Current Treatment Strategies for Multiple Myeloma

2020 ◽  
Vol 16 (1) ◽  
pp. 5-14 ◽  
Author(s):  
Andrew Branagan ◽  
Matthew Lei ◽  
Uvette Lou ◽  
Noopur Raje
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Treatment Strategies ◽  
High Dose Chemotherapy ◽  
Current Treatment ◽  
Cell Maturation ◽  
High Dose ◽  
Newly Diagnosed ◽  
Negative State ◽  
Treatment Paradigm

The treatment of multiple myeloma (MM) continues to evolve with the approval of numerous agents over the past decade. Advances in treatment have led to the incorporation of these newer therapies into the treatment paradigm, with improvements in overall survival and the possibility of deep responses including a minimal residual disease–negative state. The strategy of triplet therapies for patients with newly diagnosed MM, followed by high-dose chemotherapy and autologous stem-cell transplantation for eligible patients, and subsequently consolidation and maintenance therapy, is the current treatment roadmap for patients. However, patients with MM will ultimately develop refractoriness to antimyeloma therapies. In this article, we summarize our current practice of managing patients with MM. We highlight our approach to patients with newly diagnosed MM who are transplantation eligible and ineligible and highlight risk-adapted strategies for these patients. In addition, we discuss our approach to the management of patients with relapsed or refractory MM. Last, we review standard therapies and emerging strategies such as targeted approaches, immune-based therapies, and drugs with novel mechanisms of action. Trials evaluating chimeric antigen receptor T cells targeting B-cell maturation antigen are ongoing and are only one of several novel approaches targeting cell maturation antigen, which include the use of bispecific T-cell engager antibodies and antibody drug conjugates. Emerging therapies offer the promise of more individualized approaches in the management of patients with MM and ultimately may result in the possibility of being one step closer to curing patients with MM.

scholarly journals Primary Central Nervous System Lymphoma in Elderly Patients: Management and Perspectives

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3479
Author(s):  
Andrea Morales-Martinez ◽  
Fernando Lozano-Sanchez ◽  
Alberto Duran-Peña ◽  
Khe Hoang-Xuan ◽  
Caroline Houillier
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Elderly Patients ◽  
Treatment Strategies ◽  
Central Nervous System Lymphoma ◽  
High Dose Chemotherapy ◽  
Current Treatment ◽  
Cns Lymphoma ◽  
High Dose ◽  
Consolidation Phase

The management of elderly patients suffering from primary central nervous system (CNS) lymphoma, who represent a rapidly growing population, is challenging. Despite the advances made in PCNSL treatment, the prognosis in older patients remains unsatisfactory. The high risk of systemic and CNS toxicity induced by a high-dose chemotherapy regimen and radiation therapy, respectively, limits the use of consolidation phase treatments in elderly patients and contributes to the poor outcome of these patients. Here, we review the current treatment strategies and ongoing trials proposed for elderly PCNSL patients.

Double Autologous Transplant Versus Tandem Autologus - Non Myeloablative Allogeneic Transplant for Newly Diagnosed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 46-46 ◽  
Author(s):  
B. Bruno ◽  
M. Rotta ◽  
F. Patriarca ◽  
N. Mordini ◽  
B. Allione ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Low Dose ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
Allogeneic Hct ◽  
Autologous Transplant ◽  
Autologous Hct ◽  
Beta 2 Microglobulin

