Belantamab Mafadotin in Patients with Relapsed/Refractory AL Amyloidosis with Myeloma

Abstract Introduction: Daratumumab in combination with cyclophosphamide, bortezomib and dexamethasone (Dara/CyBorD) is the only FDA approved therapy for newly diagnosed systemic light-chain (AL) amyloidosis (N Engl J Med 2021;385:46). Belantamab mafodotin is a novel anti-BCMA immunoconjugate with humanized IgG1 anti-BCMA monoclonal antibody conjugated to a microtubule-disrupting agent, monomehtyl auristatin F (MMAF) via a non-cleavable linker (Blood 2014;123:3128). Phase I/II studies in heavily pre-treated multiple myeloma patients showed single agent clinical activity with overall response rates ranging from 30-60%, with majority of responses being durable at 13 months of follow-up. Toxicity profile included keratopathy, thrombocytopenia and anemia (Blood Cancer J 2019;9:37; Lancet Oncol 2020;21:207). Based on these results, belantamab mafadotin (BLM; Blenrep) was FDA approved for relapsed myeloma. A role for new agents such as BLM in AL has not been previously reported. Here we report outcomes of six patients who received BLM at different centers for relapsed refractory (RR) AL associated with myeloma. Methods: In this retrospective study we identified AL patients with RR disease who received at least one dose of BLM. In a multi-institutional collaboration we collected demographic, medical history, laboratory, pathologic and treatment/response data on patients with myeloma and biopsy-proven AL who had received BLM. Laboratory assessment including evaluations for hematologic and organ response was done as per standard criteria and toxicity assessed as per CTCAE v6.0. Results: We identified 6 patients, 3M/3F, from 4 centers; baseline characteristics and treatment data are provided in Table 1. Baseline median age was 61 years (range, 51-74) and median marrow plasmacytosis and iFLC were 40% (10-90) and 868mg/L (145-5324). Four patients had AL λ-type and 2 κ-type, and 5 of 6 had cardiac involvement while 3 had additional organ involvement (renal, GI, nervous system). Prior to initiating BLM the median number of lines of prior therapy was 6 (range, 5-10), including daratumumab, bortezomib and lenalidomide, and prior to initiating BLM marrow assessment showed a median plasmacytosis of 23%. BLM at 2.5 mg/kg was given as an intravenous infusion over the course of 30 minutes every three weeks after ophthalmologic exam clearance until discontinuation for progression or toxicity. At a median follow-up of 4.5 months, 5 patients (83%) achieved hematological responses (HR) with 3 (50%) achieving complete hematological responses (CR) by standard criteria (J Clin Oncol 2012;30:4541). Time to HR ranged from 3 to 150 days. Cardiac response was seen in all but 1 patient, with time to response ranging from 11 to 96 days. One patient had a renal response; response assessment is not yet available for 2 other patients with renal involvement. The most common toxicity was keratopathy (grade 1-2). BLM was held after the first dose in one patient who had been heavily pre-treated and had extensive cardiac and pulmonary AL and multiple sites of FDG-avid progressive myeloma bone disease. Two days after administration of the first dose of BLM, this 51-year-old man was admitted to hospital for dyspnea, developed atrial fibrillation and ventricular tachycardia, and briefly required cardiac resuscitation without intubation with return of spontaneous circulation after 6 minutes. This patient achieved a CR after one dose of BLM that has been stable for over 5 months with marked clinical improvement. A 62 year-old woman with cardiac and renal AL has achieved a CR durable for over 16 months with cardiac and renal responses. Conclusions: In this group of 6 patients with RR AL with myeloma, HR and cardiac response rates were impressive at 83% and 80%, respectively. One patient who had 24-hour urine protein evaluation also achieved a renal response. Time to response was rapid with 2 patients achieving HR within a week of starting treatment, and the rest within five months. Additionally, 3 of 6 patients achieved CR, 1 had no clonal plasma cells in the marrow and another clonal disease detectable only by MRD. In this retrospective multi-institutional cohort BLM resulted in rapid reduction of iFLC and induced critical organ responses. These data provide preliminary evidence for the clinical activity of BLM in RR AL. Results of the on-going phase 2 clinical trial in the European Myeloma Network (EMN27; NCT04617925) are awaited with great interest. Figure 1 Figure 1. Disclosures Sborov: Sanofi: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; SkylineDx: Consultancy. Comenzo: Karyopharm: Research Funding; Prothena Biosciences: Consultancy, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Caelum: Consultancy, Research Funding; Janssen: Patents & Royalties: WO2016187546A1, Research Funding. Kansagra: Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Cota Health: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Alynylam: Membership on an entity's Board of Directors or advisory committees.

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Long-Term Outcomes and Organ Responses with Daratumumab Therapy in Previously Treated Patients with AL Amyloidosis

Blood ◽

10.1182/blood-2019-122152 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1828-1828

Author(s):

Alfred Chung ◽

Gregory P. Kaufman ◽

Surbhi Sidana ◽

Erik Eckhert ◽

Stanley Schrier ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cardiac Response ◽

Al Amyloidosis ◽

Long Term Outcomes ◽

Advisory Committees ◽

Renal Response ◽

Cardiac Responses ◽

Previously Treated

Introduction: AL amyloidosis involves deposition of abnormally folded light chains into a wide range of tissues causing end-organ dysfunction, including in the heart and kidney. Daratumumab, a CD38-targeted antibody, has recently demonstrated efficacy in producing hematologic responses in previously relapsed/refractory disease. However, data on long-term outcomes to daratumumab, including organ responses, are lacking. Here we present the largest retrospective study to date on patients with previously treated AL amyloidosis treated with daratumumab. Methods: We conducted a retrospective analysis of relapsed/refractory AL amyloidosis patients treated at Stanford University from January 2016 to January 2019. Patients treated with daratumumab, either as monotherapy with dexamethasone (DMT) or in combination with other plasma-cell directed therapies (DCT) were included. Hematologic and organ responses were assessed by consensus guidelines. Hematologic responses were based on the maximal change in the difference between involved and uninvolved free light chains (dFLC). For cardiac response, a >30% and >300 pg/mL decrease in NT-proBNP for patients with initial baseline NT-proBNP ≥650 pg/mL was considered a response. A graded cardiac response metric was also explored with partial response (PR) representing 30-59% reduction, very good partial response (VGPR) ≥60% reduction, and complete response (CR) NT-proBNP <450 pg/mL as previously reported. For renal response, a >30% decrease (by at least 0.5 g/day) in 24-hour urine protein without worsening in creatinine or creatinine clearance by more than 25% in patients with at least 0.5 g/day pretreatment was considered a response. A graded renal response metric was also explored with PR representing 30-59% reduction in proteinuria, VGPR ≥60%, and CR ≤ 200 mg per 24-hour period. Survival data was analyzed using the Kaplan-Meier method. All time-to-event outcomes, including survival and organ responses, were determined from initiation of daratumumab. Results: Eighty-four patients were identified with baseline characteristics at start of daratumumab shown in Table 1. Median duration of follow-up was 16 months. Two-year overall survival (OS) was 83% and median OS was not reached. Median time-to-next-treatment or death was 31 months. Sixty-seven out of 80 evaluable patients (84%) achieved a hematologic response, with 47 patients (59%) achieving a VGPR or better (Figure 1). Sixty-eight patients (81%) had cardiac involvement, and among the 34 evaluable patients, 18 (53%) of evaluable patients achieved a cardiac response with a median response time of 2 months among responders. In terms of a graded cardiac response, 6 patients (18%) were able to achieve cardiac CR, 5 patients (15%) cardiac VGPR, and 7 patients (21%) PR (Figure 2). The median NT-proBNP percent reduction was 64.5% (IQR: 48.3 - 81.1%) and the median absolute reduction was 2395 pg/mL (IQR 1279.5 - 4089.5 pg/mL). Cardiac responses were associated with an improvement in OS (p<0.001, Figure 3), with landmark analysis for cardiac responses at 6-month trending towards statistical significance (100% vs. 51% at 30 months, p=0.052). Fifty-three patients (63%) had renal involvement, and among the 26 evaluable patients, 12 patients (46%) achieved a renal response with a median initial response time of 6 months among responders. Using graded response, 1 patient (4%) achieved renal CR, 7 patients (27%) renal VGPR, 4 patients (15%) renal PR, and 14 patients had no response, worsening creatinine, or were subsequently started on hemodialysis (54%) (Figure 4). The median percent reduction in proteinuria was 74.1% (IQR: 49.2 - 83.1%) and the median absolute reduction in proteinuria was 3.1 g/24 hours (IQR 2.1 - 4.9 g) among responders. There were no significant differences in OS between renal responders and non-responders. Conclusion: Daratumumab is highly effective in the treatment of previously treated AL amyloidosis, and a significant proportion of patients can achieve durable hematologic responses as well as improvements in organ function. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding. OffLabel Disclosure: Daratumumab in AL amyloidosis

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Effect of Standard Dose Versus Risk Adapted Melphalan Conditioning on Outcomes in Systemic AL Amyloidosis Patients Undergoing Frontline Autologous Stem Cell Transplant Based on Revised Mayo Stage

Blood ◽

10.1182/blood.v128.22.4627.4627 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4627-4627

Author(s):

Nidhi Tandon ◽

Surbhi Sidana ◽

Angela Dispenzieri ◽

Morie A. Gertz ◽

Francis K Buadi ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Response Rates ◽

High Dose ◽

Al Amyloidosis ◽

Advisory Committees ◽

Hepatic Involvement ◽

Multivariate Survival ◽

Versus Risk

Abstract Introduction High dose chemotherapy and autologous stem cell transplantation (ASCT) is an effective therapy for eligible patients with newly diagnosed systemic AL amyloidosis. Dose attenuated melphalan is used in patients with older age, renal dysfunction, and multi-organ involvement in an effort to limit treatment related mortality. Reducing the dose of melphalan compromises response rates and survival outcomes, but this is often contributed to frailty of these patients. The revised Mayo staging (MS) system improves risk stratification and helps develop risk-adapted therapies. We analyzed the outcomes of ASCT following standard [(200 mg/m2); SD group] versus risk adapted [(140-160 mg/m2); RD group] melphalan conditioning, in the context of the factors typically leading to dose modification. Methods Three hundred and twenty nine patients with newly diagnosed systemic AL amyloidosis who underwent conditioning with melphalan followed by ASCT at Mayo Clinic between 2006 and 2015 were identified using existing databases. The clinical and laboratory data, treatment and follow - up details were collected by chart review and analyzed retrospectively. Overall survival(OS) was defined as the time from start of initial therapy until death from any cause or last follow up. Progression free survival(PFS) was defined as the time to relapse or progression requiring change or reinstitution of treatment or death from any cause. The OS and PFS curves were estimated using Kaplan-Meier method while log rank test was used to estimate their difference. Multivariate survival analysis was performed using the Cox proportional hazards model. Results Among the 329 patients, 240 patients were in SD group and 89 patients were in RD group (1 patient received 120 mg/ m2, 2 received 160 mg/m2 and the rest received 140 mg / m2). In the SD group, median age was 58.5 years (25.6 - 72.3); 59.6% were males; 38.7% / 61.7 %/ 7.5% had cardiac / renal /hepatic involvement; and 47.1% / 35.7% / 8.8% / 8.4% had MS I/II/III/IV. In the RD group, median age was 60.8 years (40 - 73.7); 62.9% were males; 66.3% / 71.9 %/ 11.2% had cardiac / renal /hepatic involvement; and 26.2% / 32.5% / 21.2% / 20% had MS I/II/III/IV. The response rates for patients in the SD group [complete response (CR) - 53.7%, very good partial response (VGPR) - 19.6%, partial response (PR) - 12.5%, no response (NR) - 1.2%, progressive disease (PD) - 1.6%] were significantly higher than patients in the RD group (CR - 34.8%, VGPR - 20.2%, PR - 15.7%, NR - 10.1%, PD - 1.1%) (85.8 vs 70.7%; p < 0.002). The PFS and OS for both the groups according to Mayo stage are presented in Figure 1. Multivariate survival analysis for PFS and OS was performed using age (≤ vs > 70 years), serum creatinine (≤ vs > 2 mg/dL), number of major organs involved (heart, kidney, liver, gastrointestinal tract and autonomic neuropathy), MS (1 vs 2 vs 3 and 4) and dose of melphalan (SD vs RD). The dose of melphalan (p=0.0002), MS (p=0.03) and the number of organs involved (p=0.04) were significant for PFS while the dose of melphalan (p=0.0001) and the MS (p = 0.004) were significant for OS. Conclusion Reducing the dose of melphalan during conditioning for frontline ASCT in systemic AL amyloidosis renders more patients eligible for transplant but compromises on the response rates. There is no impact on PFS and OS in Mayo stage I patients. However the OS as well as PFS in Mayo stage II, III and IV were significantly lower in RD group as compared to SD group. These results suggest a suboptimal outcome with use of reduced dose melphalan, even after accounting for the pother prognostic factors, suggesting that high dose therapy should potentially be limited to those eligible to receive the full dose conditioning. Disclosures Dispenzieri: Jannsen: Research Funding; pfizer: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Takeda: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Kumar:Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Glycomimetics: Consultancy; Kesios: Consultancy; Noxxon Pharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding.

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Addition of Cyclophosphamide and Higher Doses of Dexamethasone Do Not Improve Outcomes of Patients with AL Amyloidosis Treated with Bortezomib

Blood ◽

10.1182/blood.v128.22.4500.4500 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4500-4500

Author(s):

Efstathios Kastritis ◽

Maria Gavriatopoulou ◽

Maria Roussou ◽

Despina Fotiou ◽

Dimitrios Ziogas ◽

...

Keyword(s):

Board Of Directors ◽

Plasma Cell ◽

Research Funding ◽

Response Rate ◽

Cell Clone ◽

Cardiac Response ◽

Al Amyloidosis ◽

Advisory Committees ◽

Renal Response ◽

Higher Doses

Abstract Treatment of AL amyloidosis is based on the elimination of the plasma cell clone that produces the amyloidogenic light chains. Typically, these are indolent clones and plasma cell burden is low, thus, even low dose, low toxicity, regimens may be very effective. Bortezomib is effective in targeting plasma cells. Several series have also shown that bortezomib either as single agent or in combinations, such as bortezomib with dexamethasone (VD) or with the addition of cyclophosphamide (VCD) induce high rates of hematologic CRs and organ responses. Patients with AL are frail due to multisystemic involvement and data from the treatment of frail patients with myeloma, usually elderly ones, have shown that addition of a third agent to VD does not improve outcomes and may increase toxicity. However, VCD is considered as a "standard" regimen for primary therapy of patients with AL, in most centers, but, it is not clear whether the addition of a third drug (cyclophosphamide) to bortezomib/dexamethasone (VD) further and significantly improves efficacy, given the substantial activity of bortezomib itself. Thus, we compared the outcomes of patients with AL amyloidosis who received (VD) or with VD plus a third agent (VCD). The analysis included 101 consecutive patients with biopsy confirmed AL amyloidosis, all diagnosed and treated in the Department of Clinical Therapeutics, Athens, Greece. All patients received similar supportive care and were treated in two consecutive periods (up to 2010 received VD and after 2011 received VCD). Median age was 65 years, 70% had cardiac and 71% renal involvement; Mayo stage was -1, -2 & -3 in 20%, 47% & 33% while renal stage was -1, -2 and -3 in 22%, 56% & 22% of the patients respectively. Treatment was VD in 59 (58%) and VCD in 42 (42%) patients. Compared to patients who received VCD, patients who received VD were older (median age 67 vs 60.5 years, p=0.024), were more often Mayo stage 3 (42% vs 29%, p=0.03), had lower eGFR (median 54 vs 86 ml/min/1.73 m2) but had similar distribution in renal stages. Heart, renal and nerve involvement were similar between those who received VD vs VCD (p>0.5 for all). According to our institutional guidelines for patients with AL amyloidosis schedule of bortezomib (twice per week vs weekly) and dexamethasone are adjusted to cardiac risk and presence of neuropathy. Weekly bortezomib was given in 41% of patients who received VD and vs 40% with VCD and the starting dose was 1.3 mg/m2 in 90% and 92.5% respectively. The median dose of dexamethasone for all patients was 160 mg/month, but for patients treated with VD was 240 mg/month and was 144 mg/month for those treated with VCD (p=0.01). Early mortality (<3 months from start of therapy) was 22% for patients treated with VD and 8% for patients treated with VCD, but after adjustment for Mayo stage there was no difference, and was 36% vs 29% in patients with Mayo stage 3 disease. On intent to treat a hematologic response was achieved by 72% (CR:25%, VGPR:17% , PR: 30%) and was 68% for patients treated with VD and 78% for VCD (p=0.26); after adjustment for Mayo stage there was still no difference in response rates. Regarding CR+VGPR, it was 47.5% with VD and 35% with VCD. Notably higher doses of dexamethasone or twice-weekly bortezomib schedule were not associated with significantly higher hematologic response rates or CR+VGPR rates. Organ responses occurred in 35% of patients (cardiac in 26%, renal in 42%). For VD, cardiac response rate was 29% and renal response rate was 43%, while for VCD cardiac response was 21% and renal response was 41% (p>0.5 for all comparisons). Median follow up is 3 years and median overall survival (OS) is 34 months. Median OS of patients treated with VD vs VCD was similar (33 vs 36 months, p=0.45). After adjustment for the dose and schedule of bortezomib and dexamethasone, and Mayo stage, still there was no difference in the OS between patients treated with VD vs VCD and no prognostic effect of higher doses of dexamethasone and twice weekly bortezomib was found. In conclusion, our data indicate that bortezomib even with low doses of dexamethasone is effective for the treatment of AL amyloidosis; higher doses of dexamethasone and addition of a third agent (cyclophosphamide) does not seem to have a profound effect on efficacy and survival. Our data also indicate the limits of bortezomib-based therapies, and new agents either targeting the plasma cell clone (like monoclonal antiCD38) or targeting the amyloid deposits are needed. Disclosures Kastritis: Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Terpos:Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Genesis: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria. Dimopoulos:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Predictive Factors of Overall Survival in Patients with Relapsed AL Amyloidosis Treated with Single Agent Daratumumab

Blood ◽

10.1182/blood-2021-144980 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2734-2734

Author(s):

Raphael Szalat ◽

Joshua Gustine ◽

John Mark Sloan ◽

Vaishali Sanchorawala

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Progression Free Survival ◽

Al Amyloidosis ◽

Advisory Committees ◽

Organ Response ◽

Renal Responses ◽

1Q Gain

Abstract Background: Two prospective phase II studies evaluated the efficacy of the anti-CD38 monoclonal antibody Daratumumab as a single agent (sDARA) in patients with relapsed AL amyloidosis and reported impressive hematologic and organ response rates. However, both studies included small number of patients and in one study sDARA was administered for 6 cycles (n=40) while in the other study, it was administered until hematologic progression, toxicity or for up to 24 months (n=22). Furthermore, predictive factors associated with hematologic and organ responses, and optimal duration of therapy remain unclear. Methods: We retrospectively studied the clinical and biological characteristics of patients with AL amyloidosis treated with sDARA, between April 2017 and December 2020, to identify factors associated with hematologic and organ response rates and impact on progression-free survival and overall survival (OS). Criteria for hematologic and organ response were defined according to the consensus criteria of ISA. Major organ deterioration progression-free survival (MOD-PFS) was used as a composite of endpoints from the time between sDARA initiation and whichever of the following occurred first: death, development of end stage cardiac or renal failure, or hematologic progression. OS was defined as the length of time between initiation of sDARA and the date of death or last follow-up. To account for immortal time bias, a landmark analysis for MOD-PFS and OS starting at the 12-month mark was performed to evaluate the impact of treatment duration on outcomes. Results: Eighty six patients with AL amyloidosis received sDARA. The median age was 67 years (range, 39-86) and 65% were male, 75% with lambda AL amyloidosis. Of the 86 patients, 38% had t(11;14) and 11% had 1q gain. At time of sDARA initiation, 35% of patients had >2 organs involved, including 22% with BU stage III (14% IIIa and 8% IIIb) and 13% with renal stage III disease. Majority (44%) of the patients received sDara as 2 nd line therapy, but 2% received as frontline, 21% as 3 rd line and 33% as 4 th line or more. Half of the patients (45%) were previously treated with HDM/SCT and 87% with proteasome inhibitor based regimen. Patients received a median of 12 cycles of sDARA (range 1-36) with a median follow-up time of 21.6 months (range 1.2-48.3). Hematologic CR and VGPR were achieved by 44% and 37% of patients, respectively and significantly associated with prolonged MOD-PFS and OS (Figure A and B). The median time to cardiac and renal responses were 6.8 months (range 0.9-12) and 6.7 months (range 1.8-42), respectively. At 12 months, cardiac and renal responses were observed in 47% and 61%, respectively and correlated with depth of hematologic response. The median OS and MOD-PFS were not reached (95% CI 40-NR) and 36 months (95% CI 28-NR), respectively. Achievement of cardiac response was associated with improved MOD-PFS (42 vs. 25 months; HR 0.25, 95% CI 0.08-0.78; p=0.01) and OS (NR vs 26 months; HR 0.20, 95% CI 0.04-0.89; p=0.02) and achievement of renal response was associated with improved MOD-PFS (NR vs. 13 months; HR 0.06, 95% CI 0.02-0.20; p<0.0001) and OS (NR vs. 25 months; HR 0.19, 95% CI 0.05-0.65; p=0.004). Importantly, presence of t(11;14) and number of previous lines of therapy did not impact MOD-PFS and OS. On an univariate analysis, several variables including dFLC >180 mg/L, bone marrow infiltration >10%, 24h proteinuria >3.5 g and NTproBNP >8500 pg/mL were significantly associated with lower MOD-PFS and OS, but only achievement of VGPR or CR and presence of 1q Gain were independently associated with MOD-PFS and OS (Figure C and D) on a multivariate analysis. Finally, on a landmark analysis, patients who received >12 cycles vs <12 cycles had significantly longer MOD-PFS (30 vs. 13 months; HR 0.47, 95% CI 0.31-0.72; p=0.0018)) and OS (NR vs. 15 months; HR 0.09, 95% CI 0.03-0.37; p<0.0001). Conclusion: sDARA confers very high rates of hematologic responses (81% of patients achieving >VGPR) in patients with relapsed AL amyloidosis and leads to prolonged OS and MOD-PFS, which is independent of the number of previous lines of treatment. Our data confirmed that achievement of hematologic response is a major predictor of OS and MOD-PFS in AL amyloidosis, and revealed that presence of 1q Gain is associated with lower response rate to sDARA. Longer duration of therapy (>12 cycles) with sDARA was associated with prolonged MOD-PFS and OS. Figure 1 Figure 1. Disclosures Sloan: Stemline: Honoraria; Abbvie: Honoraria; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Pharmacosmos: Membership on an entity's Board of Directors or advisory committees. Sanchorawala: Karyopharm: Research Funding; Pfizer: Honoraria; Regeneron: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Proclara: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Caleum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sorrento: Research Funding.

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Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) + Rituximab: Clinical Activity Including Survival in Patients with Recurrent/Refractory Follicular or ‘Aggressive' Lymphoma.

Blood ◽

10.1182/blood.v114.22.584.584 ◽

2009 ◽

Vol 114 (22) ◽

pp. 584-584 ◽

Cited By ~ 14

Author(s):

Nam H. Dang ◽

Mitchell R Smith ◽

Fritz Offner ◽

Gregor Verhoef ◽

Peter Johnson ◽

...

Keyword(s):

B Cell ◽

Tumor Progression ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Aggressive Lymphoma ◽

Clinical Activity ◽

Advisory Committees ◽

Time To Tumor Progression

Abstract Abstract 584 Background: CMC-544 is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. CMC-544 targets CD22, which is expressed in the majority of B cell non-Hodgkin lymphomas (NHL). The maximum tolerated dose (MTD) for single agent CMC-544 was previously determined to be 1.8 mg/m2administered IV every 28 days, and clinical activity was shown in patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Preliminary safety and efficacy data without long-term follow-up on patients with FL and non-refractory DLBCL treated with CMC-544 given in combination with rituximab was previously reported. Objectives: To assess clinical activity of CMC-544 in combination with rituximab in refractory ‘aggressive' NHL and to present long-term follow-up, including progression free survival (PFS) and overall survival (OS) of pts with relapsed FL and DLBCL. Patients and Methods: Patients were eligible if they had CD20+/CD22+ B cell NHL, which had not responded to or progressed after 1 or 2 therapies of probable clinical benefit, including at least 1 regimen containing rituximab. In patients with FL and DLBCL, subjects could have had no more than 2 prior therapies and could not be refractory to rituximab or a rituximab-containing therapy. Patients in the latter part of the study could have DLBCL, mantle cell lymphoma, transformed FL with no limit on number of prior therapies and must have had no response to, or relapse within 6 months of, the first dose of the previous rituximab-containing therapy (refractory ‘aggressive' lymphoma). After a limited dose-escalation to determine the MTD of CMC-544 in combination with rituximab, an expanded cohort at the MTD was conducted. Patients received 375 mg/m2 of rituximab IV on day 1 followed by CMC-544 on day 2 of each 28-day cycle for up to 8 cycles, provided that there was no disease progression. Results: The MTD of CMC-544 given with rituximab was confirmed as the single agent dose of 1.8 mg/m2. Enrollment is complete at 119 patients, with 110 treated with CMC-544 at the MTD of 1.8 mg/m2. Based on 112 patients, median age was 66 y (range: 20-85), 60% were male; 36% had 1 prior chemo/immunotherapy regimen, 46% had 2, and 13% had ≥3; 71% had stage III/IV disease, 38% elevated LDH, and 17% bulky disease (>7.5 cm). Patients with recurrent DLBCL were generally older, with a median age of 72 y and were thus deemed inappropriate for high-dose therapy. The most common treatment-emergent adverse events (AEs), all grades, were nausea (48%), thrombocytopenia (46%), fatigue (44%), and increased aspartate aminotransferase (AST) (34%). AEs resulting in discontinuation from treatment were most commonly hematologic AEs or elevation of ≥1 liver function test. Median follow-up is approximately 14.5 months, 10.3 months, and 2.5 months for patients with FL, recurrent DLBCL, and refractory ‘aggressive' lymphoma, respectively. The 1-year OS rate was 97% for FL and 77% for patients with recurrent DLBCL. Patients with FL (n=38) had an objective response rate (ORR) of 87%, with a median PFS of 23.6 months. Patients with relapsed DLBCL (n=40) had an ORR of 80%, with a median PFS of 15.1 months while in the rituximab-refractory pt arm (n=25) the response rate was much lower at 20%, with a median PFS of only 2 months. One year PFS was 84% for FL and 53% for recurrent DLBCL. The lower response rates and PFS in the refractory subgroup are consistent with the poor prognosis of patients with refractory 'aggressive' lymphoma. PFS in DLBCL (either de novo or from transformed follicular) with 1-2 prior therapies based on time-to-tumor progression was also analyzed. DLBCL patients with a prior time to tumor progression of less than 1 year (n=19) had an ORR of 47% (21% CR/CRu), with a median PFS of 4.3 months while DLBCL patients with a prior time to tumor progression of greater than 1 year (n=28) had an ORR of 79% (50% CR/CRu) and a median PFS of 15.1 months. Conclusion: The combination of inotuzumab ozogamicin (CMC-544) plus rituximab has a safety profile similar to that previously reported for CMC-544 alone, with hematologic, gastrointestinal, and hepatic AEs being the main toxicities. The response rates and PFS results indicate promising efficacy in patients with recurrent/refractory FL and DLBCL, These results, particularly in patients with follicular lymphoma and recurrent DLBCL, support continued clinical development of this regimen. Disclosures: Dang: Wyeth Research: Consultancy; Genentech: Consultancy, Honoraria, Speakers Bureau; Biogen: Consultancy, Speakers Bureau. Smith:Millennium: Research Funding; Genentech: Research Funding; Wyeth Research: Consultancy, Research Funding. Johnson:Wyeth Research: Membership on an entity's Board of Directors or advisory committees. Kaufman:Millenium: Consultancy; Genzyme: Consultancy; Celgene: Consultancy, Research Funding; Merck: Research Funding. Coiffier:Wyeth Research: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Czuczman:Wyeth Research: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees. Foran:Wyeth Research: Research Funding. Hua:Wyeth Research: Employment. Vandendries:Wyeth Research: Employment, Equity Ownership. Fayad:Wyeth Research: Consultancy, Research Funding.

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Phase IIa Study of Single-Agent MOR208 in Patients with Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

Blood ◽

10.1182/blood.v126.23.1528.1528 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1528-1528 ◽

Cited By ~ 4

Author(s):

Wojciech Jurczak ◽

Pier Luigi Zinzani ◽

Gianluca Gaidano ◽

Andre Goy ◽

Mariano Provencio ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Hodgkin's Lymphoma ◽

Clinical Activity ◽

Advisory Committees ◽

Cd20 Antibody ◽

Grade 3

Abstract Introduction: There remains a high unmet medical need for new therapies for patients with relapsed or refractory (R-R) B-cell non-Hodgkin's lymphoma (NHL). CD19 is a B-lymphocyte, lineage-specific surface antigen that is highly expressed by most B-cell NHLs. CD19 expression is maintained on lymphoma cells which have CD20 expression downregulated following treatment with the CD20 antibody, rituximab. Consequently, MOR208 (XmAb5574; MOR00208), an Fc-engineered, humanized, monoclonal antibody that targets CD19, may have clinical utility as a new therapeutic approach to R-R NHL. A phase I study showed MOR208 to be safe and well-tolerated with encouraging single-agent activity in patients with chronic lymphocytic leukemia (CLL); an intravenous dose of 12 mg/kg was recommended for phase II studies. Methods: This is a non-randomized, open-label, multicenter, two-stage, phase IIa study of MOR208 in adult patients with R-R NHL whose disease had progressed after at least one prior therapy containing the CD20 antibody, rituximab. In stage 1, 10 patients were to be enrolled into each of four NHL subtype-specific cohorts: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), other indolent NHL (iNHL) and mantle cell lymphoma (MCL). Patients were to receive single-agent MOR208, 12 mg/kg intravenously, weekly, for 8 weeks (2 cycles). Those with at least stable disease by the 2007 International Response Criteria could continue MOR208 treatment for an additional 4 weeks (total of 12 weeks of therapy). Patients with a complete or partial response (CR or PR) after 12 weeks could then receive MOR208 as maintenance therapy, every 2 or 4 weeks depending on the investigator's decision, until progression. In stage 2, cohorts with ≥2 responses (CR or PR) were to be expanded by at least 20 additional patients. The primary endpoint was the overall response rate (ORR). Key secondary endpoints included duration of response, safety, immunogenicity of MOR208, pharmacokinetics and pharmacodynamics. Results: The DLBCL and FL cohorts were expanded (to N=35 and N=34 patients, respectively), leading to a total enrollment of 92 patients: 56 (61%) were male; median age was 66.5 (range 35-90) years; 80 (87%) had stage III-IV disease; 41 (45%) had received ≥3 prior lines of therapy and 10 (11%) had received a prior stem-cell transplant. The investigator-assessed ORR across all NHL subtypes was 23% (21/92 patients; 16 not evaluable at cutoff) with clinical activity seen in the DLBCL (26% [9/35]; 2 CR, 7 PR); FL (26% [9/34]; 3 CR, 6 PR) and iNHL (27% [3/11]; 2 CR, 1 PR) cohorts (MCL, 0/12 responses). The iNHL cohort was not expanded as the response pattern in this subgroup was heterogeneous according to lymphoma subtype. The longest durations of response recorded to date are 15.4 months for FL and 14.2 months for DLBCL (both ongoing). Grade ≥3 non-hematologic and hematologic treatment-emergent adverse events (TEAEs) were recorded in 24 (26%) and 14 (15%) of 92 patients, respectively. The most commonly reported grade ≥3 hematologic TEAEs were neutropenia (7 [8%] of 92 patients, anemia (4 [4%]), and thrombocytopenia (4 [4%]); such TEAEs were seen most frequently in the DLBCL cohort (10 [29%] of 35 patients overall; neutropenia, 5 [14%], anemia, 4 [11%], thrombocytopenia, 2 [6%]). Dyspnea was the most commonly reported grade ≥3 non-hematologic TEAE (4 [4%] of 92 patients). Infusion-related reactions were seen in 9 (10%) of 92 patients; all were grade 1-2, except for one case of dyspnea, grade 4. There were no treatment-related deaths. Clinical activity in patients with R-R DLBCL appeared to be dependent on attaining a defined cumulative exposure (AUC0-t) over 8 weeks of around 11,000 day*µg/mL; i.e., at the data cutoff date, all 8 patients with a PR after 2 cycles showed an exposure above this potential threshold level. Conclusions: MOR208 demonstrated encouraging single-agent activity with CRs observed in patients with R-R DLBCL, FL, and iNHL. MOR208 was well tolerated without significant infusional toxicity. These data support further development of MOR208 in combination with other agents (including lenalidomide and bendamustine), and protocols for studies in patients with R-R DLBCL are now being developed. Disclosures Jurczak: CELLTRION, Inc,: Research Funding. Zinzani:Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; J&J: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Gaidano:Celgene: Research Funding; MorphoSys; Roche; Novartis; GlaxoSmithKline; Amgen; Janssen; Karyopharm: Honoraria, Other: Advisory boards. Goy:Celgene: Consultancy, Research Funding, Speakers Bureau; Allos, Biogen Idec, Celgene, Genentech, and Millennium. Gilead: Speakers Bureau. Robak:Janssen: Consultancy, Research Funding; MorphoSys AG: Consultancy, Honoraria, Research Funding. Maddocks:Novartis: Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Research Funding. Buske:Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Honoraria, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy. Korolkiewicz:MorphoSys AG: Employment. Striebel:MorphoSys AG: Employment. Blum:Morphosys: Research Funding; Gilead: Research Funding; Millenium: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Constellation Pharmaceuticals: Research Funding; Celgene: Research Funding.

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Five-Year Experience with Single-Agent Ibrutinib in Patients with Previously Untreated and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia

Blood ◽

10.1182/blood.v128.22.233.233 ◽

2016 ◽

Vol 128 (22) ◽

pp. 233-233 ◽

Cited By ~ 53

Author(s):

Susan M. O'Brien ◽

Richard R. Furman ◽

Steven E. Coutre ◽

Ian W. Flinn ◽

Jan Burger ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Lymphocytic Leukemia ◽

Advisory Committees ◽

Equity Ownership ◽

Grade 3 ◽

Over Time

Abstract Background: Ibrutinib (ibr), a first-in-class, once-daily Bruton's tyrosine kinase inhibitor, is approved by the US FDA for treatment of patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) including pts with del17p. The phase 1b/2 PCYC-1102 trial showed single-agent efficacy and tolerability in treatment-naïve (TN; O'Brien, Lancet Oncol 2014) and relapsed/refractory (R/R) CLL/SLL (Byrd, N Engl J Med 2013). We report efficacy and safety results of the longest follow-up to date for ibr-treated pts. Methods: Pts received 420 or 840 mg ibr QD until disease progression (PD) or unacceptable toxicity. Overall response rate (ORR) including partial response (PR) with lymphocytosis (PR-L) was assessed using updated iwCLL criteria. Responses were assessed by risk groups: unmutated IGVH, complex karyotype (CK; ≥3 unrelated chromosomal abnormalities by stimulated cytogenetics assessed by a reference lab), and in hierarchical order for del17p, then del11q. In the long-term extension study PCYC-1103, grade ≥3 adverse events (AEs), serious AEs, and AEs requiring dose reduction or discontinuation were collected. Results: Median age of the 132 pts with CLL/SLL (31 TN, 101 R/R) was 68 y (range, 37-84) with 43% ≥70 y. Baseline CK was observed in 41/112 (37%) of pts. Among R/R pts, 34 (34%) had del17p, 35 (35%) del11q, and 79 (78%) unmutated IGVH. R/R pts had a median of 4 prior therapies (range, 1-12). Median time on study was 46 m (range, 0-67) for all-treated pts, 60 m (range, 0-67.4) for TN pts, and 39 m (range, 0-67) for R/R pts. The ORR (per investigator) was 86% (complete response [CR], 14%) for all-treated pts (TN: 84% [CR, 29%], R/R: 86% [CR, 10%]). Median progression-free survival (PFS) was not reached (NR) for TN and 52 m for R/R pts with 60 m estimated PFS rates of 92% and 43%, respectively (Figure 1). In R/R pts, median PFS was 55 m (95% confidence intervals [CI], 31-not estimable [NE]) for pts with del11q, 26 m (95% CI,18-37) for pts with del17p, and NR (95% CI, 40-NE) for pts without del17p, del11q, trisomy 12, or del13q. Median PFS was 33 m (95% CI, 22-NE) and NR for pts with and without CK, and 43 m (95% CI, 32-NE) and 63 m (95% CI, 7-NE) for pts with unmutated and mutated IGVH, respectively(Figure 2). Among R/R pts, median PFS was 63 m (95% CI, 37-NE) for pts with 1-2 prior regimens (n=27, 3 pts with 1 prior therapy) and 59 m (95% CI, 22-NE) and 39 m (95% CI, 26-NE) for pts with 3 and ≥4 prior regimens, respectively. Median duration of response was NR for TN pts and 45 m for R/R pts. Pts estimated to be alive at 60 m were: TN, 92%; all R/R, 57%; R/R del17p, 32%; R/R del 11q, 61%; R/R unmutated IGVH, 55%. Among all treated pts, onset of grade ≥3 treatment-emergent AEs was highest in the first year and decreased during subsequent years. With about 5 years of follow-up, the most frequent grade ≥3 AEs were hypertension (26%), pneumonia (22%), neutropenia (17%), and atrial fibrillation (9%). Study treatment was discontinued due to AEs in 27 pts (20%) and disease progression in 34 pts (26%). Of all treated pts, 38% remain on ibr treatment on study including 65% of TN pts and 30% of R/R pts. Conclusions: Single-agent ibrutinib continues to show durable responses in pts with TN or R/R CLL/SLL including those with del17p, del11q, or unmutated IGVH. With extended treatment, CRs were observed in 29% of TN and 10% of R/R pts, having evolved over time. Ibrutinib provided better PFS outcomes if administered earlier in therapy than in the third-line or beyond. Those without CK experienced more favorable PFS and OS than those with CK. Ibrutinib was well tolerated with the onset of AEs decreasing over time, allowing for extended dosing for 65% of TN and 30% of R/R pts who continue treatment. Disclosures O'Brien: Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Furman:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau. Coutre:Janssen: Consultancy, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Burger:Pharmacyclics, LLC, an AbbVie Company: Research Funding; Gilead: Research Funding; Portola: Consultancy; Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Roche: Other: Travel, Accommodations, Expenses. Sharman:Gilead: Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Wierda:Abbvie: Research Funding; Genentech: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Gilead: Research Funding. Jones:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Luan:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment, Other: Travel, Accommodations, Expenses. James:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. Chu:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership.

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A Randomized Phase III Trial of Melphalan and Dexamethasone (MDex) Versus Bortezomib, Melphalan and Dexamethasone (BMDex) for Untreated Patients with AL Amyloidosis

Blood ◽

10.1182/blood.v128.22.646.646 ◽

2016 ◽

Vol 128 (22) ◽

pp. 646-646 ◽

Cited By ~ 27

Author(s):

Efstathios Kastritis ◽

Xavier Leleu ◽

Bertrand Arnulf ◽

Elena Zamagni ◽

María Teresa Cibeira ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Standard Of Care ◽

Cardiac Response ◽

Phase Iii ◽

Al Amyloidosis ◽

Advisory Committees ◽

Phase Iii Trial ◽

Hematologic Response ◽

Grade 3

Abstract Background. Current upfront treatment of light chain (AL) amyloidosis is often based on bortezomib in patients. However, data on the safety and efficacy of bortezomib in this setting mostly derive from uncontrolled, retrospective series, that are difficult to compare due to different proportion of patients with advanced disease. Here we report the analysis of a multicenter randomized phase III trial comparing MDex, a current standard of care, and MDex with the addition of bortezomib (BMDex) in newly-diagnosed AL amyloidosis that was performed in Europe and Australia (EMN-03 study, NCT01277016). Patients and Methods. Main eligibility criteria included measurable disease (M-protein >10 g/L or dFLC >50 mg/L), estimated glomerular filtration rate (eGFR) ³30 mL/min, and adequate liver function. Previously treated patients, those who had >30% bone marrow plasma cell or lytic bone lesions, NYHA class >II heart failure, grade 3 sensory or grade 1 painful peripheral neuropathy, or ECOG performance status >2 were excluded. In January 2013 the protocol was amended to include Mayo stage III patients, provided their NT-proBNP was <8500 ng/L (stage IIIa). Patients were randomized to receive either MDex (melphalan at 0.22 mg/kg and dexamethasone at 40 mg daily for 4 consecutive days every 28 days) or BMDex (bortezomib added at 1.3 mg/m2, on days 1, 4, 8, and 11 in cycles 1 and 2, and on days 1, 8, 15, and 22 in the following cycles). The primary endpoint was overall hematologic response at 3 months. Treatment was continued until completion of MDex cycle 9 or BMDex cycle 8, or achievement of CR or of at least partial response (PR) plus organ response after cycle 6, and was discontinued in case PR was not achieved by cycle 3. Enrollment is now completed (110 patients) with the last patient enrolled in February 2016 (database lock: July 25, 2016). Results. Patients' characteristics are reported in the Table. The proportion of patients experiencing at least 1 grade 3-4 severe adverse events (SAE) was similar in the MDex and BMDex arms (49% vs. 60%, P=0.11). The total number of reported adverse events per cycle was lower in the MDex group (10% vs 23%, P<0.01). Most common SAEs (MDex vs. BMDex) were cytopenia (4% vs. 7%, P=0.04), fluid retention (3% vs. 6%, P=0.02), and neuropathy (0 vs. 2%, P<0.01). One patient died within 3 months in the MDex arm and 3 in the BMDex group (P=0.28). Response was evaluated by intent to treat. Hematologic response rates after cycle 3 were 51% and 78% (P=0.001), with 28% and 53% complete response (CR) /very good partial response (VGPR) (P=0.003), in the MDex and BMDex arms, respectively. Overall hematologic response at the end of treatment, after a median of 5 cycles, was 56% and 81% (P=0.001), with 38% and 64% CR/VGPR in the MDex and BMDex arms, respectively (P=0.002). Cardiac response was reached in 8 of 33 evaluable patients treated with MDex (24%) and 10 of 26 (38%) who received BMDex (P=0.119). Renal response was attained in 17 of 35 patients (48%) in both arms. However, there was a higher proportion of cardiac progression in the MDex arm with borderline statistical significance (32% vs. 15%, P=0.054). After a median follow-up of living patients of 25 months, 26 patients (24%) died, 16 in the MDex arm and 10 in the BMDex arm with no significant difference in survival (Figure 1a). Achievement of hematologic and cardiac response at 3 months significantly improved survival (Figures 1b and 1c). Conclusion. This is the first prospective randomized trial of novel agents in AL amyloidosis. The criteria of hematologic and cardiac response are validated in the prospective setting for the first time. The primary endpoint, hematologic response at 3 months has been reached, showing more frequent and more profound hematologic responses with BMDex, preventing progression of cardiac dysfunction, with a modest increase in toxicity. This regimen can be proposed as a new standard of care in AL amyloidosis. We would like to acknowledge the European Myeloma Network, the Australasian Leukaemia and Lymphoma Group and the Leukaemia Foundation of Australia for their ongoing support, and Janssen-Cilag for partially funding the trial and providing the study drug. Disclosures Kastritis: Genesis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Mollee:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Nilelse: Research Funding. Hajek:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau:Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria. Mateos:Janssen, Celgene, Amgen, Takeda, BMS: Honoraria. Wechalekar:Takeda: Honoraria; Janssen: Honoraria; Glaxo Smith Kline: Honoraria; Celgene: Honoraria. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Sonneveld:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding. Merlini:Pfizer: Honoraria, Speakers Bureau; Millennium Takeda: Consultancy; Prothena: Honoraria; GlaxoSmithKline: Consultancy. Palladini:Prothena: Honoraria.

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EARLY Results of TOTAL Therapy 7 (TT7): High Response Rates of NEWLY Diagnosed High Risk Myeloma to Daratumumab

Blood ◽

10.1182/blood-2019-131887 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4569-4569 ◽

Cited By ~ 1

Author(s):

Frits van Rhee ◽

Sharmilan Thanendrarajan ◽

Carolina D. Schinke ◽

Jeffery R. Sawyer ◽

Adam Rosenthal ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Response Rates ◽

Newly Diagnosed ◽

Advisory Committees ◽

Early Results ◽

Research Grant

Background. The TT approach has significantly improved the outcome of multiple myeloma (MM) by combining new drugs with a regimen that comprises induction, tandem autologous stem cell transplantation (ASCT), consolidation and maintenance. However, a group of 15% of patients with high risk multiple myeloma (HRMM) have derived little benefit despite similar response rates to induction chemotherapy and ASCT when compared to low risk MM. The poor outcome of HRMM is explained by early relapse post ASCT resulting in a short progression free survival (PFS) with only 15-20% of patients surviving long-term. Daratumumab (Dara) is a human IgG1k anti-CD38 monoclonal antibody that has shown favorable results in early single-arm studies and more recently in phase III studies for relapsed/refractory and newly diagnosed MM. In TT7, we introduced Dara during all phases of therapy, including immune consolidation early post ASCT, to improve responses rate and PFS in HRMM. Methods. Patients had newly diagnosed HRMM as defined by high risk cytogenetic abnormalities, presence of extramedullary disease, >3 focal lesions on CT-PET, elevated LDH due to MM, or ISS II/III with cytogenetic abnormality. Dara (16mg/kgx1) was added to induction with KTD-PACE (carfilzomib, thalidomide, dexamethasone; and four-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide). Conditioning for tandem autologous stem cell transplantation (ASCT) was with fractionated melphalan (50mg/m2x4) (fMEL) based on prior observations that patients with adverse cytogenetics fare better with fMEL rather than single high dose MEL200mg/m2.In the inter tandem ASCT period immunological consolidation with Dara (16mg/kg) alone for 2 doses was followed by Dara (16mg/kg) on day 1 combined with K (36mg/m2) and D (20mg) weekly for 2 cycles. DaraKD was administered to avoid treatment free periods allowing for myeloma regrowth. The 2nd ASCT was followed by further immunological consolidation with Dara (16mg/k) for 2 doses, and maintenance therapy for 3 yrs with 3-months block of alternating Dara-KD (dara 16mg/kg day 1; K 36mg/m2 and dex 20mg weekly) and Dara-lenalidomide (R)D (dara 16mg/kg day 1; R 15mg day 1-21 q28 and D 20mg weekly). Results. TT7 enrolled 43 patients thus far. The median follow-up was 11 months (range: 1-22). The median age was 61 yrs (range 44-73). Sixteen patients were ≥65 yrs (37.2%). A mean of 29.4x106 CD34+ cells/kg (range: 4.6-86.4) were collected. 36 patients completed ASCT #1 (83.7%) and 18 (41.9%) ASCT #2, whilst 14 patients have proceeded to the maintenance phase. R-ISS II/III or metaphase cytogenetic abnormalities were present in 85.1 and 58.1% of patients, respectively. Elevated LDH or >3FL on CT-PET were noted in 30 and 41.8%. The 1-yr cumulative incidence estimates for reaching VGPR and PR were 87 and 83%, respectively. A CR or sCR was achieved in 68 and 46%. The 1-yr estimates of PFS and OS were 91.6 and 87.2%. 40 subjects are alive, whilst 5 progressed on study therapy and 3 subsequently died. 38 patients are progression free at the time of reporting. Dara was well-tolerated and no subjects discontinued therapy due to dara-related side effects. The CR and sCR rates compared favorably to the predecessor HRMM TT5 protocol where CR and sCR rates were 59 and 27%. Conclusion. The early results of TT7 point to increased response rates of HRMM to a dara-based TT regimen with especially higher rates of CR and sCR. Longer follow-up is required to determine if these early results translate into superior PFS and OS. Figure Disclosures van Rhee: Karyopharm Therapeutics: Consultancy; Kite Pharma: Consultancy; Adicet Bio: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy. Walker:Celgene: Research Funding. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding.

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Updated Results of a Phase II Randomized Study (ROMULUS) of Polatuzumab Vedotin or Pinatuzumab Vedotin Plus Rituximab in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood.v124.21.4457.4457 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4457-4457 ◽

Cited By ~ 22

Author(s):

Franck Morschhauser ◽

Ian Flinn ◽

Ranjana H Advani ◽

Catherine S. Diefenbach ◽

Kathryn Kolibaba ◽

...

Keyword(s):

Follicular Lymphoma ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Clinical Activity ◽

Advisory Committees ◽

Advisory Boards ◽

Grade 5 ◽

Grade 3

Abstract Background: Previously reported results from an ongoing study of polatuzumab vedotin (PoV) and pinatuzumab vedotin (PiV), antibody drug conjugates (ADC) containing the anti-mitotic MMAE targeting CD79b (PoV) and CD22 (PiV), showed clinical activity in combination with rituximab (R) in relapsed/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Here we report updated results of ADC + R at the RP2D of 2.4 mg/kg and initial results of PoV + R in r/r FL at the PoV dose of 1.8 mg/kg. Methods: Pts were randomized to receive PoV or PiV + R (ADC 2.4 mg/kg + R 375 mg/m2). In a separate non-randomized cohort (Cohort C), r/r FL pts were treated with PoV (1.8 mg/kg) + R. ADC + R was given every 21 days. Tumor assessments were performed every 3 months. Results: As of 21 February 2014, 59 pts received PoV + R (39 DLBCL; 20 FL), 63 PiV + R (42 DLBCL; 21 FL); 20 r/r FL pts were treated in Cohort C. Median time of follow-up was 10 mo. for PoV + R, 9 mo. for PiV + R, and 5 mo. for Cohort C. Median prior therapies [DLBCL, 3 (1-10); FL, 2 (1-8)] were balanced among the randomized treatment (tx) arms, median prior therapies in Cohort C was 2 (1-13); overall 44% were R refractory. Median tx cycles in DLBCL: 6 PoV (range 1-16) and 7 PiV (1-15); FL: 10 PoV (3-17), 7 PiV (1-14), and 6 Cohort C (2-10). Overall safety profiles of both regimens in the randomized arms receiving 2.4 mg/kg ADC were similar. The most common tx-emergent adverse events (AE) ≥25%: fatigue (55%), diarrhea (43%), nausea (37%), peripheral neuropathy (PN) (39%), neutropenia (27%), constipation (26%), sensory PN (25%), and decreased appetite (25%). Grade ≥ 3 AE >3%: neutropenia (24%), diarrhea (6%), dyspnea (5%), febrile neutropenia (4%), hyperglycemia (4%), fatigue (3%), and thrombocytopenia (3%). Serious AEs were reported in 43% and 36% of PiV and PoV treated pts, respectively. Discontinuation of study treatment for AE was reported in 49% and 41% of PiV and PoV treated pts, respectively. Thirty-five pts discontinued treatment due to PN with a median time to discontinuation of 5.6 mo. PN reversibility was observed following treatment interruptions and ADC dose modifications. Two of 9 Grade 5 AEs (sepsis, urosepsis) were attributed to CD22 ADC; no Grade 5 AEs were attributed to CD79b ADC. In Cohort C the most common tx-emergent AE ≥ 25%: fatigue (55%), nausea (45%), neutropenia (40%), sensory PN (30%), diarrhea (25%), constipation (25%) and pyrexia (25%). Grade ≥ 3 neutropenia was reported in 7 pts; no other Grade ≥ 3 AE was reported in >1 pt. Serious AE were reported in 5 pts. Two pts discontinued study treatment for AE. No Grade 5 AEs were reported. Overall response rate (ORR), complete (CR) and partial (PR) response rates, n (%) [95% CI], and median PFS in DLBCL (95% CI) are shown in the table. Median PFS in the FL cohorts are not reported due to insufficient follow-up duration. Table PoV (CD79b) + R PiV (CD22) + R PoV [1.8 mg/kg] + R (Cohort C) R/R DLBCL ORR CR PR mPFS (mo.) N=39 22 (56%) [41, 71] 6 (15%) [7, 30] 16 (41%) [26, 58] 5.4 (2.8-8.4) N=42 24 (57%) [41, 72] 10 (24%) [12, 39] 14 (33%) [20, 48] 5.2 (4.1-NR) N/A R/R FL ORR CR PR N=20 14 (70%) [47, 86] 8 (40%) [21, 64] 6 (30%) [14, 53] N=21 13 (62%) [40, 80] 2 (10%) [2, 30] 11 (52%) [30, 72] N=16 7 (44%) [20, 70] 0 7 (44%) [20, 70] Pharmacokinetic profiles were similar for both ADCs across DLBCL and FL with no free MMAE accumulation. Pts receiving PoV at 1.8 mg/kg had proportionately lower exposure of antibody conjugated MMAE compared to pts treated at the 2.4 mg/kg dose level. Conclusions: PoV and PiV + R were generally well-tolerated with similar toxicity profiles. Neutropenia, PN, and diarrhea were the principal toxicities. Similar efficacy was observed with both ADCs in heavily pretreated pts with DLBCL. The higher CR rate with PoV + R compared to PiV + R suggests greater clinical activity in r/r FL. Lower overall response rates were observed in r/r FL pts treated with a lower dose of PoV. Results based on longer follow-up to further assess differences in safety and tolerability between the two PoV doses in r/r FL will be presented. Additional data of pts who received crossover ADC + R treatment following documented disease progression on initial ADC + R treatment will also be presented. Combination studies of PoV + R with chemotherapy and with ADC schedules to reduce PN are ongoing or in planning. Disclosures Morschhauser: Genentech/roche: Honoraria, travel grants Other; Celgene: advisory boards, advisory boards Other, Honoraria. Off Label Use: obinutuzumab and lenlidomide in relapsed follicular lymphoma. Flinn:Genentech, inc.: Research Funding. Advani:Genentech, inc.: Research Funding. Diefenbach:Genentech, inc.: Research Funding. Press:Genentech, inc.: Research Funding. Chen:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees. Salles:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Tilly:Genentech, inc.: Research Funding. Cheson:Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Assouline:Roche: Honoraria, Research Funding. Dreyling:Roche: Honoraria, Research Funding. Hagenbeek:millenium: Membership on an entity's Board of Directors or advisory committees. Zinzani:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees. Yalamanchili:Genentech, inc.: Employment. Lu:Genentech, inc.: Employment. Jones:Genentech, inc.: Employment. Jones:Genentech, inc.: Employment. Chu:Genentech, inc.: Employment. Sharman:Gen: Research Funding.

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