposing such surveillance will identify myeloma-defining events (MDEs) early and consequently hasten treatment, prevent complications and improve outcomes. To what extent this approach is successful is not well established. We aimed to compare disease characteristics, end organ involvement and outcomes between SMM patients who progressed to active MM vs newly diagnosed MM (NDMM) patients. Methods We performed a two-center real-world case-control retrospective cohort study. Consecutive patients receiving first line treatment for MM after progressing from SMM were identified; each was matched by age and year of diagnosis (±2 years) to a patient first presenting as NDMM. SMM, MM, MDEs and response were defined by the International Myeloma Working Group (IMWG) criteria (2014, 2016); progression-free survival (PFS) and overall survival (OS) were calculated from active MM diagnosis. Data was extracted in 07/2023. Results We identified two cohorts of newly diagnosed MM patients, presented between 09/2008and 02/2023: Post SMM (P-SMM, N=57) and De novo MM patients (D-MM, N=57). Median follow up time was 38.6 months (IQR 23.3 - 72.7). There were no differences in baseline demographics between gender (p=.19), and median age: 73.4 (range 42 - 88) in the P-SMM group and 72.9 (range 42 - 92) in the D-MM (p=.75). Comparing MDEs using SLiM-CRAB criteria between groups, more patients in the D-MM group presented with hypercalcemia (p=.02) and lytic lesions (p=.03). Other domains were similar between groups: anemia (p=.68), renal failure (p=.59), FLC ≥100 (p=.76), % bone marrow plasma cells (BMPC) ≥ 60 (p=.11). D-MM patients had higher ISS/R-ISS at presentation: ISS ≥ II (30 vs 11, p=.004) and R-ISS ≥ II (31 vs 13, p=.002). Additional disease characteristics were balanced at diagnosis of active MM: heavy chain (p=.53), light chain type (p=.69), M-Protein level (p=.23), extra medullary disease (p=.14), Al amyloidosis (p=.13), and high-risk cytogenetics (p=.65). Bone involvement was more frequent in D-MM vs P-SMM patients, with significantly more pathological fractures (p=.006), bone pain (p=.001), and a detrimental bone disease (p=.001) (defined as combination of pathological fracture and/or ≥ 3 lytic lesions) (Figure 1B). Significantly higher rates of hospital admissions for upfront therapy initiation were seen in the D-MM group compared with P-SMM, 18 vs 7 (p=.008), as well as more potentially irreversible MDEs (pathological fractures and/or renal injury): 43 (p=.009) vs 31 (41.9%) respectively. Treatment patterns were balanced excluding bortezomib used more often in the D-MM (p=.009) and daratumumab in the P-SMM group (p=.03). Best response rates to upfront therapy were comparable between groups, (p=.71) as well as ≥ very good partial response (VGPR) rates (p=.88), 52.4% vs 47.6% in P-SMM and D-MM respectively. Frequency of skeletal imaging tests up-to 2-year period prior to active MM diagnosis were associated with lower rates of detrimental bone disease (p=.006). Despite the similar ≥ VGPR rates between cohorts, PFS was longer in the P-SMM group vs D-MM group, 39.6 vs 21.6 months, respectively (log-rank 0.01). A superior PFS in P-SMM group vs D-MM remained after correction for % BMPC at diagnosis (46.2% vs 58.8%, p=.03). OS was also longer, not reached vs 93.7 months (log-rank=.047) (Figure 1A). Conclusions Patients who develop active MM post SMM clinic surveillance presented with a lower disease burden, as well as reduced rates of detrimental bone disease and potentially irreversible MDEs. P-SMM patients had favorable PFS and OS rates. This may reflect effectiveness of SMM monitoring resulting in lower disease burden at time of treatment onset; favorable long-term outcomes may also be affected by variability in treatment patterns between groups. Another possible explanation is that patients with more indolent MM biology may have extended periods of precursor condition, hence increasing their likelihood to be diagnosed by incidental laboratory tests during their SMM phase.

Daratumumab, Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) Alone in Transplant-Ineligible Asian Patients with Newly Diagnosed Multiple Myeloma: Final Analysis of the Phase 3 Octans Study

Introduction: Daratumumab is a human IgGκ monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action and has shown clinical efficacy for the treatment of multiple myeloma (MM). In an updated analysis of the global phase 3 ALCYONE study, D-VMP demonstrated a significant progression-free survival (PFS) benefit compared to VMP in transplant-ineligible patients with newly diagnosed MM (NDMM). A prior analysis of the phase 3 OCTANS study (median follow-up, 12.3 months) also showed a favorable clinical benefit/risk profile for D-VMP versus VMP in transplant-ineligible Asian patients with NDMM. Here, we report results from the final analysis of OCTANS, with a median follow-up of &amp;gt;3 years. Methods: The randomized, phase 3 OCTANS study (NCT03217812) enrolled Asian patients with NDMM who were ineligible for autologous stem-cell transplant due to age or presence of comorbidities. Patients were randomized 1:2 (VMP:D-VMP) to receive up to nine 42-day cycles of VMP (bortezomib 1.3 mg/m 2 SC twice weekly in Cycle 1 and weekly in Cycles 2-9, and melphalan 9 mg/m 2 and prednisone 60 mg/m 2 orally on Days 1-4 of each cycle) or D-VMP (VMP + daratumumab 16 mg/kg IV weekly in Cycle 1, every 3 weeks in Cycles 2-9, and every 4 weeks thereafter until disease progression). Per a protocol amendment, patients receiving daratumumab IV were permitted to switch to daratumumab SC 1,800 mg (same schedule as IV) on Day 1 of any cycle. The primary endpoint was achievement of a very good partial response (VGPR) or better. Results: A total of 220 patients were randomized to D-VMP (n = 146) or VMP (n = 74). At the time of the final analysis, with a median follow-up of 41.2 months, the rate of VGPR or better was significantly higher with D-VMP versus VMP (80.1% vs 47.3%; P &amp;lt;0.0001; Table). The rate of measurable residual disease negativity (10 -5) was also higher with D-VMP versus VMP (40.4% vs 10.8%; P &amp;lt;0.0001). D-VMP continued to show a significant improvement in PFS versus VMP (median, 38.7 vs 19.2 months; HR, 0.35; 95% CI, 0.23-0.52; P &amp;lt;0.0001; Table, Figure), as well as a longer time to subsequent antimyeloma therapy (median, 46.8 vs 20.6 months; HR, 0.31; 95% CI, 0.20-0.47; P &amp;lt;0.0001). However, median overall survival was not yet reached for either group. The overall safety profile of D-VMP was consistent with that observed for the primary analysis. Grade 3/4 treatment-emergent adverse events (TEAEs) were reported for 133 (92.4%) patients who received D-VMP and 60 (84.5%) patients who received VMP and were primarily hematologic events; nonhematologic grade 3/4 TEAEs in ≥10% of patients included pneumonia (D-VMP, 31.3% vs VMP, 18.3%), hypokalemia (15.3% vs 4.2%), and hypertension (13.2% vs 8.5%). Grade 3/4 infection TEAEs were reported for 67 (46.5%) and 22 (31.0%) patients who received D-VMP or VMP, respectively. Serious TEAEs were reported for 75 (52.1%) and 28 (39.4%) patients in the D-VMP and VMP groups, respectively, and TEAEs led to treatment discontinuation in 6 (4.2%) and 4 (5.6%) patients, respectively. The incidence of infusion-related reaction TEAEs in the D-VMP group was 33.3%, which is consistent with that previously reported for daratumumab; most events were of grade 1 or 2 severity. The risk of immunogenicity to daratumumab was low, with 1 of 130 evaluable patients testing positive for daratumumab antibodies. Within the D-VMP group, 76 patients switched from daratumumab IV to SC administration. Among these patients, 64 (84.2%) patients preferred SC administration, 7 (9.2%) preferred IV administration, and 15 (19.7%) had no preference on ≥1 of 2 surveys. Of the 64 patients who preferred SC administration, primary reasons included treatment administration time (84.4%), more comfortable administration process (57.8%), less caregiver burden (31.2%), and fewer administration-related reactions (26.6%). Conclusions: With a median follow-up of &amp;gt;3 years, this final analysis of OCTANS demonstrated a continued clinical benefit with D-VMP versus VMP in Asian patients, with PFS improvement comparable to that observed in the global ALCYONE study (HR, 0.35 vs 0.42, respectively). No new safety concerns were identified for D-VMP with extended follow-up. In addition, daratumumab SC administration was preferred by the majority of patients who switched from daratumumab IV. These results further support the use of daratumumab IV or SC in combination with VMP in transplant-ineligible Asian patients with NDMM.