Abstract Allogeneic approaches employing low dose TBI nonmyeloablative conditionings reported a dramatic reduction of transplant-related mortality (TRM) compared to conventional high dose regimens in newly diagnosed multiple myeloma (MM) (Maloney et al, Blood, 2003). The role of allografting, however, compared to autologous HCT remains to be determined. From September 1999 to July 2004, 241 consecutive MM patients, up to the age of 65, were diagnosed at five academic Italian Institutions. Overall, 194/241 had natural siblings (Table 1): 158/194 (81%) were HLA typed, while 36/194 (19%) were not typed for the following reasons: patients not eligible for high dose chemotherapy (n. 14); siblings not eligible for peripheral hematopoietic cell (PHC) donation (n.11); patient refusal to high dose chemotherapy (n. 9), unknown (n.2). Seventy-six/158 (48%) with a matched donor were offered a tandem autologous- nonmyeloablative allogeneic HCT approach. Eventually, 56/76 (73%), the “auto-allo group”, were enrolled while 20 did not enter the tandem program as 5 siblings (5/76, 7%) were not eligible for PHC donation, 5 patients refused an allogeneic HCT, and 10 patients preferred allografting as a possible salvage treatment. Of 102 patients without matched donors or after refusal to allografting, 73, “double-auto group”, underwent a standard double autologous transplant while 29 received less intense treatments because of clinical conditions or patient preference. Table 1 Newly diagnosed pts 241 With sibs/without sibs 194 /47 (total 241) HLA typed /not HLA typed 158 /36 (total 194) Matched sibs /No matched sibs 76 /82 (total 158) Auto-Allo”/“Double Auto”/Other”“ 56 /73 /29 (total 158) After induction chemotherapy, patients of both groups underwent G-CSF mobilised autografting with high dose melphalan (200 mg/m2). In the “auto-allo” group, the autologous HCT was followed, 2-4 months later, by low dose (2.0 Gy) TBI, allogeneic PHC infusion, and post transplant mycophenolate mofetil and cyclosporin. In the “double-auto group”, patients received a second autologous HCT. Patients characteristics were as follows: age: 54 (range 34–65) vs 53 (range 33–64) (p=ns); stage III myeloma: 77% vs 64% (p=0.03); beta 2 microglobulin > 2,5 mg/dl: 75% vs 59% (p=0.005), for the “auto-allo group” and for “the double-auto group”, respectively. At the time of this analysis, 56/56 of the “auto-allo group” and 55/73 of “the double-auto group” had completed the transplant programs. After median follow up of 3 years (range 11–80 months), TRM was 11% vs 4% (p=0.09); complete remission rates, defined as the disappearance of the monoclonal paraprotein by immunofixation, were 46% vs 16% (p=0.0001); overall survivals were 84% versus 62% (p=0.003); progression free survivals were 75% vs 41% (p=0.00008); event free survivals were 61% (34/56)% vs 38% (30/73) (p=0.006) in the “auto-allo group” and in the “double-auto” group, respectively. Longer follow up is needed, however data suggest that the “auto- non myeloablative allo” approach is not inferior to “double autologous” HCT in newly diagnosed MM.

Bendamustine, Bortezomib and Dexamethasone (BBD) As First-Line Treatment of Patients with Multiple Myeloma Who Are Not Candidates for High Dose Chemotherapy: Toxicity Comparison of Two Dose Schedules

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4047-4047 ◽  
Author(s):  
Jesus G. Berdeja ◽  
Michael R. Savona ◽  
James Essell ◽  
Patrick Murphy ◽  
Luis Chu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Herpes Zoster ◽  
Research Funding ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
Off Label Use ◽  
First Line ◽  
Off Label ◽  
Grade 3

