Stringent complete response (sCR) in patients (pts) with newly diagnosed multiple myeloma (NDMM) treated with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (DEX).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8011-8011
Author(s):  
Andrzej J. Jakubowiak ◽  
Kent A. Griffith ◽  
Dominik Dytfeld ◽  
David H. Vesole ◽  
Sundar Jagannath ◽  
...  
Keyword(s):  
Residual Disease ◽  
Phase 1 ◽  
Significant Proportion ◽  
Progression Free Survival ◽  
Complete Response ◽  
Multiparameter Flow Cytometry ◽  
Cell Transplant ◽  
Rapid Reduction ◽  
Highly Active

8011 Background: Combination treatment (tx) with CFZ, LEN, and DEX (CRd) is well tolerated and highly active in NDMM. In a phase 1/2 study, CRd provided rapid reduction of disease by 68% after cycle (C) 1 and 94% ≥partial response (PR) at a median of 8C, including 65% ≥very good PR and 53% ≥near CR (nCR), which improved to 79% ≥nCR after C12 (ASH 2011, Abstr 631). Here, we examine the clinical significance of the response rates with longer follow-up. Methods: Pts with NDMM were treated in 28-day (d) C with CFZ 20–36 mg/m2 IV (d1, 2, 8, 9, 15, 16), LEN 25 mg PO (d1–21) and DEX 40/20 mg PO weekly (C1–4/5–8). After C4, autologous stem cell transplant (ASCT) candidates achieving ≥PR could collect stem cells but then continued CRd with the option to proceed to ASCT. After C8, pts received CRd maintenance, using the last tolerated doses, with LEN/DEX at the same schedule but a modified CFZ schedule (d1, 2, 15, 16). Response was assessed by IMWG criteria plus nCR. Results: As of Nov 30, 2011, median follow-up was 14 mo (range 4–25) with 33/53 (62%) pts achieving ≥nCR and 42% sCR. After a median of 13C (range 1–25), 36 pts completed C8 and continued CRd maintenance, 64% achieving sCR. 20/22 pts in CR evaluated for minimal residual disease (MRD) by multiparameter flow cytometry had no MRD. Progression-free survival (PFS) rate was 97% at 12 and 92% at 24 mo. All pts who achieved sCR have maintained response for a median of 9 mo (range 1–20). Extended CRd tx was well tolerated. During CRd maintenance, the most common toxicities (all grades) were lymphopenia (30%), leukopenia (26%), and fatigue (25%), and peripheral neuropathy remained limited (11%, all G1/2). There were no tx discontinuations due to toxicity during maintenance and limited dose modifications (CFZ 19%, LEN 28%, DEX 31%). Conclusions: CRd is highly active in NDMM, providing rapid and deep responses. Extended tx was well tolerated and resulted in improved depth of response with a high sCR rate and a significant proportion of pts without evidence of MRD. Responses were durable with very promising PFS. All pts who achieved sCR remained on CRd with sustained sCR. These results compare favorably to other frontline regimens.

Daratumumab (DARA) maintenance or observation (OBS) after treatment with bortezomib, thalidomide and dexamethasone (VTd) with or without DARA and autologous stem cell transplant (ASCT) in patients (pts) with newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 2.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8004-8004
Author(s):  
Philippe Moreau ◽  
Pieter Sonneveld ◽  
Keyword(s):  
Interim Analysis ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Autologous Stem Cell Transplant ◽  
Second Primary ◽  
Cell Transplant ◽  
Open Label ◽  
Depth Of Response

8004 Background: D-VTd plus ASCT was approved for transplant-eligible (TE) NDMM based on part 1 of CASSIOPEIA. We report a prespecified interim analysis of CASSIOPEIA part 2: DARA maintenance vs OBS in pts with ≥partial response (PR) in part 1, regardless of induction/consolidation (ind/cons) treatment. Methods: CASSIOPEIA is a 2-part, randomized, open-label, phase 3 study in TE NDMM. Pts received 4 cycles ind and 2 cycles cons with D-VTd or VTd. 886 pts who achieved ≥PR were rerandomized to DARA 16 mg/kg IV Q8W for up to 2 yr (n = 442) or OBS (n = 444) until progressive disease per IMWG. Pts were stratified by ind (D-VTd vs VTd) and depth of response (minimum residual disease [MRD] status and post cons response ≥PR). Primary endpoint was progression-free survival (PFS) after second randomization. This interim analysis assessed efficacy and safety after 281 PFS events. A preplanned hierarchical procedure tested key secondary endpoints: time to progression (TTP), ≥complete response (CR), MRD negativity rates by NGS and overall survival (OS). Results: At median follow-up of 35.4 mo, median PFS was not reached (NR) with DARA and 46.7 mo with OBS (HR 0.53; 95% CI 0.42–0.68; P <0.0001). PFS advantage for DARA was consistent across most subgroups. However, a prespecified analysis showed significant interaction with ind/cons treatment arm ( P< 0.0001). PFS HR for DARA vs OBS was 0.32 (95% CI 0.23–0.46) in the VTd arm and 1.02 (0.71–1.47) in the D-VTd arm. Median TTP was NR for DARA vs 46.7 mo for OBS (HR 0.49; 95% CI 0.38–0.62; P <0.0001). More pts in the DARA vs OBS arm achieved ≥CR (72.9% vs 60.8%; OR 2.17; 95% CI 1.54–3.07; P <0.0001). MRD negativity (in ≥CR pts at 10-5) was 58.6% with DARA vs 47.1% with OBS (OR 1.80; 95% CI 1.33–2.43; P= 0.0001). Median OS was NR in either arm. Most common (≥2.5%) grade 3/4 adverse events (AEs) with DARA vs OBS were pneumonia (2.5% vs 1.4%), lymphopenia (3.6% vs 1.8%), and hypertension (3.0% vs 1.6%). Serious AEs occurred in 22.7% (DARA) vs 18.9% (OBS) of pts; the most common (≥2.5%) was pneumonia (2.5% vs 1.6%). 13 (3.0%) pts discontinued DARA due to an AE. The rate of infusion-related reactions was 54.5% (DARA-naïve pts) and 2.2% (prior DARA pts); 90% were grade 1/2.Second primary malignancies occurred in 5.5% (DARA) vs 2.7% (OBS) of pts. Conclusions: CASSIOPEIA part 2 demonstrated a clinical benefit of DARA maintenance in TE NDMM pts, with significantly longer PFS for DARA vs OBS. With current follow-up, maintenance PFS benefit appeared only in pts treated with VTd as ind/cons. Pts who received D-VTd ind/cons with or without DARA maintenance achieved similar PFS; longer follow-up is needed for PFS2 and OS. DARA significantly increased deeper response and MRD negativity rates vs OBS, and was well tolerated with no new safety signals. Clinical trial information: NCT02541383.

Personalized, ctDNA analysis to detect minimal residual disease and identify patients at high risk of relapse with multiple myeloma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8029-8029
Author(s):  
Binod Dhakal ◽  
Shruti Sharma ◽  
Svetlana Shchegrova ◽  
Minu Maninder ◽  
Meenakshi Malhotra ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Residual Disease ◽  
Prognostic Significance ◽  
Unmet Need ◽  
Progression Free Survival ◽  
Multiparameter Flow Cytometry ◽  
High Dose ◽  
Blood Samples ◽  
Ctdna Analysis

8029 Background: Despite treatment with high-dose chemotherapy followed by autologous stem cell transplantation (AHCT), MM patients invariably relapse. MRD-negativity post-AHCT has emerged as the most important prognostic marker. Currently, MRD in MM is monitored via bone marrow aspirate sampling. Marrow MRD assays are limited by the spatial heterogeneity of marrow MM localization; extramedullary disease and sampling variability of marrow aspiration. Sensitive, non-invasive blood-based MRD assay is an unmet need. ctDNA as a noninvasive biomarker can be utilized to predict relapse in MM. Here we attempt to evaluate MRD using ctDNA in AHCT recipients with MM. Methods: In this retrospective, single-center study, we analyzed ctDNA MRD in blood samples collected from 28 patients with MM after upfront AHCT. A total of 80 plasma timepoints were available pre and post AHCT with a median follow-up of 92.4 months. Multiparameter flow cytometry (MFC) at 10-4 level was used to assess the MRD from the BM biopsy. Individual bone marrow aspirates or FFPE slides from the time of MM diagnosis and matched normal blood were whole-exome sequenced, and somatic mutations were identified. MRD assessment at 3 months post-AHCT was performed by ctDNA analysis using a personalized, tumor-informed (SignateraTM, bespoke mPCR NGS assay). The prognostic value of ctDNA was evaluated by correlating MRD status with clinical outcomes. Results: Table provides the baseline disease characteristics. Median age was 67 [41-75] years and 16 [57.1%] were males. ctDNA was detectable in 70.8% (17/24) of pre-AHCT, 53.6% (15/28) of ̃3 months post-AHCT, and 39.2% (11/28) of patients during the surveillance phase post-AHCT. Of the 15 ctDNA MRD positive patients, 93.3% (n=14) experienced relapse on follow-up (hazard ratio: 5.64; 95% CI: 1.8-17; p=0.0003). Patients negative for ctDNA at 3 months post-AHCT had significantly superior progression-free survival (PFS) compared to positive (median PFS, 84 months vs. 31 months; p=0.003) The positive predictive value (PPV) for relapse among patients positive for ctDNA at 3 months post-AHCT was 93.3%, and significantly higher than marrow MFC of 68.4%. Conclusions: Our study shows the feasibility that a tumor-informed assay on archival blood samples is predictive of relapse post-AHCT. Future prospective studies with real-time marrow NGS and ctDNA samples are needed to define the role of ctDNA in MM and its prognostic significance.[Table: see text]

scholarly journals Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study

Leukemia ◽  
2020 ◽  
Vol 34 (7) ◽  
pp. 1875-1884 ◽  
Author(s):  
Nizar J. Bahlis ◽  
Meletios A. Dimopoulos ◽  
Darrell J. White ◽  
Lotfi Benboubker ◽  
Gordon Cook ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Open Label ◽  
Refractory Multiple Myeloma ◽  
Open Label Phase ◽  
Intent To Treat ◽  
Line Of Therapy

Abstract In POLLUX, daratumumab (D) plus lenalidomide/dexamethasone (Rd) reduced the risk of disease progression or death by 63% and increased the overall response rate (ORR) versus Rd in relapsed/refractory multiple myeloma (RRMM). Updated efficacy and safety after >3 years of follow-up are presented. Patients (N = 569) with ≥1 prior line received Rd (lenalidomide, 25 mg, on Days 1–21 of each 28-day cycle; dexamethasone, 40 mg, weekly) ± daratumumab at the approved dosing schedule. Minimal residual disease (MRD) was assessed by next-generation sequencing. After 44.3 months median follow-up, D-Rd prolonged progression-free survival (PFS) in the intent-to-treat population (median 44.5 vs 17.5 months; HR, 0.44; 95% CI, 0.35–0.55; P < 0.0001) and in patient subgroups. D-Rd demonstrated higher ORR (92.9 vs 76.4%; P < 0.0001) and deeper responses, including complete response or better (56.6 vs 23.2%; P < 0.0001) and MRD negativity (10–5; 30.4 vs 5.3%; P < 0.0001). Median time to next therapy was prolonged with D-Rd (50.6 vs 23.1 months; HR, 0.39; 95% CI, 0.31–0.50; P < 0.0001). Median PFS on subsequent line of therapy (PFS2) was not reached with D-Rd versus 31.7 months with Rd (HR, 0.53; 95% CI, 0.42–0.68; P < 0.0001). No new safety concerns were reported. These data support using D-Rd in patients with RRMM after first relapse.

Treatment outcome with the combination of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) for newly diagnosed multiple myeloma (NDMM) after extended follow-up.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8543-8543 ◽  
Author(s):  
Andrzej J. Jakubowiak ◽  
Dominik Dytfeld ◽  
Kent A. Griffith ◽  
Jagoda Jasielec ◽  
Kathryn McDonnell ◽  
...  
Keyword(s):  
Low Dose ◽  
Phase 1 ◽  
Complete Response ◽  
High Rate ◽  
Cell Transplant ◽  
Depth Of Response ◽  
Cycle 24 ◽  
Dose Modifications ◽  
Clinical Trial Information