A Randomized Phase II Study of Daratumumab, Ixazomib, and Dexamethasone (DId, Arm A) Vs Daratumumab, Bortezomib and Dexamethasone (DVd) Followed By Daratumumab, Did (Arm B) in Newly Diagnosed Multiple Myeloma (DeRIVE) Study

Introduction: The safety and efficacy established by daratumumab (a CD38 monoclonal antibody)-based induction therapies for both transplant-eligible myeloma patients (based on CASSIOPEIA, and GRIFFIN trials) and transplant-ineligible patients (based on MAIA trial) have gained an accelerated momentum for adoption into regular clinical practice. In this context, to find the most optimal non-IMID based daratumumab-combination therapy as induction, we conducted a randomized phase 2 study to evaluate the safety and efficacy for in-class transition from bortezomib to ixazomib, stratified by transplant-eligibility and R-ISS. Methods: Patients were randomized to receive Arm A [daratumumab, ixazomib and dexamethsone (DId) X 8 cycles)] or Arm B [(daratumumab, bortezomib and dexamethsone (DVd) x 3) followed by (DId x 5 cycles)] for the primary endpoint of ≥ very good partial response rate (VGPR) rate post-induction cycle 8. Several other secondary endpoints were evaluated including safety, overall repsonse rate (ORR), progression free survival (PFS) and overall survival (OS). Standard dosing schedule was used [DId: daratumumab IV 16 mg/kg on days 1, 8, 15, 22 every 28 days x 2 cycles; then on days 1, 15 every 28 days x 6 cycles and every 28 days during maintenance (or 1800 mg SC at the same schedule), ixazomib - 4 mg PO on Days 1, 8, and 15 every 28 days and dexamethasone - 40 mg PO on days 1, 8, 15 and 22 every 28 days; DVd: daratumumab IV 16 mg/kg on days 1, 8, 15, 22 every 28 days x 2 cycles; then on days 1, 15 every 28 days x 6 cycles and every 28 days during maintenance (or 1800 mg SC at the same schedule), bortezomib - 1.3 mg/m2 SC on days 1, 4, 8 and 11 every 21 day and dexamethasone - 40 mg PO on days 1, 8, 15 and 22 every 28 days]. Transplant eligible patients may receive stem cell collection and transplant after cycle 8. During the maintenance phase, patients receive DId as maintennace therapy for a total of 32 cycles. 52 subjects were enrolled at Winship Cancer Institute of Emory University between 07/2019 and 05/2022. Results: The median age was 64 years for the 48 evaluable subjects [25 (52%) in arm A, 68 (48-87) and 23 (48%) in arm B, 61 (37-80), p&amp;lt;0.25]. 56% of the cohort was male (64 vs 48%, p=0.20), 48% were black (40% vs 56.5%, p=0.245). 20.8% had t(11;14), 29.2% had 1q abnormalities, 70.8% had hyperdiploidy, 25% had complex karyotype and 10.4% were high-risk [defined as presence of del17p, t(4;14) or t(14;16)]. 38 (81%) patients underwent an autologous stem cell transplant (72% in Arm A and 90.9% in Arm B, p=1.00). The primary endpoint favored arm B (Arm A vs Arm B ≥VGPR rate: 28% vs 56.5%, p&amp;lt;0.043). Similarly, the ORR favored arm B as well (Arm A vs Arm B ORR: 76% vs 95.7%, p&amp;lt;0.062). Post transplant ≥VGPR rates and ORR were 88.9% vs 95%, p=0.458 and 100% vs 100%, p=NS, respectively. At a median follow up of 35.2 months, 80% of the patients remain progression free as shown in figure 1. The adverse event profile was similar across both cohorts (grade 3/4 events occurred in 6 (24%) vs 7 (30%) for Arm A and B, respectively, p=0.27). There was no grade 3/4 peripheral neuropathy (PN), though grade 1/2 PN were higher in Arm B. There were two secondary primary malignancy reported in Arm B (prostate adenocarcinoma, esophageal adenocarcinoma). All together the safety signals were comparable between both arms. Conclusion: This is one of the first studies showing the safety and efficacy of non-IMID based dara-combination induction therapies with in-class transition of bortezomib to ixazomib yielding higher response rates post-induction and post-transplant without compromising on the safety. 3-year PFS rate of close to 80% across both arms is for daratumumab and proteasome inhibitor combination therapy are highly encouraging and may be an alternative regimen for patients that may not tolerate IMIDs or that have a contraindication to receive IMIDs.

Efficacy and Safety Analysis of Carfilzomib-Containing Regimen in the Treatment of Multiple Myeloma：a Multicenter Real-World Study

Purpose To investigate the efficacy and safety of carfilzomib-containing regimens in the treatment of multiple myeloma（MM） in different lines of treatment. method The clinical data of 55 multiple myeloma patients who received carfilzomib treatment in 10 medical centers in Shandong from January 2022 to March 2023 were retrospectively analyzed , and grouped according to the number of MM treatment lines, they were divided into group A : newly diagnosed multiple myeloma ( NDMM ), group B : patients with first relapse, and group C : patients treated with carfilzomib in the third line or above. Del ( 17p ), t ( 4;14 ), t ( 14;16 ) were defined as high-risk cytogenetic abnormalities result All patients with multiple myeloma were treated with the combined regimen based on carfilzomib, including 24 patients in group A , 9 patients in group B , and 22 patients in group C. Among all patients, there were 27 cases ( 49.1% ) of high-risk cytogenetics, and 13 cases with ECOG score ≥ 3 points ( 23.6% ), 10 cases ( 18.2 ) had eGFR &amp;lt;30 ml/min. The median follow-up time of patients in group A , group B and group C was 8 months, 9 months and 8 months. The overall response rate ( ORR ) was 91.7% , 88.9% and 77.3% for patients in Arms A , B and C who started carfilzomib, respectively . The ≥very good partial response ( VGPR ) rates were 75% and 66.7% for Arm A and B patients , respectively , while the ≥VGPR rate for Arm C patients was 41.0% . The negative rate of minimal residual disease ( MRD , sensitivity: 10 -6 ) in group A was 62.5% ( 15/24 ). Follow - up deadline is March 2023 On the 31st , the median progression-free survival ( PFS ) time and median overall survival ( OS ) time of patients in the three groups were not reached. After the application of carfilzomib, the incidence rate of grade 3-4 adverse events ( AE ) was 32.7% ( 18/55 ). The main hematological adverse reactions were anemia, thrombocytopenia, lymphopenia and neutropenia. Non-hematological adverse reactions were mainly infusion-related adverse reactions and infections. in conclusion Carfilzomib-based regimens in the treatment of multiple myeloma have good curative effect and safety, and the first-line and first-time relapse patients have better curative effect.

