scholarly journals Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials

2017 ◽  
Vol 35 (25) ◽  
pp. 2900-2910 ◽  
Author(s):  
Juan-Jose Lahuerta ◽  
Bruno Paiva ◽  
Maria-Belen Vidriales ◽  
Lourdes Cordón ◽  
Maria-Teresa Cedena ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Bone Marrow Involvement ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Pooled Analysis ◽  
Disease Stage ◽  
Cox Models ◽  
Depth Of Response ◽  
The Impact

Purpose To perform a critical analysis on the impact of depth of response in newly diagnosed multiple myeloma (MM). Patients and Methods Data were analyzed from 609 patients who were enrolled in the GEM (Grupo Español de Mieloma) 2000 and GEM2005MENOS65 studies for transplant-eligible MM and the GEM2010MAS65 clinical trial for elderly patients with MM who had minimal residual disease (MRD) assessments 9 months after study enrollment. Median follow-up of the series was 71 months. Results Achievement of complete remission (CR) in the absence of MRD negativity was not associated with prolonged progression-free survival (PFS) and overall survival (OS) compared with near-CR or partial response (median PFS, 27, 27, and 29 months, respectively; median OS, 59, 64, and 65 months, respectively). MRD-negative status was strongly associated with prolonged PFS (median, 63 months; P < .001) and OS (median not reached; P < .001) overall and in subgroups defined by prior transplantation, disease stage, and cytogenetics, with prognostic superiority of MRD negativity versus CR particularly evident in patients with high-risk cytogenetics. Accordingly, Harrell C statistics showed higher discrimination for both PFS and OS in Cox models that included MRD (as opposed to CR) for response assessment. Superior MRD-negative rates after different induction regimens anticipated prolonged PFS. Among 34 MRD-negative patients with MM and a phenotypic pattern of bone marrow involvement similar to monoclonal gammopathy of undetermined significance at diagnosis, the probability of “operational cure” was high; median PFS was 12 years, and the 10-year OS rate was 94%. Conclusion Our results demonstrate that MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group. MRD negativity should be considered as one of the most relevant end points for transplant-eligible and elderly fit patients with MM.

Minimal residual disease (MRD) status pre- and post- high-dose therapy/autologous stem (HDC/ASCT) cell transplantation for multiple myeloma (MM) in the era of novel agents.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8605-8605
Author(s):  
Adetola Kassim ◽  
Jeremy Scott McDuffie ◽  
Claudio A Mosse ◽  
Bipin N. Savani ◽  
John P. Greer ◽  
...  
Keyword(s):  
Residual Disease ◽  
Prognostic Significance ◽  
Proteasome Inhibitors ◽  
Progression Free Survival ◽  
Novel Agents ◽  
Disease Stage ◽  
High Dose ◽  
Free Survival ◽  
Depth Of Response ◽  
The Impact

8605 Background: MRD assayed by multi-parameter flow cytometer (MFC), has prognostic significance after HDT/ASCT for MM (Paiva et. al. 2008). The frequency of MRD negativity (-) after induction therapy using novel agents such as immunomodulatory drugs like lenalidomide (IMiDs), and proteasome inhibitors like bortezomib, is unknown. The impact of HDT/ASCT on MRD status in this patient group has not been studied. Methods: We performed a retrospective study of all MM patients undergoing HDT/ASCT (January 2010 - December 2012) in our institution. No restrictions on inclusion were made based on the International Myeloma Working Group response criteria. All patients had novel agents as part of their initial induction regimen. Statistical analysis was by SPSS software (V 12.0). MRD status was determined by MFC on bone marrow samples pre- HDC/ASCT [M1] and post- HDC/ASCT (D100 [M2] and I year [M3]). MFC was done with antibodies against CD45, CD19, CD138, CD38, CD20, CD56, and anti-k and l cytoplasmic antibodies. Results: MRD status was available on 91 patients pre-transplant. Of these patients, 80 had MFC recorded at M2 and 17 patients had MFC recorded at M3. Fifty-eight percent were male and 76% were Caucasian. Forty percent received IMiDs, while 60% got proteasome based therapies. Of the 91 patients with MRD pre-HDC/ASCT, 58% (53/91) were MRD (-), and of these patients 89% (41/46) remained MRD (-) at M2. 48 patients were MRD positive (+) pre-HDC/ASCT, 58% (20/34) became MRD (-) at M2. Age, cytogenetic risk, disease stage, number of chemotherapy cycles or immunofixation status had no impact on MRD status. There were only 6 relapses in the cohort, thus the impact of MRD status on progression-free survival could not be studied. Conclusions: Novel agents improve depth of response pre-transplant. HDC/ASCT increases MRD negativity post-transplant. MRD status could aid better timing of HDC/ASCT or adoption of a risk-adapted strategy for high-risk patients. MRD status validation in a prospective cohort is underway at our center (NCT01215344). With future follow-up, the impact of MRD on progression-free survival in the era of novel agents will be determined.

