scholarly journals Joint modeling and simulation of M‐protein dynamics and progression‐free survival for alternative isatuximab dosing with pomalidomide/dexamethasone

Author(s):  
Hoai‐Thu Thai ◽  
Nadia Gaudel‐Dedieu ◽  
Marc Cerou ◽  
Geraldine Ayral ◽  
Jean‐Baptiste Fau ◽  
...  
2020 ◽  
Vol 13 (6) ◽  
pp. 1345-1354
Author(s):  
Xiaoyu Yan ◽  
Xu Steven Xu ◽  
Katja C. Weisel ◽  
Maria‐Victoria Mateos ◽  
Pieter Sonneveld ◽  
...  

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2111-2111 ◽  
Author(s):  
Heinz Ludwig ◽  
Katja Weisel ◽  
Maria Teresa Petrucci ◽  
Xavier Leleu ◽  
Anna Maria Cafro ◽  
...  

Abstract Background Olaptesed, an L-stereo-isomer RNA aptamer, binds and neutralizes the chemokine CXCL12. By interaction with the chemokine receptors CXCR4 and CXCR7, CXCL12 is responsible for trafficking and homing of normal and malignant blood cells to the bone marrow. Preclinical studies have shown synergistic activity of CXCL12-targeting and anti-myeloma agents, specifically bortezomib (BTZ). Thus, targeting the myeloma niche may increase treatment efficacy. Aims This open label single arm study was conducted to assess the activity and safety of olaptesed when added to the combination of BTZ and dexamethasone (DEX) in patients with relapsed / refractory multiple myeloma (MM). Patients and Methods Twenty-eight relapsed or refractory MM patients (males:females 14:14) were enrolled and treated according to a dose titration design. Olaptesed was administered intravenously at doses increasing from 1 mg/kg to 2 mg/kg and 4 mg/kg in cycles 1, 2 and 3, respectively, at 1 hour prior to bortezomib administration. During cycles 4 to 8, olaptesed was dosed at the highest individually titrated dose. BTZ (1.3 mg/m2) was given on days 1, 4, 8 and 11 as intravenous injection. Oral DEX (20 mg) was added on the day of and on the day after BTZ administration. Response was evaluated based on the uniform IMWG response criteria (Rajkumar SV et. al. Blood 2011; 117: 4691-5). Plasma cell mobilization was studied after a pilot dose of 1 to 4 mg/kg olaptesed administered to the initial 10 patients before start of the regular treatment regimen. Results From Aug 2012 to Feb 2014 we enrolled 28 patients who had received a median of 2 (range 1-6) lines of prior therapy. Pretreatments were lenalidomide (LEN) in 20, BTZ in 14 and carfilzomib in 1 patient. Ten patients had autologous stem cell transplantations prior to entering this study. The patient population enrolled presented predominantly with advanced disease and with adverse outcome predictors. Ten patients had ISS stage III. High-risk cytogenetics were identified in 9 of the 20 patients (45%) with FISH testing available for t(4;14), t(14;16) and/or del17p. Eleven patients were refractory to their last prior treatment, which contained BTZ in 8 cases. After two early withdrawals, 26 patients were available for outcome evaluations. The median number of completed cycles was 8. Progression led to treatment termination in 8 patients. The dose of olaptesed was titrated to 4 mg/kg in all 18 patients treated for 3 or more cycles. The single dose of olaptesed administered to 10 pilot-patients effectively mobilized plasma cells, which increased by approximately 200% for up to 3 days. Based on “best response” of the 26 evaluable patients, the overall response rate was 73%: Two patients (8%) achieved a complete response (CR), 6 patients (23%) a very good partial response (VGPR) and 11 patients (42%) a partial response (PR). Minimal response was recorded in 2 patients (8%), 4 patients (15%) had stable disease and 1 patient (4%) progressive disease. In the 9 evaluable patients with high-risk cytogenetics, the clinical responses were similar. The ORR was 67% with VGPR in 3 (33%) and PR in 3 (33%) patients. Of the 14 patients pre-treated with BTZ, 1 had a CR and 8 a PR (ORR 64%). M-protein decreased rapidly from treatment cycle 1 to cycle 4 with a decrease of ≥50% being observed in 15 of the 26 evaluable patients. Figure 1 shows a waterfall plot of the maximum observed decrease in M-protein. Figure 1: Waterfall Plot of Maximum M-Protein Change Figure 1:. Waterfall Plot of Maximum M-Protein Change Median progression-free survival (PFS) of the evaluable population was 6.5 months. It was also 6.5 months in the 9 patients with high-risk cytogenetics and 6.3 months in the 14 patients pre-treated with BTZ (Figure 2). The median follow-up was 6.3 months. Figure 2: Progression-Free Survival Figure 2:. Progression-Free Survival Treatment with olaptesed in combination with BTZ-DEX was safe and well tolerated without any appreciable increase in adverse events. Conclusions A single dose of olaptesed effectively mobilized plasma cells. Olaptesed in combination with BTZ and DEX resulted in an ORR rate of 73% and PFS of 6.5 months. Response rates and PFS were similar in patients with or without high risk cytogenetic features or with or without previous exposure to BTZ. The combination regimen was well tolerated. These findings merit further exploration of this strategy in randomized trials. Disclosures Weisel: NOXXON Pharma AG: Consultancy. Petrucci:Celgene: Honoraria; Jannsen-Cilag: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria. Leleu:Janssen, Celgene, leopharma, Takeda, Amgen, Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Laurent:Bristol-Myers Squibb: Honoraria. Kruschinski:NOXXON Pharma AG: Employment. Dümmler:NOXXON Pharma AG: Employment. Riecke:NOXXON Pharma AG: Employment. Engelhardt:NOXXON Pharma AG: Consultancy.