Efficacy and safety of venetoclax in patients with relapsed/refractory multiple myeloma: a meta-analysis

BackgroundVenetoclax is clinically active in treating relapsed/refractory multiple myeloma (RRMM). This study evaluated the efficacy and safety of venetoclax or venetoclax with other agents in treating RRMM.MethodsPubMed, Web of Science, Embase, and Cochrane Library were comprehensively searched. We included studies investigating the efficacy and safety of venetoclax or venetoclax with other agents in treating RRMM. Overall response rates (ORR), stringent complete response rates (sCR), complete response rates (CR), very good partial response rates (VGPR), partial response rates (PR), stable disease (SD), progressive disease (PD) and adverse events were synthesized using either a random-effects model or a fixed-effects model.ResultsA total of 7 clinical trials with 482 patients with RRMM were included. Concerning venetoclax with other agents, the pooled ORR, sCR, CR, VGPR, PR, SD, and PD were 0.76 (95% CIs: 0.62, 0.87), 0.11 (95% CIs: 0.04, 0.21), 0.18 (95% CIs: 0.11, 0.26), 0.16 (95% CIs: 0.12, 0.25), 0.29 (95% CIs: 0.25, 0.34), 0.07 (95% CIs: 0.05, 0.10), and 0.11 (95% CIs: 0.04, 0.23). The overall rate of adverse events ≥ Grade 3 was 0.84 (95% CIs: 0.77, 0.91). The most common non-hematologic adverse events were nausea, diarrhea, fatigue, back pain, and vomiting; hematologic adverse events included thrombocytopenia, neutropenia, anemia, leukopenia, and lymphopenia.ConclusionsThis study indicates that venetoclax alone or in combination with other agents reveals favorable treatment responses and acceptable adverse events in treating RRMM.

Indolent Lymphoma: High CR and VGPR Rate with Fixed Duration Bendamustine, Rituximab and Acalabrutinib in Waldenstroms Macroglobulinaemia (BRAWM)

Background: Waldenström's macroglobulinaemia (WM) is an uncommon lymphoproliferative disorder. Although many options are available, an optimal first-line therapy for WM has not been defined. We postulated that combining bendamustine and rituximab (BR) with a next generation BTK inhibitor would result in deeper responses as measured by complete response (CR) and very good partial response (VGPR) rates, and provide a longer duration of response. Objectives: The primary objective of this trial is to document the CR and VGPR rates Methods: The BRAWM clinical trial combines BR with acalabrutinib in a one-year, fixed duration treatment course including six cycles of BR and 12 months of acalabrutinib (6 months of monotherapy). This ongoing trial is taking place at 9 clinical sites across Canada and 44 patients have been enrolled as of July 1, 2023, with a recruitment goal of 59. Results: Median age of participants was 68; 34 were male; 3 participants were low risk, 21 intermediate and 20 high risk. 27 participants completed combination therapy, 17 completed monotherapy and 7 were followed-up at 18 months, and 3 at 24 months after first dose. Table 1 shows the observed Clinical Responses using 6 th IWWM; 2 participants improved from a VGPR to a CR between cycles 7 and 12, both of whom have not reached month 18 for assessment. The interim primary endpoint of combined CR and VGPR rate is 13/17 (77%), with no participants having progressed at this interim analysis. 3 participants discontinued treatment early: 1 at cycle 7 (with a VGPR) who experienced an adverse event requiring treatment; 1 at cycle 3 with inter-current illness, and 1 at cycle 2 for personal reasons not related to treatment. The total observed Treatment Related Adverse Events (TRAEs) in combination therapy was 188 amongst 35 participants, and n= 24 in 10 participants during monotherapy. There were 24 Grade 3/4 TRAEs (combination n= 20, monotherapy n= 4). Total observed Serious Adverse Events was 18, and 7 TRSAEs 7; 6 during combination therapy (3 febrile neutropenia and 1 for each fever, allergic reaction and bowel obstruction) and 1 pneumonia during monotherapy. Grade 3/4 TRAEs resulted in 29 dose interruptions in 13 participants, and 2 dose reductions. Mutational analysis of participants with adequate sample for assessment (n=35), showed 33 with MYD88 mutation, 10 with a CXCR4 mutation, and 1 with a TP53 mutation. Minimal residual disease (MRD) analysis of Peripheral Blood (PB) and Bone Marrow, using next generation sequencing, is underway. Initial review shows that most evaluable patients (those with samples at two or more time-points) have become MRD undetectable in PB. Uni- and multi-variate analyses of variables that may be associated with outcomes is underway. Conclusions: Bendamustine, rituximab and acalabrutinib front-line therapy for WM is safe and well tolerated and initial clinical results show that this treatment induces a high percentage of CR + VGPRs. Table 1: Clinical Responses using 6 th IWWM. *The 2 participants observed to have a CR at month 12 have not reached month 18 for progression or survival follow-up.

Ibrutinib and venetoclax as primary therapy in symptomatic, treatment-naïve Waldenström macroglobulinemia

AbstractConcurrent Bruton tyrosine kinase and BCL2 inhibition has not yet been investigated in Waldenström macroglobulinemia (WM). We performed an investigator-initiated trial of ibrutinib and venetoclax in symptomatic treatment-naïve patients with MYD88-mutated WM. Patients received ibrutinib 420 mg once daily (cycle 1), followed by a ramp-up of venetoclax to 400 mg daily (cycle 2). The combination was then administered for 22 additional 4-week cycles. The attainment of very good partial response (VGPR) was the primary end point. Forty-five patients were enrolled in this study. The median baseline characteristics were as follows: age 67 years, serum IgM 43 g/L, and hemoglobin 102 g/L. Seventeen patients (38%) carried CXCR4 mutations. Nineteen patients (42%) achieved VGPR. Grade 3 or higher adverse events included neutropenia (38%), mucositis (9%), and tumor lysis syndrome (7%). Atrial fibrillation occurred in 3 (9%), and ventricular arrhythmia in 4 (9%) patients that included 2 grade 5 events. With a median follow-up of 24.4 months, the 24-month progression-free survival (PFS) and overall survival (OS) rates were 76% and 96%, respectively, and were not impacted by CXCR4 mutations. The median time on therapy was 10.2 months, and the median time after the end of therapy (EOT) was 13.3 months. Eleven of the 12 progression events occurred after EOT, and the 12-month PFS rates after EOT were 79%; 93% if VGPR was attained, and 69% for other patients (P = .12). Ibrutinib and venetoclax induced high VGPR rates and durable responses after EOT, although they were associated with a higher-than-expected rate of ventricular arrhythmia in patients with WM, leading to early study treatment termination. This trial was registered at www.clinicaltrials.gov as #NCT04273139.

Ixazomib and daratumumab without dexamethasone (I-Dara) in elderly frail patients with RRMM: Results of the multicenter phase 2 study (IFM 2018-02) of the Intergroupe Francophone du Myélome (IFM).

8054 Background: Frailty is associated with inferior outcome in older myeloma patients, especially in the relapse setting.1,2 This adverse prognosis is mainly related to a high discontinuation rate for treatment (Tx) related adverse events (AE). Dexamethasone is responsible of a high rate of infections and metabolic AE. We present here the updated results from the phase 2 study I-Dara evaluating efficacy and tolerability of Ixazomib-Daratumumab without Dexamethasone in elderly frail patients with relapsed myeloma (RRMM) (NCT03757221). Methods: Ixa-Dara naïve RRMM patients received oral Ixazomib (4 mg: days 1, 8, 15), IV Daratumumab (16 mg/kg; days 1, 8, 15, 22, cycles 1-2; days 1, 15, cycles 3-6; days 1, cycles 7+) and IV Methylprednisolone before Daratumumab (100 mg at day 1, 8, cycle 1 and then 60 mg). They were enrolled after 1 or 2 prior therapy if their frailty score was ≥ 2 by IMWG score. The primary endpoint was ≥ very good partial response rate (VGPR) at one year. Secondary endpoints included ORR, PFS, OS &amp; toxicity according to NCI-CTCAE version 5. Results: Sixty-three patients were screened and 55 enrolled between 03/2018 and 09/2021. Patient were at first (n = 36) or second relapse (n = 19). Thirty-five patients (64%) were previously exposed to bortezomib, 37 (67%) were previously exposed to lenalidomide (Len) and 23 (42 %) were refractory to Len. Median age was 82 (72-93). All patients had a frailty score ≥2 and 13 (24 %) had a 3 or 4 frailty score. In 41 patients ISS at diagnosis was stage I (n = 11), II (n = 18) or III (n = 12). Seventeen (36%) patients harbored high-risk (HR) cytogenetic, including t(4;14) (n = 8) or del17p (n = 10). The median duration of Tx (DOT) in 14 pts with ongoing Tx was 22 mos [min-max: 16-40] at data cutoff (January, 19)]. The median DOT in 41 pts who stopped Tx was 10 mos [min-max: 0-31]: 28 had progressive disease (PD). Fourteen patients died during the study: Daratumumab-related bronchospasm (D1C1); Ixazomib-related overdose (C2), sepsis (n = 3), pneumonia (n = 2), PD (n = 7). Regarding toxicity, 31 pts had a ≥grade 3 AE (55%). The most common grade 3-4 AE were thrombocytopenia (n = 10), other cytopenias (n = 5), anemia (n = 3), infection (n = 6), gastrointestinal disorders (n = 5) and hypertension (n = 3). The ≥VGPR rate is 32 % @ 1 year (34 % overall) with an ORR of 70% @ 1 year (74 % overall). In Len refractory patients the ≥VGPR rate is 40% @ 1 y and the ORR 70 %, in HR patients the ≥VGPR rate is 60 % and ORR 80%. With a median follow-up of 23.0 mos median PFS is 18.5 mos and median OS NR (75% OS estimated at 27.9 mos). Conclusions: In this elderly frail population Ixa-Dara is a feasible combination with favorable efficacy profile even in Len refractory and HR cytogenetic patients. Early toxicity remains a concern in this population eventhough more manageable with Dara SC. Late benefit is consistent with one third of patients still on treatment. Clinical trial information: NCT03757221 .