scholarly journals Clinical value of measurable residual disease testing for assessing depth, duration, and direction of response in multiple myeloma

2020 ◽  
Vol 4 (14) ◽  
pp. 3295-3301
Author(s):  
Joaquin Martinez-Lopez ◽  
Sandy W. Wong ◽  
Nina Shah ◽  
Natasha Bahri ◽  
Kaili Zhou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Decision Making ◽  
Residual Disease ◽  
Clinical Care ◽  
Progression Free Survival ◽  
Clinical Decision ◽  
Routine Practice ◽  
Clinical Value ◽  
The Impact ◽  
Measurable Residual Disease

Abstract Few clinical studies have reported results of measurable residual disease (MRD) assessments performed as part of routine practice. Herein we present our single-institution experience assessing MRD in 234 multiple myeloma (MM) patients (newly diagnosed [NDMM = 159] and relapsed [RRMM = 75]). We describe the impact of depth, duration, and direction of response on prognosis. MRD assessments were performed by next-generation sequencing of immunoglobulin genes with a sensitivity of 10−6. Those achieving MRD negativity at 10−6, as well as 10−5, had superior median progression-free survival (PFS). In the NDMM cohort, 40% of the patients achieved MRD negativity at 10−6 and 59% at 10−5. Median PFS in the NDMM cohort was superior in those achieving MRD at 10−5 vs &lt;10−5 (PFS: 87 months vs 32 months; P &lt; .001). In the RRMM cohort, 36% achieved MRD negativity at 10−6 and 47% at 10−5. Median PFS was superior for the RRMM achieving MRD at 10−5 vs &lt;10−5 (PFS: 42 months vs 17 months; P &lt; .01). Serial MRD monitoring identified 3 categories of NDMM patients: (A) patients with ≥3 MRD 10−6 negative samples, (B) patients with detectable but continuously declining clonal numbers, and (C) patients with stable or increasing clonal number (≥1 log). PFS was superior in groups A and B vs C (median PFS not reached [NR], NR, 55 respectively; P &lt; .001). This retrospective evaluation of MRD used as part of clinical care validates MRD as an important prognostic marker in NDMM and RRMM and supports its use as an endpoint in future clinical trials as well as for clinical decision making.

Minimal Residual Disease Studies in Multiple Myeloma Patients Achieving Complete Remission after Autologous Peripheral Blood Stem Cell Transplantation (APBSCT) by RQ-PCR.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2418-2418 ◽  
Author(s):  
M. E. Sarasquete ◽  
R. García-Sanz ◽  
A. Balanzategui ◽  
P. Martínez-Sánchez ◽  
J. Martínez-López ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Progression Free Survival ◽  
High Rate ◽  
Taqman Probe ◽  
Patient Specific ◽  
Standard Curve ◽  
The Impact ◽  
Minimal Residual

