Renal Response in Patients (Pts) With Relapsed Refractory Multiple Myeloma (RRMM) and Severe Renal Impairment (RI): Interim Data From a Large Observational, Prospective Study

2015 ◽  
Vol 15 ◽  
pp. e289
Author(s):  
A. García-Guiñon ◽  
E. Morales ◽  
F. Escalante ◽  
M.S. Durán ◽  
E. González ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Impairment ◽  
Prospective Study ◽  
Severe Renal Impairment ◽  
Renal Response ◽  
Refractory Multiple Myeloma ◽  
Observational Prospective Study

Lenalidomide and Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma; Dosing of Lenalidomide According to Renal Function and Effect On Renal Impairment.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3871-3871
Author(s):  
Meletios A. Dimopoulos ◽  
Dimitrios Christoulas ◽  
Maria Roussou ◽  
Efstathios Kastritis ◽  
Magdalini Migkou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Renal Impairment ◽  
Performance Status ◽  
Prior Treatment ◽  
Renal Response ◽  
Refractory Multiple Myeloma ◽  
Dvt Prophylaxis ◽  
Grade 3 ◽  
Abnormal Renal Function

Abstract Abstract 3871 Poster Board III-807 Lenalidomide and dexamethasone (RD) is an active regimen for the management of relapsed and/or refractory multiple myeloma (MM). Over the last 2 years consecutive patients with pre-existing peripheral neuropathy grade ≥ 2 were treated with RD, regardless of their performance status and renal function. Patients with disease refractory to thalidomide, bortezomib and dexamethasone (i.e. progressive disease during treatment or within 60 days of treatment completion) were also included. Lenalidomide was administered on days 1 to 21 according to creatinine clearance (CrCl): 25 mg/day for CrCl >50 ml/min, 10mg/day for CrCl 30-50 ml/min, 15 mg every other day for CrCl 15-30 ml/min and for patients on dialysis, 15 mg three times per week on the day after dialysis. Dexamethasone was administered at a dose of 40mg PO on days 1 to 4 and 15 to 18 for the first 4 cycles and only on days 1 to 4 thereafter. RD was repeated every 28 days till disease progression or unacceptable toxicity. All patients received DVT prophylaxis with aspirin 100 mg/day unless there were already on coumadin or LMWH for pre-existing DVT or for other indications, usually atrial fibrillation. So far, 46 patients have been included and their characteristics were: median age was 69 years (range 43-87 years); median lines of prior therapy were 3 (range 1-6); prior treatment with thalidomide-containing regimens: 74% of patients (thalidomide-refractory: 68% of patients); prior treatment with bortezomib-containing regimens: 78% of patients (bortezomib-refractory: 56%); dexamethasone-refractory: 61% of patients; performance status ≥2: 33% of patients; LDH >300 IU/dl (normal value >225 IU/dl): 13% of patients; extramedullary involvement: 9% of patients; renal impairment (RI), defined as CrCl <50 ml/min: 28% of patients (range of CrCl: 13-49 ml/min). Thirty-six patients started with lenalidomide dose of 25mg/day and 10 patients with dose adjusted to renal function (10mg/day: 7 patients, 15mg every other day: 2 patients, 15 threetimes a week after dialysis: 1 patient). Response according to IMWG criteria include: CR: 17%, vgPR:5%, PR: 38%, SD: 22%, PD: 18% (PR or better: 60%). At least PR was observed in 43% of thalidomide-refractory patients, in 76% of bortezomib-refractory patients and in 20% of patients with high LDH. At least PR was documented in 60% of patients with RI and in 58% without RI. Median time to progression was 9 months and median overall survival was 16 months. Main toxicities include: neutropenia (grade 3/4): 26%; thrombocytopenia (grade 3/4): 11%; other toxicities (any grade): fatigue 50%, infections 28%, constipation 17%, diarrhea 15% and skin toxicity 11%. DVT prophylaxis with aspirin was administered to 39 patients (84%) and no patient developed DVT. Dose-reductions of lenalidomide were necessary in 46% of patients. There were no statistical differences in the incidence of adverse events in patients with normal or abnormal renal function. More specifically grade 3/4 thrombocytopenia and neutropenia occurred in 10% versus 11% (p=0.92) and 31% versus 10% (p=0.190) of patients with normal and abnormal renal function, respectively. The effect of treatment on RI reversal was also evaluated: 2 patients achieved complete renal response (i.e. baseline CrCl <50 ml/min improving to ≥60 ml/min) and 2 patients achieved minor renal response (baseline CrCl <15 ml/min improving to 15-29 ml/min or baseline CrCl 15-29 ml/min improving to 30-59 ml/min).Thus, in 4 of 10 patients with RI, treatment with RD resulted in improvement of renal function. We conclude that RD is an active treatment in patients with relapsed/refractory MM, even in patients with more heavily pretreated disease that those in the original report (Dimopoulos et al, N Engl J Med 2007;357:2123). RD is active in thalidomide and bortezomib refractory patients. With dosing of lenalidomide according to renal function, RD can be administered to patients with RI (who may not have other treatment options) without excessive toxicity. Furthermore, RD may improve the renal function in a subset of patients with RI. Disclosures: Dimopoulos: CELGENE: Honoraria.

Reversibility of Renal Failure in Newly Diagnosed Patients with Multiple Myeloma and the Role of Novel Agents.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 955-955 ◽  
Author(s):  
Maria Roussou ◽  
Efstathios Kastritis ◽  
Dimitrios Christoulas ◽  
Magdalini Migkou ◽  
Maria Gavriatopoulou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Renal Impairment ◽  
High Dose ◽  
Newly Diagnosed ◽  
Agent Based ◽  
Renal Response ◽  
Group A ◽  
Group B ◽  
Novel Agent

Abstract Abstract 955 Renal impairment (RI) is a common complication of multiple myeloma (MM) and is associated with increased mortality. High dose dexamethasone-based regimens have been extensively used for the initial management of patients with MM presenting with RI. Recently, novel agent-based regimens have been introduced in the frontline management of MM. The purpose of our analysis was to assess the effect of novel agent-based regimens on the rate of RI improvement and compare their efficacy with conventional chemotherapy (CC) plus dexamethasone (Dexa) in newly diagnosed MM patients. Over the last decade, 82 patients with newly diagnosed MM and RI, defined as creatinine clearance (CrCI) <50ml/min, received frontline treatment in our Center. Patients were divided into three groups: group A: 28 patients who received CC plus Dexa-based regimens (VAD, VAD-like regimens, melphalan plus Dexa); group B: 38 patients who received IMiDs-based regimens (thalidomide or lenalidomide with high dose Dexa and/or cyclophosphamide or melphalan) and group C: 16 patients who received bortezomib-based regimens with Dexa. Renal complete response (RCR) was defined as a sustained increase of baseline CrCI to >60ml/min. Renal partial response (RPR) was defined as an increase of CrCI from<15 to 30-50ml/min. Renal minor response (RMR) was defined as sustained improvement of baseline CrCI of<15ml/min to 15-29 ml/min, or, if baseline CrCI was 15-29 ml/min, improvement to 30-59 ml/min. Patients in group B were older than those of groups A and C (p=0.01) while more patient in group C had light chain only MM than in groups A and B (p=0.04). There were no significant differences in the severity of RI, Bence Jones proteinuria, hypercalcemia or ISS stage among the three groups. Improvement of renal function, recorded as RMR or better, was achieved more frequently in patients treated with novel agents (group B: 87% and in group C: 94%) than in patients treated with CC plus Dexa-based regimens (64%, p=0.024). Among 9 patients who required renal dialysis 3 became independent of this procedure after treatment. We subsequently focused our analysis in major renal responses (RPR or RCR), because this endpoint is clinically more relevant. RCR was achieved in 43% of patients in group A, in 50% in group B and in 69% of patients in group C (p=0.2) and RCR+RPR rates were 50% and 57% and 81% for groups A, B and C respectively (p=0.1). Creatinine clearance <30 ml/min was associated with a significantly lower probability of RCR or RPR only in patients treated with CC plus Dexa- or with IMiDs-based regimens (p<0.01), but not in patients treated with bortezomib (p=0.529). The probability of RPR+RCR was similar for patients treated with IMiDs compared to CC plus Dexa-based regimens (p=0.619). In multivariate analysis bortezomib–based regimens (p=0.02, OR: 7, 95% CI 1.5-25) and CrCl>30 ml/min (p=0.002, OR: 6.1, 95% CI 2.5-22.5) were independently associated with a higher probability of RCR+RPR. The median time to RPR was similar for patients treated with IMiDs compared to CC plus Dexa-based regimens (2.2 months for Group A, 1.5 months for Group B, p=0.587) but it was significantly shorter for Group C (0.7 months, p=0.017). Other factors associated with a shorter time to ≥RPR included CrCl>30 ml/min (p=0.039) and age<75 (p=0.089). In multivariate analysis bortezomib–based regimens (p=0.004, OR: 3 95% CI 1.6-6.7) and CrCl>30 ml/min (p=0.006, OR: 2.5 95% CI 1.3-4.5) were independently associated with a shorter time to ≥RPR. In landmark analysis (time was one month in order to reduce bias due to early deaths), rapid improvement of renal function (≤1 month) was associated with a trend for a longer survival compared to patients who achieved renal response later (>1 month) (47 vs. 21 months, p=0.19). Myeloma response to treatment was 58%, 68% and 79% for the three treatment groups respectively and was associated with renal response (p=0.024), though less strongly with a major renal response (p=0.061). Our data indicate that novel agent-based regimens can improve renal function in most patients; furthermore bortezomib-based regimens improve renal function to a higher degree and significantly more rapidly than CC plus Dexa-based or IMiD-based regimens even in patients with severe renal impairment. We conclude that bortezomib-based regimens may be the preferred treatment for newly diagnosed myeloma patients who present with renal impairment. Disclosures: Dimopoulos: JANSSEN-CILAG: Honoraria; CELGENE: Honoraria.

Lenalidomide Is Effective Treating Patients With Relapsed Multiple Myeloma and Very Severe Renal Impairment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5401-5401
Author(s):  
Cristina M. Joao ◽  
Fernando Gomes ◽  
Catarina Geraldes ◽  
Joana Maria Parreira ◽  
Manuel L Neves ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Impairment ◽  
Dose Adjustment ◽  
Board Member ◽  
Severe Renal Impairment ◽  
Response Duration ◽  
Advisory Board ◽  
Second Primary ◽  
Primary Tumors ◽  
Second Primary Tumors

Abstract Introduction Patients with multiple myeloma (MM) and severe renal impairment (SRI) have shorter survival and are often excluded from clinical trials. In these patients the use of Lenalidomide (Len) is based in pharmacokinetic models and because of the risk of increased toxicity, Len dose must be adjusted to renal function. Purpose To evaluate the outcomes of relapsed MM patients (RMM) with SRI (baseline creatinine clearance (CrCl) <30ml/min) treated with Lenalidomide-dexamethasone (Lendex), including patients under hemodyalisis. Methods We conducted a retrospective multicenter study in four Portuguese referral hospitals. All consecutive patients with RMM and SRI treated with Lendex between January 2007 and December 2012 were included. Lendex treatment was considered as the administration of low doses of dexamethasone and Len doses between 25mg/d and 5mg every other day. We evaluated the efficacy (response rate (RR), response duration and impact on renal function) and the relevant toxicities (myelo and neurotoxicity, thrombotic and infectious complications and second primary tumors). Results We retrospectively analyzed 22 patients with SRI and RMM treated with Lendex (median CrCl at start of Lendex was 19 ml/min with 13 patients under dialysis): 55% males; median age at diagnosis 63yo; median age at start of Lendex 68yo (51-79); main subtypes were IgGk (45%) and IgGλ (18%); 3 patients with high-risk cytogenetics; 5 plasmocytomas; 1 amyloidosis; 77% received Lenalidomide ≤10mg/d x 21 days in monthly cycles; median 8 cycles (2-50). Median number of previous lines was 2 (1-6). The global RR was 72% (16/22; 12 patients with ≥PR); 6 pts had progressive disease. Five out of 6 (83%) of the patients who progressed with Lendex had prior exposure to thalidomide. Median follow-up from start of Lendex was 14 months (2 – 62). The median time until maximal response was 3 months and the median response duration was 31 months (5 – 55) and in 58% (7/12) the response was longer than 2 years. Eighteen percent had renal improvement (median CrCl improvement of 44ml/min) but all the 13 patients on hemodyalisis maintained the need for this treatment. The treatment was interrupted in 3 cases because of adverse events and all the patients were on thromboprophylaxis with aspirin. In the long-term responders a continuous Len dose adjustment was required mainly because of myelo and neurotoxicity and the dexamethasone dose was reduced according to toxicities (metabolic, fatigue and psychiatric effects). There were no critical infections or second primary tumors. Conclusions CrCl<60 ml/min is a cut-off for Lenalidomide dose reduction. In our experience, after initial dose-adjustment of therapy, there should be a continuous process of dose-adjustment taking into account the individual tolerance, even without additional renal impairment. Lendex dosing adjusted according to CrCl does not negatively impact response or the rate of side effects. It may also have a potential to reverse RI and induce long duration of response. We concluded that Lendex is an effective and safe treatment regimen for relapsed MM patients with severe renal insufficiency. Disclosures: Joao: yassen: member of advisory board, member of advisory board Other; Celgene: member of advisory board, member of advisory board Other. Esteves:Celgene: member of advisory board, member of advisory board Other; Yassen: member of advisory board, member of advisory board Other.

MM-008: A Phase 1 Trial Evaluating Pharmacokinetics and Tolerability of Pomalidomide + Low-Dose Dexamethasone in Patients with Relapsed or Refractory and Refractory Multiple Myeloma and Renal Impairment

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4730-4730 ◽  
Author(s):  
Jeffrey Matous ◽  
David S Siegel ◽  
Sagar Lonial ◽  
R. Donald Harvey ◽  
Claudia Kasserra ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Impairment ◽  
Creatinine Clearance ◽  
Research Funding ◽  
Platelet Transfusion ◽  
Low Dose ◽  
Phase 1 ◽  
Employment Equity ◽  
Refractory Multiple Myeloma ◽  
Equity Ownership

Abstract Background: Pomalidomide (POM) is indicated for patients (pts) with relapsed or refractory multiple myeloma (RRMM) who received ≥ 2 prior therapies including lenalidomide and bortezomib and demonstrated progression on or within 60 days of completion of the last treatment (Tx). Renal impairment (RI) is a common comorbidity of multiple myeloma (MM) occurring in 20% to 40% of pts (Eleutherakis-Papaikovou, et al. Leuk Lymphom, 2007; Knudsen, et al., Eur J Haematol, 2000). POM is extensively metabolized, with < 5% eliminated renally as the parent drug (Hoffmann, et al., Cancer Chemother Pharmacol, 2013). POM in combination with low-dose dexamethasone (LoDEX) has shown efficacy in pts with RRMM and moderate RI (creatinine clearance [CrCl] < 30-44 mL/min), but pts with severe RI (CrCl < 30 mL/min; serum creatinine> 3 mg/dL) were excluded from most trials (Siegel, et al., Blood. 2012; Weisel, et al., J Clin Oncol, 2013). MM-008 is a multicenter, open-label, phase 1 study assessing the pharmacokinetics (PK) and safety of POM + LoDEX in pts with RRMM and normal or severely impaired renal function. Methods: Pts withRRMM (≥ 1 prior Tx) and normal kidney function or mild RI (creatinine clearance [CrCl] ≥ 60 mL/min; Cohort A—control arm), severe RI (CrCl < 30 mL/min) not requiring dialysis (Cohort B), and severe RI requiring dialysis (Cohort C) were eligible. Cohort A received POM 4 mg, and Cohort B received POM 2 or 4 mg on days 1-21 of a 28-day cycle, following a 3 + 3 dose-escalation design. Cohort B results informed the 4 mg dosing of Cohort C. All cohorts received DEX 40 mg (20 mg for pts aged > 75 yrs) on days 1, 8, 15, and 22. Tx continued until progression or unacceptable toxicity. Dose-limiting toxicities (DLTs) were defined as any of the following: grade (Gr) 4 neutropenia, febrile neutropenia, Gr 4 thrombocytopenia that is a ≥ 30% decrease in platelets from baseline and requires > 1 platelet transfusion, Gr 3 thrombocytopenia with significant bleeding (requiring hospitalization and/or platelet transfusion), Gr 4 infection, or ≥ Gr 3 other non-hematologic toxicity related to POM. Serial plasma samples were analyzed to generate PK parameters. Updated PK and AE data for all cohorts will be presented. Results: As of July 17, 2014, updated data for 16 treated pts were available (8 in Cohort A; 3 in Cohort B at 2 mg; 4 in Cohort B at 4 mg; and 1 in Cohort C). Median age was 67 yrs (range, 46-76 yrs), 56% were male, all had Eastern Cooperative Oncology Group performance status 0 or 1, and a median time from diagnosis of 3.8 yrs (range, 0.6-12.5). No DLTs in cycle 1 were reported for any cohort. The most common Gr ≥ 3 adverse events (AEs) were neutropenia, anemia, infection, and fatigue (Table). Median relative dose intensity was consistent across cohorts: 90% (Cohort A), 90% (Cohort B; 2 mg), 100% (Cohort B; 4 mg) and 100% (Cohort C). Three pts discontinued due to AEs (2 in Cohort A and 1 in Cohort B 4 mg); no deaths have occurred during treatment phase. Conclusion: MM-008 is an ongoing trial prospectively evaluating the PK and safety of POM + LoDEX in pts with RRMM and severe RI. Preliminary PK data support mean dose-normalized exposure in pts with RRMM being similar between those with severe RI and those with no or mild RI at the clinical dose of 4 mg; early tolerability data (after one cycle) are encouraging. Table Cohort A(n = 8) Cohort B(n = 3) Cohort B(n = 4) Cohort C(n = 1) Cohort Characteristics POM dose 4 mg 2 mg 4 mg 4 mg CrCl (mL/min) ≥ 60 mL/min < 30 mL/min without dialysis < 30 mL/min without dialysis < 30 mL/min with dialysis Safety Dose-limiting toxicities (n) N/A 0 0 0 Grade 3/4 AEs (n) Neutropenia 4 2 1 0 Anemia 3 1 2 0 Infection 3 2 0 0 Fatigue 2 0 0 0 N/A: Not applicable (4 mg POM is approved dose for population) Disclosures Matous: Celgene Corp: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Siegel:Celgene Corp: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Lonial:Onyx: Consultancy; BMS: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: Consultancy. Harvey:Celgene Corp: Research Funding. Kasserra:Celgene Corp: Employment, Equity Ownership. Li:Celgene Corp: Employment, Equity Ownership. Chen:Celgene Corp: Employment. Doerr:Celgene Corporation: Employment. Sternas:Celgene Corp: Employment, Equity Ownership. Zaki:Celgene : Employment, Equity Ownership. Jacques:Celgene Corp: Employment, Equity Ownership. Shah:Celgene Corp: Consultancy, Research Funding.

scholarly journals Efficacy and Safety of Melphalan 140mg/m2 Conditioned Autologous Stem Cell Transplantation in Elderly Pre-Dialysis and Dialysis Patients with Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5822-5822
Author(s):  
Hatem Ali ◽  
Baharani Jyoti ◽  
Shankaranarayana Paneesha ◽  
Richard Lovell ◽  
Alex George Kanellopoulos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Renal Impairment ◽  
Stem Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Severe Renal Impairment ◽  
Efficacy And Safety ◽  
Dialysis Patients ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Introduction: Information is currently available for the efficacy and safety of autologous stem cell transplantation (ASCT) conditioned with melphalan in multiple myeloma patients with mild to moderate chronic kidney disease. However, little information is available on ASCT in patients with severe renal impairment or those on dialysis with multiple myeloma. This population is usually not considered for ASCT due to a high risk of mortality. One retrospective study provides data on ASCT conditioned mainly with 200mg/m2 melphalan with high treatment related mortality (TRM) at 15%. Here we present safety and efficacy data on dose reduced melphalan (140/m2) conditioned ASCT in patients with severe renal impairment or haemodialysis at the time of transplant with a TRM of 0%. Patients and methods: We identified and report on 10 ASCT procedures carried out on 9 (7 males and 2 females) myeloma patients with a glomerular filtration rate (eGFR) of 35 ml/min/1.73m2 or less between 2006 and 2016. Median age was 58(51-74) years. Five patients were on haemodialysis at diagnosis and 4 went into ASCT while on haemodialysis. Six patients had light chain multiple myeloma. Initial therapy was bortezomib based in 6 patients, with 4 receiving thalidomide and 1 received both thalidomide and bortezomib pre ASCT. Most patients were mobilised with G-CSF alone and only 1 received cyclophosphamide and G-CSF. ASCT was conditioned in all cases with 140mg/m2of Melphalan. Patients on hemofiltration were supported during ASCT as per institutional guidelines. We collected data on response, stem cell collection, engraftment, progression free survival (PFS), overall survival (OS) and treatment related mortality (TRM). Results: Median follow up for the whole group was 24 (6-114) months. Pre ASCT 6 patients were in VGPR and 3 in PR. The median cell dose collected was 6.92×10 6 CD34 cells/kg (range 3.06-8.27). The median time to neutrophil engraftment (absolute neutrophil count>0.5×109/L) and platelet engraftment (>20×109/L) was at day 13 and 15 respectively. The TRM at day+100 was 0%. Post ASCT best responses were as follows-7 patients were in VGPR; 1 in PR and 1 progressed. The median PFS was 24months and median OS was 27 months. At the time of data collection only one person had died. The cause of death was disease progression with refractory disease. One patient became free of haemodialysis pre ASCT, one after ASCT and 1 more dropped frequency of dialysis sessions from 3 to 2 per week. Discussion: Autologous stem cell transplant using low dose Melphalan (140mg/m2) as consolidation post a bortezomib based induction therapy is an effective and safe treatment option for the pre-dialysis and dialysis patients with multiple myeloma. In our hands the TRM is extremely low suggesting the lower dose to be more appropriate than melphalan at 200mg/m2. It provides good PFS and in some cases freedom from haemodialysis. Further prospective trials are needed to confirm these findings. Disclosures Paneesha: Abvie: Honoraria. Kishore:celgene: Other: travel grant.

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