Indolent lymphoma: Bendamustine, rituximab and acalabrutinib in Waldenstroms Macroglobulinemia (BRAWM)

Background: Waldenström’s macroglobulinaemia (WM) is an uncommon lymphoproliferative disorder. Many options are available, however, an optimal first-line therapy for WM has not be defined. We postulated that combining bendamustine and rituximab (BR) with a next generation BTK inhibitor would result in deeper responses as measured by complete response (CR) and very good partial response (VGPR) rates, and provide a longer duration of response. Objectives: The primary objective of this trial is to document the CR and VGPR rates Methods: The BRAWM clinical trial combines BR with acalabrutinib in a fixed duration treatment course including six cycles of BR and 12 months of acalabrutinib. This trial is taking place at 8 clinical sites across Canada and 33 patients have been enrolled, with a recruitment goal of 59. Results: A pre-defined interim analysis of the first 30 enrolled patients showed; median age of patients was 66; 25 were male; two patients were low risk, 14, intermediate and 15 high risk. Seventeen patients completed combination therapy, 9 completed monotherapy and 2 were followed-up at 18 months (6 months post therapy). Clinical results to date: Two patients discontinued treatment early; 1 at cycle 7 (with a VGPR) but experienced an adverse event requiring treatment; 1 at cycle 3 with possible disease progression. There were 186 treatment related adverse events (TRAEs) among 25 of 30 participants; 5 participants did not experience a TRAE; 163 of these occurred during combination therapy; 23 during monotherapy in 7 of 17 participants, where 10 participants did not experience a TRAE. During combination therapy, 16 of the 163 TRAE’s were grade 3; neutropenia (n = 8), including 2 that were febrile neutropenia, n = 1 for each: atrial fibrillation, transaminitis, cellulitis, fatigue and pulmonary emphysema. An additional five were also considered serious and included febrile neutropenia (n = 2), and n = 1 for each fever, allergic reaction and bowel obstruction. During monotherapy, there were no serious TRAEs. There were 2 grade 3 events during monotherapy in two different patients; decreased neutrophil count, and syncope. There were 21 dose interruptions in 11 participants, all but one of whom returned to regular dosage. Of assessed patients, 20/20 have MyD88 mutations, 4/20 have a CXCR4 mutation, and none had a TP53 mutation. Minimal residual disease (MRD) analysis using next generation sequencing of the IgV regions will be reported. Conclusions: Bendamustine, rituximab and acalabrutinib front-line therapy for WM is safe and well tolerated and initial clinical results show that this treatment induces a high percentage of VGPRs. The research was funded by: AstraZeneca Keywords: Combination Therapies, Indolent non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. N. L. Berinstein Consultant or advisory role: AstraZeneca Research funding: AstraZeneca, Merck, IMV N. Forward Honoraria: AstraZeneca, AbbVie, BeiGene, Celgene/BMS, IMV, Kite, Janssen, Pfizer, Roche, Servier Research funding: Astellas, AstraZeneca, IMV, Merk, MorphoSys, Seattle Genetics, Roche Other remuneration: Speaker Fees: Pfizer, BeiGene, AstraZeneca M. Shafey Consultant or advisory role: Jansen, Roche Canada, Kite/Gilead, Novartis, BeiGene, Incyte, Abbvie, BMS, AstraZeneca A. Nikonova Consultant or advisory role: Forus, Janssen, Astra Zeneca, Apotex, Incyte Educational grants: Janssen D. MacDonald Honoraria: Abbvie, Astra Zeneca, Beigene, BMS, Incyte, Kite Gilead, Roche, and Seattle Genetics D. Villa Consultant or advisory role: AZ, BeiGene, Janssen, Roche, Kite/Gilead, Merck, BMS/Celgene, ONO Pharmaceuticals. Honoraria: AZ, BeiGene, Janssen, Roche, Kite/Gilead, Merck, BMS/Celgene, ONO Pharmaceuticals. Research funding: Roche, AstraZeneca I. Sandhu Honoraria: Celgene/BMS, Kite/Gilead, Janssen, Sanofi, FORUS, Pfizer M. Aljama Consultant or advisory role: Jansen, Sanofi, Pfizer, Beigene J. Larouche Consultant or advisory role: Incyte, Gilead Research funding: Incyte, Astra-Zeneca, Genmab

Efficacy and Safety of Oral Ixazomib (Ixa), Intravenous (IV) Daratumumab (Dara), and IV/Oral Dexamethasone (Dex; IDd) in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM) and 1-3 Prior Therapies: Results of the Final Analysis of a Phase 2 Study