Abstract Multiple myeloma (MM) remains as an incurable disease although new therapies can achieve a high rate of complete remissions (CR). Unfortunately, most patients ultimately relapse due to the persistence of minimal residual disease (MRD), and only a minority could be cured. Detection and quantification of these cells is an important tool for monitoring these patients and predicting a potential relapse. Here we analyze by RQ-PCR the MRD in MM patients achieving CR in order to classify them into different risk categories. MATERIAL AND METHODS: 38 MM patients uniformly treated according to the GEM-2000 (Spanish group for Myeloma) protocol, and that have achieved CR following PBSCT were included in the study. 22 were IgG, 9 IgA, 6 B-J and 1 non-secretory (κ/λ 21/16). 27 were male & 11 female with a median age of 58 (range 48–65). Bone marrow samples obtained at diagnosis and 3 months after transplant were analyzed. Complete (VDJH) and incomplete (DJH) Ig rearrangements were amplified with the Biomed-2 strategy (Leukemia2003;17:2257). PCR clonal products were sequenced on an ABI Prism 377 Sequence detector. VH, DH and JH segments were identified by comparing with germinal sequences on V-Base and BLAST databases. An ASO primer at the N-region was designed for each patient with the OLIGO 6.0 software. RQ-PCR was then performed on an ABI Prism 7700 using the ASO specific forward primer, a JH reverse intronic primer (JH1–6) and a TaqMan probe (JH1,2,4,5, JH3 or JH6) to amplify the patient specific rearrangement. Sample quality and quantity was controlled evaluating the standard curve of the albumin gene amplification. MRD was calculated according to ΔCT method. RESULTS: In 14 out of the cases included in the study, MRD investigation was not possible because the N-region was not longer enough to design the ASO primer (n=3), poor quality in the diagnostic sample to obtain the standard curve (n=8) or low plasma cell infiltration at diagnosis to obtain correct dilutions (n=3). The remaining 24 patients were classified into different risk groups according to the MRD level obtained 3 months after transplantation with a cut-off point of 0.01% tumor cells. Thus, progression free survival (PFS) was longer in those patients with MRD< 10−4 (p=0.03, figure 1A). By contrast, upon comparing the impact on PFS of immofixation (IFX) in these 24 patients that were in CR (defined by conventional electrophoresis criteria), it was observed that patients with IFX (−) didn’t showed a different outcome from those IFX (+) (figure 1B). CONCLUSION: In summary, although RQ-PCR is a labor and time-consuming technique, it is an useful tool for monitoring MRD in MM. The level of 10−4 can contribute to classify patients into 2 groups (high and low MRD) with different risk of relapse that can be used to design specific therapies.

Doxil, Vincritine, Reduced Frequency Dexamethasone in Combination with Thalidomide (DVd-T) Is Associated with Higher Overall and Progression Free Survival as Compared to DVd in Patients with Multiple Myeloma (MM).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2557-2557 ◽  
Author(s):  
Khaldoun Almhanna ◽  
Revathi Suppiah ◽  
Rachid Baz ◽  
Mary Ann Karam ◽  
Beth Faiman ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow Involvement ◽  
Pegylated Liposomal Doxorubicin ◽  
Progression Free Survival ◽  
Disease Stage ◽  
P Value ◽  
Free Survival ◽  
Number Of Patients

Abstract Background: Although initially responsive to chemotherapy, multiple myeloma ultimately relapses. Replacing Adriamycin with pegylated liposomal doxorubicin in the VAD regimen results in a regimen with better safety profile (less neutropenia, alopecia, fewer hospital and clinic visit). DVd resulted in normalizing the angiogenic process however this did not improve PFS or OS. Thalidomide because of its antiangiogenic, immunomodulatory effects and chemo-sensitizing activity through modulating integrins was added to the DVd regimen. Adding the thalidomide to the DVd regimen resulted in an overall response rate of 89% with a CR/NCR rate of 49 % as compared to 60% and 18 % respectively for the DVd. At this stage it is not clear if the quality of response affects outcome in multiple myeloma patients receiving conventional dose therapy. To better assess the prognostic implication of improved quality responses and to define the role of up front Thalidomide, we compared the DVd to the DVd-T regimen by retrospectively reviewing the two trial data, the follow up for both trials is mature. It is still not clear whether thalidomide is more appropriately used up front or in the management of relapse. Methods: we recruited a total of 68 patients in our DVd trial versus 105 patient in the DVd-T trial. A total of 155 patients in both groups were evaluable for follow-up and response (58 received DVd and 97 received DVd-T). Patients were matched for age, disease prognosticators, disease stage, and bone marrow involvement. The newly diagnosed patients were comparable in both groups except for the b 2 microglobulin which was higher in the DVd-T group as compared to the DVd (3.2 vs. 5.0; respectively. p0.05). In the relapsed/refractory group of patients, all variables were comparable. Results: The median follow up was 5 years for the DVd group and 2 years for the DVd-T group. Median age for the DVd was 62 years, which was similar to the DVd-T. For the DVd vs. the DVd-T group of patients achieving complete and near complete remission was 17% vs. 49.5% respectively with a p value of 0.001. Progression free survival was significantly longer for the DVd-T regimens vs. the DVd (28 vs. 13 months p= 0.0002) Figure 1., and for over all survival the median is not reached for the DVd-T vs. 28 months for he DVd (p=0.006). Conclusion: we conclude that the addition of thalidomide significantly improved the quality of response and this appears to translate in to a PFS and OS benefit. While, recently published SWOG data suggests that the overall survival is determined by the duration of the PFS and not the quality of the response, this discrepancy could be related to the small number of patients in our study or the lack of use of biologic immune modulators among SWOG patients. Figure Figure

The role of complete response in multiple myeloma

Blood ◽  
2009 ◽  
Vol 114 (15) ◽  
pp. 3139-3146 ◽  
Author(s):  
Jean-Luc Harousseau ◽  
Michel Attal ◽  
Herve Avet-Loiseau
Keyword(s):  
Multiple Myeloma ◽  
Progression Free Survival ◽  
Complete Response ◽  
High Dose ◽  
Prognostic Impact ◽  
Free Survival ◽  
Depth Of Response ◽  
The Impact ◽  
Good Partial Response

AbstractIn multiple myeloma (MM), the impact of complete response (CR) could be shown only after introduction of high-dose therapy plus autologous stem cell transplantation (ASCT). In the context of ASCT, achieving CR (negative immunofixation and normal bone marrow) or at least very good partial response is associated with longer progression-free survival and in most studies longer survival. With novel agents, high CR rates are achieved and this prognostic impact of CR is being shown as well, both in relapsed and in newly diagnosed MM. However the benefit of CR achievement depends on the type of treatment and is not identical for all patients. In elderly patients, treatments inducing more CR may be more toxic. Although CR achievement is necessary in patients with poor-risk disease, it might not be as critical for long survival in more indolent MM. CR achievement is not the only objective of treatment because it is possible to further improve the depth of response and the outcome by continuing treatment after CR achievement. Finally, there are several levels of CR and in the future it will be necessary to confirm the prognostic impact of immunophenotypic or molecular CR or of CR defined by imaging procedures.

Clinical Significance of Sensitive Flow-MRD Monitoring in Elderly Multiple Myeloma Patients on the Pethema/GEM2010MAS65 Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3390-3390 ◽  
Author(s):  
Bruno Paiva ◽  
Maria Angeles Montalbán ◽  
Noemi Puig ◽  
Lourdes Cordon ◽  
Joaquin Martinez-Lopez ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Plasma Cells ◽  
Residual Disease ◽  
Response Assessment ◽  
Complete Response ◽  
Prognostic Information ◽  
The Moment ◽  
The Impact

Abstract The genetic heterogeneity of multiple myeloma (MM) makes it unlikely that established or novel chemotherapy could be equally effective in all genetic subgroups. Therefore, genetics alone is insufficient to fully capture different disease outcomes, and there is growing body of evidence showing that detection of minimal residual disease (MRD), using immunophenotypic or molecular-based approaches, also provides powerful independent prognostic information particularly among transplant-eligible patients. However, it is perhaps in elderly MM, the major patient subgroup and in which optimal balance between efficacy and toxicity is critical, that sensitive response assessment could help to tailor patients’ treatment. Here, we used for the first time sensitive 8-color multidimensional flow cytometry (cut-off of 10-5) to monitor MRD among elderly MM patients included in the PETHEMA/GEM2010MAS65 trial (sequential chemotherapy with 9 cycles of bortezomib-melphalan-prednisone (VMP) followed by 9 cycles of lenalidomide-low dose dexamethasone (Rd), or alternating cycles of VMP and Rd up to 18 cycles). A single 8-color antibody combination (CD45-PacB/CD138-OC515/CD38-FITC/CD56-PE/CD27-PerCPCy5.5/CD19-PECy7/CD117-APC/CD81-APCH7) was used to detect phenotypically aberrant clonal plasma cells (PCs), and MRD-negativity was defined when &lt;20 clonal PCs were detected among ≥2.000.000 leukocytes (&lt;0.001%). MRD assessment was centralized in three PETHEMA/GEM laboratory-cores, cytometrists were blinded to all clinical data, and results were prospectively uploaded into a locked intranet dataset. Median follow-up of the series was 27 months, and time-to-progression (TTP) / overall survival (OS) was measured from the moment of MRD assessment. First, we evaluated the MRD status at cycle 9 of chemotherapy (n=117), and no significant differences were observed for MRD-negative rates between the sequential vs alternating regimens (23% vs 25%; P = .86). However, when we focused on patients in complete response (CR; n=41) and compared the quality of CR achieved in each arm according to patients’ MRD status, we found significantly higher frequencies of MRD-negative rates after the sequential vs alternating schema (75% vs 40%; P = .03). Patients in CR attaining MRD-negativity at cycle 9 showed a significantly prolonged TTP (100% vs 41% at 2-years; P = .001) as well as OS (100% vs 71% at 2-years; P= .03) as compared to patients in CR but with persistent MRD cells. To understand the kinetics of MDR response with sequential vs alternating 18 cycles of chemotherapy, we focused on 72 patients with paired Flow-MRD assessments at cycles 9 and 18. No MRD-negative patients at cycle 9 turned into MRD-positive at cycle 18; however, 21% of MRD-positive patients at cycle 9 became MRD-negative at cycle 18, with no significant differences between rates of transformation after sequential vs alternating regimens (P = .23). At the end of cycle 18, MRD-negative rates among patients randomized to the sequential vs alternating schema were of 48% vs 31% (P = .08), and the quality of CR (according to patients’ MRD status) was slightly but not significantly superior in the sequential vs alternating arm (66% vs 48%; P = .16). Again, patients in CR at cycle 18 attaining MRD-negativity showed superior TTP as compared to those in CR with persistent MRD: TTP at 2-years of 83% vs 56% (P= .06). We also compared the impact of Flow-MRD among cytogenetically defined standard- and high-risk [+1q, t(4;14), t(14;16), and/or del(17p)] patient subgroups (n=125). As expected, standard-risk patients attaining MRD-negativity had significantly prolonged TTP as compared to MRD-positive patients (94% vs 58% at 2-years; P = .035); however, also high-risk cytogenetic patients achieving Flow-CR showed significantly superior TTP (median not reached vs 10 months; P= .001). In summary, we unravel the clinical impact of sensitive Flow-MRD monitoring (10-5) among elderly MM patients in which attaining MRD-negativity, particularly early in therapy, translated into virtually relapse-free intervals at 2-years. In parallel, we also show the value of sensitive MRD kinetics to understand the benefit of additional (sequential or alternating) chemotherapy to further reduce MRD levels, as well as the significance of Flow-MRD among cytogenetically defined standard- and high-risk patents. Disclosures Paiva: Millenium: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Ocio:Array Biopharma: Honoraria, Research Funding. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Oriol:Celgene Corporation: Consultancy. Gutierrez:Celgene: Honoraria; Janssen: Honoraria. Blade:Janssen: Honoraria; Celgene: Honoraria. Lahuerta:Janssen: Honoraria; Celgene: Honoraria. Mateos:Celgene: Honoraria; Janssen: Honoraria. San Miguel:Janssen: Honoraria; Celgene: Honoraria.