2012 ◽  
Vol 32 (2) ◽  
pp. 240-254 ◽  
Author(s):  
Haoda Fu ◽  
Yanping Wang ◽  
Jingyi Liu ◽  
Pandurang M. Kulkarni ◽  
Allen S. Melemed

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-44
Author(s):  
Hoai-Thu Thai ◽  
Nadia Gaudel-Dedieu ◽  
Marc Cerou ◽  
Bernard Sebastien ◽  
Helgi van de Velde ◽  
...  

Background: Isatuximab (Isa) is a CD38 monoclonal antibody with multiple modes of action for killing tumor cells through direct tumor targeting and immune cell engagement (Moreno, Clin Cancer Res, 2019). The addition of Isa to pomalidomide (P) and dexamethasone (d) was associated with a significant and clinically meaningful benefit in progression-free survival (PFS) in heavily pre-treated patients with relapsed/refractory multiple myeloma (RRMM) (ICARIA-MM, NCT02514668) (Attal, Lancet, 2019). Isa, in combination with Pd, is approved in the United States, the European Union, Canada, Australia, Switzerland, and Japan for the treatment of adult patients with RRMM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. Aim: The objectives were to characterize the relationship between serum M-protein kinetics and PFS in RRMM using data from the Phase 3 ICARIA-MM study and to simulate expected longitudinal serum M-protein and PFS when switching to a hypothetical monthly dosing regimen after 6 months. Methods: A joint model of serum M-protein dynamics and PFS was developed using data from 256 evaluable ICARIA-MM patients. Patients received Isa intravenously at 10 mg/kg once weekly (QW) for 4 weeks, then every other week (Q2W) for 28-day cycles in combination with standard Pd (Isa-Pd) or Pd alone in the control arm. A tumor growth inhibition model was used to describe the serum M-protein kinetics under treatment effects of Isa-Pd or Pd alone, in which Isa exposure was predicted using individual PK parameters obtained from the population PK analysis (Fau, Population Approach Group in Europe, 2019) and Pd exposure was predicted from K-PD model using dosing history. Trial simulations were then performed using individual PK/PD parameters of ICARIA-MM patients to evaluate whether efficacy is maintained after switching to a monthly dosing regimen. Results: The joint model identified the instantaneous changes (slope) in serum M-protein as the best on-treatment predictor for PFS and also identified baseline patient characteristics impacting serum M-protein kinetics (serum albumin and serum β2 microglobulin on the baseline serum M-protein levels and the non-IgG type on the serum M-protein growth rate, the serum M-protein slope), and PFS (presence of plasmacytomas). Non-IgG MM patients have similar behavior on serum M-protein kinetics for the first 60 weeks even with higher exposure and similar progression free survival compared to IgG MM patients supporting the non-dose adjustment based on IgG status. Clinical trial simulation of the ICARIA-MM Isa-Pd regimen demonstrated that switching all patients on treatment at 6 months to a monthly Isa regimen would shorten the median time to progression (TTP) (i.e. increase in serum M-protein greater than 25% and an absolute increase greater than 5 g/L compared to nadir) by 4.1 weeks and would shorten median PFS by 2.3 weeks (from 14.03 to 13.45 months). Based on TTP criteria, patients with no risk of earlier progression (57.7%) due to 6 months switch tend to have lower baseline tumor burden (lower serum M-protein and lower percent of bone marrow plasma cell) and better prognostic factors (higher glomerular filtration rate, higher albumin, lower β2 microglobulin). At 6 months, 85% of these patients had predicted stable "at least" VGPR status. Conclusions: Trial simulations supported the choice of the approved isatuximab 10 mg/kg QW/Q2W regimen and showed that switching to a monthly Isa regimen after 6 months may reduce clinical benefit in overall population. However, a subpopulation of patients with good prognosis and obtaining stable at least VGPR status by 6 months may switch to a monthly regimen after 6 months without compromising disease progression risk; this hypothesis will be tested in a prospective clinical trial. Model-based drug development has been successfully applied to support treatment decisions in RRMM patients. Disclosures Thai: Sanofi: Current Employment. Gaudel-Dedieu:Sanofi: Current Employment. Cerou:Sanofi: Current Employment. Sebastien:Sanofi: Current Employment. van de Velde:Sanofi: Current Employment, Current equity holder in publicly-traded company. Semiond:Sanofi: Current Employment. Veyrat-Follet:Sanofi: Current Employment.


2018 ◽  
Vol 21 ◽  
pp. S382-S383
Author(s):  
F Felizzi ◽  
I Bennett ◽  
M Pletscher ◽  
P Thuresson ◽  
N Paracha ◽  
...  

2005 ◽  
Vol 23 (24) ◽  
pp. 5668-5674 ◽  
Author(s):  
Shaji Kumar ◽  
S. Vincent Rajkumar ◽  
Robert A. Kyle ◽  
Martha Q. Lacy ◽  
Angela Dispenzieri ◽  
...  

Purpose Monoclonal gammopathy of undetermined significance (MGUS) progresses to multiple myeloma or another related plasma cell disorder (PCD) at a rate of approximately 1% per year. Identification of patients with MGUS at high risk of progression will allow development of preventive strategies. We studied the prognostic value of circulating plasma cells (PCs) in patients with MGUS to predict progression. Patients and Methods Patients were eligible for this retrospective analysis if they were seen at the Mayo Clinic between 1984 and 1997, were diagnosed with MGUS, and had an analysis of the peripheral blood for circulating PCs by the slide-based immunofluorescence method. Patients were observed for progression to another PCD. Results Three hundred twenty-five patients were eligible and 63 (19%) had circulating PCs. Patients with circulating PCs were twice as likely (hazard ratio, 2.1) to experience progression to another PCD (most commonly myeloma), compared with those without circulating PCs (95% CI, 1.1 to 4.3; P = .03). In patients with circulating PCs, the median progression-free survival was 138 months compared with a median not yet reached for those without circulating PCs (P = .028). The median overall survival also was shorter for those with circulating PCs. Other factors with prognostic value were high levels of M protein and non–immunoglobulin G heavy-chain type. Conclusion The presence of circulating PCs, especially when combined with other known prognostic factors such as M protein concentration and immunoglobulin isotype, identify a group of individuals with MGUS at higher risk of progression to overt multiple myeloma.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3099-3099
Author(s):  
Shaji Kumar ◽  
Martha Lacy ◽  
Angela Dispenzieri ◽  
Suzanne Hayman ◽  
S. Vincent Rajkumar ◽  
...  

Abstract Background: High dose therapy (HDT) and stem cell transplant has been shown to improve survival in patients with myeloma and remains the standard of care. However, the reported results of initial HDT in these patients reflect the combined effect of the initial therapy and the HDT. The contribution of HDT on its own is often difficult to analyze in this group of patients with varying degree of response to initial therapy. In this single institution retrospective study, we have analyzed the results of HDT in a group of patients with measurable disease at the time of HDT. Methods: We identified patients from our transplant database, who had measurable disease at the time of initiation of transplant as defined by a serum M protein of ≥ 1.0 g/dL, 24 hour urine M-protein ≥ 200 mg or a bone marrow plasma cell % of ≥ 30. Details regarding the clinical outcome were obtained from the database and from patient clinical records. Chi square test was used for comparison of nominal variables and t-test for continuous variables. Kaplan Meier analysis was used for comparing survival and Cox proportional hazards was employed to identify predictors of progression free and overall survival. Responses were defined by the EBMTR criteria, using the measurements at the time HDT and the lowest measurement obtained. VGPR required a 90% reduction in the serum M component with urine protein < 100 mg/24 hours. Results: A total of 440 patients were studied; 271 (61.5%) of whom had a transplant within one year of their diagnosis. Among the 271 patients, 140 (52%) were in the initial plateau, 99 (36%) failed to achieve a PR to initial therapy and 32 (12%) were in their first relapse. Given the known differences in the outcome between these groups of patients, those receiving an early transplant were analyzed separately. The response rates included CR (24%), VGPR (7%), PR (52%), MR or less (17%) and among the late transplants CR (23%), VGPR (8%), PR (61%) and MR or less (8%). The median progression free survival was 23.6 mos and the overall survival from HDT was 62 mos. In a multivariate analysis, presence of cytogenetic abnormalities (RR: 2.5) and high plasma cell labeling index (≥ 1%) (RR: 2.4) at HDT and failure to achieve a CR or VGPR (RR: 1.7) were prognostic for decreased progression free survival post HDT. In a similar model, only high PCLI (RR: 2.8) and abnormal cytogenetics (RR: 2.5) at HDT predicted for poor overall survival after transplant. Conclusion: This study provides a sense of the contribution of HDT, independent of the initial therapy, by determining responses based on the immediate pre-transplant disease measurements and the best values observed post transplant. In this group of patients with residual measurable disease after the initial therapy, HDT therapy leads to complete responses in nearly a quarter of the patients and a VGPR in another 7%, an outcome associated with better progressin free survival. While measurements at transplant do not correlate strictly with response to initial therapy, the aim of this study was to understand the individual contribution of HDT in these patients. Thus some of the patients who would have been classified as having a partial response to induction and HDT may be classified as non-responders in this analysis. These numbers will provide a historical comparison for trials evaluating novel consolidation therapies for myeloma.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3098-3098
Author(s):  
David A. Irvine ◽  
Michael J. Barnett ◽  
Ryan Brinkman ◽  
Donna L. Forrest ◽  
Donna E. Hogge ◽  
...  

Abstract Induction chemotherapy followed by autologous stem cell transplant (ASCT) has become standard treatment for symptomatic myeloma patients. Our strategy has been to use the Dex component of the VAD protocol alone for 2–4 cycles as induction. Between January 1998 and May 2005, 406 pts were referred to us for treatment of multiple myeloma. We retrospectively reviewed all pts in order to determine the rate and depth of response to Dex, to determine if response predicted overall survival (OS) or progression free survival (PFS) and assess factors predictive of response. Of 406 pts, 124 were excluded due to prior therapy, no treatment or lack of response data. Analysis was performed on 282 pts all of whom received single agent Dex as primary therapy for newly diagnosed myeloma given at 40mg on days 1–4, 9–12, 17–20 every 28 days for at least two cycles. 40% were female and 60% male and median age was 56. Myeloma subtypes were: IgA 21%; IgG 56%; light chain (LC) 17%, nonsecretory 2% and others 1.4%. Cytogenetic information was available in 51% of pts with 53 confirmed as having a deletion on chromosome 13 (del13q). Response to Dex induction therapy was as follows; nCR [no M protein, IF not performed] 4%, PR1 [>90% reduction in M protein/involved Ig subtype] 10%, PR2 [>50% reduction] 43%, MR [>25% reduction] 20%, no response (NR) [within 25% of base level] 14% and progressive disease (PD) [increase by >25%] 7%. 241 proceeded to transplantation; 212 underwent auto SCT with a melphalan based conditioning regimen after stem cell mobilization with cyclophosphamide and GCSF, 29 had an allo SCT. We evaluated the effect of del13q, International Staging System (ISS), b2Microglobin (b2M), sex, age, Salmon-Durie stage, hypercalcemia, Ig subtype, creatinine and hemoglobin at diagnosis (Hgbdx) on response to Dex, OS and PFS from treatment initiation. Univariate analysis showed that OS was significantly affected by Hgbdx >/≤10g/dl, ISS score and b2M >/≤3.5 while PFS was influenced by b2M <3.5, ISS score, and best response to Dex (p<0.001) with those reaching PR1 achieving a median PFS of 1181d and PR2, MR, NR and PD having median PFS of 1031d, 729d, 825d, 61d respectively. In the group proceeding to HDT similar relationships were noted with PFS post transplant (PFSB) significantly affected by ISS score (median survival for ISS I, II and III 1201d, 848d, 621d respectively) [p=0.047], b2M <3.5 (median survival 1225d vs. 621d) [p=0.013] and best response to Dex. Multivariate analysis confirmed depth of response to Dex as a prognostic factor in PFSB. Analysis of factors which might predict which patients are most likely to respond well to Dex using the chi square contingency table demonstrated that ISS score, B2M>2.5 and Ig subtype significantly influenced response (p<0.05). In conclusion; 43% of pts do not achieve at least a PR with single agent Dex induction, and 7% progress. Despite subsequent treatment with high dose Melphalan and autotransplant in most patients in this study, the depth of response to Dex remains predictive of PFS. While it is unknown whether this reflects disease biology, it seems rational to evaluate new lines of anti-myeloma therapy in an attempt to improve depth and frequency of response and evaluate whether this influences long-term PFS.


Sign in / Sign up

Export Citation Format

Share Document