Introduction The development of more effective therapies has improved the prognosis for pts with MM, however most will ultimately relapse. The oral proteasome inhibitor (PI) Ixa is approved with lenalidomide (len)-dex (IRd) for pts with ≥1 prior therapy, & the monoclonal antibody Dara is approved in various regimens, including with bortezomib-dex (DVd). In CASTOR (DVd vs Vd; Palumbo NEJM 2016), Vd was limited to 8 cycles; however, prolonged PI therapy is associated with improved outcomes. The IDd regimen with oral Ixa may enable longer-term PI therapy than with DVd. In this prospective, open-label, multicenter, phase 2 study (NCT03439293) we used a treat-to-progression approach to evaluate IDd in RRMM. Methods Ixa/Dara-naïve pts with RRMM (1-3 prior therapies) received oral Ixa (4 mg; days [d] 1, 8, 15), IV Dara (16 mg/kg; d 1, 8, 15, 22, cycles 1-2; d 1, 15, cycles 3-6; d 1, cycles 7+), & IV (required before first Dara dose only) or oral dex (20 mg; d 1, 2, 8, 9, 15, 16, 22, 23) in 28-d cycles. The primary endpoint was ≥very good partial response (VGPR) rate. Secondary endpoints included: overall response rate (ORR), progression-free survival (PFS), time to progression (TTP), overall survival (OS), & safety. Health-related quality of life (HRQoL; exploratory endpoint) was assessed with EORTC QLQ-C30 & QLQ-MY20. We report data from the final analysis, conducted 1 year (y) after 50% of PFS events had occurred (data cut-off: 1/1/2022). Results Sixty-one pts were enrolled: median age was 69 y (≥75 y, 19.7%); 49.2/36.1/14.8% of pts had International Staging System stage I/II/III disease; 34.4% were len-refractory; 26.2% & 42.6% had high-risk [del(17p), t(4;14), t(14;16)] & expanded high-risk (high-risk &/or amp1q21) cytogenetics, respectively; 59.0/26.2/14.8% had received 1/2/3 prior lines. Pts had received a median of 16 IDd cycles; 24.6% were ongoing at data cut-off. Relative dose intensity was ≥80-<100% for Ixa/Dara/dex in 37.7/67.2/24.6% of pts. In 59 response-evaluable pts, the confirmed ≥VGPR rate was 32.2% compared with 23.7% & 30.5% at the first & second interim analyses (IA1, IA2), respectively; ORR was 66.1% (Figure). In 12 pts aged ≥75 y: ≥VGPR rate was 16.7%; ORR was 50.0%. In 21 len-refractory pts: ≥VGPR rate was 28.6%; ORR was 61.9%. In 16 pts with high-risk cytogenetics: ≥VGPR rate was 25.0%; ORR was 50.0%. In 25 pts with expanded high-risk cytogenetics: ≥VGPR rate was 28.0%; ORR was 56.0%. Minimal residual disease (MRD) was evaluated at time of complete response (CR) in 8 pts, of whom 6 were evaluable: 4/6 (66.7%) pts were MRD-negative (threshold level 10-5); 3/6 (50.0%) pts maintained MRD-negative status at 6 & 12 cycles post-CR achievement. After a median follow-up of 31.6 months (mos; 41 events), median PFS was 16.8 mos (95% confidence interval [CI]: 10.1-23.7). Median TTP was 21.1 mos (35 events; 95% CI: 10.2-27.9). With 18 deaths, 1-y OS rate was 91.4% (95% CI: 80.6-96.3). Median time to ≥VGPR & ORR was not estimable (NE; range: 1.0-40.8 mos) & 2.7 mos (range: 0.9-31.6), respectively. In 21 len-refractory pts, after a median follow-up of 35.9 mos (12 events), median PFS was 12.6 mos (95% CI: 5.6-NE). Pt-reported HRQoL was maintained during treatment with IDd. Ixa pharmacokinetics were comparable to those observed in the approved triplet (IRd) & single-agent maintenance studies. Any-grade (G) & G≥3 treatment-emergent adverse events (TEAEs) occurred in 96.7% & 54.1% of pts, respectively. Common (>25%) any-G TEAEs were diarrhea (42.6%), anemia (27.9%), & thrombocytopenia (26.2%); common (>10%) G≥3 TEAEs were thrombocytopenia (11.5%) & pneumonia (11.5%). 44.3% of pts had serious AEs, most frequently pneumonia (9.8%) & COVID-19 pneumonia (4.9%). 18.0% of pts had any-G peripheral neuropathy (PN, 1.6% G≥3). TEAEs led to dose modifications in 62.3% of pts (Ixa 39.3%, Dara 36.1%, dex 44.3%), dose reductions in 36.1%, & discontinuation of any study drug in 16.4%. There were 5 on-study deaths (all unrelated to study drug). Conclusions This final analysis of a phase 2 study in pts with RRMM showed a positive risk-benefit profile for IDd: ≥VGPR rate was 32.2% (increased from IA1 & 2), median PFS was 16.8 mos (comparable to that seen with DVd in CASTOR; Mateos CLML 2020), & HRQoL was maintained. The discontinuation rate due to TEAEs was low with no new safety signals identified & a low rate of any-G PN. Furthermore, IDd was also active in pts aged ≥75 y, len-refractory pts, & those with high-risk & expanded high-risk cytogenetics. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effectiveness and Safety of Ixazomib in Combination with Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma in a Real-Life Population in France: The Remix Study

Background Ixazomib (IXA) is an oral proteasome inhibitor (PI) used in combination with lenalidomide and dexamethasone (IXA-Rd) for patients (pts) with relapsed and/or refractory multiple myeloma (RRMM). Efficacy and safety have been demonstrated in the phase 3 Tourmaline-MM1 clinical trial (1), which has recently reported the longest median overall survival (mOS) in phase III studies of Rd-based triplets (53.6 months, mo) (2). The REMIX study has been conducted since IXA became available in France in 2017. It is the largest cohort of RRMM pts receiving IXA-Rd combination in real life. The final analysis was performed with a median follow-up of 28.7 mo. Methods REMIX is a non-interventional, prospective study conducted in 59 sites (public and private) in pts with RRMM in France. To be eligible pts had to receive IXA-Rd in second line or later and IXA had to be initiated concomitantly to Rd (pts who started lenalidomide (lena) more than 6 weeks before IXA were excluded). After inclusion, pts were assessed every 3 mo during 24 mo and then every 6 mo as per standard practice. Analysis comprised OS, progression-free survival (PFS), overall response rate (ORR), very good partial response (VGPR) and tolerance. The analysis was conducted for the overall population and in subgroups of interest: age and lines of treatment (L2, L3 or L4+). Results A total of 376 eligible pts were included. Median age was 71 years (y) with 18.4% of patients aged ≥80y. At IXA-Rd initiation, 48.8% of pts were frail and 21.8% had renal clearance ≤50 ml/min. Comorbidities were reported in 62.8% of pts, including diabetes (8.8%), renal disease (8.8%) or solid tumour (6.4%). At inclusion, the cytogenetic risk was standard, high or unknown in 44.4%, 12% and 43.6% of pts, respectively. MM was diagnosed at a median of 4y before IXA-Rd initiation. 44.5% of pts had previous autologous stem cell transplantation (ASCT). IXA-Rd was initiated in L2, L3 or advanced lines (L4+) in 60.4%, 18.1% and 21.5% of pts, respectively. Regarding previous treatment received, 66.0% of pts had received IMID (including 39.2% lena and 11.7% pomalidomide), 93.1% had received PI (including 91.7% bortezomib and 7.5% carfilzomib) and 13.9% had received daratumumab. Most pts were previously exposed to lena in L3 (73.5% of L3, n=50/68, for a median duration of 16 mo) and L4+ (91.3% of L4+, n=73/81, for 17 mo) compared to L2 (10.6% of L2, n=24/227, for 18 mo). Out of all pts, 26, (7.9%) were considered lena-refractory during previous therapy. The median washout (WO) period between lena discontinuation and IXA-Rd start was 22.8 mo (SD: ±23.9). IXA was used for a median of 12.4 mo (13 cycles) at a 4-mg dose for 90.4% of pts. The median PFS (mPFS) was 19.1 mo (95% CI: 14.9-21.5) for the overall cohort, with a mPFS of 21.5 mo (95% CI: 19.2-24.8) for L2 (n=213), 21.9 mo (95% CI: 16.2-28.7) for L3 (n=65) and 5.8 mo (95% CI: 4.8-9.4) for L4+ (n=80). In the subgroups of pts aged <80y (n=293) and ≥80y (n=65), mPFS were 19.1 mo (95% CI: 15.9-21.9), and 17.4 mo (95% CI: 10.8-23.0), respectively. The mOS was not reached for the overall cohort; 36mo and 48mo OS rates were respectively 58.3% (95% CI: 52.6%-63.9%) and 52.4% (95% CI: 44.2%-60.5%). The 36mo OS rates were 63.4% (95% CI: 56.1-70.8%), 68.9% (95% CI: 57.1-80.7%) and 35.3% (95% CI: 23.9-46.7%) in L2, L3 and L4+ pts respectively. Among the 331 pts with available response according to investigators, the ORR was 73.1% (79.8% in L2, 70% in L3 and 54.4% in L4+ patients) and the VGPR rate was 45% (52.7% in L2, 41.7% in L3 and 25% in L4+ pts). IXA discontinuation was reported in 74.1% of pts (n=278). Discontinuation was related to AE in 21% of cases (n=79). Serious adverse events (SAE) were reported in 54.3% (n=204), including 57 (15.2%) pts with SAE considered related to IXA. Most frequent (>10%) AEs were diarrhoea (52%), thrombocytopenia (45.9%), asthenia (29.7%), neutropenia (23.6%) and anaemia (22.3%). Conclusion The REMIX study reported a mPFS in real-world conditions of 19.1 mo consistent with MM1 (20.6 mo), while half of patients were considered frail and 39.2% had previously received lenalidomide. The effectiveness in third line of treatment is similar to that in second line but was lower in L4+ as expected (5.7 mo). mOS is not reached at 48mo which aligns with MM1 final analysis. Reported AEs are consistent with the known safety profile of Ixazomib. Funding Takeda Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

KarMMa-2 Cohort 2c: Efficacy and Safety of Idecabtagene Vicleucel in Patients with Clinical High-Risk Multiple Myeloma Due to Inadequate Response to Frontline Autologous Stem Cell Transplantation

**Co-lead authors Introduction Patients (pts) with multiple myeloma (MM) who do not achieve a deep response post-autologous stem cell transplantation (ASCT) have an increased risk of progressive disease (PD) death (van de Velde Eur J Haematol 2017) and a high unmet medical need. In the pivotal phase 2 KarMMa study (NCT03361748), treatment with the B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy idecabtagene vicleucel (ide-cel) led to frequent, deep, and durable responses in pts with relapsed and refractory MM (RRMM) who were triple-class exposed and refractory to last treatment (Munshi N Engl J Med 2021). KarMMa-2 is a multicohort, phase 2, multicenter trial (NCT03601078) of ide-cel in RRMM and in clinical high-risk MM. The efficacy and safety of ide-cel in cohort 2c pts with MM who had an inadequate response to frontline therapy with ASCT are presented. Methods Eligible pts in cohort 2c had newly diagnosed MM (NDMM), received ≥3 cycles of induction therapy (including a proteasome inhibitor, immunomodulatory agent, and dexamethasone), and had an inadequate response to ASCT (single or tandem), defined as less than very good partial response (VGPR) at 70-110 days after last ASCT, without use of consolidation or maintenance therapy. Pts had ECOG performance status (PS) ≤1. After lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2 × 3), pts received a single infusion of ide-cel at dose range 150-450 × 106 CAR+ T cells. At investigator discretion, pts could receive maintenance therapy post-infusion. The primary endpoint was complete response (CR) rate (CRR; CR and stringent CR) per investigator and IMWG Uniform Response Criteria. Secondary endpoints included overall response rate (ORR; ≥ partial response), VGPR rate (VGPRR), time to response (TTR), duration of response, PFS, overall survival, safety, and pharmacokinetics (PK). Exploratory endpoints included assessment of soluble BCMA (sBCMA) level, and minimal residual disease negativity (MRD-) by aggregation of next-generation sequencing and EuroFlow (<10-5 nucleated cells) data with interpolation to reduce missing/indeterminate data points. Efficacy and safety were analyzed in all pts who received ide-cel; PK, sBCMA, and MRD- were analyzed in evaluable pts. Results Ide-cel was successfully manufactured and infused in 31/32 enrolled pts. Median age was 64 y; 67.7% of pts had ECOG PS 0. At study entry, 41.9% pts had R-ISS stage I disease, 16.1% had stage II, and none had stage III; 9.7% pts had high-risk cytogenetics, 3.2% had bone marrow biopsy-determined high tumor burden (≥50% bone marrow CD138+ plasma cells), and 6.5% had extramedullary disease. At data cut-off (14 Mar 2022), median follow-up was 27.5 mo (range 22-31). CRR was 74.2% (95% CI 55.4-88.1), and ORR was 87.1% (95% CI 70.2-96.4) (Table 1). Median TTR was 1 mo (range 0.9-2.8). Time to event endpoint results are in Table 1. Grade (Gr) 3-4 adverse events (AEs) on or after ide-cel infusion were reported in 29 (93.5%) pts, most commonly, neutropenia in 25 (80.6%) pts, leukopenia in 9 (29.0%), and anemia in 7 (22.6%). No Gr 5 AEs were reported. Grade 1 CRS occurred in 14 (45.2%) pts, Gr 2 in 4 (12.9%), and no pts had ≥Gr 3 (Table 1). Investigator-identified neurotoxicity (NT) occurred in 2 (6.5%) pts, one had Gr 1 and one had Gr 3. Robust cell expansion was seen in 31 evaluable pts (Table 2) despite low tumor burden, as assessed by sBCMA level (range 6.5-154.0 ng/mL at infusion, n = 30). Ide-cel cellular expansion was higher in pts who achieved ≥CR vs <CR with ide-cel (Table 2). sBCMA was cleared within 2 mo post-ide-cel infusion in 24/31 (77.4%) evaluable pts, including in 22 who had ≥CR. Among 23 pts with ≥CR, 16 (69.6%; 95% CI, 49.1-84.4) pts had MRD− at 6 mo post-ide-cel infusion. At 12 mo, MRD− was seen in 17/27 (62.9%; 95% CI 44.2-78.5) evaluable pts, regardless of CR status and in 16/23 (69.6%; 95% CI 49.1-84.4) evaluable pts who had ≥CR. Of note, of the 16 pts, 11 sustained MRD− at 24 mo, 2 pts did not have 24 mo data available, and data for 3 pts were indeterminate. Conclusions Ide-cel treatment resulted in frequent, deep, and durable responses in pts with an inadequate response to frontline ASCT. Early deep clearance of tumor was seen in pts with ≥CR after ide-cel treatment and was sustained at 2 y. Lower incidence of CRS and NT were seen in these pts vs those treated with ide-cel in later lines. These results support a favorable clinical benefit-risk profile of ide-cel in NDMM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Initial Results of a Phase 1 Study of Daratumumab, Ixazomib, and Dexamethasone in Newly Diagnosed and Previously Treated AL Amyloidosis

Background: Systemic light chain (AL) amyloidosis is a rare disease that is characterized by the tissue deposition of misfolded protein aggregates, leading to progressive organ dysfunction and significant morbidity and mortality. Novel therapeutic combinations with improved safety, tolerability, and efficacy profiles remain a paramount need. We herein report initial results of a phase 1 investigator-initiated study evaluating the safety and preliminary efficacy of the novel combination of the anti-CD38 monoclonal antibody (mAb) daratumumab, the oral proteasome inhibitor ixazomib, and dexamethasone (DId) in AL amyloidosis (NCT03283917). Methods: This phase 1, single center, open-label study enrolled AL amyloidosis patients (pts) who were either treatment naïve or previously treated with evidence of clonal relapse or with refractory disease defined as less than a hematologic very good partial response (VGPR) to prior therapy. Key exclusion criteria included NT-proBNP ≥8500 ng/L, clinically overt myeloma (hypercalcemia and/or bone lesions), and previous ixazomib or anti-CD38 mAb therapy. Treatment was administered on a 28-day cycle for up to 12 cycles with daratumumab weekly x 8 weeks, then every other week x 16 weeks, and then every 4 weeks thereafter. Daratumumab was initially administered intravenously (16 mg/kg) but later changed to subcutaneous injection (1800 mg) with a protocol amendment. Ixazomib was administered orally 4 mg on days 1, 8, and 15, and dexamethasone administered 20 mg weekly for cycle 1 and increased to 40 mg weekly for cycle 2 and beyond depending on patient tolerance. The primary study endpoint is to confirm the safety and tolerability of DId in AL amyloidosis. Key secondary endpoints include hematologic response rate and organ (cardiac and renal) response rates. Planned enrollment is 20 pts with toxicity monitoring in cohorts of 5 pts. Results: A total of 18 pts have been dosed to-date including 13 treatment-naïve pts and 5 previously treated pts with a median of 1 prior line of therapy. Baseline characteristics are summarized in the Table. Median age was 66 (range 39-75), 8 (44%) pts were female, and 3 (17%) pts were Black. Median baseline difference between the involved and uninvolved free light chain (dFLC) was 194 mg/L (range 71-2787), and 6 of 17 (35%) pts with available FISH testing had t(11;14). Median number of organs involved was 2 (range 1-4), including 9 (50%) pts with cardiac involvement and 11 (61%) pts with renal involvement. Overall hematologic response rate (≥PR) on treatment was 100%, ≥VGPR rate 72%, and complete response (CR) rate 11%. Cardiac response rate was 43% among 7 response evaluable pts (baseline NT-proBNP ≥650 ng/L), and renal response rate was 36% among 11 pts. Among 5 previously treated pts, there were 4 hematologic VGPRs and 1 hematologic CR. The median number of DId treatment cycles was 8.5, with 7 (39%) pts completing all 12 treatment cycles, and treatment is ongoing in 3 (17%) pts. Intent to proceed with high dose chemotherapy and autologous stem cell transplantation was the most common reason for early treatment discontinuation (4 pts, 22%). The most common treatment emergent adverse events (TEAEs) of any grade regardless of attribution were anemia (56%), thrombocytopenia (56%), dyspnea (56%), fatigue (56%), hypoalbuminemia (56%), and nausea (56%). The most common grade 3 or 4 TEAEs (≥20%) were lymphopenia (33%), lung infection (22%), and thrombocytopenia (22%). Treatment emergent peripheral neuropathy (PN) was 28% (all grade 1 and 2), among whom 4 of 5 pts had baseline amyloid PN, other PN, and/or prior bortezomib exposure. There were 3 deaths on study, all unrelated to treatment (1 related to post-operative complications from small bowel obstruction due to congenital Meckel's diverticulum, 1 related to progressive hepatic amyloidosis, and 1 related to pulmonary embolus in setting of COVID-19 infection). Conclusion: Treatment with DId in both newly diagnosed and previously treated AL amyloidosis pts is safe at standard doses of daratumumab and ixazomib with a predictable and manageable AE profile compatible with the expected toxicities of the individual study drugs. Preliminary efficacy is seen with deep (≥VGPR) hematologic responses attained in the majority of pts. These results support the use of DId as a therapeutic option in AL amyloidosis with longer follow-up needed to assess the depth and durability of hematologic and organ responses. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Ixazomib and daratumumab without dexamethasone (I-Dara) in elderly frail RRMM patients: A multicenter phase 2 study (IFM 2018-02) of the Intergroupe Francophone du Myélome (IFM).

