Search

8007 Background: The BCMA × CD3 bispecific antibody teclistamab (tec; JNJ-64007957) redirects CD3+ T cells to mediate T-cell activation and subsequent lysis of BCMA-expressing myeloma cells. The multicohort, open-label, phase 1/2 MajesTEC-1 study is investigating safety/efficacy of tec in patients (pts) with RRMM who previously received ≥3 lines of therapy (LOT). In phase 1, the recommended phase 2 dose (RP2D) of tec was identified as a weekly subcutaneous dose of 1.5 mg/kg preceded by step-up doses of 0.06 and 0.3 mg/kg. Initial results from pts treated with the tec RP2D in phase 1/2 (no prior exposure to an anti–BCMA-targeted treatment), demonstrated that tec was well tolerated with encouraging efficacy. Here we present updated results from pts treated at the RP2D, including additional pts and longer follow-up. Methods: Eligible pts were aged ≥18 years, had documented MM (per IMWG criteria), and had received ≥3 prior LOT including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody. Prior BCMA-targeted therapy was not permitted in Phase 1. Pts received tec at the RP2D. The primary endpoint was overall response rate (assessed per IMWG 2016 criteria). Adverse events (AEs) were graded per CTCAE v4.03 (cytokine release syndrome [CRS] and ICANS graded per ASTCT guidelines). Data cutoffs for safety and efficacy (N = 165) were Sep 7 and Nov 9, 2021, respectively. Results: Median pt age was 64 y (range 33–84); 58% were male, and median prior LOT was 5 (range 2–14); 100% were triple-class exposed, 70% were penta-drug exposed, 78% were triple-class refractory, and 30% were penta-drug refractory. ORR was 64% (95% CI 56–72), with a complete response or better achieved in 30% of pts. Responses were durable and deepened over time; median duration of response (DOR) was not reached. The 12-mo DOR rate was 66% (95% CI 49–79). The majority of pts who responded to treatment in the first cycle had a reduction in soluble BCMA. The most common hematologic AEs were neutropenia (65%; grade 3/4: 57%), anemia (50%; grade 3/4: 35%), thrombocytopenia (38%; grade 3/4: 21%), and lymphopenia (34%; grade 3/4: 32%). Infections occurred in 104 pts (63%; grade 3/4: 35%). The most common nonhematologic AE was CRS (72%; grade 3: 0.6%; no grade 4/5); median time to CRS onset (range) was 2 days (1–6) and median duration was 2 days (1–9). Five pts (3%) reported a total of 9 ICANS events (all grade 1/2; 7 were concurrent with CRS; all resolved). There were no treatment-related deaths. No pts required a teclistamab dose reduction due to AEs. Conclusions: Current data with ̃9 months of follow-up reaffirm the deep and durable responses that have been observed with tec in pts with highly refractory MM, with no new safety signals. Additional data with longer follow-up, including subgroup analyses and PFS, will be presented. Clinical trial information: NCT04557098.

8033 Background: As multiple myeloma (MM) negatively affects patients’ (pts) health-related quality of life (HRQoL), assessment of patient-reported outcomes (PROs) in addition to clinical outcomes is important. Teclistamab (tec; JNJ-64007957) is an off-the-shelf bispecific antibody that redirects CD3+ T cells to mediate T-cell activation and subsequent lysis of BCMA-expressing MM cells. Initial results from the pivotal cohort of the phase 1/2 MajesTEC-1 study demonstrated that tec was well tolerated with encouraging efficacy in pts who received ≥3 prior lines of treatment (LOT; including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody). Here we report PROs from this cohort. Methods: Pts (aged ≥18 years) had documented RRMM (International Myeloma Working Group criteria), progressive/measurable disease, and had previously received ≥3 prior LOT; prior anti-BCMA treatment (tx) was not allowed. Pts received weekly subcutaneous tec at the recommended phase 2 dose (1.5 mg/kg with step-up doses of 0.06 and 0.3 mg/kg). PROs were assessed at screening and every even cycle (cycles 2–8 reported here) using the EORTC QLQ-C30 (range: 0–100; higher scores indicate better global health status [GHS] but greater symptom severity [symptom scales]) and the EuroQol 5-dimensional descriptive system (visual analog scale [VAS] range: 0 [worst imaginable health state] to 100 [best imaginable]). Tx effect was assessed by a mixed-effects model with repeated measures; the proportion of pts with meaningful improvement was defined as a change ≥10 points. Time to worsening was determined using the Kaplan-Meier estimate. Results: A total of 110 pts were included (median follow-up: 7.8 mos). Overall PRO compliance rates were high (baseline [BL]: 85–90%; cycles 2–8: 80–94%). Tec improved overall HRQoL as evidenced by improvements in GHS scores (cycles 2–8) and reduction in pain (-4.2 [cycle 2] to -15.1 [cycle 8]; Table), with no overall change in physical functioning and fatigue. The proportions of pts with meaningful improvements from BL at cycle 8 were GHS: 50%; physical functioning: 35%; pain: 65%; fatigue: 73%; 50% of pts reported meaningful improvement in their overall health (VAS). Median time to improvement from baseline was ̃1.5 months (with nausea/vomiting and fatigue taking longer to improve), while median time to worsening (all symptoms) ranged from 2 months to not estimable. Conclusions: Consistent with clinical outcomes, pts treated with tec reported rapid, clinically meaningful improvements in HRQoL. Clinical trial information: NCT04557098. [Table: see text]

8013 Background: Tec (JNJ-64007957) is a BCMA x CD3 bispecific antibody (Ab) that redirects CD3+ T cells to mediate T-cell activation and subsequent lysis of BCMA-expressing myeloma cells. MajesTEC-1 is a multicohort, open-label phase 1/2 study of tec in pts with RRMM who previously received ≥3 prior lines of therapy (LOT). Results from a pooled analysis of phase 1 and phase 2 cohort A (median follow-up 7.8 mo) demonstrated an overall response rate (ORR) of 62.0% in pts with no prior anti-BCMA treatment (tx). We present initial results from cohort C, in which pts had prior exposure to an anti-BCMA tx. Methods: Eligible pts (age ≥18 y) had documented MM per IMWG criteria and had received ≥3 prior LOT including a PI, an IMiD, an anti-CD38 Ab, and an anti-BCMA tx (chimeric antigen receptor T [CAR-T] or Ab drug conjugate [ADC]). Pts were enrolled into a Simon’s stage design, receiving weekly subcutaneous tec 1.5 mg/kg preceded by step-up doses of 0.06 and 0.3 mg/kg. Primary endpoint was ORR (per IMWG 2016 criteria). AEs were graded per CTCAE v4.03; cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) were graded per ASTCT guidelines. Results: As of Sep 7, 2021, 38 pts in cohort C received tec (63% male; median age 63.5 y [range 32–82]; median prior LOT 6 [range 3–14]). 32 (84%) pts were refractory to last LOT; 25 (66%) were refractory to an anti-BCMA tx. Of 25 pts evaluated for efficacy, 16 (64%) had prior ADC, 11 (44%) prior CAR-T (2 pts received both). With median follow-up of 6.9 mo (range 0.7–8.7), ORR was 40% (95% CI 21–61). 5 pts (20%) achieved a complete response or better. The ORR (95% CI) was 38% (15–65) in ADC-exposed pts and 45% (17–77) in CAR-T–exposed pts. Most responses occurred rapidly; 7/25 pts had responses that deepened over time. Median time (range) to first and best response was 1.2 mo (0.2–4.9) and 2.1 mo (1.1–5.7), respectively. Median duration of response was not reached. The safety profile was comparable with that observed in BMCA tx-naive pts, with no new safety concerns. 16 pts (42%; grade 3/4 26%) had infections. Most common AEs (n = 38) were CRS (63%; all grade 1/2; median [range] time to CRS onset: 3 d [2–6], duration of CRS: 2 d [1–4]), neutropenia (55%; grade 3/4 50%), thrombocytopenia (42%; grade 3/4 29%), anemia (39%; grade 3/4 29%), and lymphopenia (40%; grade 3/4 37%). One pt had grade 3 ICANS that resolved with supportive care; pt remains on tx. No pts developed anti-tec Abs. Baseline BCMA expression was comparable with that observed in BCMA tx-naive pts. Updated efficacy and safety data will be presented for 40 pts. Conclusions: Initial results of serial targeting of BCMA with tec following ADC or CAR-T tx suggest a promising ORR with responses occurring early and deepening over time. A well-tolerated safety profile was observed in pts previously treated with anti-BCMA tx. Clinical trial information: NCT04557098.

Additional file 3: Table S2. Summary of changes in laboratory values from baseline. The median changes in hematological laboratory values from baseline are summarized for patients in the Safety population by minimum, maximum, EOT. Baseline indicates assessment prior to first dose. EOT, end of treatment; max, maximum; min, minimum.

Additional file 2: Table S1. Summary of AEs. Summary of treatment-emergent AEs of all grades and grades 3 to 4 in the Safety population. Adverse events of any grade with an incidence of at least 20%, as well as events of grade 3 or 4 with an incidence of at least 3%. AE, adverse event.

Additional file 1: Figure S1. Patient disposition. Patient disposition diagram for the 89 patients that were screened. aInformed Consent Form signed. bCompletion of protocol treatment is defined as six cycles of therapy. cCompletion of study phase is defined as being followed up to Day 181 after the last treatment, regardless of the number of doses of moxetumomab received.

Additional file 1. SUPPLEMENTARY INFORMATION: Supplemental Methods; Table S1. Patient Disposition; Table S2. Safety Summary; Figure S1. SYMPATICO study schemas; Figure S2. Schema to determine randomized phase 3 dosing; Figure S3. Metabolic laboratory values and abnormalities in one patient with laboratory TLS; Supplementary Figure S4. Overall survival.

Additional file 4: Figure S2. Mean serum creatinine over time. Creatinine levels over time (mean +/– SD) from the intent-to-treat population are shown; N = 80.

Additional file of Moxetumomab pasudotox in heavily pre-treated patients with relapsed/refractory hairy cell leukemia (HCL): long-term follow-up from the pivotal trial