Abstract Abstract 4047 Background: Despite significant advances, multiple myeloma is an incurable plasma cell disorder with an eventual fatal outcome. In newly diagnosed MM, combinations of bortezomib, steroids and alkylating agents, such as melphalan and prednisone, have achieved response rates in excess of 70% and have been established as a standard of care in patients (pts) who are ineligible for high dose chemotherapy. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective as a single agent and in various combinations for the treatment of relapsed/refractory MM (Poenisch et al, 2007, Fenk et al, 2007). In this study, the combination of bendamustine, bortezomib and dexamethasone (BBD) was evaluated as a first-line therapy for patients with MM. Methods: Patients with newly diagnosed active multiple myeloma who were not candidates for high-dose chemotherapy and met standard eligibility criteria with regards to renal, hepatic and hematologic function were enrolled. The original treatment schema (schema A) consisted of: bendamustine 80 mg/m2 IV on days 1, 4; bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11; and dexamethasone 40 mg on days 1, 2, 3, 4 with cycles repeating every 28 days. Patients had the option to continue on maintenance bortezomib. An interim analysis found this combination to be efficacious but relatively toxic. As a result the treatment schema was amended to the following (schema B): bendamustine 80 mg/m2 IV on days 1, 2; bortezomib 1.3 mg/m2 IV on days 1, 8, 15; and dexamethasone 20 mg on days 1, 2, 8, 9, 15, 16 every 28 days for a total of 8 cycles or 2 cycles beyond documented CR, whichever occurred first. Again, patients had the option to continue maintenance bortezamib. Acyclovir or equivalent viral prophylaxis was recommended on schema A and became required on schema B. Responses were assessed using the IMWG criteria. AEs were assessed using the CTCAE Version 4.0. We report the results of an interim safety assessment of the amended BBD combination and compare the results to those seen with the original regimen. Results: Treatment schema A accrued 18 patients between 5/2010 and 2/2011. Ten patients were accrued from 10/2011 and 4/2012 and treated on treatment schema B. The median ages of treatment schemas A and B were 75 and 72.5 respectively, with all other characteristics within expected distributions and no major differences between the groups. No grades 4 hematologic Adverse Events (AEs) were seen. Grade 3 hematologic AEs were similar in both arms seen in 33% of patients on treatment schema A and 40% of patients on treatment schema B. Grade 3/4 non-hematologic AEs were seen in 72% of patients on treatment schema A and 60% of patients on treatment schema B. Although the preliminary Serious Adverse Events (SAEs) were similar with 39% of patients on treatment schema A compared to 30% of patients on treatment schema B, a large proportion of patients on treatment schema A (39%) were unable to complete the study due to toxicity or related issues. The incidence and severity of neuropathy and herpes zoster infections were significantly different between the two schemas. Schema A had 72% of patients with any grade neuropathy, with 56% being grade 2 or worse while schema B had 40% of the patients with any grade neuropathy, all but one grade 1. Likewise, 44% of patients on the original treatment reported herpes zoster while there were no cases of herpes zoster reported for patients on the revised treatment schema. Thus far, the early response rates appear similar. Schema A had an ORR of 78% (56% >vgPR) while schema B had an ORR of 90% (40% >vgPR). Conclusions: The combination of bendamustine, bortezomib and dexamethasone is feasible and efficacious in an elderly patient population. Using the revised schema, we were able to lower treatment toxicity without adversely impacting initial efficacy. Updated results will be presented at the meeting. Disclosures: Off Label Use: Off-label use of Bendamustine in the treatment of Multiple Myeloma. Chu:Millennium: Research Funding; Cephalon: Research Funding.

Influence of First-Line Regimens on the Outcomes of High-Dose Chemotherapy with Autologous Hematopoietic Stem-Cell Transplantation for Patients with Newly Diagnosed Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 931-931 ◽  
Author(s):  
Bimalangshu R. Dey ◽  
Benjamin Cox ◽  
A. Jo Chien ◽  
Martin Caron ◽  
Steven L. McAfee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
First Line ◽  
Conventional Chemotherapy ◽  
Hematopoietic Stem ◽  
Group 2 ◽  
Group 1

Abstract Randomized trials that incorporated high-dose chemotherapy (HDC) plus autologous hematopoietic stem-cell transplantation (Au-HSCT) into the early treatment of patients with newly diagnosed multiple myeloma demonstrated superior overall and event-free survival (EFS) in patients 65 years of age or younger, who received Au-HSCT, as compared with patients who received conventional chemotherapy. Based on these encouraging results, Au-HSCT is recommended for patients with myeloma as part of their initial treatment, and today, myeloma is the most common indication for HSCT in the world. All patients in these trials received four to six months of conventional chemotherapy prior to HDC and Au-HSCT. In practice, however, both in the community as well as in academic hospitals, patients are undergoing Au-HSCT after being treated with various first-line regimens, including chemotherapeutics, high-dose dexamethasone (HDex), immunomodulatory drugs such as thalidomide and recently, proteasome inhibitors. In this retrospective study, we examined the impact of first-line therapy on the outcomes following Au-HSCT. Our objective was to compare two treatment groups - chemotherapy versus non-chemotherapy, prior to Au-HSCT - with respect to survival after Au-HSCT. Between 1997 and 2004, 37 previously untreated evaluable patients with myeloma, received either chemotherapy (group 1, n=25; vincristine, adriamycin and dexamethasone (VAD), n=24; melphalan and prednisone (MP), n=1) or non-chemotherapy regimens (group 2, n=12; HDex, n=9; thalidomide plus HDex, n=3), then received HDC followed by cyclophosphamide plus granulocyte colony stimulating factor-mobilized HSCT. The median age of patients in group 1 was 58 (range, 44–73) years and in group 2 was 55 (range, 41–67) years; 22 patients in group 1 (88%) and 10 patients in group 2 (83%) had stage III disease; the median times from diagnosis to HSCT were 6 (range, 5–16) and 8 (range, 5–25) months, respectively, in groups 1 and 2. The rates of complete and near-complete response were 44% in group 1 and 42% in group 2; the rates of partial responses were also similar: 48% and 42% respectively. The median duration of EFS was 31 (range, 7–89) months, and the median overall survival (OS) was 55 (range, 12–98) months in group 1, as compared with group 2 where EFS and OS were 21 (range, 12–40) and 31 (range, 16–76) months, respectively. The EFS at 3 years was 44% in group 1 and 25% in group 2, and OS at 5 years was 32% in group 1 and 8% in group 2 (statistically not significant). In conclusion, patients with newly diagnosed myeloma, when treated with chemotherapy prior to Au-HSCT, may have long-term overall and EFS advantages, as compared with patients who are treated with first-line non-chemotherapy regimens. The reasons for the longer duration of response in the chemotherapy group despite similar response rates in the two groups are unknown, but may be due to more effective suppression of residual disease or non-specific damage to the marrow microenvironment, which is necessary for the growth of myeloma cells. Although, the difference in survival outcomes following Au-HSCT between the two groups did not achieve statistical significance, our results raise an important question regarding the “adequacy” of different first-line regimens prior to Au-HSCT, and therefore, justify the need for prospective randomized studies to evaluate optimal pre-AuHSCT induction therapy.

Phase 2 Clinical Trial of Oral Lenalidomide, Cyclophosphamide, and Prednisone (RCP) for Newly Diagnosed Multiple Myeloma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2882-2882 ◽  
Author(s):  
Attaya Suvannasankha ◽  
Sherif Farag ◽  
Robin A O'Bryant ◽  
Lisa L Wood ◽  
Rafat Abonour
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Treatment Protocol ◽  
Median Number ◽  
High Dose Chemotherapy ◽  
M Protein ◽  
Hematological Toxicity ◽  
High Dose ◽  
Newly Diagnosed ◽  
Intent To Treat

Abstract Abstract 2882 Poster Board II-858 Background: Effective and convenient regimen is appealing for Multiple Myeloma (MM) therapy. Lenalidomide and dexamethasone combination is highly effective in MM. However, at the FDA approved dose, dexamethasone related toxicity remains problematic. We previously reported that oral cyclophosphamide and prednisone, when combined with thalidomide, was active and well tolerated in relapsed MM (Oncologist Jan, 2007). Using the similar approach, we now explore the efficacy of all oral, dexamethasone-sparing combination of lenalidomide, cyclophosphamide and prednisone in newly diagnosed MM. Methods: The treatment protocol consisted of lenalidomide given orally at a dose of 25 mg daily on days 1–21 of a 28-day cycle, cyclophosphamide at a dose of 50 mg b.i.d. days 1–21 of a 28-day cycle, and prednisone 50 mg q.o.d. Patients also received an aspirin once daily as thromboprophylaxis. Response was defined as a decrease in serum monoclonal (M) protein by 50% or higher and a decrease in urine M protein by at least 90% or to a level less than 200 mg/24 hours. Responses were assessed on intent to treat basis. Results: Twenty-one patients were enrolled from October 2007 to July 2009. The median age was 67 years (range, 41-76). 7 patients (33%) had ISS stage II and 3 (14%) had stage III disease. The median number of cycles was 6 (range: 1 – 6). The response is not evaluable in 4 patients who are still undergoing the first cycle of therapy. Among the remaining 17 patients, the over all response rate was 94%. The best response based on intent to treat basis was 83%, including CR: 1 (6%), nCR: 1 (6%), VGPR: 3 (18%), PR: 11 (65%) and less than PR: 1 (6%). Overall, 14 of the 21 enrolled patients have discontinued study treatment. Reasons for treatment discontinuation are: completed study per protocol (10), disease progression (1), and adverse event (1) and alternate treatment (1). Hematologic toxicities were the most common with grade 3 neutropenia seen in 10 patients. Infections were seen in 10 patients (5, febrile neutropenia and 5, with normal ANC). Non hematologic toxicities were fatigue, gastrointestinal side effects, neuropathy and mood swings. Specifically, neuropathy was reported in 5 patients. All were grade I. Five patients had grade 4 metabolic abnormalities (2 renal failure attributed to dehydration and tumor lysis, 2 hyperglycemia. and 1 hypokalemia). Five patients had dose adjustments, most commonly due to hematological toxicity attributed to lenalidomide or cyclophosphamide. Seven patients had stem cell collection. In all, sufficient numbers of stem cells were collected for the transplantation use. To date, five have undergone high dose chemotherapy and stem cell transplantation. Three patients with PR on RCP achieved VGPR. Response is not yet evaluable in the 2 remaining patients. Conclusions: The combination of lenalidomide, cyclophosphamide, and prednisone (RCP) has excellent activity in the setting of newly diagnosed myeloma. Overall toxicities were manageable. Myelosuppression was a significant toxicity and attenuated with dose reductions. The study is still ongoing with the total accrual goal of up to 48 patients. The updated data for response and toxicities will be presented at the ASH Annual Meeting. Disclosures: Abonour: Celgene: Honoraria; Millennium: Honoraria.

A Phase II Trial of Combined Bendamustine, Bortezomib and Dexamethasone in Newly Diagnosed Multiple Myeloma (MM) Patients Who Are Not Candidates for High-Dose Chemotherapy: Results of a Planned Interim Safety Analysis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2943-2943 ◽  
Author(s):  
Jesus G. Berdeja ◽  
Daniel R. Couriel ◽  
Patrick Murphy ◽  
Ralph V. Boccia ◽  
Victor Priego ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Interim Analysis ◽  
Sensory Neuropathy ◽  
Response Rates ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Grade 3

Abstract Abstract 2943 Background Despite significant advances, multiple myeloma is an incurable plasma cell disorder with an eventual fatal outcome. In newly diagnosed MM, combinations of bortezomib, steroids and alkylating agents, such as melphalan and prednisone, have achieved response rates in excess of 70% and have been established as a standard of care in patients (pts) who are ineligible for high dose chemotherapy. Bendamustine is a bi-functional alkylating agent with a purine-like benzimidazole ring effective as single agent and in combination with steroids, thalidomide and bortezomib for the treatment of MM. Pönisch et al reported an overall response of 61% and CR of 15% in pts with relapsed/refractory MM using the combination of bendamustine, bortezomib and prednisone. In this study, the combination of bendamustine, bortezomib and dexamethasone (BVD) was tested for efficacy and safety in newly diagnosed pts with active MM who are not candidates for high-dose chemotherapy. Methods Patients with newly diagnosed active multiple myeloma who were not candidates for high-dose chemotherapy and met standard eligibility criteria with regards to renal, hepatic and hematologic function were enrolled. Pts were treated with bendamustine 80 mg/m2 on days 1, 4, bortezomib 1.3 mg/m2 on days 1, 4, 8, 11 and dexamethasone 40 mg on days 1, 2, 3, 4 every 28 days for a total of 8 cycles or 2 cycles beyond documented CR, whichever occurred first. Responses were assessed using the IMWG criteria. We report on the preliminary efficacy and safety results of a planned interim analysis of the BVD combination. Results Between May 2010 and February 2011, 18 pts were enrolled, all evaluable for toxicity. The median age was 75 (range 56–82); nine (50%) pts were DS stage III; seven (39%) pts had a B2M ≥ 5mg/L. Cytogenetics and FISH analysis for 13 del, t4;14, t14;16, and 17p del were available for all but 1 pt; 8 (44%) pts had at least 1 chromosomal abnormality, while 9 (50%) pts had none. At the time of data cut off, pts completed a median of 5.5 cycles (range 1–8); with 11 (61 %) receiving at least 4 cycles; and 5 (28%) receiving 8 cycles. Seven (39%) pts remain on study and 10 have discontinued therapy (1 disease progression and 3 deaths on study [2 cardiac arrest, 1 pulmonary emboli; all 3 determined to be unrelated to treatment], 1 MD discretion, 1 non-compliance, 1 pt request, 2 poor tolerance, 1 intercurrent illness) and 1 completed treatment. The most common grade 3/4 adverse events, occurring in more than 10% of pts, were leucopenia (17%), neutropenia (11%), myalgia (17%) and sensory neuropathy (11%). Twelve pts had treatment emergent sensory neuropathy: 5 (28%) grade 1, 5 (28%) grade 2 and 2 (11%) grade 3. Of the 17 patients evaluable for response, 15 had at least a PR for an ORR of 88% (9 (53%) VGPR, 6 (35%) PR, 2 (12%) SD). The presence of cytogenetic abnormalities did not seem to have a strong impact on response rates, with 88% of pts with 1 or more abnormalities responding compared to 88% with none. The median time to best response was 9 weeks. Conclusions In this planned interim analysis, the combination of BVD produced a high ORR, however the current schedule is relatively toxic in this pt population. The majority of the non-hematological toxicities appear to be related to bortezomib and dexamethasone. For this reason, the protocol was amended where bortezomib and dexamethasone are now dosed weekly (days 1, 8, and 15). The amended trial is currently accruing. Disclosures: Off Label Use: Bendamustine in myeloma. Flinn:Cephalon and Millenium: Research Funding.

Immunophenotypical Sequential MRD Assessment in AML for Prediction of Relapse and Definition of Putative Future Intervention Time Points.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3012-3012
Author(s):  
Nicole Feller ◽  
Peter C. Huijgens ◽  
Angele Kelder ◽  
Guus Westra ◽  
Gert Ossenkoppele ◽  
...  
Keyword(s):  
Residual Disease ◽  
Treatment Strategies ◽  
Sampling Period ◽  
High Dose Chemotherapy ◽  
Post Treatment ◽  
High Dose ◽  
Time Points ◽  
Definition Of ◽  
Time Point

Abstract Immunophenotypical assessment of minimal residual disease (MRD) has been shown by us (Feller et al, Leukemia18:1380, 2004) and others (San Miguel et al., Blood98: 1746, 2001, Venditti et al., Blood96: 3948, 2000) to be predictive for clinical outcome in AML both in patients treated with standard chemotherapy (SD) and high dose chemotherapy followed by autologous (AutoTQ) or allogeneic (AlloTQ) transplantation. Directly after consolidation therapy using a cut-off of 0.11% in the high MRD group the risk of relapse was 7.2 fold than in the low MRD group (Feller et al., 2004). Using that cut-off level, in the present study another important issue, i.e. sequential MRD assessments after end of treatment were done to i) prove consistancy of low MRD% in patients that remain in CR, ii) prove the ability to predict relapse using increase of MRD% and iii) assess the minimally required inter-sampling period to make MRD assessment clinically useful. To enable such 124 samples of 33 patients (<60 years) were included: 16 after SD, 8 after AutoTQ and 9 after AlloTQ. All time points refer to post-treatment periods, time point zero reflecting end of therapy. Of 16 patients studied after SD, 15 had MRD <0.11%. Of these, 12 are in CR with a median follow-up of 30.5 (range 9–46) months. In these 12 patients MRD remained consistently <0.11 %, (mean of 3 sequential MRD assessments per patient). Of these 15 patients 3 relapsed after 9, 9 and 26 months, but in these cases the last time point of MRD assessment (still <0.11%) unfortunately was at least 6 months before relapse. One patient who started with MRD>0.11 relapsed within 2 months after that MRD assessment. Of 8 patients studied after AutoTQ, 6 had MRD <0.11%. Of these, 4 are in CR with a follow-up of 6, 15, 40 and 72 months. Again, MRD remained consistently <0.11% (mean of 3 assessments per patient). Of these 6 patients 2 relapsed after 13 and 43 months, with relapse predictable using 3 months assessment intervals. Two patients had >0.11% MRD and relapsed after 5 and 11 months and within 3 months after the last MRD assessment, with no previous sign of forthcoming increase. Of 9 patients studied after AlloTQ, 2 had MRD <0.11%; thet are still in remission after 47 and 53 months. Again, MRD remained consistently <0.11 % (6 and 7 MRD assessments in these 2 patients). Of these 9 patients 2 relapsed too fast to have the opportunity to assess MRD. In addition, 5/9 had MRD >0.11%, of whom 2/5 relapsed after 6 and 7 months which was 4 and 2 months resp., after their last MRD assessment, with no previous sign of forthcoming increase. A remarkable phenomenon was observed in the other 3/5 patients: a large drop in MRD% down to detection level (0.01%) occurred 3–10 months after end of therapy. 2 of these 3 patients are still in CR (at 11 and 33 months), 1/3 relapsed after 26 months, 5 months after last MRD assessment with no previous sign of increase. The unique decrease of MRD% may be speculated to result from graft versus leukemia effects. These results show: 1) consistently low MRD% in sequential MRD assessments during persisting CR; 2) increases of MRD% which consistently predict relapse; 3) a minimally required inter-sampling period of 3 months for patients with MRD <0.11% and probably <3 months for patients with MRD>0.11%; 4) a strong decrease of MRD in part of the allogeneically transplanted patients. Results show the feasibility of sequential post-treatment MRD assessment that ultimately will contribute to design of post-treatment strategies in AML.

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