8000 Background: Frail patients with multiple myeloma have an inferior outcome, especially in the relapse setting. This adverse prognosis is mainly related to a high discontinuation rate due to treatment (Tx) related adverse events. The aim of this phase 2 study is to evaluate efficacy and tolerability of Ixazomib-Daratumumab (I-Dara) without Dexamethasone in elderly frail patients with relapsed myeloma (RRMM) (NCT03757221). Methods: Ixa-Dara naïve RRMM patients received oral Ixazomib (4 mg: days 1, 8, 15), IV Daratumumab (16 mg/kg; days 1, 8, 15, 22, cycles 1-2; days 1, 15, cycles 3-6; days 1, cycles 7+) and IV Methylprednisolone before Daratumumab (100 mg at day 1, 8, cycle 1 and then 60 mg). They were enrolled after 1 or 2 prior therapy if their frailty score was ≥ 2 by IMWG score. The primary endpoint was ≥ very good partial response rate (VGPR) at one year. Secondary endpoints included ORR, PFS, OS &amp; toxicity according to NCI-CTCAE version 5. Results: Sixty-three patients were screened and 55 enrolled between 03/2018 and 09/2021. Patient were at first (n = 36) or second relapse (n = 19). Thirty-three patients (60%) were previously exposed to bortezomib, 37 (67%) were previously exposed to lenalidomide (Len) and 20 (36 %) were refractory to Len. Median age was 82 (72-93). All patients had a frailty score ≥2 and 13 (24 %) had a 3 or 4 frailty score. In 41 patients ISS at diagnosis was stage I (n = 11), II (n = 18) or III (n = 12). Seventeen (36%) patients harbored high-risk (HR) cytogenetic, including t(4;14) (n = 8) or del17p (n = 10). The median duration of Tx among 28 pts with ongoing Tx was 10 months [5-32] at data cutoff (February, 2)]. The median duration of Tx among 27 pts who stopped Tx was 6 months [0-18]: 18 had progressive disease. Nine patients died during the study: Daratumumab-related bronchospasm (D1C1); Ixazomib-related overdose (C2); sepsis (n = 4), progressive disease (n = 3). Regarding toxicity, 27 pts had a ≥grade 3 AE (49%). The most common grade 3-4 toxicities were thrombocytopenia (n = 9), other cytopenias (n = 4), infection (n = 8), hypertension (n = 3) and gastrointestinal disorders (n = 3). Fourteen out of 28 were SAE including 5 infections, 1 bronchospasm, 1 acute respiratory failure and 2 ixazomib overdoses. Overall response rate, including minimal response, was 86 % with a ≥VGPR rate of 32 % in the whole group. In Len refractory patients the ORR was 82 % and ≥VGPR 41%, in HR cytogenetic patients ORR was 85 % and ≥VGPR 46%. With a median follow-up of 11.6 months median PFS is 16 months and median OS NR (76% estimated at one year). Conclusions: In this elderly frail population Ixa-Dara is a feasible combination with favorable efficacy profile even in Len refractory and HR cytogenetic patients. Early toxicity remains a concern in this population eventhough more manageable with Dara SC. Clinical trial information: NCT03757221.

Comparative efficacy of teclistamab (tec) versus current treatments (tx) in real-world clinical practice in the prospective LocoMMotion study in patients (pts) with triple-class exposed (TCE) relapsed/refractory multiple myeloma (RRMM).

8016 Background : Pts with TCE RRMM who have been exposed to ≥3 lines of therapy (LOT) have a poor prognosis and limited tx options. Tec is a B-cell maturation antigen × CD3 bispecific antibody being evaluated in MajesTEC-1 (NCT04557098), a single-arm, phase 1/2 study in pts with RRMM who were TCE to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody and received ≥3 LOT. Since MajesTEC-1 lacks a control arm, we assessed the comparative efficacy of tec vs tx currently used in real-world clinical practice (RWCP) by creating an external real-world control arm from LocoMMotion (NCT04035226), a prospective study of RWCP efficacy and safety outcomes in pts with TCE RRMM who received ≥3 LOT. Methods: An external control arm for MajesTEC-1 was created from pts in LocoMMotion (248 pts, clinical cutoff May 21, 2021) who met MajesTEC-1 eligibility criteria. Individual pt-level data from MajesTEC-1 were included from 150 pts treated with tec (1.5 mg/kg weekly) at a clinical cutoff of Sep 7, 2021. Inverse probability of tx weighting with average tx effect on the treated was used to adjust for imbalances in baseline covariates of prognostic significance (refractory status, International Staging System stage, time to progression on prior LOT, extramedullary disease, number of prior LOT, time since diagnosis, average duration of prior LOT, age, hemoglobin, lactate dehydrogenase, creatinine clearance, Eastern Cooperative Oncology Group performance status, gender, type of MM, and prior transplant). Comparative efficacy of tec vs RWCP was estimated for overall response rate (ORR), very good partial response (VGPR) rate, complete response or better (≥CR) rate, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). For binary endpoints (ORR, VGPR rate, and ≥CR rate), relative effect of tec vs RWCP was estimated with an odds ratio, transformed into a response-rate ratio (RR) and 95% confidence interval (CI), derived from weighted logistic regression. A weighted Cox proportional hazards model was used to compute hazard ratios (HRs) and 95% CIs for time-to-event endpoints (DOR, PFS, and OS). Results: Baseline characteristics were well balanced between the 2 cohorts after reweighting the external RWCP cohort. Pts treated with tec had improved outcomes vs tx used in RWCP: ORR (RR 2.31; 95% CI 1.75–2.87; P&lt; 0.0001), VGPR rate (RR 5.54; 95% CI 3.38–7.70; P&lt; 0.0001), ≥CR rate (RR 91.50; 95% CI 12.66–661.43; P&lt; 0.0001), DOR (HR 0.17; 95% CI 0.08–0.36; P&lt; 0.0001), PFS (HR 0.47; 95% CI 0.34–0.67; P&lt; 0.0001), and OS (HR 0.69; 95% CI 0.46–1.05; P= 0.08). Conclusions : Tec showed significantly improved efficacy over RWCP for almost all outcomes, highlighting its potential as a highly effective tx option for pts with TCE RRMM who have been exposed to ≥3 LOT.