Background. Lenalidomide has proved safe and effective in multiple myeloma (MM), particularly in elderly patients. Furthermore, it has been showed that lenalidomide enhanced rituximab-mediated antibody-dependent cell-mediated cytotoxicity. Unexpectedly, lenalidomide (25 mg/d on days 21/28) along with rituximab (375 mg/m²/wk) produced clinically significant acute anemia in patients with WM, most of them received 25mg/day with no improvement when the dose was reduced (Treon et al. CCR, 2009). No cause was attributable to the occurrence of this adverse event. Thus, we sought to perform a study with incremental concentrations of single agent lenalidomide to determine the maximum tolerated dose (MTD) of lenalidomide in WM, and possibly unravel the cause of anemia upon treatment with lenalidomide. Methods. RV-WM-0426 is a multicenter phase I/II dose escalation open label study of lenalidomide in relapse/refractory WM. Lenalidomide was given oral daily 21 / 28 days per cycles for 1 year, at escalated dose of 15 to 20 then 25mg across cohorts of 3 to 6 patients each during the phase 1 part, then followed by 9 patients to recruit in the phase 2 part at the maximum tolerated dose (MTD). The primary endpoint was the MTD, secondary endpoint included response rate (International WM Workshop) and response duration, safety, measurements of free light chain assays, and PFS and OS. Results. 17 patients were enrolled in the study, the median age was 69 (range 48-81), with 7 patients older than 75, 70% were male. 53% had adverse IPSS 3. The median hemoglobin level was 11.2 (95%CI 9.9-12.5), median M spike level 26.5 (95%CI 23-40), 23% had clearance creatinin below 60ml/min. The median number of prior lines was 1 (range 1-8), all patients but 2 exposed to alkylating agents, 30% to nucleoside analogues, 47% to the monoclonal antibody mabthera, none of the patients have had a transplantation. The median time from diagnosis to study entry was 3 years (range 2-15). At the highest dose tested, 20 mg, 2 patients had dose-limiting toxicity, septic syndrome during grade 4 neutropenia and severe fatigue, respectively. The MTD was thus established at the 15 mg/day 21 days out of 28. 7/17 (41%) patients completed one year of single agent lenalidomide at 15mg day 21/28. Single agent lenalidomide in WM provided an overall response (minimal response (MR) and better) on an intent-to-treat basis at 15mg/day of 36%, and an extra 2 patients had a prolonged stable disease (SD). A flare effect (transient initial increase of the M spike) was observed in 5 patients. With a median follow-up of 36 months, 14 have progressed with a median time to progression of 16 months (95%CI 5.5-26), with 35% of patients with a PFS greater than 24 months. One patient died with a 5-year overall survival (OS) of 91%. The most common adverse event (AE ≥ 10%) was fatigue of at least grade 2, reported in 50% of the patients. The incidence rate of grade 3 and greater hematological AE at 15mg was 14% for anemia, 43% for neutropenia, and no thrombopenia observed. 78% experienced a non hematological AE of at least grade 2, but only 2 patients had a grade 3 AE, nephrotic syndrome and cramps. No second primary malignancy (SPM) nor thromboembolic event were reported to date. Only 21% of patients had dose reduction with a median time of 7 months, and 35% had study drug interruption related to an AE with a median time of 4 months. Conclusion. The MTD of lenalidomide is 15mg/day given on days 21/28 in relapse and refractory WM. Lenalidomide is active in the treatment of RRWM and the safety profile appeared manageable, essentially of grade 2 AEs. Future studies may look into combinations to lenalidomide and continuous therapeutic effect in WM at the determined MTD. Disclosures Leleu: Janssen, Celgene, leopharma, Takeda, Amgen, Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tournilhac:mundipharma: Honoraria, Other, Research Funding; GSK: Honoraria, Other, Research Funding; Roche: Honoraria, Other, Research Funding. Leblond:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background. POEMS syndrome is a rare form of B cell dyscrasia combining a proliferation usually of plasma cells, a polyneuropathy, osteocondensing bone lesions and multiple other clinical signs. The pathogenesis is not well understood but VEGF plays a major role. In patients with one or two sclerotic plasmacytoma and no bone marrow involvement, first line therapy should include radiation. For patients with diffuse sclerotic lesions, bone marrow involvement or absence of any bone lesion and for those who have not demonstrated stabilization of their disease 3 to 6 months after completing radiation systemic therapy is indicated, the most effective being high dose chemotherapy with autologous stem cell transplant (ASCT). Radiation of a single lesion is effective in about every other case and is accompanied by a fairly slow improvement of the neurological symptoms, often after initial worsening. ASCT seems to be accompanied by a number of important complications, in particular engraftment syndrome. Outside these 2 treatments there is no consensus therapy. Lenalidomide (LEN), a drug without serious neurological toxicity, has the advantage of being both anti-angiogenic and cytotoxic to malignant plasma cells (Richardson PG, Blood 2002;100(9):3063-7). We have recently reported a series of 20 French patients with POEMS syndrome treated by LEN with a good efficacy. We now report the first 27 patients of a prospective phase II trial using LEN + dexamethasone (LEN-DEX), 2 cycles preceding radiation or high dose treatment trying to obtain a rapid clinical response and to avoid engraftment syndrome or 9 cycles followed by 1 year LENalone in patients who cannot receive radiation or ASCT. Methods. Newly diagnosed or relapsing patients with POEMS syndrome who needed to be treated were eligible. Patients who can be treated by local radiation or intensive treatment with stem cell support receive two 28 day cycles of LEN 25 mg PO Days 1-21 and DEX 40 mg PO Days 1,8,15,22 before radiation or intensive treatment (Group 1), the other patients receive 9 cycles of the same LEN-DEX (Group 2) and then 12 cycles of continuous low dose LEN (10 mg). LEN dose was tapered to 10 mg for patients with a creatinine clearance between 30 and 50 ml/min and DEX to 20 mg for patients above 75 years of age and for those who were frail patients. Main eligibility criteria included a diagnosis of POEMS syndrome according to criteria by Dispenzieri et al (Am J Hematol 2012;87(8):804-14), an age of 18 or more, a creatinine clearance above 30 ml/min, no prior treatment with or contraindication to LEN and no uncontrolled thrombosis. Serum and plasma VEGF, serum electrophoresis, immunofixation and free light chain measurements were centrally monitored. Neurologic evaluations were performed using the Overall Neuropathy Limitations Scale (ONLS), the Neurological Impairment Scale (NIS) and the 10 meter walk test (10MWT). The primary endpoint was evaluation of the effectiveness of LEN-DEX combination using biological responses (decrease of monoclonal protein and serum VEGF level) and secondary endpoints were clinical and particularly neurological responses. Results. Twenty-seven patients have been included in 12 centres, median age was 61 (range 32-75), the median follow-up was 6.6 months (range 2-24). Eighteen patients were in group 1, with radiotherapy in 10 patients and ASCT in 8 patients; 9 patients were in group 2. Nineteen patients were in first line and 8 already treated. Only 2 patients experienced grade 3-4 adverse events due to LEN (cytopenia) and 2 patients had allergic rashes, no thrombotic event occurred. No engraftment syndrome was noted in the 5 patients already treated with ASCT. To date, no patient have died. Evolution of VEGF median values in serum and plasma, M-spike and dFLC levels and evolution of neurological measurements are reported in table 1. Neurological improvement was very rapid in some patients, using ONLS and 10MWT 11/18 evaluable patients had a neurological improvement after 2 cycles with an improvement of 1 or more of the ONLS score and/or change of 0.1 m/s or more in the 10MWT. Only one patient who progressed after nine cycles received another therapy. Conclusion. This is the first prospective trial of LEN-DEX in POEMS syndrome. This combination seems well tolerated in this disease with a good efficacy on VEGF measurements and rapid neurological improvement in the majority of patients. Updated data will be presented at the meeting. Figure 1 Figure 1. Disclosures Jaccard: Celgene: Drug supply to Trial Other. Tournilhac:mundipharma: Honoraria, Other, Research Funding; GSK: Honoraria, Other, Research Funding; Roche: Honoraria, Other, Research Funding. Moreau:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Summary With increasing number of therapies available for the treatment of multiple myeloma, it is timely to examine the course of patients' journeys. We investigated patient characteristics, treatment durations and outcomes, and symptom burden across the treatment pathway in Belgium, France, Germany, Italy, Spain, Switzerland and the UK. In total, 435 physicians retrospectively reviewed 4997 patient charts. Profiles of patients diagnosed with multiple myeloma during the last 12 months were similar across countries; bone pain was the most common presentation. Median duration of first‐line therapy was 6 months, followed by a median treatment‐free interval of 10 months; both these decreased with increasing lines of therapy, as did time to progression. Depth of response, as assessed by the treating physician, also decreased with each additional line of therapy: 74% of patients achieved at least a very good partial response at first line, compared with only 11% at fifth line. Deeper responses were associated with longer time to progression, although these were physician‐judged. Toxicities and co‐morbidities increased with later treatment lines, and were more likely to have led to discontinuation of treatment. These real‐world data provide an insight into patient outcomes and treatment decisions being made in clinical practice.

Real-world data describing management of patients with multiple myeloma are limited. A European (Belgium, France, Germany, Italy, Spain, Switzerland, UK) observational chart review was conducted to address this. Physicians completed questionnaires for every patient seen during a 2-4-week observation period, regardless of treatment status. A total of 435 physicians completed 7635 cross-sectional chart reviews. Overall, 47% of patients were undergoing anti-tumour drug treatment, 42% had previously received ≥1 line of treatment and 12% had never received anti-tumour drug treatment. Of the patients treated by oncologists, onco-haematologists or internists, 95% received, or were expected to receive, at least one line of anti-tumour drug treatment, 61% received ≥2 lines of therapy and 38% received ≥3 lines. Except in the UK, the most commonly used induction therapies contained bortezomib (48%); lenalidomide was the most commonly used first-line maintenance therapy (45%) and second- and third-line agent overall (60% and 52% of patients at those lines, respectively). Bortezomib retreatment was used in 47% of patients who received it first line. Treatment patterns became more diverse with subsequent treatment lines. This study provides insight into real-world treatment patterns in Europe. While treatment practices are broadly similar across countries, some notable differences in the agents used exist.

Pomalidomide is a distinct oral IMiD immunomodulatory agent with direct antimyeloma, stromal-support inhibitory, and immunomodulatory effects. The pivotal, multicenter, open-label, randomized phase 3 trial MM-003 compared pomalidomide + low-dose dexamethasone vs high-dose dexamethasone in 455 patients with refractory or relapsed and refractory multiple myeloma after failure of bortezomib and lenalidomide treatment. Initial results demonstrated significantly longer progression-free survival and overall survival with an acceptable tolerability profile for pomalidomide + low-dose dexamethasone vs high-dose dexamethasone. This secondary analysis describes patient outcomes by treatment history and depth of response. Pomalidomide + low-dose dexamethasone significantly prolonged progression-free survival and favored overall survival vs high-dose dexamethasone for all subgroups analyzed, regardless of prior treatments or refractory status. Both univariate and multivariate analyses showed that no variable relating to either the number (≤ or > 3) or type of prior treatment was a significant predictor of progression-free survival or overall survival. No cross-resistance with prior lenalidomide or thalidomide treatment was observed. Patients achieving a minimal response or better to pomalidomide + low-dose dexamethasone treatment experienced a survival benefit, which was even higher in those achieving at least a partial response (17.2 and 19.9 months, respectively, as compared with 7.5 months for patients with less than minimal response). These data suggest that pomalidomide + low-dose dexamethasone should be considered a standard of care in patients with refractory or relapsed and refractory multiple myeloma regardless of prior treatment. ClinicalTrials.gov: NCT01311687; EudraCT: 2010-019820-30. ispartof: Haematologica vol:100 issue:10 pages:1334-9 ispartof: location:Italy status: published