Induction Therapy for Newly Diagnosed Multiple Myeloma

2019 ◽  
pp. e176-e186 ◽  
Author(s):  
Barry Paul ◽  
Brea Lipe ◽  
Enrique M. Ocio ◽  
Saad Z. Usmani
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Residual Disease ◽  
Newly Diagnosed ◽  
Depth Of Response ◽  
Drug Access ◽  
Current Review ◽  
Disease Biology ◽  
Frontline Therapy ◽  
Minimal Residual

The frontline therapy for newly diagnosed multiple myeloma (MM) has continued to evolve over the last 10 years. There has been a growing emphasis on achieving the best depth of response in the context of minimal residual disease negativity, given its prognostic correlation with superior overall survival. Another important area of emphasis has been to improve prognostication and staging by including information on disease biology. There also a growing appreciation of global differences in drug access and patterns of care. The current review explores each of these areas and how best to incorporate the emerging induction regimens in to schema of MM therapy.

scholarly journals Prognostic and Predictive Factors in Newly Diagnosed Multiple Myeloma Patients with Early Mortality with Prediction Matrix and Three and Five-Year Overall Survival

2021 ◽  
Author(s):  
Howard R. Terebelo ◽  
Leo Reap
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Residual Disease ◽  
Survival Rates ◽  
Early Death ◽  
Mortality Prediction ◽  
Early Mortality ◽  
Standards Of Care ◽  
Newly Diagnosed ◽  
Disease Biology

Survival rates for newly diagnosed multiple myeloma have increased to a remarkable 8–12 years. Novel agents, autologous stem cell transplantation, monoclonal antibodies, improvements in supportive care and attention to minimal residual disease negative all have aided this remarkable journey. With these treatments we are identifying tools to achieve complete remissions. Prognostic factors have an important role in selecting proper patient approaches for trial designs. Prognostic and predictive clinical biomarkers have shaped staging and treatment selections for newly diagnosed multiple myeloma. Here we review the Early Mortality Prediction Matrix to identify those at risk of an early death (<6 months) incorporating both disease biology with patient fitness. We also review current standards of care for multiple myeloma and provide a three and five-year overall survival prediction matrix. We review benefits for MRD negativity and Next-Gen Sequencing. These tools will help clinicians improve upon reducing early mortality in newly diagnosed multiple myeloma patients and provide further framework for improving survival by assessing clinical, biologic and individual multiple myeloma patients.

Analysis of minimal residual disease in bone marrow by NGF and in peripheral blood by mass spectrometry in newly diagnosed multiple myeloma patients enrolled in the GEM2012MENOS65 clinical trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8010-8010
Author(s):  
Noemi Puig ◽  
Bruno Paiva ◽  
Teresa Contreras ◽  
M. Teresa Cedena ◽  
Laura Rosiñol ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Peripheral Blood ◽  
Prognostic Value ◽  
Residual Disease ◽  
Newly Diagnosed ◽  
Time Points ◽  
Minimal Residual

8010 Background: Analysis of minimal residual disease (MRD) in the bone marrow (BM) of patients with multiple myeloma (MM) is accepted by the IMWG to evaluate treatment efficacy and is a well-established prognostic factor. However, there is an unmet need to explore the clinical value of MRD in peripheral blood (PB). Methods: Newly diagnosed MM patients enrolled in the GEM2012MENOS65 trial received six induction (Ind) cycles of bortezomib, lenalidomide, and dexamethasone (VRD) followed by autologous stem cell transplantation (ASCT) and 2 further cycles of consolidation (Cons) with VRD. MRD was analyzed in BM using Next Generation Flow (NGF) and in serum by Mass Spectrometry (MS) using IgG/A/M, κ, λ, free κ and free λ specific beads, both after Ind, at day 100 after ASCT, and after Cons. Sequential samples from the first 184 patients were analyzed. Results: Results of both methods were in agreement (NGF+/MS+ and NGF-/MS-) in 83% of cases post-Ind (152/184), 80% post-ASCT (139/174) and 76% post-Cons (128/169). Stratifying by the log range of MRD by NGF, discordances (NGF+/MS- and NGF-/MS+) seemed to increase at the lower MRD ranges, being 22%, 21% and 19% from ≥10−5 to <10−4 and 21%, 21%, 23% at ≥x10−6(post-Ind, ASCT and Cons, respectively). Analysis of discordances showed that they could be partly explained by the higher percentages of cases found to be positive by MS as compared by NGF at part of the time-points analyzed and at each log range of MRD. From ≥10−5 to <10−4, MRD was detected by NGF in 36%, 28%, 20% of cases post-Ind, ASCT and Cons, respectively vs MS in 37%, 29%, 21% of them; at ≥x10−6, NGF was positive in 11%, 14%, 19% of cases vs MS in 23%, 19% and 16% of them. Considering NGF as a reference, the negative predictive value (NPV) of MS per MRD range (≥10−5 to <10−4 and ≥x10−6, respectively) was: post-Ind: 83% (p<0,0001), 94% (p=0,034); post-ASCT 86% (p<0,0001), 90% (p=0,022); post-Cons 89% (p<0,0001), 85% (p=0,0469). Despite these discordances, the prognostic value of each technique in terms of undetectable MRD and progression-free survival (PFS) was consistent at all time-points (Table) and further, discordant cases (NGF+/MS- and NGF-/MS+) did not display a significantly different PFS as compared to NGF-/MS- cases. Conclusions: The results of MRD assessed by NGF in BM and by MS in PB show a significant concordance and are associated with a similar prognostic value analyzed in terms of PFS. Given its high NPV, MRD in peripheral blood by MS provides a gateway for BM aspiration/biopsy and MRD assessment by NGF.[Table: see text]

Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma

2021 ◽  
pp. JCO.21.01045
Author(s):  
Pieter Sonneveld ◽  
Meletios A. Dimopoulos ◽  
Meral Beksac ◽  
Bronno van der Holt ◽  
Sara Aquino ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Primary Study ◽  
Controlled Clinical Trial ◽  
Newly Diagnosed ◽  
Consolidation Treatment ◽  
Minimal Residual

PURPOSE To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively ( P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without ( P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease–negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable. CONCLUSION Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.

scholarly journals PF630 MINIMAL RESIDUAL DISEASE MONITORING AND DEPTH OF RESPONSE IN MULTIPLE MYELOMA

HemaSphere ◽  
2019 ◽  
Vol 3 (S1) ◽  
pp. 268
Author(s):  
J. Martinez-Lopez ◽  
S. Wong ◽  
N. Shah ◽  
N. Bahri ◽  
T. Martin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Disease Monitoring ◽  
Depth Of Response ◽  
Minimal Residual Disease Monitoring ◽  
Minimal Residual

ECOG-ACRIN EAA181: Effective quadruplet utilization after treatment evaluation (EQUATE)—a randomized phase 3 trial for newly diagnosed multiple myeloma (NDMM) not intended for early autologous transplantation.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS8052-TPS8052
Author(s):  
Shaji Kumar ◽  
Zihan Wei ◽  
Michael A. Thompson ◽  
Bradley Snyder ◽  
Matthias Weiss ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Induction Therapy ◽  
Residual Disease ◽  
Intensive Therapy ◽  
Autologous Transplantation ◽  
Chronic Obstructive ◽  
Newly Diagnosed ◽  
Operating Characteristics ◽  
Obstructive Pulmonary Disease ◽  
Depth Of Response

TPS8052 Background: The monoclonal antibody (MoAb) daratumumab (dara) has been approved for treatment of newly diagnosed Multiple Myeloma (NDMM) in combination with lenalidomide (len) and dexamethasone (DRd) in patients who are not eligible to undergo stem cell transplantation (SCT). Ongoing trials are examining the role of adding bortezomib (Btz) to DRd, but it remains unclear if all patients benefit from a quadruplet regimen. Availability of sensitive assays to detect measurable/minimal residual disease (MRD) in MM and emerging data demonstrating significant prognostic value for attaining MRD negativity, offers an unprecedented opportunity to develop individualized treatment approaches. An important question is to identify who benefits from adding a fourth drug to the MoAb-IMiD triplet, thus individualizing therapy based on depth of response. We hypothesize that prolonged intensive therapy with the addition of Btz for consolidation and maintenance after DRd induction therapy for NDMM will improve survival outcomes with a more pronounced effect when used in MRD positive patients. Methods: Patients with NDMM, R-ISS Stage I or II, who are not eligible to undergo SCT or those willing to defer SCT to first relapse and have not received more than 1 cycle of any NDMM therapy will be enrolled, provided they have measurable disease, adequate organ and marrow function, have received no more than once cycle of therapy for MM and significant peripheral neuropathy or chronic obstructive pulmonary disease. Importantly, a dominant clone should be identified by lymphotrack assay for future MRD monitoring. Once enrolled, induction therapy will be in 28 day cycles consisting of daraSC (1800 mg) weekly for 2 cycles, every other week for cycles 3-6 and then every 4 weeks for 9 cycles, along with len 25 mg days 1-21 of each cycle and dex 40 mg (20 mg for those > 75 years) weekly. At end of 9 cycles (induction), patients will undergo MRD testing by next generation sequencing and will be classified into MRD positive or negative subgroups. Using MRD as an integral biomarker, the trial employs a randomized biomarker-stratified design as proposed by Freidlin et al. to determine efficacy for each MRD subgroup. Patients will be stratified by MRD status and R-ISS stage and randomized to receive 9 cycles of consolidation with DRd, without (control arm) or with (experimental arm) Btz (1.3 mg/m2 weekly for 3 of 4 weeks), followed by DR maintenance until progression The primary endpoint is consolidation OS. Sample size considerations rest on estimates of MRD subgroup prevalence at the end of induction and operating characteristics establishing the treatment effect within the MRD positive subgroup as primary and MRD negative subgroup as key secondary. The total accrual goal is 1450 patients. Clinical trial information: NCT04566328.

Minimal residual disease in multiple myeloma: an important tool in clinical trials

2021 ◽  
Vol 16 ◽  
Author(s):  
Alessandro Gozzetti ◽  
Monica Bocchia
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
New Drugs ◽  
Next Generation ◽  
Depth Of Response ◽  
Next Generation Sequencing Ngs ◽  
Future Therapy ◽  
Minimal Residual

: Minimal residual disease (MRD) detection represents a great advancement in multiple myeloma. New drugs are now available that increase depth of response. The International Myeloma Working Group recommends the use of next-generation flow cytometry (NGF) or next-generation sequencing (NGS) to search for MRD in clinical trials. Best sensitivity thresholds have to be confirmed, as well as timing to detect it. MRD has proven as the best prognosticator in many trials and promises to enter also in clinical practice to guide future therapy.

Identification Of a Partial Fragment Of SERPINA3 For Acute Leukemia Diagnosis and Minimal Residual Disease Assessment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2604-2604
Author(s):  
Wei Song ◽  
Jiuwei Cui ◽  
Wei Li ◽  
Guanjun Wang ◽  
Yan Li
Keyword(s):  
Mass Spectrometry ◽  
Overall Survival ◽  
Acute Leukemia ◽  
Residual Disease ◽  
Healthy Controls ◽  
Newly Diagnosed ◽  
Serum Samples ◽  
Svm Algorithm ◽  
Partial Fragment ◽  
Minimal Residual

Abstract Background Detection and eradication of minimal residual disease (MRD) is a key issue that assesses response and relapse of treatment of acute leukemia (AL). However, there is no serum biomarker available for diagnosis of AL and assessment of MRD. The serum peptides, especially low molecular weight peptides, contain important information for cancer diagnosis. In this study, we analyzed serum peptidomic profiling of AL patients to screen biomarkers for AL diagnosis and MRD assessment. Methods Serum samples from 105 patients with AL and 40 healthy controls were analyzed by bead fractionation/MALDI-TOF-MS.There are 30 newly diagnosed patients, 30 AL patients with hematological CR (AL-HCR), 30 AL patients with molecular complete remission (AL-MR) and 15 AL patients with relapse. The characteristics of the AL patients was shown in table 1. The peptides from the serum were purified and isolated by copper-chelated magnetic beads and analyzed by MALDI-TOF-MS. The peptide identification was performed using a nano-liquid chromatography-electrospray ionization-tandem mass spectrometry (nano-LC/ESI-mass spectrometry/mass spectrometry) system. Serum peptide patterns from all serum samples were analyzed and intensity of each peptides peak was calculated to screen differential peptides. Diagnostic models of differential peptides using SVM algorithm were established to discriminate AL patients from healthy controls and discriminate AL patients with different remission degree. The overall survival of the patients was estimated using Kaplan-Meier log rank survival analysis. Results SVM algorithm was utilized to generate models of serum peptidomic patterns to discriminate patients with AL from the control and different remission degree. A sensitivity of 96% and a specificity of 100% were obtained for distinguishing all AL patients from healthy controls. The model for distinguishing newly-diagnosed AL patients from AL patients with AL-HCR obtained a sensitivity of 88% and a specificity of 100%. And a sensitivity of 92% and a specificity of 100% were obtained for distinguishing AL-CR from AL-MR group. Statistical analysis revealed that a peptide with m/z 4468 may serve as a serum biomarker for MRD assessment, and that its intensity gradually decreased with increase of remission degree (figure 1). In healthy controls, the intensity of m/z 4468 was similar to that of the AL-MR group. And its intensity in the relapse group was significantly higher than that of the AL-MR group. There was no significant difference between newly-diagnosed AL group and relapse AL group. Moreover, the high intensity of m/z 4468 was significantly associated with poor overall survival (p = 0.03) ( figure 2). Finally, the peptide of m/z 4468 was identified as a partial fragment of SERPINA3. Conclusion The diagnostic model of serum peptidomic pattern could discriminate AL patients from healthy controls, and also distinguish AL patients with different remission degree with high sensitivity and specificity. The peptide of m/z 4468 identified as a partial fragment of SERPINA3 was significantly correlated with MRD level and its high intensity was associated with poor prognosis in patients with AL. In summary, a fast, sensitive and minimally invasive approach was developed in our study, and it may potentially facilitate the screening of MRD and provide useful information for AL prognosis predication. Disclosures: No relevant conflicts of interest to declare.

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