Marrow Minimal Residual Disease Negativity Research Articles

Clinical Implication of Minimal Residual Disease By Multiparameter Flow Cytometry in Light Chain Amyloidosis

We evaluated bone marrow minimal residual disease (MRD) by multiparameter flow cytometry (sensitivity 10 -5) in 91 patients with light chain amyloidosis (AL). The overall MRD negative rate was 42.9% (n=39). The MRD negative rate among patients in complete response, very good partial response, and less than PR was 61.5% (24/39), 35.7% (10/28), and 0% (0/11), respectively. There were no significant differences in baseline characteristics regarding age, light chain burden, and organ involvement, while lower proportion of male sex and cytogenetics t(11;14) by FISH was observed in MRD negative patients. Patients with MRD negativity had a numerically higher proportion of cardiac response (54.8% vs 40.5%, P=0.224) and renal response (52.6% vs 41.7%, P=0.474). After a median follow-up time of 29.0 months, patients with MRD negativity had a near significantly longer event-free survival (EFS, defined as hematological progression/organ dysfunction/initiation of next-line therapy and death) from treatment initiation than patients with MRD positivity (NR vs 38.8 months, P=0.078). The 5-year overall survival (OS) for patients with MRD negativity and MRD positivity were 82.7% and 67.8%, respectively (P=0.229).

Persistance or Reappearance of Serum Monoclonal Protein Detected By Mass Spectrometry Is a Major Prognostic Factor in Patients with Newly Diagnosed Multiple Myeloma

Introduction: Durability of minimal residual disease (MRD) based on bone marrow examination is associated with a progression-free survival (PFS) benefit when it is undetected for >6-12 months. However, MRD assessment is limited by the heterogeneous involvement of bone marrow and invasive nature of the procedure. In contrast, Mass-Fix is a mass spectrometry based blood test that can detect small amounts of monoclonal protein. Herein, we hypothesize that achieving sustained Mass-Fix negativity for at least 6 or 12 months, improves outcomes compared to patients with nonsustained Mass-Fix negativity. In addition, we assess the clinical outcome of patients with loss of Mass-Fix negativity. Methods: This retrospective cohort study included consecutive patients seen at Mayo Clinic Rochester with newly diagnosed multiple myeloma (MM). Patients achieving at least very good partial response, and who had serial Mass-Fix testing every 6-12 months were included in this study. MRD in bone marrow aspirate was measured by flow cytometry (threshold 1 tumor cell/105 white blood cells). The Kaplan Meier or Simon-Makuch methods were used to graph the survival function. Progression-free survival was defined from diagnosis or the landmark point (2 years after diagnosis) to progression or death from any cause. Results: We identified 443 patients with NDMM, between May 1, 2017 and May 31, 2020. Among these, 274 patients had marrow MRD examination during their follow-up. With a median follow-up of 41 months from diagnosis, 56% of patients achieved Mass-Fix negativity, 43% marrow MRD negativity, and 23% achieved both Mass-Fix and MRD negativity. Most patients received a bortezomib-lenalidomide-dexamethasone induction followed by autologous transplantation (73%). In a 2 year landmark analysis, patients achieving Mass-Fix negativity had a better PFS at 2-years from landmark (4 years from diagnosis) than patients who did not (86.7% vs. 70.0% , p<0.001). Similarly, in a landmark analysis, patients with negative marrow MRD had a better PFS than those with positive MRD (88.1% vs. 62.5%, p=0.027). However, overall survival was similar between patients achieving Mass-Fix or MRD negativity and those who did not. In patients with Mass-Fix negativity, 76% and 71% achieved sustained Mass-Fix negativity for ≥6 and ≥12 months, respectively. In a landmark analysis, a significant difference in 2-year PFS was observed between patients with sustained Mass-Fix negativity ≥6 months and < 6 months (94.1% vs. 78.9%, p=0.013, Figure 1A). Patients with sustained Mass-Fix negativity≥12 months and < 12 months had a better 2-year PFS in a landmark analysis (94.4 vs. 80.2, p=0.019). Similarly, in a landmark analysis, patients with sustained marrow MRD negativity for ≥12 months had a better 2-year PFS from the landmark (4 years from diagnosis) than patients with MRD negativity for <12 months (91.8% vs. 72.8%, p<0.001). Patients achieving both sustained Mass-Fix and marrow negativity for ≥6 months had a better 2-year PFS from the landmark than patients who did not in a landmark analysis (91.5% vs. 73.1%, p=0.001). In our cohort, 33% of patients achieving Mass-Fix negativity had a subsequent loss of Mass-Fix negativity by 4 years; median duration of Mass-Fix negativity was 27 months (95% CI 25-30 months). Nearly half of patients with loss of Mass-Fix negativity (39/81) had eventually progressive disease (PD) according to IMWG criteria. In a 2-year landmark analysis, 2-year PFS (4 years from diagnosis) was better in patients with ≥2 consecutive negative Mass-Fix than in patients with loss of Mass-Fix negativity (88.1% vs. 68.6%, p<0.001, Figure 1B). Patients with loss of Mass-Fix negativity after the first year following diagnosis had a better 2-year overall survival than patients with conversion before 1 year in a landmark analysis (100.0% vs. 90.6%, p=0.045). Finally, patients who achieved sustained Mass-Fix negativity for ≥6 months had a better 4-year PFS than patients with loss of sustained Mass-Fix negativity with Simon-Makuch method (94.0% vs. 28%, p<0.001). Conclusions: In summary, this study demonstrates that sustained Mass-Fix negativity may represent a robust evaluation of prognosis and disease control. Moreover, loss of Mass-Fix negativity is associated with a worse outcome and could be used as a marker for earlier treatment interventions in MM. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical implications of loss of bone marrow minimal residual disease negativity in multiple myeloma

AbstractMultiple myeloma (MM) patients frequently attain a bone marrow (BM) minimal residual disease (MRD) negativity status in response to treatment. We identified 568 patients who achieved BM MRD negativity following autologous stem cell transplantation (ASCT) and maintenance combination therapy with an immunomodulatory agent and a proteasome inhibitor. BM MRD was evaluated by next-generation flow cytometry (sensitivity of 10−5 cells) at 3- to 6-month intervals. With a median follow-up of 9.9 years from diagnosis (range, 0.4-30.9), 61% of patients maintained MRD negativity, whereas 39% experienced MRD conversion at a median of 6.3 years (range, 1.4-25). The highest risk of MRD conversion occurred within the first 5 years after treatment and was observed more often in patients with abnormal metaphase cytogenetic abnormalities (95% vs 84%; P = .001). MRD conversion was associated with a high risk of relapse and preceded it by a median of 1.0 years (range, 0-4.9). However, 27% of MRD conversion-positive patients had not yet experienced a clinical relapse, with a median follow-up of 9.3 years (range, 2.2-21.2). Landmark analyses using time from ASCT revealed patients with MRD conversion during the first 3 years had an inferior overall and progression-free survival compared with patients with sustained MRD negativity. MRD conversion correctly predicted relapse in 70%, demonstrating the utility of serial BM MRD assessment to complement standard laboratory and imaging to make informed salvage therapy decisions.

A Multicenter, Phase II Study of Ibrutinib Plus FCR (iFCR) As Frontline Therapy for Younger CLL Patients

A Multicenter, Phase II Study of Ibrutinib Plus FCR (iFCR) As Frontline Therapy for Younger CLL Patients

Efficacy and Safety of Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Immunoglobulin D Multiple Myeloma

Immunoglobulin D (IgD) multiple myeloma (MM) is a rare subtype of MM that carries a worse prognosis than non-IgD subtypes. Compared with non-IgD subtypes, IgD MM is associated with a shorter survival time. The application of chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed or refractory multiple myeloma (R/R MM) has increasing evidence as an efficacious treatment. This study was designed to investigate efficacy and safety of chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory IgD MM (R/R IgD MM). In this single-arm, phase 2 trial, patients diagnosed with R/R IgD MM were infused with either a combination of anti-B-cell maturation antigen and anti-CD19 CAR T-cells or anti-CD19 CAR T-cells alone, with subsequent evaluation of therapeutic response and treatment-related toxicities. At the data cutoff date, 7 patients were enrolled in our study, and all patients achieved response based on the International Myeloma Working Group Uniform Response Criteria. Six patients achieved stringent complete remission (sCR) within 60 days after CAR T-cell infusion (median time 58 days, range 18 to 90 days), and 1 patient with extramedullary disease achieved minimal response (MR) at 30 days after infusion. Bone marrow minimal residual disease (MRD) negativity was achieved in all patients, and the median time to achieve MRD negativity was 22 days (range 14 to 60 days). The most common grade 3 to 4 treatment-related toxicities were hematological toxicities. All patients experienced cytokine release syndrome (CRS), although CAR T-cell-related neurotoxicity was not observed. In our study, CAR T-cell therapy showed encouraging efficacy in the patients with R/R IgD MM, achieving high rates of sCR and MRD negativity. Aside from CRS and prolonged hematologic toxicities, other adverse reactions were mild, suggesting that this is a well-tolerated treatment with a high therapeutic potential.

Molecular response after obinutuzumab plus high-dose cytarabine induction for transplant-eligible patients with untreated mantle cell lymphoma (LyMa-101): a phase 2 trial of the LYSA group

Obinutuzumab monotherapy has shown promising efficacy in mantle cell lymphoma. We aimed to investigate the activity of obinutuzumab plus DHAP (dexamethasone, high-dose cytarabine, and cisplatin), measured by minimal residual disease quantitative (q)PCR status in the bone marrow after four cycles. LyMa-101 was a prospective, open-label, single-arm, phase 2 trial. Participants were enrolled from 28 hospitals in France. Newly diagnosed patients with mantle cell lymphoma (aged 18 to <66 years) who were eligible for autologous stem-cell transplantation received four cycles of obinutuzumab plus DHAP (obinutuzumab 1000 mg/m2 intravenously on days 1, 8, and 15 at cycle 1 and day 1 at cycles 2, 3, and 4; dexamethasone 40 mg intravenously on days 1-4, cytarabine 2 g/m2 intravenously every 12 h on day 1, and according to local investigator, cisplatin 100 mg/m2 by continuous infusion over 24 h on day 1 or carboplatin area under the curve 5 or oxaliplatin 130 mg/m2) every 21 days before transplantation, and 3 years of obinutuzumab (1000 mg/m2 every 2 months) maintenance followed by minimal residual disease-based obinutuzumab on-demand maintenance. The primary outcome was minimal residual disease negativity in the bone marrow after four cycles of obinutuzumab plus DHAP at the end of induction, measured in the efficacy set (all minimal residual disease-informative [bone marrow or peripheral blood] patients who received at least one dose of obinutuzumab). Obinutuzumab plus DHAP was considered effective if bone marrow minimal residual disease negativity was 70% or more by intention to treat. The trial is closed to recruitment and registered with ClinicalTrials.gov, NCT02896582. 86 patients were enrolled between Nov 29, 2016, and May 2, 2018. 81 patients completed induction, 73 underwent autologous stem-cell transplantation, and 69 started maintenance therapy. 55 (75%) of 73 patients in the efficacy set reached minimal residual disease negativity in bone marrow at end of induction. According to the protocol definition, 18 (25%) of 73 patients in the efficacy set were minimal residual disease-positive: 12 patients who were minimal residual disease-positive in the bone marrow, plus two patients who progressed during induction, and four patients who did not have minimal residual disease assessment. The most common grade 3-4 treatment-emergent adverse events were anaemia (grade 3, 26 [31%] of 85 patients; grade 4, three [4%] of 85 patients) and neutropenia (grade 3, 13 [15%] of 85 patients; grade 4, 32 [38%] of 85 patients). 58 serious adverse events occurred during the induction phase. There were no treatment-related deaths. Obinutuzumab plus DHAP is a well tolerated regimen and has good activity for inducing minimal residual disease negativity in the bone marrow of transplant-eligible patients with mantle cell lymphoma. Obinutuzumab plus DHAP has potential activity as induction chemotherapy, with bone marrow minimal residual disease negativity potentially predicting long-term disease control. Roche SAS.

Clinical implications of loss of minimal residual disease (MRD) negativity in multiple myeloma.

8514 Background: Attainment of MRD negativity in multiple myeloma (MM) patients is increasingly considered an optimal therapeutic endpoint, but little is known about the MRD evolution in those who achieve this milestone. We investigated the clinical implication of loss of MRD negativity or MRD conversion in patients with ≥VGPR. Methods: We identified and followed 606 patients achieving a sustained ≥VGPR with bone marrow MRD negativity(≥ 2 consecutive reading) following treatment on a total therapy protocol and with a median follow-up of 10 y. All patient had negative PET and MRI DWIBS at enrollment. Serial BM aspirate MRD was determined by 8-color next generation flow (NGF, EuroFlow) with a minimal sensitivity of 10−5 cells. Results: Most MM patients were considered low risk with a UAMS GEP70 score of ≤ 0.66 (92%; 495/538) . While 60% (364/606) of patients had sustained MRD negativity, the remaining 40% (242/606) experienced MRD conversion with a 5.7 y median time from ASCT and 6.3 y from diagnosis. The risk of clinical relapse was significantly elevated in patients with MRD conversion compared to sustained MRD negativity (73%, 177/242 vs. 5%, 18/364; R.R. = 3.5; P&lt; 0.0001). The median level of MRD positivity (&gt; 0.2 ratio of MM cells to normal plasma cells) also highly correlated with relapse ( P&lt; 0.0001). Loss of MRD negativity preceded clinical relapse by a median time of 1.1 years. Loss of MRD negativity without clinical relapse was seen in 27% (65/242). MRD conversion was associated with an inferior PFS and OS (PFS: 10.2 y vs. NR; P &lt; 0.0001, H.R. 18.7; 95% CI 13.3 - 26.3 and OS: 26.1 y vs. NR; P= 0.01, H.R. 1.7; 95% CI 1.1 - 2.6). Furthermore, when MRD conversion was within 5 y of diagnosis compared &gt; 5 y, patients had a worse OS ( P &lt; 0.0001, H.R. 17.2; 95% CI 7.8 – 37.8). We also observed that MRD conversion later than 5 years from diagnosis did not affect the OS. In a subset of patients (n = 144) the timing of first MRD negativity following treatment was available. Attainment of MRD negativity within 6 months of diagnosis compared to any time after 6 months was predictive of future MRD conversion (65%, 17/26 vs.42%, 49/118; P = 0.03) and clinical relapse (54%, 14/26 vs.28%, 33/118; P = 0.02). Conclusions: MRD conversion occurs in a significant proportion of MM patients (40%) on long-term follow-up and predicts future clinical relapse. Significance of MRD conversion has a temporal relationship from diagnosis and portray inferior clinical outcome particularly within 5 years of diagnosis.

Impact of minimal residual negativity using next generation flow cytometry on outcomes in light chain amyloidosis.

We evaluated bone marrow minimal residual disease (MRD) negativity in 44 patients with light chain (AL) amyloidosis using next generation flow cytometry (sensitivity ≥1 × 10-5 ; median events analyzed: 8.7 million, range: 4.8 to 9.7 million). All patients underwent MRD testing in 2 years from start of therapy (median: 7 months). The overall MRD negative rate was 64% (n = 28). The MRD-negative rate after one-line of therapy was 71% (20/28). And, MRD negative rates were higher with stem-cell transplant as first-line therapy (86%, 18/21) vs chemotherapy alone as first-line treatment (29%, 2/7), P = .005. The MRD negative rate amongst patients in complete response was 75% (15/20), and in very good partial response, 50% (11/22). There were two patients in partial response/rising light chains (with renal dysfunction) who were MRD negative. There were no differences in baseline characteristics of MRD negative vs MRD positive patients, except younger age amongst MRD-negative patients. Patients with MRD negativity were more likely to have achieved cardiac response at the time of MRD assessment, 67% (8/12) vs 22% (2/7), P = .04. Renal response rates were similar in both groups. Progression free survival was assessed in the 42 patients achieving CR or VGPR. After median follow-up of 14 months, the estimated 1-year progression free survival in MRD negative vs MRD positive patients was 100% (26 patients, 0 events) vs 64% (16 patients, five events), P = .006, respectively. MRD assessment should be explored as a surrogate endpoint in clinical trials and MRD risk-adapted trials may help optimize treatment in AL amyloidosis.

Qip-Mass Spectrometry in High Risk Smoldering Multiple Myeloma Patients Included in the GEM-CESAR Trial: Comparison with Conventional and Minimal Residual Disease IMWG Response Assessment

Qip-Mass Spectrometry in High Risk Smoldering Multiple Myeloma Patients Included in the GEM-CESAR Trial: Comparison with Conventional and Minimal Residual Disease IMWG Response Assessment

Phase I/II Trial of Lenalidomide and High-Dose Melphalan with Autologous Stem Cell Transplantation for Relapsed Myeloma: Updated Results

IntroductionWhile high dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) is an accepted part of up front therapy for patients with multiple myeloma (MM), the role of this treatment modality for relapsed patients is still evolving. In light of data suggesting safety and synergy in combining novel therapeutics with traditional cytotoxic chemotherapy, we hypothesized that lenalidomide could be safely combined with high dose melphalan in the salvage auto-HCT setting and yield a meaningful duration of disease control.MethodsWe conducted a phase I/II study of lenalidomide and high dose melphalan + auto-HCT. MM patients with relapsed or progressive disease were treated with 7 days of oral lenalidomide (doses of 25, 50, 75 or 100 mg daily for the 7 days) on days (-8) to (-2). High dose melphalan (total of 200 mg/m2) was administered as 100 mg/m2 IV on days (-3) and (-2) followed by auto-HCT on day 0. The Eff-Tox method of Thall, Cook, and Estey was used for dose escalation with cohorts of 3 to maximize the trade-off between efficacy and toxicity, defined as CR at day 90 and regimen-related death, graft failure, or select grade 3+ events within 30 days after transplant, respectively. Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) and the log-rank test was used to assess univariate differences between dose levels. Bayesian logistic regression and survival time models were used for multivariable analyses, with posterior probabilities greater than 0.95 or less than 0.05 considered significant. Initial results after 12.3 months of follow-up were published in 2015; we now present an update with 39.8 months of follow-up.Results57 patients were enrolled, of which 18 (32%) had received a prior auto-HCT. A total of 3, 5, 24 and 25 patients received 25, 50, 75 and 100 mg of lenalidomide, respectively. Median age at auto-HCT was 60 (34-72) years. Median prior lines of treatment were 3 (1-11). Twenty-two patients (39%) were lenalidomide-refractory at study entry. Patient characteristics did not differ significantly between the lenalidomide dose levels. In total, only 2 dose-limiting toxicities were seen, both at dose level 75 mg. Two patients died of nonrelapse causes (viral infection 1, cardiac failure 1) for a treatment-related mortality of 4%. Median time to both neutrophil and platelet engraftment was 11 days. One patient developed a second primary malignancy (squamous cell cancer of the skin). 63% received maintenance therapy, (54% lenalidomide-based). By day +90, 8 patients (14%) had achieved a complete response (CR), 17 (30%) a very good partial response (VGPR), and 17 (30%) a partial response (PR), with no significant differences in response rates among the 4 lenalidomide dose levels. Best responses were PR: 26%, VGPR: 18%, near CR: 18%, CR: 7%, stringent CR: 23% for a ≥VGPR rate of 66. 23% achieved bone marrow minimal residual disease negativity by flow cytometry. Median time to achieve best response was 92 days (range: 16-732). One patient (2%) had progressive disease and 3 patients (5%) achieved only stable disease. Multivariable Bayesian logistic regression revealed that high-risk cytogenetics, (deletion 13q, t(4:14) or del 17p) by conventional cytogenetics or (t(4:14), t(14:16) or del17p by fluorescent in-situ hybridization), bone marrow disease burden and number of prior lines of treatment were each significantly associated with a lower probability of reaching CR by day 90. With a median follow up of 39.8 months (range: 0.5- 66.9), median PFS was 17.1 months (95% CI: 10.8 - 23.0, Figure 1) and median OS was 48.0 months (95% CI: 22.6 months, not estimated, Figure 2). There was no significant effect of dose level on PFS or OS. Multivariable Bayesian survival time models found high-risk cytogenetics to be significantly harmful to both OS and PFS. In addition, degree of plasma cell infiltration of bone marrow before auto-HCT was significantly harmful to PFS.Conclusion: Lenalidomide up to 100 mg PO daily x 7 can be safely combined with high dose melphalan and auto-HCT. Longer follow-up demonstrates PFS and OS as comparable to other salvage treatments for MM, suggesting that this regime can be applied as a part of the sequence of therapies for these patients. [Display omitted] [Display omitted] DisclosuresOrlowski:Takeda Pharmaceuticals: Research Funding. Champlin:Intrexon: Equity Ownership, Patents & Royalties; Ziopharm Oncology: Equity Ownership, Patents & Royalties.

Initial Results of a Multicenter, Phase II Study of Ibrutinib Plus FCR (iFCR) As Frontline Therapy for Younger CLL Patients

Initial Results of a Multicenter, Phase II Study of Ibrutinib Plus FCR (iFCR) As Frontline Therapy for Younger CLL Patients

Pooled Multi-Trial Analysis of Venetoclax Efficacy in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia

Pooled Multi-Trial Analysis of Venetoclax Efficacy in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia