scholarly journals Investigation on the Relationship between Initial Dose and Treatment Duration of Lenalidomide for Multiple Myeloma

2017 ◽  
Vol 43 (10) ◽  
pp. 563-568
Author(s):  
Hiromu Tanigawa ◽  
Eiseki Usami ◽  
Michio Kimura ◽  
Tadashi Yano ◽  
Tomoaki Yoshimura ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Initial Dose ◽  
Treatment Duration ◽  
The Relationship

scholarly journals Copy number signatures predict chromothripsis and clinical outcomes in newly diagnosed multiple myeloma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kylee H. Maclachlan ◽  
Even H. Rustad ◽  
Andriy Derkach ◽  
Binbin Zheng-Lin ◽  
Venkata Yellapantula ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Copy Number ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Flexible Tool ◽  
Whole Exome ◽  
Hematological Cancers ◽  
Relationship Of ◽  
The Relationship ◽  
Validation Series

AbstractChromothripsis is detectable in 20–30% of newly diagnosed multiple myeloma (NDMM) patients and is emerging as a new independent adverse prognostic factor. In this study we interrogate 752 NDMM patients using whole genome sequencing (WGS) to investigate the relationship of copy number (CN) signatures to chromothripsis and show they are highly associated. CN signatures are highly predictive of the presence of chromothripsis (AUC = 0.90) and can be used identify its adverse prognostic impact. The ability of CN signatures to predict the presence of chromothripsis is confirmed in a validation series of WGS comprised of 235 hematological cancers (AUC = 0.97) and an independent series of 34 NDMM (AUC = 0.87). We show that CN signatures can also be derived from whole exome data (WES) and using 677 cases from the same series of NDMM, we are able to predict both the presence of chromothripsis (AUC = 0.82) and its adverse prognostic impact. CN signatures constitute a flexible tool to identify the presence of chromothripsis and is applicable to WES and WGS data.

scholarly journals Myeloma Proteins, Bence Jones Proteins and Normal Immunoglobulins in Multiple Myeloma

Blood ◽  
1967 ◽  
Vol 30 (3) ◽  
pp. 265-287 ◽  
Author(s):  
VINCENT CAGGIANO ◽  
JANET CUTTNER ◽  
ALAN SOLOMON
Keyword(s):  
Multiple Myeloma ◽  
Response To Therapy ◽  
Treatment Schedule ◽  
Myeloma Protein ◽  
Mean Values ◽  
Multiple Components ◽  
The Mean ◽  
Therapeutic Protocols ◽  
The Relationship ◽  
Chain Type

Abstract The relationship between the anomalous and normal immunoglobulins was studied through measurement of myeloma protein (MP), Bence Jones protein (BJP), and the normal γG, γA, γM and γD-globulin levels in a large group of patients with multiple myeloma. These determinations were made prior to and after initiation of three different therapeutic protocols. Thirteen out of 18 patients had at least a 25 per cent reduction in MP or BJP within 6 months. This response was characterized by considerable variation both in the rate and period of time before the anomalous proteins decreased. The type of response was independent of (1) light chain type (K or L) of G or A-MP, (2) heavy chain subgroup or genetic (Gm) factors of G-MP, and (3) electrophorectic mobility of the MP. The ratio among multiple components of heterogenous G or A-MP was not altered by therapy. The initial level of MP, in the case of patients with G-MP, may be one factor in the type of response observed. The rate of reduction of MP and BJP was extremely rapid in patients who received prednisone in conjunction with melphalan. It appeared that synthesis of anomalous γ-globulin components was completely suppressed with this treatment regimen. This type of response was not observed in patients treated with melphalan alone. The mean values for each of the normal immunoglobulin (IG) classes (γG, γA, γM and γD-globulin) were reduced below normal. Two classes, γA and γD-globulin, were particularly low. Prior to therapy, however, the extent of reduction of each IG class varied in an individual patient. An inverse relationship was found for γM-globulin and G-MP levels. Part of the normal γG-globulin in patients with G-MP was determined by measurement of Vi (γ2c) levels. Different patterns of response to therapy were noted for each class of IG. More commonly, the response of a normal IG was independent of the response of the anomalous protein and furthermore, could not be related to a particular treatment schedule. In some instances, therapy contributed to further suppression of normal IG levels.

Primary Hyperparathyroidsm, Amyloid and Multiple Myeloma: An Unusual Association

2005 ◽  
Vol 50 (1) ◽  
pp. 32-34 ◽  
Author(s):  
E P Pest ◽  
C McQuaker ◽  
J A Hunter ◽  
D Moffat ◽  
A J Stanley
Keyword(s):  
Multiple Myeloma ◽  
Systemic Amyloidosis ◽  
Unusual Association ◽  
The Relationship

We report the case of a 76 year-old woman with a diagnosis of Primary Hyperparathyroidsm and Systemic Amyloidosis, in whom subsequent investigations revealed the presence of Multiple Myeloma. We discuss the relationship between these conditions and the implications for management.

Concentration-QTc (C-QTc) Analysis of the MDM2 Inhibitor KRT-232 (formerly AMG 232) in Subjects with Advanced Solid Tumors, Multiple Myeloma, or Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5768-5768
Author(s):  
Adekemi Taylor ◽  
Martine Allard ◽  
Cecile Kresja ◽  
Dana Lee ◽  
Greg Slatter
Keyword(s):  
Multiple Myeloma ◽  
Steady State ◽  
Solid Tumors ◽  
Upper Bound ◽  
Myeloid Leukemia ◽  
Employment Equity ◽  
Equity Ownership ◽  
The Mean ◽  
The Relationship ◽  
Mdm2 Inhibitor

Introduction: KRT-232 is a potent and selective, targeted small molecule inhibitor of human mouse double minute 2 (MDM2) homolog interactions with tumor protein 53 (p53). MDM2 prevents p53 activation and reduces p53-mediated transcription and cell cycle control. KRT-232 is under development by Kartos Therapeutics for treatment of myelofibrosis, polycythemia vera, acute myeloid leukemia (AML) and Merkel cell carcinoma (see NCT03662126, NCT03669965, NCT03787602). The KRT-232 no effect-level for in vitro inhibition of hERG function (10 μM) was approximately 147- and 73-fold greater than KRT-232 unbound Cmax concentrations for steady state doses of 240 mg and 480 mg, respectively, based on population pharmacokinetic (PK)-derived parameters for subjects with AML (Ma et al. submitted, ASH 2019). The primary objective of this analysis was to evaluate the relationship between KRT-232 plasma concentration and changes in heart rate-corrected QT interval duration (QTc) in oncology patients treated in Amgen studies 20120106 (Gluck et al. Invest New Drugs; in press, NCT01723020) and 20120234 (Erba et al. Blood Adv 2019; NCT02016729). Methods Study 20120106 was a 2-part Phase 1 dose-exploration and dose-expansion monotherapy study in advanced solid tumors or multiple myeloma. KRT-232 doses of 15 mg (n=3), 30 mg (n=3), 60 mg (n=4), 120 mg (n=7), 240 mg (n=76), 300 mg (n=4), 360 mg (n=4) and 480 mg (n=6) were administered daily (QD) for 7 days in 21-day cycles. Subjects received up to 31 cycles of treatment. Study 20120234 was a Phase 1b study evaluating KRT-232 alone and in combination with trametinib in relapsed/refractory AML. Subjects received the following KRT-232 doses: 60 mg (n=14; n=10 co-administered with 2 mg trametinib daily [excluded from C-QTc analysis]); n=4 as single agent), 90 mg (n=4), 180 mg (n=5), 240 mg (n=3), and 360 mg (n=10). Doses were administered QD for 7 days in 14-day cycles. Subjects received up to 46 cycles of treatment. In both studies, time-matched PK and ECG measurements were collected intensively during Cycle 1 and less frequently at other visits. Triplicate 12-lead ECG data (N=3) were read by a central laboratory. A linear mixed effects model using R (v 3.5.2) was used to analyze the relationship between KRT-232 plasma concentrations and the QT interval corrected using Fridericia's method (QTcF). Effects of baseline QTcF, study, sex and tumor type on C-QTc were investigated. The upper bound of 2-sided 90% CIs for the mean QTcF change from baseline (ΔQTcF) predicted at Cmax was compared to the 10 ms threshold of regulatory concern (FDA Guidance: E14(R3) 2017; Garnett et al. Pharmacokinet Pharmacodyn 2018). Results ECG and PK data for this analysis were available from 130 subjects. The final model was a linear mixed-effect model with parameters for intercept, KRT-232 concentration-ΔQTcF slope, and baseline QTcF effect on the intercept. Diagnostic plots indicated an adequate model fit. The final C-QTc model was used to predict mean ΔQTcF and associated 2-sided 90% CI mean steady-state KRT-232 Cmax at doses up to the maximum clinical dose of 480 mg QD, in subjects with AML or solid tumors. The mean and upper bound of the 90% CI of ΔQTcF were predicted not to exceed 10 ms at doses of up to 480 mg QD in subjects with AML, multiple myeloma or solid tumors. Mean (90% CI) predicted ΔQTcF values at 480 mg QD were 2.040 (0.486, 3.595) ms for subjects with solid tumors and 4.521 (2.348, 6.693) ms for subjects with AML (Figure A). The KRT-232 concentrations at which the upper bounds of 90% CI of mean ΔQTcF are predicted to reach 10 ms and 20 ms are 4298 ng/mL and 7821 ng/mL, respectively. These concentrations are 2.2- and 4-fold higher, respectively, than the predicted mean steady-state Cmax for 480-mg KRT-232 in subjects with solid tumors, and 1.4- and 2.5-fold higher, respectively, than the corresponding mean steady-state Cmax in subjects with AML. Conclusion Since the mean and upper bound of the 90% CI of mean ΔQTcF were predicted not to exceed 10 ms at KRT-232 doses of up to 480 mg QD in solid tumor or AML patients, KRT-232 should not result in clinically meaningful QT prolongation at the doses currently under investigation in Kartos clinical trials. Disclosures Taylor: Certara Strategic Consulting: Consultancy, Employment. Allard:Certara Strategic Consulting: Consultancy, Employment. Kresja:Kartos Therapeutics: Employment, Equity Ownership. Lee:Kartos Therapeutics: Employment, Equity Ownership. Slatter:Kartos Therapeutics: Employment, Equity Ownership. OffLabel Disclosure: KRT-232 (formerly AMG 232) is a small molecule MDM2 inhibitor

MRI-Detectable Focal Lesions (FL) in Multiple Myeloma (MM) at Relapse Frequently Involve Novel Sites Not Involved at Diagnosis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5124-5124 ◽  
Author(s):  
Ronald Walker ◽  
L. Jones-Jackson ◽  
Eric Rasmussen ◽  
M. Miceli ◽  
Elias Anaissie ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
General Trend ◽  
M Protein ◽  
Focal Lesions ◽  
Extramedullary Tumor ◽  
Mri Scans ◽  
The Relationship ◽  
Baseline Examination

Abstract Macrofocal lesions (FL) in the medullary space are a hallmark of mm readily detected by MRI scans, both at diagnosis and at relapse. In this study we evaluated, among 25 patients enrolled in TT II, with FL at relapse and a preceding clinical CR (by M protein and marrow examinations) the relationship to presence and location of FL at diagnosis. On relapse, 17/25 (68%) had fewer FL, 5/25 (20%) had the same number of FL, 3/25 (12%) had more FL than on baseline examination. There was a general trend for the larger FL at baseline to still be present on relapse (Table 1). Despite the trend to fewer focal lesions on relapse compared to baseline, 11/25 (44%) of patients presented with FL in new sites that were not present on baseline. Finally, in relapsing patients, 4/25 (16%) presented with new sites of extramedullary tumor (EMD). These data establish that although there are usually fewer MRI-defined FL on relapse than on baseline examination, the vast majority of FL on relapse represent new areas of macrofocal disease that were not present at diagnosis. MRI FL Persisting from Baseline to Relapse (n=25) Size (cm) Baseline FL Present upon Relapse % < 0.5 1/2 50 0.5–1cm 8/10 80 1–2 cm 13/18 72 > 2 cm 10/16 63 All Sizes 26/36 72

scholarly journals The Relationship between Multiple Myeloma with Renal Failure and Metastatic Calcification

2018 ◽  
Vol 2018 ◽  
pp. 1-6
Author(s):  
Takanori Fukuta ◽  
Takayuki Tanaka ◽  
Yoshinori Hashimoto ◽  
Hiromi Omura
Keyword(s):  
Multiple Myeloma ◽  
Renal Failure ◽  
Blood Vessels ◽  
Hormone Level ◽  
Maintenance Hemodialysis ◽  
Metastatic Calcification ◽  
The Right ◽  
End Stage ◽  
The Relationship ◽  
Tomography Scan

While cases of multiple myeloma (MM) with metastatic calcification have been reported, the mechanisms for this calcification have yet to be explained. We observed a case of MM in a patient with end-stage renal failure who developed vascular and pulmonary calcification. A 51-year-old male was diagnosed with Bence-Jones type MM and required maintenance hemodialysis. He was treated with bortezomib-dexamethasone, vincristine-doxorubicin-dexamethasone, the M2 protocol, and lenalidomide-dexamethasone (Rd) therapy. During the sixth cycle of Rd therapy, he complained of pain in both lower legs. Well-demarcated ulcers with severe pain had developed on the right lower leg, both exterior thighs, and penis. We found that the patient’s serum intact parathyroid hormone level was elevated, while it had previously been permissively controlled. Computed tomography scan showed widespread centrilobular opacities of the bilateral lungs and high-density lesions along small blood vessels in the trunk and all four extremities. Histological calcifications were identified in small blood vessels and the alveolar walls. The risk of metastatic calcification in MM appears to be associated with renal failure, but not with MM itself.

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