What Is the Frequency of Transplant-Eligible Multiple Myeloma Patients Being Cured? the Impact of an MGUS-like Signature at Diagnosis and MRD-Negativity

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 725-725 ◽  
Author(s):  
Bruno Paiva ◽  
Maria Belen Vidriales ◽  
Noemi Puig ◽  
Teresa Cedena ◽  
Lourdes Cordon ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Binding Site ◽  
Residual Disease ◽  
Limit Of Detection ◽  
Survival Rates ◽  
Progression Free Survival ◽  
Classification Model ◽  
The Impact

Abstract Introduction: Although multiple myeloma (MM) is typically described as an incurable disease, it has been shown in recent years that a small fraction of patients may reach more than 10-years progression-free survival (PFS), which is considered as the minimum threshold to identify patients in "operational cure". However, because of the scarcity of available data there is significant lack of knowledge in MM regarding the frequency of cases attaining operational cure, nor the existence of biomarkers that could prospectively predict such curability. Methods: Herein, we sought to define the frequency as well as the biomarkers predictive of operational cure in a large series of uniformly-treated transplant-eligible patients enrolled in the PETHEMA/GEM2000 protocol (VBMCP/VBAD followed by HDT/ASCT and 2 years of maintenance with interferon and prednisone). Patients' follow-up was updated at the time of abstract submission, and the median follow-up of the series is now of 12-years. We used an automated multiparameter flow cytometric (MFC) classification model focused on the analysis of the bone marrow plasma-cell compartment to identify among newly diagnosed symptomatic MM those with MGUS-like vs. MM-like phenotypic signatures. Minimal residual disease (MRD) was monitored using a first-generation 4-color MFC assay (CD38-FITC / CD56-PE / CD19-PerCPCy5.5 / CD45-APC) with a limit of detection of 10-4. PFS and overall survival (OS) were measured from the time of diagnosis. Results: From a total of 1075 patients enrolled in the GEM2000 protocol, 763 were eligible for this analysis because they either relapsed or died during the first 10-years from diagnosis (n=666; 87%), or remained progression-free and alive for more than 10-yers (n=97; 13%); accordingly, all patients remaining progression-free and alive but for which the follow-up was inferior to 10-years were excluded from the analysis. We then investigated the biomarkers that could help to identify patients reaching operational cure after HDT/ASCT. As compared to the vast majority of cases, patients reaching >10-years PFS (13%) had significantly less frequent anemia (76% vs. 60%, respectively; P=.002), as well as more frequent Durie-Salmon stage IA (14% vs. 6%; P=.004), MGUS-like signature as determined by the automated MFC algorithm (28% vs. 6%; P<.001), complete response (CR) after HDT/ASCT (51% vs. 35%; P=.003), and MRD-negativity by MFC (72% vs. 31%; P<.001). Other biomarkers such as ISS, LDH, ploidy and proliferation were not significantly different among patients reaching >10-years PFS vs. those who relapsed earlier. On multivariate analysis, only the presence of an MGUS-like signature at baseline (P=.04; HR: 3.9) and MRD-negativity at day+100 after HDT/ASCT (P=.006; HR: 6.3) emerged as independent predictive markers for >10-years PFS; anemia, Durie-Salmon and CR status were not retained in the logistic regression model. Accordingly, patients with an MFC-defined baseline MGUS-like signature reaching MRD-negativity after HDT/ASCT (n=14) had a median PFS of 10-years and a 10-year OS rate of 79%, which were significantly superior to those observed among cases with MM-like signatures being MRD-negative (n=54) or positive (n=99) after therapy [median PFS of 6 and 3 years (P<.001); 10-year overall survival rates of 55% and 19% (P<.001)]. Conclusions: We demonstrated that operational cure (i.e.: >10-years PFS) was possible for 13% of transplant-eligible MM patients before the era of novel agents. Curability rates were particularly frequent among patients with a benign phenotypic signature at diagnosis and MRD negativity after HDT/ASCT, suggesting a remarkable clinical benefit of attaining deep remissions after intensive treatment for patients with early MM. Disclosures Paiva: Sanofi: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Onyx: Consultancy; BD Bioscience: Consultancy; EngMab AG: Research Funding; Binding Site: Consultancy; Celgene: Consultancy. Puig:The Binding Site: Consultancy; Janssen: Consultancy. Mateos:Takeda: Consultancy; Celgene: Consultancy, Honoraria; Onyx: Consultancy; Janssen-Cilag: Consultancy, Honoraria. San Miguel:Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Onyx: Honoraria; Sanofi-Aventis: Honoraria; Novartis: Honoraria; Millennium: Honoraria; Janssen-Cilag: 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 Sustained Minimal Residual Disease Negativity With Daratumumab in Newly Diagnosed Multiple Myeloma: MAIA and ALCYONE

Blood ◽  
2021 ◽  
Author(s):  
Jesus F. San-Miguel ◽  
Hervé Avet-Loiseau ◽  
Bruno Paiva ◽  
Shaji K Kumar ◽  
Meletios A A Dimopoulos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Pooled Analysis ◽  
Response To Therapy ◽  
Newly Diagnosed ◽  
Intent To Treat ◽  
Minimal Residual

In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone; D-Rd) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone; D-VMP). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10-5) occurred for patients achieving complete response (CR) or better, and after ≥CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving ≥CR. In MAIA, (D-Rd, n=368; Rd, n=369), and ALCYONE (D-VMP, n=350; VMP, n=356), the median duration of follow-up was 36.4 months and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS versus control groups. In a pooled analysis, patients who were MRD negative had improved PFS versus patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. ClinicalTrials.gov identifier NCT02252172 (MAIA); NCT02195479 (ALCYONE).

scholarly journals Front-line Management of Multiple Myeloma – How Can We Best Assess the Depth of Response?

2015 ◽  
Vol 11 (2) ◽  
pp. 105
Author(s):  
Michel Delforge ◽  
Keyword(s):  
Multiple Myeloma ◽  
Complete Remission ◽  
Residual Disease ◽  
Clinical Importance ◽  
Response Assessment ◽  
Front Line ◽  
Significant Group ◽  
New Agents ◽  
Depth Of Response ◽  
Minimal Residual

The outcome for patients with multiple myeloma (MM) is gradually improving due to the introduction of several new agents with strong antimyeloma activity. Both younger (transplant-eligible) and elderly patients benefit from this therapeutic progress. Although complete remission can be achieved in a significant group of MM patients, the majority of these patients will relapse because of the persistence of minimal residual disease. In this editorial, we discuss the different assays for response assessment in myeloma together with their limitations and clinical importance.

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