8543 Background: We previously reported results from a phase 1/2 trial of CRd in NDMM (NCT01029054), demonstrating a high rate (42%) of stringent complete response (sCR) and overall favorable efficacy /safety after a median of 12 cycles of treatment (tx) and a median follow-up of 13 mo (Jakubowiak et al Blood, 2012). Here we report updated results after extended tx and additional 12 mo of follow-up. Methods: Patients (pts) received 28-day (d) cycles of carfilzomib (CFZ) 20–36 mg/m2 IV (d1, 2, 8, 9, 15, 16), lenalidomide (LEN) 25 mg PO (d1–21), and dexamethasone 40/20 mg PO wkly (cycles 1–4/5–8). For cycles 8–24, CRd was given with a modified CFZ schedule (d1, 2, 15, 16) and then LEN alone after cycle 24. Stem cell transplant was an option after cycle 4. Response was assessed by IMWG plus nCR. Results: As of Nov 2012, 53 pts had received a median of 22 CRd cycles (range 2–24); 7 pts opted for transplant; 24 continued LEN maintenance for median 8 mo (range 1–10). Median follow-up was 25 mo (range 5–37). With extended tx, the CR rate was 64%; sCR improved from 42% to 53%, ≥nCR from 62% to 72%, and ≥VGPR from 81% to 87% (follow-up 13 vs 25 mo); ≥PR remained at 98%. Immunophenotypic CR (IMWG) was achieved in 22/26 evaluated pts. Of pts in sCR, 25% had high-risk cytogenetics per IMWG. In pts who did not proceed to transplant (n=46), the sCR was 59%, CR 70%, ≥nCR 78%, ≥VGPR 91%, and ≥PR 100%. Over the course of tx, depth of response improved. Median time to ≥VGPR was 4 cycles (range 2–17), ≥nCR 4.5 cycles (range 2–15), and sCR 10 cycles (range 4–30); 2 pts converted to sCR during LEN maintenance. At 2 years, the estimated PFS rate was 94% and OS was 98%; for pts with sCR, rates were 96% and 100%, respectively. Adverse event types, rates, and dose modifications during extended tx were comparable with those previously reported. There was 1 death off study due to disease progression. Conclusions: Extended follow-up showed that depth of response continued to improve over the course of prolonged CRd tx, resulting in exceptional CR, sCR, and PFS. Extended tx continued to be well tolerated. The results compare favorably with historical studies in both transplant and non-transplant NDMM. Clinical trial information: NCT01029054.

Consolidation Therapy with Subcutaneous (SC) Alemtuzumab After Fludarabine and Rituximab (FR) Induction Therapy Improves the Complete Response (CR) Rate in Chronic Lymphocytic Leukemia (CLL) and Eradicates Minimal Residual Disease (MRD) but Is Associated with Severe Infectious Toxicity: Final Analysis of CALGB Study 10101.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 210-210
Author(s):  
Thomas S Lin ◽  
Kathleen A Donohue ◽  
John C. Byrd ◽  
Margaret S Lucas ◽  
Eva Hoke ◽  
...  
Keyword(s):  
Residual Disease ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Hematologic Toxicity ◽  
Consolidation Therapy ◽  
Varicella Zoster ◽  
Grade 3

Abstract Abstract 210 Background: Alemtuzumab (Campath-1H) is approved for the treatment of CLL. CALGB sought to determine whether alemtuzumab can improve the CR rate and eradicate MRD after induction chemoimmunotherapy by performing a phase II study administering FR followed by alemtuzumab consolidation to previously untreated, symptomatic CLL patients (pts). We previously reported preliminary toxicity data (Lin et al. ASH 2007) and now report final toxicity and response data. Methods: Pts received fludarabine 25 mg/m2 IV on days 1–5, and rituximab 50 mg/m2 IV on day 1, 325 mg/m2 on day 3, and 375 mg/m2 on day 5 of cycle 1 and then only on day 1 of cycles 2–6, repeated every 28 days for up to 6 cycles. Four months after the last fludarabine dose, pts with stable (SD) or responsive disease by NCI 96 criteria received SC alemtuzumab 3 mg on day 1, 10 mg on day 3, and 30 mg on day 5, and then thrice weekly thereafter for 6 weeks (18 total doses). Pts received standard Pneumocystis (PCP) and Varicella zoster virus prophylaxis and were monitored weekly by PCR for Cytomegalovirus (CMV) viremia. When unacceptable serious infectious toxicity was noted in pts who received alemtuzumab after achieving CR from FR induction, the study was amended so that only PR or SD pts received alemtuzumab after FR. Results: Median age of pts (n=102) was 61 years (range, 23–82), 74% were male, and 30% were Rai stage III/IV. FR was well tolerated; 93% of pts received at least 3 cycles, and 77% completed all 6 cycles. Overall, complete and partial response (OR, CR, PR) rates after FR induction were 90%, 29% and 61%, and 15% were MRD negative by flow cytometry. Fifty-eight pts received alemtuzumab, and 42 (72%) completed the planned 6 weeks of therapy. OR, CR, and PR rates after alemtuzumab (n=58) were 91%, 66% and 26%, and 50% were MRD negative. Twenty-eight of 45 pts (62%) in PR after FR who received alemtuzumab attained CR. Of 11 pts in CR after FR who received alemtuzumab, 5 were MRD negative prior to consolidation and 3 of the other 6 converted to MRD negative afterwards. By intent-to-treat for all patients enrolled, OR, CR, and MRD negativity were attained by 90%, 57% and 42% of pts. With a median follow up of 34 months, median progression free survival (PFS) was 37 months (95% CI, 33–43 months); PFS was 73% and overall survival (OS) 86% at 2 years. Two-year PFS (76% vs 70%, p=0.54) and OS (84% vs 88%, p=0.89) were similar for pts who did and did not receive alemtuzumab. Similarly, there were no differences in PFS or OS among the 30 pts in CR after FR whether or not they received alemtuzumab, although the numbers were small. Grade 3–4 neutropenia and thrombocytopenia were observed in 43% and 19% of pts during alemtuzumab therapy. Grade 3–4 non-hematologic toxicity was observed in 41% of pts, including 19% infections and 19% febrile neutropenia, during alemtuzumab therapy. As we previously reported, 5 pts in CR after FR who received alemtuzumab died from infections (viral meningitis, Listeria meningitis, Legionella pneumonia, CMV and PCP pneumonia), and one pt in PR after FR who received alemtuzumab died of Epstein-Barr (EBV) viremia without evidence of EBV lymphoma. These grade 5 toxicities occurred both during and for up to 7 months after alemtuzumab therapy. Conclusions: Alemtuzumab consolidation improved the CR and MRD negative rates after FR induction. However, alemtuzumab consolidation resulted in significant toxicity, particularly severe infections in pts who achieved a CR after FR induction. Longer follow up is needed to determine if the improved CR and MRD negative rates following alemtuzumab consolidation will eventually result in improved PFS or OS, especially among pts who achieved a PR after FR induction. Disclosures: Lin: GlaxoSmithkline: Consultancy, Employment; Genentech: Consultancy; Bayer: Consultancy. Off Label Use: Use of alemtuzumab as consolidation therapy. Byrd:Genentech: Consultancy, Research Funding. Link:Genentech: Consultancy. Rai:Genentech: Consultancy; Bayer: Consultancy.

Updated phase 1 results of teclistamab, a B-cell maturation antigen (BCMA) × CD3 bispecific antibody, in relapsed/refractory multiple myeloma (MM).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8007-8007
Author(s):  
Amrita Y. Krishnan ◽  
Alfred L. Garfall ◽  
Maria-Victoria Mateos ◽  
Niels W.C.J. van de Donk ◽  
Hareth Nahi ◽  
...  
Keyword(s):  
Median Time ◽  
T Cell Activation ◽  
Cell Activation ◽  
Residual Disease ◽  
Phase 1 ◽  
Complete Response ◽  
Low Grade ◽  
Exposure Profile ◽  
Grade 3

8007 Background: BCMA-targeted immunotherapies offer considerable promise for relapsed/refractory MM. Teclistamab (JNJ-64007957) is a BCMA × CD3 bispecific IgG4 antibody that redirects CD3+ T cells to BCMA-expressing MM cells. We present updated results of patients (pts) treated at the recommended phase 2 dose (RP2D) in the first-in-human phase 1 study of teclistamab. Methods: Eligible pts had MM and were relapsed, refractory or intolerant to established therapies. Primary objectives were to identify the RP2D (part 1) and characterize safety and tolerability of teclistamab at the RP2D (part 2). Teclistamab was given intravenously (IV; range 0.3–19.2 µg/kg [biweekly]; range 19.2–720 µg/kg [weekly]) or subcutaneously (SC; range 80.0–3000 µg/kg weekly) in different cohorts, with step-up dosing used for ≥38.4 µg/kg doses. Adverse events (AEs) were graded by CTCAE v4.03 (cytokine release syndrome [CRS] by Lee et al 2014). Response was assessed per IMWG criteria. Results: As of Feb 4, 2021, 156 pts received teclistamab (IV n = 84; SC n = 72). The RP2D, identified as weekly SC 1500 µg/kg teclistamab with 60.0 and 300 µg/kg step-up doses, was given to 40 pts (median follow-up 4.3 mo [range 1.1–10.4+]). Pts dosed at the RP2D (median age, 62.5 y [range, 39–84]; 65% male) had received a median of 5 prior lines of therapy (range 2–11; 100% triple-class exposed; 65% penta-drug exposed; 83% triple-class refractory; 35% penta-drug refractory; 85% refractory to their last line of therapy). There were no dose-limiting toxicities at the RP2D in part 1. The most common AEs at the RP2D were CRS (70%; grade 3/4 0) and neutropenia (60%; grade 3/4 40%); grade 1 neurotoxicity was reported in 1 (3%) pt. Median time to CRS onset was later with SC vs IV dosing (day after SC injection vs day of IV infusion). The overall response rate in response-evaluable pts treated at the RP2D (n = 40) was 65%; 58% achieved a very good partial response or better and 30% achieved a complete response (CR) or better; median time to first confirmed response was 1.0 mo (range 0.2–3.1). At the RP2D, median duration of response was not reached; 23 of 26 responders (88%), after median follow-up of 5.3 mo (range 1.2–10.4+), were alive and continuing on treatment with responses deepening over time. Of 14 evaluable pts across all cohorts, 9 with CR were minimal residual disease–negative at 10-6. At the RP2D, teclistamab exposure was sustained across the dosing interval and exceeded target levels, and consistent T cell activation was observed. Conclusions: Teclistamab at the RP2D (weekly 1500 µg/kg SC) was well-tolerated and showed encouraging efficacy with durable, deepening responses, supporting further investigation as monotherapy and in combination with other agents. With the extended exposure profile at the RP2D and delayed and low-grade CRS observed with SC administration, alternative SC dosing strategies are being explored. Clinical trial information: NCT03145181.

Multiparameter Flow Cytometry Remission Is the Most Relevant Prognostic Factor for Multiple Myeloma Patients Who Undergo Autologous Stem Cell Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 737-737
Author(s):  
Bruno Paiva ◽  
Maria-Belén Vidriales ◽  
Jorge Cerveró ◽  
Gema Mateo ◽  
Jose J. Pérez ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
Stem Cell ◽  
Plasma Cells ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Patient Specific ◽  
Multiparameter Flow Cytometry ◽  
Cell Transplant ◽  
Post Transplant

Abstract Minimal residual disease (MRD) assessment is standard in many hematologic malignancies but is considered investigational in multiple myeloma (MM). We report a prospective analysis of the prognostic importance of MRD detection by multiparameter flow cytometry (MFC) in 295 newly diagnosed MM patients uniformly treated in the GEM2000 protocol (VBMCP/VBAD induction plus autologous stem cell transplant [ASCT]). MRD status by MFC was determined at day 100 post-ASCT. Persistent myelomatous plasma cells (MM-PCs) were detected by MFC in 170 patients (58%), who were considered MRD-positive. Progression-free survival (PFS; median 71 vs 37 months, P < .0001) and overall survival (OS; median not reached vs 89 months, P = .002) were longer in patients who were MRD-negative versus MRD-positive at day 100 post-ASCT, with a 5-year PFS rate of 60% and 22% (P < .0001), respectively. Similar prognostic differentiation was seen in 147 patients who achieved immunofixation (IFx) negative complete response post-ASCT. The 5-year PFS rate was 62% in MRD-negative patients (n=94) versus 30% in MRD-positive patients (n=53; P < .0001), and the respective 5-year OS rates were 87% versus 59% (P = .009). Moreover, MRD− IFx− and MRD− IFx+ patients had significantly longer PFS than MRD+ IFx− patients (median 71, 65, and 37 months, respectively, P = .0002). By multivariate analysis, only MRD status by MFC at day 100 post-ASCT and FISH cytogenetics were identified as independent prognostic factors for PFS, and only MRD status by MFC and age were identified for OS. The relative risks of progression and death among MRD-positive versus MRD-negative patients were 3.64 (P = .002) and 2.02 (P = .02), respectively. Finally, a subgroup of 157 patients in which MRD information was available both pre- and post-ASCT were analyzed. Patients who were MRD-positive both pre- and post-transplant (n=93) had the worst prognosis; patients who were MRD-positive pre-ASCT but improved to MRD-negative post-ASCT (n=48) had an intermediate prognosis, and patients who were MRD-negative both pre- and post-transplant (n=16) had the best prognosis. The 5-year PFS and OS rates in these three prognostic subgroups were 25%, 57%, and 80%, respectively (P = .0001), and 59%, 78%, and 100%, respectively (P = .06). In summary, our results show that MRD evaluation by MFC is a very useful technique to identify patients at different risk of progression. This type of analysis, particularly when performed post-ASCT, may contribute to the design of patient-specific maintenance treatment approaches, as well as the evaluation of the potential benefits of consolidation therapies.

Very Good Partial Response and Complete Response Predict Superior Overall Survival and Progression Free Survival After Single Autologous Stem Cell Transplant in Patients with Multiple Myeloma,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4111-4111
Author(s):  
Victor H Jimenez-Zepeda ◽  
Donna E. Reece ◽  
Suzanne Trudel ◽  
Christine Chen ◽  
Andrew Winter ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Progression Free Survival ◽  
Complete Response ◽  
Autologous Stem Cell Transplant ◽  
Novel Agents ◽  
Cell Transplant ◽  
Free Survival ◽  
The Impact

Abstract Abstract 4111 In multiple myeloma (MM), the impact of complete response (CR) and very good partial response (VGPR) achievement has been shown mostly after introduction of high dose therapy (HDT) supported by autologous stem cell transplant (ASCT). Recently, the IFM group reported the impact of achievement of CR and VGPR in double ASCT. The purpose of this study is to confirm the prognostic value of CR/VGPR in a large group of patients treated with single ASCT. Methods All consecutive patients who underwent single ASCT at Princess Margaret Hospital between January 2000 and December 2007 were evaluated. Patients were mobilized with cyclophosphamide and G-CSF and majority were conditioned with melphalan 200mg/m2. Response to therapy was assessed according to the IMWC including VGPR. Progression Free Survival (PFS) and Overall Survival (OS) were measured from transplant date to the date of death or last follow-up. OS and DFS were analyzed using the Kaplan-Meier Method. The Cox proportional hazard model was used to assess CR and VGPR and some other prognostic markers at presentation such as age, B2Mg> 460 μmol/L, LDH> 350 IU/L, CRP> 20mg/L, albumin<35g/L and creatinine > 200 μmol/L. All p-values were 2-sided and statistically significant if <0.05. Results 788 patients were identified for the study; their median age was 56 years (30–73). Patient's characteristics are listed in Table 1. Response was assessed at day 100 after ASCT and showed a CR of 6%, PR of 37.5%, and VGPR of 53% (Overall Response rate of 95.5%). Median OS and PFS for the group were 77.43 months and 20.63 months respectively. The median OS and PFS were significantly better for patients who achieved CR/VGPR, 104.5 months versus 51.7 months, and 26.3 months versus 13.53 months respectively. With a median follow-up of 44 months there is no significant difference in OS for those patients who achieved VGPR/CR after induction therapy with novel agents. However, PFS is better in those patients receiving novel agents who achieved VGPR/CR (Median PFS of 24.63months versus 12.4 months respectively (p=0.01). Multivariate analysis shows CR/VGPR as an independent prognostic factor for OS and PFS (Fig 1 and 2). B2Mg> 460 μmol/L, LDH> 350 IU/L, CRP > 20mg/L, albumin<35g/L and creatinine > 200 μmol/L failed to be important factor for survival in the multivariate analysis. Our data suggests that VGPR/CR is clearly important in the pre-novel agents era and for the smaller group of patients who had novel agents induction there is a benefit in PFS and with a longer follow-up perhaps in OS. In conclusion, VGPR/CR remains a simple and powerful indicator in the context of single ASCT and should be considered a relevant objective for MM treatment. Table 1. Clinical characteristics of patients with Multiple Myeloma undergoing single ASCT Clinical characteristic N=788 Median Range % Age (years) 58 31–74 Male 59.4% Female 40.6% Hemoglobin (g/L) 114 54–180 Creatinine (μmol/L) 107 28–1409 B2-microglobulin ((μmol/L) (N=718) 508 260–7270 Albumin (g/L) (N=650) 38 23–54 IgG 51.1% IgA 31.3% IgM 0.4% IgD 0.7% Biclonal 9.9% Not Detected 6.6 Kappa 59.4% Lambda 32.9% Biclonal 2% Not Detected 5.7% Calcium (μmol/L) 2.29 1.62–4.66 LDH (IU/L) (N=754) 235 50–1470 Induction Treatment: 52.2% VAD 22.8% Dexamethasone 6.3% TD 2.3% CP 3.8% DPACE/DTPACE 1.7% DVD 8% CyBORD 2% VD Ab: VAD: Vincristine, Adriamycin and dexamethasone, TD: Thalidomide and Dexamethasone; CP: Cyclophosphamide and Prednisone, DVD: Doxil, Velcade and Dexamethasone, CyBORD: Cyclophosphamide, Bortezomib and Dexamethasone and VD: Valcade and Dexamethasone Disclosures: Jimenez-Zepeda: J & J: Honoraria. Reece:Bristol, Meyers, Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Johnson&Johnson: Research Funding; Merck: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Millennium: Research Funding; Amgen: Honoraria. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria.

scholarly journals Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial

Blood ◽  
2020 ◽  
Vol 136 (8) ◽  
pp. 936-945 ◽  
Author(s):  
Peter M. Voorhees ◽  
Jonathan L. Kaufman ◽  
Jacob Laubach ◽  
Douglas W. Sborov ◽  
Brandi Reeves ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Complete Response ◽  
Newly Diagnosed ◽  
Depth Of Response ◽  
Grade 3 ◽  
Intent To Treat

Abstract Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with newly diagnosed multiple myeloma (NDMM). The addition of daratumumab (D) to RVd (D-RVd) in transplant-eligible NDMM patients was evaluated. Patients (N = 207) were randomized 1:1 to D-RVd or RVd induction (4 cycles), ASCT, D-RVd or RVd consolidation (2 cycles), and lenalidomide or lenalidomide plus D maintenance (26 cycles). The primary end point, stringent complete response (sCR) rate by the end of post-ASCT consolidation, favored D-RVd vs RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval, 0.87-2.82; 1-sided P = .068) and met the prespecified 1-sided α of 0.10. With longer follow-up (median, 22.1 months), responses deepened; sCR rates improved for D-RVd vs RVd (62.6% vs 45.4%; P = .0177), as did minimal residual disease (MRD) negativity (10−5 threshold) rates in the intent-to-treat population (51.0% vs 20.4%; P &lt; .0001). Four patients (3.8%) in the D-RVd group and 7 patients (6.8%) in the RVd group progressed; respective 24-month progression-free survival rates were 95.8% and 89.8%. Grade 3/4 hematologic adverse events were more common with D-RVd. More infections occurred with D-RVd, but grade 3/4 infection rates were similar. Median CD34+ cell yield was 8.2 × 106/kg for D-RVd and 9.4 × 106/kg for RVd, although plerixafor use was more common with D-RVd. Median times to neutrophil and platelet engraftment were comparable. Daratumumab with RVd induction and consolidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT02874742.

scholarly journals Efficacy of venetoclax plus rituximab for relapsed CLL: Five-year follow-up of continuous or limited-duration therapy

Blood ◽  
2021 ◽  
Author(s):  
Shuo Ma ◽  
John F. Seymour ◽  
Danielle M. Brander ◽  
Thomas J. Kipps ◽  
Michael Y. Choi ◽  
...  
Keyword(s):  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Continuous Exposure ◽  
Duration Of Response ◽  
Long Term Follow Up ◽  
Discontinue Therapy ◽  
Limited Duration

We report long-term follow-up of the phase 1b study of venetoclax and rituximab (VenR) in patients with relapsed chronic lymphocytic leukemia (CLL), including outcomes with continuous or limited-duration therapy. Patients received venetoclax daily (200-600 mg) and rituximab over 6 months, then venetoclax monotherapy. Patients achieving complete response (CR), CR with incomplete marrow recovery (CRi), or undetectable minimal residual disease (uMRD) assessed by flow cytometry (&lt;10-4 cutoff) were allowed, but not required, to discontinue therapy, while remaining on study and could be re-treated with VenR upon progression. Median follow-up for all patients (N=49) was 5.3 years. Five-year rates for overall survival, progression-free survival, and duration of response were 86% (95% CI, 72-94), 56% (40-70), and 58% (40-73), respectively. Of the 33 deep responders (CR/CRi or uMRD), 14 remained on venetoclax monotherapy (continuous therapy), and 19 stopped venetoclax therapy (limited-duration therapy) after a median of 1.4 years. Five-year estimates of ongoing response were similar between continuous (71% [95% CI, 39-88]) or limited-duration therapy (79% [49-93]). Six of 19 patients in the latter group had subsequent disease progression, all &gt;2 years off venetoclax (range, 2.1-6.4). Four patients were re-treated with VenR, with partial responses observed in the 3 evaluable to date. VenR induced deep responses that were highly durable with either continuous or limited-duration therapy. Retreatment with VenR induced responses in patients with CLL progression after discontinuing therapy. Continuous exposure to venetoclax in deep responders does not appear to provide incremental benefit. ClinicalTrials.gov ID: NCT01682616

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