Inferior Outcomes of Patients with Quad and Penta-Refractory Multiple Myeloma (MM) Compared to Those of Patients Who Have Been Quad and Penta Exposed

Abstract Background: Despite significant advancements in MM therapies, patients with quad-refractoriness (refractory to proteasome inhibitors: bortezomib and carfilzomib, and immunomodulatory drugs: lenalidomide and pomalidomide) and penta-refractoriness (additional refractoriness to CD-38+ monoclonal antibody daratumumab) have a poor prognosis in terms of short progression-free survival (PFS) and overall survival (OS). This is a retrospective, single institutional study comparing the outcomes of patients with quad and penta-refractory MM to patients who were quad and penta-exposed, but not refractory. Methods: Consecutive patients from the John Theurer Cancer Center at Hackensack Meridian School of Medicine who were quad and penta-exposed and/or refractory between the dates of 1/1/2015 and 3/1/2021 were identified. Quad-exposed was defined as having had prior exposure to bortezomib, carfilzomib, lenalidomide and pomalidomide. Penta-exposed was defined as having prior exposure to bortezomib, carfilzomib, lenalidomide and pomalidomide and daratumumab. Penta or quad refractory was defined as having stable disease (as best response) or progressive disease while on all of the above drugs, per International Myeloma Working Group (IMWG) definition of refractory. Patients were excluded if they had missing data or if they did not meet the above definitions. Baseline characteristics, high-risk status, ISS, treatment history, treatment response, drugs at first relapse and survival outcomes were obtained retrospectively from the electronic medical record and entered into database. High-risk cytogenetics were defined as the presence of t(4;14), t(14;16) or del 17p; 1q21 gain or amplification; 1p del; t(6;14); t(14;20). Baseline patients' characteristics were summarized descriptively by quad and penta-exposed groups. PFS and OS were estimated using the Kaplan-Meier method. Univariate and multivariable adjusted Cox proportional hazard regression models examined factors affecting OS. Results: A total of 162 patients met the inclusion criteria: 18/162 (11%) were quad or penta-exposed, 32/162 (20%) were quad-refractory, and 112/162 (69%) were penta-refractory. Median age was 62 (55-69), IgG subtype (59%), and 62/162 (38.5%) had high-risk cytogenetics. The median number of lines prior was 6 (range 4-8) among all patients, and 7 (range 5-9) in the penta-refractory group. 133/162 (82.1%) had prior autologous-stem cell transplant (ASCT). Extramedullary disease was present in 40/162 (25.2%). Plasma cell leukemia was present in 14/162 (8.8%). For those who were penta-refractory, the median time from quad to penta-refractory status was 10.2 months (95% confidence interval (CI), 3.57-16.57). See Table 1. Figure 1 shows PFS and OS from the time of becoming quad or penta-exposed or refractory (T0 ). The median PFS after T0 was 11.86 months (95% CI, 6.5-26.6) for combined quad and penta-exposed, compared to 3.88 months (95% CI, 2.99-5.17) for quad and penta-refractory patients. With a median follow-up of 5.14 months (Range, 0-52.4), the median OS for all patients was 7.43 months (95% CI, 5.8- 12.94). (Figure 1A). With a median follow-up time of 4.45 months (Range, 0-52.38), the median OS for patients who were quad or penta-refractory was 5.97 months [95% CI. 4.44-8.23], compared to OS not reached (NR) for quad or penta-exposed, with a median follow-up of 11.86 months. (Figure 1B). At least one subsequent treatment regimen was employed after T0 in 85% of the patients. (Figure 1C). Multivariable adjusted analysis (Table 2) revealed that patients ≥62 had inferior OS compared to those < 62 (p -value=0.046). Furthermore, patients who had ≤10 months between becoming quad- and penta-refractory had inferior OS compared to patients with >10 months (p=0.031). OS was not significantly affected by high risk versus standard cytogenetics or drugs used at first relapse. Conclusion: MM patients with quad and penta-refractory disease have significantly worse outcomes compared to patients with quad and penta-exposed MM: older age (> 62 years) and a short interval (< 10 months) between becoming quad and penta-refractory confer an adverse prognosis. Prospective studies are required to confirm these findings. Penta and quad-refractory multiple myeloma continues to represent a vulnerable population with an unmet need for therapeutic approaches. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Continuous Infusion Cyclophosphamide as Salvage Therapy for Relapsed or Refractory Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.4942.4942 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4942-4942

Author(s):

Binu Malhotra ◽

David L Porter ◽

Edward A. Stadtmauer ◽

Stephen J. Schuster ◽

Dan T. Vogl

Keyword(s):

Multiple Myeloma ◽

Continuous Infusion ◽

Median Duration ◽

Progressive Disease ◽

Conflicts Of Interest ◽

Progression Free Survival ◽

Cell Transplant ◽

Free Survival ◽

Refractory Multiple Myeloma

Abstract Abstract 4942 Background Patients with relapsed or refractory multiple myeloma (MM) are resistant to most therapies. In this study, we assess the efficacy and tolerability of continuous infusion (CI) cyclophosphamide in a group of heavily pre-treated patients with relapsed/refractory MM. Methods Charts of all patients treated with CI cyclophosphamide for relapsed/refractory MM between 01/2003 and 12/2008, at the Hospital of University of Pennsylvania, were identified and reviewed. Patients who had received at least one cycle of CI cyclophosphamide were included for the analysis. The dose of cyclophosphamide ranged between 200-300 mg/m2/day CI for 4 days. Duration of each cycle was planned at 28 days. Response was assessed using the international uniform response criteria for MM. Toxicity was assessed using the National Cancer Institute Common Toxicity Criteria, version 4. Results We treated 24 patients with CI cyclophosphamide. The median age was 60.5 years (range 33-75 years) and 66% were male. Patients had received a median of 5 prior regimens (range 2.0 to 11.0) and the median duration of time from diagnosis to treatment with CI cyclophosphamide was 5 yrs (range 0.38-22 yrs). Cyclophosphamide was started in 19 patients for management of progressive disease, and in 5 patients for lack of response or adverse effects from prior therapies. Prior therapies included: bortezomib (in all patients), lenalidomide (in 96% of patients) and autologous stem cell transplant (ASCT - once in 46%, and twice in 29%) among others. The median number of cyclophosphamide cycles administered until the time of last follow up was 4.0 (range 1.0-43.0). Treatment was ongoing in 4 patients at the time of last follow up, and two patients with stable disease were being observed without therapy. Median overall survival for all patients was 22.3 months (95% CI 10.04-34.53) and median progression free survival (PFS) was 7.4 months (95%CI 4.12-10.69). Partial response was noted in 4 patients, who had a median duration of response of 4.2 months and median time to best response of 0.8 month. Disease was stabilized in 14 additional patients. Disease progressed despite therapy in 6 patients, and in 4 of those progressive disease was evident from cycle one. Cytopenias were noted in 8 patients, with 4 related to the treatment with cyclophosphamide, but in only one case did this lead to discontinuation of therapy. Conclusion In our experience with 24 patients, monthly cycles of continuous infusion cyclophosphamide was a safe and effective method of treating relapsed or refractory multiple myeloma resulting in a prolonged progression free survival in very heavily pretreated patients. Disclosures No relevant conflicts of interest to declare.

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Prognostic Molecular Stratification in Relapsed/Refractory Multiple Myeloma - Results of the Pomalidomide Mukseven (NCT02406222) Biomarker Trial

Blood ◽

10.1182/blood-2019-123640 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4327-4327

Author(s):

James Croft ◽

Andrew Hall ◽

Amy L Sherborne ◽

Katrina Walker ◽

Sidra Ellis ◽

...

Keyword(s):

Multiple Myeloma ◽

Flow Cytometry ◽

T Cell ◽

High Risk ◽

Real World ◽

Research Funding ◽

Unmet Need ◽

Employment Equity ◽

Equity Ownership

Background Treatment of relapsed/refractory multiple myeloma (RRMM) remains challenging as durable remissions are achieved in patient sub-groups only. Identifying patients that are likely to benefit prior to or early after starting relapse treatments remains an unmet need. MUKseven is a trial specifically designed to investigate and validate biomarkers for treatment optimization in a 'real-world' RRMM population. Design In the randomized multi-center phase 2 MUKseven trial, RRMM patients (≥2 prior lines of therapy, exposed to proteasome inhibitor and lenalidomide) were randomized 1:1 to cyclophosphamide (500 mg po d1, 8, 15), pomalidomide (4 mg days 1-21) and dexamethasone (40 mg; if ≥75 years 20 mg; d1, 8, 15, 21) (CPomD) or PomD and treated until progression. All patients were asked to undergo bone marrow (BM) and peripheral blood (PB) bio-sampling at baseline, cycle 1 day 14 (C1D14, on-treatment) and relapse. For biomarker discovery and validation, IGH translocations were profiled by qRT-PCR, copy number aberrations by digital MLPA (probemix D006; MRC Holland), GEP by U133plus2.0 array (Affymetrix), PD protein markers by IHC and PB T-cell subsets by flow cytometry for all patients with sufficient material. Primary endpoint was PFS, secondary endpoints included response, OS, safety/toxicity and biomarker validation. Original planned sample size was 250 patients but due to a change in UK standard of care during recruitment with pomalidomide becoming available, a decision was made to stop recruitment early. Results In total, 102 RRMM patients were randomized 1:1 between March 2016 and February 2018. Trial entry criteria were designed to include a real-world RRMM population, permitting transfusions and growth factor support. Median age at randomization was 69 years (range 42-88), 28% of patients had received ≥5 prior lines of therapy (median: 3). Median follow-up for this analysis was 13.4 months (95% CI: 12.0-17.5). 16 patients remained on trial at time of analysis (median number of cycles: 19.5; range 8-28). More patients achieved ≥PR with CPomD compared to PomD: 70.6% (95% CI: 56.2-82.5%) vs. 47.1% (CI: 32.9-61.5%) (P=0.006). Median PFS was 6.9 months (CI: 5.7-10.4) for CPomD vs. 4.6 months (CI: 3.5-7.4) for PomD, which was not significantly different as per pre-defined criteria. Follow-up for OS is ongoing and will be presented at the conference. High-risk genetic aberrations were found at following frequencies: t(4;14): 6%, t(14;16)/t(14;20): 2%, gain(1q): 45%, del(17p): 13%. Non-high risk lesions were present as follows: t(11;14): 22%, hyperdiploidy: 44%. Complete information on all high-risk genetic markers was available for 71/102 patients, of whom 12.7% had double-hit high-risk (≥2 adverse lesions), 46.5% single-hit high-risk (1 adverse lesion) and 40.8% no risk markers, as per our recent meta-analysis in NDMM (Shah V, et al., Leukemia 2018). Median PFS was significantly shorter for double-hit: 3.4 months (CI: 1.0-4.9) vs. single-hit: 5.8 months (CI: 3.7-9.0) or no hit: 14.1 months (CI: 6.9-17.3) (P=0.005) (Figure 1A). GEP was available for 48 patients and the EMC92 high-risk signature, present in 19% of tumors, was associated with significantly shorter PFS: 3.4 months (CI: 2.0-5.7) vs. 7.4 (CI: 3.9-15.1) for EMC92 standard risk (P=0.037). Pharmacodynamic (PD) profiling of cereblon and CRL4CRBN ubiquitination targets (including Aiolos, ZFP91) in BM clots collected at baseline and C1D14 is currently ongoing. Preliminary results for the first 10 patients demonstrate differential change of nuclear Aiolos (Figure 1C), with a major decrease in Aiolos H-scores in 7/10 patients from baseline to C1D14 and reconstitution at relapse. T-cell PB sub-sets were profiled at baseline and C1D14 by flow cytometry. Specific sub-sets increased with therapy from baseline to C1D14, e.g. activated (HLA-DR+) CD4+ T-cells, as reported at last ASH. CD4+ T-cell % at baseline was associated with shorter PFS in these analyses in a multi-variable Cox regression model (P=0.005). PD and T-cell biomarker results will be updated and integrated with molecular tumor characteristics and outcome. Discussion Our results demonstrate that molecular markers validated for NDMM predict treatment outcomes in RRMM, opening the potential for stratified delivery of novel treatment approaches for patients with a particularly high unmet need. Additional immunologic and PD biomarkers are currently being explored. Disclosures Croft: Celgene: Other: Travel expenses. Hall:Celgene, Amgen, Janssen, Karyopharm: Other: Research funding to Institution. Walker:Janssen, Celgene: Other: Research funding to Institution. Pawlyn:Amgen, Janssen, Celgene, Takeda: Other: Travel expenses; Amgen, Celgene, Janssen, Oncopeptides: Honoraria; Amgen, Celgene, Takeda: Consultancy. Flanagan:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Garg:Janssen, Takeda, Novartis: Other: Travel expenses; Novartis, Janssen: Research Funding; Janssen: Honoraria. Couto:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Wang:Celgene Corporation: Employment, Equity Ownership. Boyd:Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Pierceall:Celgene: Employment. Thakurta:Celgene: Employment, Equity Ownership. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria. Brown:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy.

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Autologous stem cell transplantation versus no transplant in patients above 70 with multiple myeloma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e20509 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e20509-e20509

Author(s):

Christopher Lemieux ◽

Lori S. Muffly ◽

David Joseph Iberri ◽

Andrew Rezvani ◽

Robert Lowsky ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

High Risk ◽

Progression Free Survival ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Free Survival ◽

First Line Therapy ◽

Included Patient

e20509 Background: We evaluated outcomes of patients with multiple myeloma (MM) ≥ 70 years who were seen for Autologous Stem Cell Transplant (ASCT) consult, based on whether they underwent transplant vs. non-transplant treatment. Methods: 138 patients with MM ≥ 70 years (median 71, range 70-78) were evaluated in the BMT clinic from 1/2010 to 11/2019 for a transplant consult. Results: Of the 138 patients, 53 proceeded to ASCT. ASCT was not pursued in 85 patients despite most (79%) being eligible for transplant. Reasons for deferring ASCT in eligible patients included patient preference (48%, n = 32) and physician preference (52%, n = 35). 68 patients were seen during first-line therapy, of which 29 underwent upfront transplant. The remainder were seen at second-line or beyond. There was no difference in baseline characteristics among the 113 patients with available follow-up (ASCT = 53, non-ASCT = 60), including median age (71 vs. 72 years, p = 0.4), high-risk cytogenetics (41% vs. 31%, p = 0.4), high-risk HCT-CI (32% vs. 20% p = 0.2), and ISS stage III (34% vs. 27%, p = 0.6). In the 53 patients who underwent transplant, conditioning melphalan dose was 200 mg/m2 (75%, n = 40) and 140 mg/m2 (25%, n = 13). Day 100 transplant related mortality was 0% (n = 0). Progression-free survival (PFS) and overall survival (OS) were compared in patients who were seen for consultation within 1 year of diagnosis (n = 80). With a median follow-up of 27 months, median PFS amongst patients ≥ 70 years undergoing ASCT (n = 39) was 47 months compared to 34 months in the non-ASCT (n = 41) group, p = 0.006. Median OS was not reached in either group. Estimated 5-years OS was 76% in the ASCT group and 82% in the non-ASCT group (p = 0.6). There was no difference in PFS of patients ≥ 70 undergoing ASCT compared to a cotemporaneous cohort of patients < 70 (n = 639) from our institution (47 vs. 57 months, p = 0.3). Conclusions: Selected patients ≥ 70 years with MM undergoing ASCT have better PFS compared to patients with similar characteristics who do not undergo ASCT. ASCT is safe in this older population and outcomes were similar compared to younger patients. [Table: see text]

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Intensified Chemotherapy Regimen for Very High Risk Childhood B-Precursor Acute Lymphoblastic Leukemia (B-ALL): Results From Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05–01

Blood ◽

10.1182/blood.v120.21.3563.3563 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3563-3563

Author(s):

Lynda M. Vrooman ◽

Kristen E. Stevenson ◽

Marian Harris ◽

Donna S. Neuberg ◽

Stephen E. Sallan ◽

...

Keyword(s):

High Risk ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Total Duration ◽

Pcr Analysis ◽

High Dose ◽

Induction Phase ◽

Cell Transplant ◽

Very High

Abstract Abstract 3563 Background: High levels of minimal residual disease (MRD) at the end of 4-weeks of multiagent induction chemotherapy have been shown to be associated with a high risk of subsequent relapse in pediatric patients (pts) with B-ALL. Published reports indicated that pediatric B-ALL pts with high end-induction MRD had event-free survival (EFS) rates < 50% when treated with standard chemotherapy.[Zhou, Blood 2007; Borowitz Blood 2008] Pts with high-risk (HR) cytogenetic abnormalities, such as low hypodiploidy and MLL gene rearrangements (MLL-R) also have a high relapse risk. On DFCI ALL Consortium Protocol 05–01, we piloted an intensified regimen for B-ALL pts with high end-induction MRD and/or HR cytogenetics. Methods: Between 2005–2010, 482 evaluable pts aged 1–18 years with B-ALL were enrolled. Pts were initially classified as standard-risk (SR) or high-risk (HR) based on NCI age/WBC criteria. MRD was prospectively evaluated at the end of the 4-week induction phase via RQ-PCR analysis of IgH or TCR rearrangements. Results were reported as the ratio of copy numbers of target gene:GAPDH; a ratio >0.001 was considered high MRD. Pts with high MRD or HR cytogenetics (hypodiploidy with <45 chromosomes or MLL-R) were reclassified at the end of induction phase as very high risk (VHR), and received 2 additional chemotherapy cycles beginning at week 7 (cycle 1: cyclophosphamide, low-dose cytarabine, 6-MP; cycle 2: high-dose cytarabine, etoposide, dexamethasone, L-asparaginase), followed by the DFCI ALL Consortium HR consolidation phase, including 30 weeks of L-asparaginase and doxorubicin to a cumulative dose of 300 mg/m2. After consolidation, pts received a standard maintenance phase. Total duration of treatment was 25 months. Results: 51 pts (11%) were classified as VHR, 25 of whom had been initially classified as SR and 26 as HR. 35 VHR pts had high end-induction MRD as the sole VHR criterion; 16 had HR cytogenetics. 9 pts relapsed (all marrow-involved) and 1 pt developed a secondary AML. There were no deaths in first remission. With median follow-up of 4.4 yrs, the 5-yr EFS (95% confidence interval) for all 51 VHR pts was 76% (60,87)[Figure 1] and 5-yr overall survival was 81% (60,92). The 5-yr EFS was 81% (59,90) for the 35 pts with high MRD. Conclusion: Intensification of chemotherapy (without stem cell transplant) resulted in a relatively favorable EFS in VHR B-ALL pts (defined by the presence of either high end-induction MRD or HR cytogenetics). More pts and longer follow-up will be necessary to confirm these promising results. Disclosures: No relevant conflicts of interest to declare.

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Survival and treatment patterns of patients with relapsed or refractory multiple myeloma in France — a cohort study using the French National Healthcare database (SNDS)

Annals of Hematology ◽

10.1007/s00277-021-04522-y ◽

2021 ◽

Author(s):

Cyrille Touzeau ◽

Nadia Quignot ◽

Jie Meng ◽

Heng Jiang ◽

Artak Khachatryan ◽

...

Keyword(s):

Multiple Myeloma ◽

Real World ◽

Unmet Need ◽

Autologous Stem Cell Transplant ◽

Treatment Patterns ◽

Cell Transplant ◽

Healthcare Database ◽

Refractory Multiple Myeloma ◽

National Healthcare ◽

Patient Groups

AbstractOver the past decade, several drugs have been approved for the treatment of relapsed or refractory multiple myeloma (RRMM). This retrospective study, using the French National Healthcare database (SNDS), describes the treatment patterns and outcomes of patients with RRMM treated in real-world clinical practice in France. Patients were adults, with a diagnosis of multiple myeloma, who initiated second-line (2L) treatment approved for use in France between 2014 and 2018; this included bortezomib, carfilzomib, daratumumab, ixazomib, lenalidomide, or pomalidomide. Data were analyzed overall, by first-line (1L) autologous stem cell transplant (ASCT) status and by lenalidomide treatment status at 2L. In total, 12987 patients with RRMM were included in the study (mean age 69.5 years); 27% received an ASCT at 1L, and 30% received a lenalidomide-sparing regimen at 2L. Overall, and among the ASCT and non-ASCT subgroups, most patients received a bortezomib-based regimen at 1L, whereas lenalidomide-based regimens were most common at 2L. Among patients who received a lenalidomide-sparing regimen at 2L, this was most often a proteasome inhibitor-based regimen. Mortality rate was 26.1/100 person-years, and median (95% confidence interval) survival from 2L initiation was 32.4 (31.2–33.6) months. Survival differed by various factors, shorter survival was reported in the non-ASCT group, those receiving a lenalidomide-sparing regimen at 2L, older patients (≥ 70 years), and those with multiple comorbidities. This analysis provides insight into the real-world use of approved novel MM treatments and highlights an ongoing unmet need to improve outcomes, particularly for selected patient groups.

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Pomalidomide, Bortezomib and Dexamethasone (PVD) for Patients with Relapsed Lenalidomide Refractory Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v124.21.304.304 ◽

2014 ◽

Vol 124 (21) ◽

pp. 304-304 ◽

Cited By ~ 22

Author(s):

Martha Q. Lacy ◽

Betsy R. LaPlant ◽

Kristina M Laumann ◽

Shaji Kumar ◽

Morie A Gertz ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Phase I ◽

Dose Level ◽

Phase Ii ◽

Research Funding ◽

Phase 1 ◽

Progression Free Survival ◽

Cell Transplant ◽

Refractory Multiple Myeloma

Abstract Background: Pomalidomide is an immunomodulatory agent (IMiD®) that has been approved for treatment of relapsed and refractory multiple myeloma (MM). Combinations of IMiDs and proteasome inhibitors offer the potential for deeper and more durable responses due to enhanced efficacy. Preliminary results of a phase 1 study of twice weekly bortezomib with pomalidomide have been reported with promising results (Richardson, ASH 2012). This phase I/II trial was designed to evaluate the maximum tolerated doses (MTD) as well as safety and efficacy of the combination of pomalidomide, once weekly bortezomib and dexamethasone (PVD) in patients with relapsed, lenalidomide refractory, MM. Patients and methods: We included patients with relapsed MM who had 1-4 prior lines of therapy and were resistant or refractory to lenalidomide. In the phase I portion of the trial, dose level 1 consisted of pomalidomide 4 mg days 1-21 PO, bortezomib 1.0mg/m2 days 1,8,15, and 22 IV or SQ and dexamethasone 40 mg days 1,8,15, and 22 PO, given every 28 days. Bortezomib was increased to 1.3mg/m2 for dose level 2 and and was adopted for the phase 2 portion. The primary aim of the phase I cohort was to determine the MTD of the combination, and for the phase II cohort was to evaluate the confirmed response rate (PR, VGPR, or CR) in relapsed refractory MM. Response was assessed by the IMWG criteria and toxicity was graded using the CTCAE v4.0. Results: 50 patients were accrued between March 2012 and July 2014 (dose level (DL)1: 3, DL 2: 6, Phase II: 41). We describe results in 47 patients treated at MTD and phase II. Median age was 66, 51% were female and median time from diagnosis to study was 46 months (15-142). Twenty five percent had mSMART defined high-risk status. Median number of prior regimens was 3. All patients had prior lenalidomide, 68% had stem cell transplant, 17% received thalidomide, 56% had alkylators and 57% had bortezomib. With median follow up of 9 months, 72% remain progression free, 96% are alive and 66% remain on treatment. The most common AEs at least possibly attributable to the combination were anemia, fatigue, leukopenia and thrombocytopenia; however, the majority of these were grade 1-2. Grade ≥3 AEs (regardless of attribution) that occurred in at least 3 patients included neutropenia (29), leukopenia (15), lung infection (6), lymphopenia (8) dyspnea (3) and syncope (3). DVT/PE occurred in one patient. Among the 42 patients who were evaluable, confirmed responses (PR, VGPR, or CR) were seen in 34 (81%) including sCR (3), CR (5), VGPR (8), PR (18). Confirmed responses were seen in 9 of 11( 82%) high risk patients. Median progression free survival was 17.7 months (95%CI: 9.5-NA). Conclusions: PVD is a highly effective combination in patients refractory to lenalidomide with confirmed responses in over 80%. Weekly administration of bortezomib enhanced the tolerability and convenience of this regimen. Toxicities are manageable, mostly consisting of mild cytopenias with no significant neuropathy or DVT. PVD is a highly attractive option in patients with relapsed and refractory MM. Disclosures Lacy: Celgene: Research Funding. Lust:Senesco: PI Other. Fonseca:Medtronic, Otsuka, Celgene, Genzyme, BMS, Lilly, Onyx, Binding Site, Millennium, AMGEN: Consultancy, patent for the prognostication of MM based on genetic categorization of the disease. He also has sponsored research from Cylene and Onyx Other, Research Funding. Stewart:Celgene: Consultancy; Novartis: Consultancy; Array BioPharma: Consultancy; BMS: Consultancy; Millenium: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding.

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Two Year Update of Phase II Trial of Pembrolizumab, Lenalidomide and Dexamethasone As Post -Autologous Stem Cell Transplant Consolidation in Patients with High-Risk Multiple Myeloma

Blood ◽

10.1182/blood-2019-125155 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1911-1911 ◽

Cited By ~ 2

Author(s):

Meena Bansal ◽

David S. Siegel ◽

Jaeil Ahn ◽

Rena Feinman ◽

David H. Vesole ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Autologous Stem Cell Transplant ◽

Cell Transplant ◽

Advisory Committees ◽

Best Response ◽

Grade 3

Introduction: Patients with high-risk multiple myeloma (HRMM) who have undergone autologous stem cell transplant (ASCT) will inevitably relapse and have a progression free survival (PFS) ranging from 8-14 months (Gaballa et al, American Journal of Hematology, 2016) and 24-39 months while on lenalidomide (Len) maintenance therapy (Jackson et al, The Lancet Oncology, 2019). Unlike in solid tumors, PD-1 blockade has no single agent activity in relapsed and refractory multiple myeloma (MM) patients suggesting that immune stimulating agents, immunomodulatory agents (IMiDs), such as lenalidomide (Len) or pomalidomide (Pom) are necessary in combination with anti-PD-1 blockade to increase depth and duration of response post-ASCT. The Keynote-023 study revealed an overall response rate (ORR) of 76% with the combination of pembrolizumab (Pem), Len and dexamethasone (Dex). Similarly, the Keynote 135 study using the combination of Pem, Pom, and Dex revealed an ORR of 60%. Unfortunately, the phase III studies comparing an IMiD vs Pem with the IMiD upfront at the early relapsed setting were halted because of increased deaths on the Pem arm and a decreased median PFS. With our Phase II study currently on clinical hold by the FDA, we are presenting here the 2-year follow-up of the original patient cohort including some preliminary safety and efficacy data of Pem-Len-Dex in HRMM patients as post-ASCT consolidation (NCT02906332). Methods: Patients with HRMM who have undergone induction therapy followed by single or tandem melphalan-based ASCT were considered eligible 2-6 months post ASCT. HRMM criteria are defined by any of the following: ISS stage 3; del 13q by cytogenetics; FISH with 1q amplification, 1p deletion (del), p53 del, t(4;14), t(14;16), t(14;20), hypodiploidy; or a high-risk gene expression profile score. Patients were excluded if they had progression of disease at time of screening or if there was evidence of organ dysfunction. Patients received Pem 200 mg IV at day 1;Len 25 mg po daily at days 1-14; and Dex 40 mg daily at days 1,8,15 of a 21-day cycle for a total of 2 cycles and then an additional 2 cycles of Pem + Len without Dex at the same dose and frequency. Survival outcomes post-ASCT were measured using the log-rank test. Results: Of 15 patients screened, 12 received at least one dose of therapy and were deemed evaluable. One patient withdrew consent and did not follow up after cycle 2. Baseline characteristics are shown in Table 1. Thirty-three percent were ISS 3, 66.7% had a p53 deletion by FISH, 41.6% received induction Bortezomib-Len-Dex; 33% received induction Carfilzomib-Len-Dex, and the remaining 24.9% received other bortezomib-based induction. Best ORR during the 2 year follow up showed 8 patients (73%) achieving stringent complete remission, 2 patients (18%) showing complete remission and 1 (9%) achieving very good partial remission. Table 2 shows best response to treatment by cycle of therapy. Table 3 shows best response during follow-up visits, which were 3 months apart. Of the 11 patients who completed therapy, 8 had minimal residual disease (MRD) status assessed and among them, 7 were MRD negative by flow cytometry, tested 30 days after the fourth cycle. With a median follow-up of 32.2 months, median PFS was 27.6 months. The PFS rates at 1 year and 2 year are 91.3% and 65.2%, respectively. All patients had adverse events (AEs), AEs were attributed to Pem, Len, or Dex rather than from ASCT. Of the 90 AEs that were reported, 5.6% were grade 3 and 94% were grade 1 or 2 (Table 3). The most common hematologic AE was neutropenia (41.7%), with 3 pts (25%) grade 1 and 2, and 2 pts (16.6%) grade 3. The most common non-hematologic AEs were intermittent constipation (16.6%), diarrhea (16.6%), fatigue (8.3%), and increased ALT (8.3%) and were graded as 1 or 2. Non-hematologic grade 3 AEs occurred in 2 pts and included hypoxia and maculopapular rash. There was 1 serious AE, H. influenza pneumonia requiring inpatient admission, which was not considered to be related to Pem. Conclusions: The combination of Pem, Len, and Dex given to HRMM patients in the post-ASCT consolidation setting is well tolerated. In comparison to historical controls of HRMM patients post-ASCT with a median PFS of 8-14 months, the PFS rates of 91.3% and 65.2% at 1 and 2 year post-ASCT respectively suggest an efficacy signal for the use of Pem, Len, and Dex as post-ASCT consolidation. Larger prospective studies are needed to validate these results. Disclosures Siegel: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Biran:Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding.

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Long-term follow-up results of a multicenter first-in-human study of the dual BCMA/CD19 Targeted FasT CAR-T GC012F for patients with relapsed/refractory multiple myeloma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.8014 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 8014-8014

Author(s):

Hua Jiang ◽

Baoxia Dong ◽

Li Gao ◽

Li Liu ◽

Jian Ge ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Median Duration ◽

Human Study ◽

Standard Of Care ◽

Single Infusion ◽

Refractory Multiple Myeloma ◽

Best Response ◽

Car T

8014 Background: The dual CAR-T GC012F developed on the novel FasT CAR-T platform targeting B cell maturation antigen (BCMA), and CD19 was designed to improve depth of response and overall efficacy for CAR-T as therapy for Multiple Myeloma. Here, we present updated data for study (NCT04236011; NCT04182581) including additional pts treated. Methods: From October 2019 to July 2020, 19 heavily pretreated Relapsed/Refractory Multiple Myeloma (RRMM) pts (age 27-71) with a median of 5 prior lines (range 2-9) received a single infusion of GC012F. 94.7% (18/19) were high risk (HR- defined by mSMART), 5 pts had extramedullary disease, 1 pts presented with plasma cell leukemia, and 15/19 were refractory to last therapy. 4/19 pts had received prior anti- CD38, 18/19 pts prior IMiD. 18/19 pts were refractory to PI, 17 pts to IMiD, 3 pts being primary refractory. After lymphodepletion over 2-3 days (30 mg/m2/d, 300mg/ m2/d Flu/Cy) CAR-T cells were administered as single infusion at 3 dose levels: 1x105/kg (DL1) n=1, 2x105/kg (DL2) n=9 and 3x105/kg (DL3) n=9. Results: As of Jan 12, 2021 cut-off, 19 pts were evaluated for response. Overall response rate (ORR) was 94.7% - all responses VGPR or better (94.7% - 16/18 sCR, 2/18 VGPR) with all pts MRD- by flow cytometry (10-4-10-6) - earliest response d 28 post infusion. 100% of pts achieved a reduction of paraprotein, 18/19 a 100% reduction. Best response was MRD- sCR in 16/19 patients (84.2%). In DL3 (n=9) 4 additional pts were response evaluable for 6 mth follow-up: 100% (9/9) of pts achieved MRD-sCR as best response, 87.5% (7/8) of response evaluable pts maintained MRD-sCR at landmark analysis of 6 mths. At data cut off, the median time to follow up was 13.8 mths (6.1-16.4) – median duration of response not yet reached. Cytokine Release Syndrome (CRS) and ICANs were graded by ASBMT criteria: grade 1-2 n=16 (84.2%), grade 3 n=2 (10.5%). Median duration of CRS was 4 d (1-8 d). No grade 4/5 CRS or ICANS were observed. 2 deaths occurred on study and were assessed as not related to therapy – one reported previously; one patient was diagnosed with pseudomonas pneumonia on Day 52, refused life-saving treatment and passed. CAR-T median Tmax was 10 d (range 8-14d), median peak copy number (Cmax) was 127548 (16,011-374,346) copies /ug DNA with long duration of persistence of up to 60 weeks at time of data cut off. Patients continue to be monitored for safety and efficacy. Conclusions: BCMA-CD19 dual FasT CAR-T GC012F showed early, deep and durable responses with a high ORR (94.7% - VGPR and better) including a high MRD- sCR rate (DL3=100%, n=9) in high risk RRMM pts including those refractory to anti-CD38, PI and IMIDs with a favorable safety profile consistent with previous findings. BCMA-CD19 dual FasT CAR-T GC012F may present a new treatment approach for patients with RRMM including those with high-risk features refractory to standard of care. Clinical trial information: NCT04236011; NCT04182581.

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Thalidomide Based Regimens for Treatment of Unfit Patients with Relapsed and Refractory Multiple Myeloma: a Monocentric Experience

Blood ◽

10.1182/blood.v116.21.5048.5048 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5048-5048

Author(s):

Alessandro Moscetti ◽

Francesca Saltarelli ◽

Maria Paola Bianchi ◽

Bruno Monarca ◽

Giacinto La Verde

Keyword(s):

Multiple Myeloma ◽

Side Effects ◽

Response Rate ◽

Conflicts Of Interest ◽

Therapeutic Option ◽

Alkylating Agents ◽

High Dose ◽

Refractory Multiple Myeloma ◽

Unfit Patients

Abstract Abstract 5048 Thalidomide, an immunomodulating drug with antiangiogenic activity, is an efficacious therapeutic option for unfit patients with multiple myeloma. Its efficacy may be increased by the addiction of steroids or other cytotoxic drugs such melphalan or cyclophosphamide. In this study we assessed the efficacy and toxicity of thalidomide based regimens as savage therapy in a series of elderly patients with relapsed/refractory multiple myeloma. Previous treatments included at least one therapy (range 1–4), such as high dose dexamethasone, alkylating agents, anthracyclines, IFN-α and autologous graft. Thalidomide 50–200 mg/die was administered orally in a total of 16 patients (median age 73.8 years, range 59–84) with relapsed/refractory multiple myeloma observed in our Hematology Department between May 2004 and January 2010. Oral dexamethasone or prednisone was added to the treatment. All patients continued therapy until relapse or progression and were prospectively followed-up including accurate monitoring of side effects. Response to thalidomide was assessed according to the European Group for Blood and Marrow Transplantation criteria. The median follow-up time was 25.6 months (range 8 – 68). Overall response rate was 81.2% (13/16 patients) with a median duration of response of 26.7 months (range 7 – 67): 3 patients showed a very good partial remission, 10 partial response, 1 stable disease and 2 progression of disease. During follow-up, 6 patients died (3 due to progression, 2 due to other neoplasm, 1 due to heart failure), 10 patients are still alive (2 VGPR and 7 PR in continuous therapy, 1 PD in third line therapy). No response was observed in 3/16 patients (18.7%). Despite the following side effects, mild to moderate bradycardia (25%, 1 needed PMK positioning and 1 dose reduction), peripheral sensitive polyneuropathy (18.7%) and constipation (6%), no patient discontinued therapy. This study shows that thalidomide based regimens are an effective therapy with a high response rate and manageable side effects when used in patient with multiple myeloma with relapsed/refractory disease. Disclosures: No relevant conflicts of interest to declare.

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Multiple Myeloma In Patients Under 40 Years Old Is Associated With High-Risk Features and Worse Outcomes

Blood ◽

10.1182/blood.v122.21.5359.5359 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5359-5359 ◽

Cited By ~ 7

Author(s):

Caitlin L. Costello

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

High Risk ◽

Conflicts Of Interest ◽

Young Patients ◽

Age At Diagnosis ◽

Cancer Center ◽

Common Disease ◽

High Dose

Background The median age of patients diagnosed with multiple myeloma (MM) is approximately 70 years old. It is an uncommon malignancy in persons younger than 40 years, representing only 2% of all patients diagnosed with MM. It has been suggested that young patients may present with more aggressive and less common disease features, frequently delaying the initial diagnosis and thereby affecting outcomes. With this background, we explored the outcome of young MM patients presenting to our institution over the past thirteen years. Methods We performed a retrospective review of a cohort of 236 patients with MM who received treatment for active MM at the University of California, San Diego Moores Cancer Center between January 2000 and July 2013. The demographics and disease features of patients up to 40 years of age at diagnosis were analyzed using descriptive statistics. The survival outcomes of these young patients were compared with the remainder of the cohort using the Kaplan-Meier method. Results Nineteen (6.5%) out of the 236 patients with MM were ²40 years of age at diagnosis, with a median age of 35.5 years old. The median follow-up of this group of young patients was 42 months (range 5-92). The patient and disease characteristics are outlined in Table 1. Seven young patients (37%) had MM with no heavy chain component, including light chain only secreting or non-secretory disease. Seven patients (37%) had a non-IgG paraprotein. Nine (56%) patients presented with extramedullary plasmacytomas. Two (10%) patients had plasma cell leukemia. All patients received at least one treatment regimen that included a novel agent. Fifteen patients (79%) had received high-dose therapy, and four patients (21%) underwent allogeneic stem cell transplantation (SCT) after at least one prior autologous SCT. The 5-year and 7-year overall survival (OS) from diagnosis was 51.7% and 28%, respectively, and the median OS was 60.7 months. In contrast, the median OS of patients ≥41 years old at diagnosis was 78.6 months (p=0.15, figure 1). Conclusion In this single center study with long follow up, we demonstrate that patients diagnosed with MM ²40 years of age exhibit several high-risk features and frequently present with advanced stage disease. Despite the use of novel agents in this population, there is a statistical trend towards a worse outcome with an 18-month difference in median overall survival when compared to older patients with MM. More aggressive treatment strategies are needed to improve survival in this young patient population. Disclosures: No relevant conflicts of interest to declare.

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