A single-center retrospective analysis of 100 consecutive cases treated with lenalidomide/bortezomib/dexamethasone in newly diagnosed multiple myeloma

Objective: To investigate the efficacy and safety of lenalidomide combined with bortezomib and dexamethasone (RVD) in patients with newly diagnosed multiple myeloma (NDMM). Methods: A total of 100 consecutive NDMM patients treated with RVD from August 2016 to September 2020 at Peking University People's Hospital were retrospectively analyzed, including response, drug toxicity, follow-up and survival, and subgroup analysis. Results: The median follow-up time was 19.5 (2.0-57.0) months. For patients undergoing autologous stem cell transplantation (ASCT) after RVD regimen, the objective response rate (ORR)/complete response+stringent complete response (CR+sCR)/≥very good partial response (VGPR) rates were 100%, 73.3% (33/45), 95.6% (43/45) respectively. For 54 patients not receiving transplantation, the ORR/CR+sCR/≥VGPR rates were 79.6% (43/54), 18.5% (10/54), 51.9% (28/54) respectively. As to the survival analysis, 2-year progression free survival (PFS) rates were 84.5% and 70.9% in transplant and non-transplant patients respectively (P=0.102). Two-year overall survival (OS) rates were 100% and 80.8% in transplant and non-transplant patients respectively (P=0.003). The common hematologic adverse events (AEs) were thrombocytopenia (33%) and neutropenia (25%). Abnormal liver function (43%) and peripheral neuropathy (24%) were recognized more as non-hematologic AEs. Conclusion: RVD as front-line regimen has high efficient response rate and acceptable safety in Chinese NDMM patients.

Bortezomib-cyclophosphamide-dexamethasone induction/consolidation and bortezomib maintenance for transplant-eligible newly diagnosed multiple myeloma: phase 2 multicenter trial

ABSTRACT Objectives: We conducted a phase II trial to prospectively evaluate the efficacy and safety of bortezomib-cyclophosphamide-dexamethasone (VCD) induction, autologous stem cell transplantation (ASCT), VCD consolidation, and bortezomib maintenance in transplant-eligible newly diagnosed multiple myeloma (NDMM) patients in Japan (UMIN000010542). Methods: From 2013 to 2016, 42 patients with a median age of 58 (range 42–65) years with NDMM were enrolled in 15 centers. The primary endpoint was the complete response (CR) /stringent CR (sCR) rate after transplantation, and overall/progression-free survival rates were also evaluated. Results: Following induction therapy, the overall response rate was obtained in 71% of patients, including a CR/sCR of 10% and a very good partial response (VGPR) of 26%. Twenty-six of the 42 patients completed ASCT following the protocol and CR/sCR and VGPR rate 100 days after ASCT was 26% and 17%, respectively. During consolidation therapy, 3 of the 24 patients achieved deeper responses. Eight of the 18 patients completed 2-year bortezomib maintenance without disease progression and grade 3/4 toxicities. Five patients were VGPR or partial response after ASCT but maintained response with 2-year bortezomib maintenance. Two-year overall and progression-free survival rates were 92.5% (95% confidence interval [CI]: 78.5%−97.5%) and 62.6% (95% CI: 45.8%−75.5%), respectively. Grade 3/4 toxicities (≥ 10%) included neutropenia (19%) and anemia (17%) in induction, and thrombocytopenia (29%) in consolidation. Conclusion: VCD induction/consolidation and bortezomib maintenance with ASCT for NDMM resulted in a high CR/sCR rate and provided good overall/progression-free survival in Japan.

Myeloma Patients with Deletion of 17p: Impact of Tandem Transplant and Clone Size

IntroductionThe presence of deletion 17p or monosomy 17 (del(17p)/-17) detected by fluorescence in situ hybridization (FISH) is well-established as a high-risk (HR) factor in multiple myeloma (MM). The del(17p)/-17 clone size and the clinical impact in patients that have ≥60% involved nuclei is controversial. Optimal treatment is also controversial, with tandem autologous stem cell transplantation (ASCT) explored but not uniformly adopted in the real world (ENM02, StaMMina). At our center, we have routinely offer tandem transplantation for del(17p)/-17 and now review our experience over a 10-year period, including the significance of del(17p)/-17 genetic variations on outcomes.MethodsWe performed a retrospective chart review of all patients identified with del(17p)/-17 patients who were offered tandem transplant and underwent at least one ASCT at Princess Margaret Cancer Centre from 2009-2019. Patient and disease characteristics, responses, and survival outcomes were collected from the Myeloma and Transplant databases and electronic patient records under REB approval.ResultsPatient, disease, and treatment characteristics.We identified 100 patients with del(17p)/-17 who underwent ASCT at our center. These patients were separated into three groups: those with a deletion of the TP53 locus (57%), those that had monosomy 14 (17%), and those with a relative loss the TP53 locus (eg. aneusomy or polyploidy,13%). The median % of nuclei with del(17p) was 39% (range 5-93%), with 27 (25%) over 60%. 28% of patients carried at least one other cytogenetic abnormality besides del(17p), most commonly t(4;14). All patients were intended for tandem transplant, but only 69 (69%) completed both transplants. Reasons for not proceeding to a second transplant were: patient declined (29%), toxicity (26%), clinical trial (19%), progression prior to the second transplant (13%), with one early death (3%). Median age at transplant was 61 years (range 40-72); most were male (61%) with advanced R-ISS II and III (97%).The most common induction regimen used was cyclophosphamide, bortezomib and dexamethasone (CYBORD)(87%), with 10% requiring a 2 nd induction regimen for inadequate response/progression. Standard conditioning was melphalan 200mg/m 2 for both first and second transplants. Median time from diagnosis to first ASCT was 5.9 months (range 3-24) and time from first to second transplant was 3.3 months (range 1-7). Most patients (90; 84%) received maintenance therapy post-transplant: 47% lenalidomide, 29% multiple agents (commonly lenalidomide and a proteasome inhibitor)Response and survival outcomesAfter induction, the rate of VGPR (very good partial response) or greater was 53%, increasing to 73% after 1 st ASCT, 85% after 2 nd ASCT. At a median follow-up of 32 months (range 3-130), the median PFS for all patients was 39.2 months 95% CI (24.1-46) and median OS was not yet reached (NYR) (95% CI 57.9-NYR). When analyzed by whether single or tandem transplant was performed, median PFS was 21.8 months (95% CI 10.3-43.3) for single ASCT, and 42.1 months (95% CI 32.8-NYR) for tandem ASCT (P=0.0096). The median OS was 57.6 months for single ASCT (95% CI 22.2-86.5), but NYR for tandem ASCT (95% CI 105.6-NYR) (p=0.0022).On subgroup analysis, patients with ≥60% del(17p) achieved a median PFS 45 months (95% CI 14.4-NYR) and median OS 68.5 months (95% CI 20.9-68.5), median was only PFS 24.9 months (95% CI0.4-NYR) and median OS 29.3 months (95% CI 0.4-68.5) for those who received single ASCT. (table1)TP53 signal pattern analysis (table 2) showed the median OS for patients with monosomy 17 was NYR, while it was 105.7 months for patients with deletion, and 86.5 months for those with relative loss. Median PFS was 43.3 months for the monosomy group, 32.8 months for deletion group, and NYR for relative loss.ConclusionsOur experience shows that MM patients with del(17p)/-17 appear to have deeper responses and improved outcomes with more aggressive tandem transplantation. However, approximately 1/3 of our patients intended for tandem transplant did not undergo a second transplant, identifying a focus of future investigation and optimization. Our analysis also suggests that clone size of del(17p) >60% does impact OS negatively, but improved with tandem transplantation. The type of deletion also appears to affect outcomes with deletion having worse PFS but not worse OS. [Display omitted] DisclosuresPrica: Astra-Zeneca: Honoraria; Kite Gilead: Honoraria. Reece: Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Millennium: Research Funding; Sanofi: Honoraria; BMS: Honoraria, Research Funding; Karyopharm: Consultancy, Research Funding; GSK: Honoraria. Trudel: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Roche: Consultancy; Sanofi: Honoraria; Pfizer: Honoraria, Research Funding. Chen: Beigene: Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy.