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.

The Role of Novel Agents on Reversibility of Renal Impairment in Newly Diagnosed Patients with Multiple Myeloma; a Single Center Experience on 112 Patients,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3961-3961
Author(s):  
Meletios A Dimopoulos ◽  
Maria Roussou ◽  
Maria Gkotzamanidou ◽  
Erasmia Psimenou ◽  
Despoina Mparmparoussi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Multivariate Analysis ◽  
Renal Impairment ◽  
Median Time ◽  
Novel Agents ◽  
Newly Diagnosed ◽  
Renal Response ◽  
Group B

Abstract Abstract 3961 Renal impairment (RI) is a frequent complication of multiple myeloma (MM). Proteasome inhibitors and immunomodulatory drugs (IMiDs) are used as frontline therapy for MM but their effect on renal function recovery has not been clearly defined. To address this issue we studied 112 patients with newly diagnosed MM and RI who were treated in the Department of Clinical Therapeutics of the University of Athens, over the last decade. RI was defined as an estimated glomelural filtration rate (eGFR) ≤60 ml/min, using the simplified MDRD formula. Patients were divided into three groups; group T included 53 patients who received thalidomide-based regimens (with dexamethasone alone, with dexamethasone and melphalan or cyclophosphamide, or with VAD); group B included 30 patients who received bortezomib-based regimens (with dexamethasone alone, with dexamethasone and thalidomide or with cyclophosphamide) and group L included 29 patients who received lenalidomide-based regimens (with dexamethasone or with melphalan and prednisone). Lenalidomide dose was adjusted for the degree of RI according to current recommendations. Renal complete response (CRrenal) was defined as a sustained increase of baseline eGFR to >60 ml/min, renal partial response (PRrenal) as an increase of eGFR from <15 to 30–50 ml/min and renal minor response (MRrenal) as sustained improvement of baseline eGFR of <15 ml/min to 15–29 ml/min, or, if baseline eGFR was 15–29 ml/min, improvement to 30–59 ml/min. Patients in groups T and L were older than those of group B (p=0.0001). Anemia (Hb <10 g/dl) was more frequent in patients of group L (p=0.007). There were no significant differences in the severity of RI, or other clinical and laboratory parameters among the three groups. An improvement of renal function, recorded as MRrenal or better, was achieved more frequently in patients treated with bortezomib-(83%) or thalidomide-based regimens (77%) than in patients treated with lenalidomide-based regimens (55%, p=0.033). We subsequently focused our analysis in major renal responses (at least PRrenal) since this endpoint is clinically more relevant. CRrenal was achieved in 53% of patients in group T, in 70% in group B and in 34% in group L (p=0.014), while CRrenal+PRrenal rates were 55%, 80% and 38% for groups T, B and L, respectively (p=0.004). eGFR <30 ml/min was associated with a significantly lower probability of at least PRrenal (p=0.016). In multivariate analysis bortezomib-based regimens (OR: 8.8, 95% CI: 2–37, p=0.003) and thalidomide-based regimens (OR: 2.85, 95% CI: 1.01–8, p=0.046) were associated with higher probability at least PRrenal than lenalidomide-based regimens. Other factors that were independently associated with higher probability of at least PRrenal, were baseline eGFR >30 ml/min (OR: 4.85, 95% CI: 1.9–12.5, p=0.001) and age ≤65 years (OR: 3.8, 95% CI: 1.07–13.5, p=0.038). The median time to first renal response was longer for patients of group L compared to those of group T (5.5 months vs. 1.5 months, p=0.038) and it was significantly shorter for patients of group B (0.85 months, p=0.001). The median time to major renal response was 1.1 months for bortezomib-based and 2.7 months for thalidomide-based regimens, and exceeds 6 months for lenalidomide-based regimens (p=0.002). In multivariate analysis bortezomib-based regimens (OR: 3.12, 95% CI: 1.35–7.2, p=0.008) and baseline eGFR >30 ml/min (OR: 1.93, 95% CI: 1.13–3.3, p=0.015) were independently associated with a shorter time to ≥PRrenal. Myeloma response to treatment was 61%, 83% and 83% for the three treatment groups, respectively and was associated with any renal response (≥MRrenal; p=0.008) and with a major renal response (CRrenal+PRrenal; p=0.001). Among 8 patients who required dialysis (group T 4 patients, group B 4 patients), 4 patients (2 in each group) became independent of this procedure. This is the first analysis which compared the role of the three novel agents in MM patients presenting with RI. Our data indicate that novel agent-based regimens can improve renal function in the majority of patients with RI. However, bortezomib- and thalidomide-based regimens are more efficacious than lenalidomide-based regimens in this setting. Furthermore, bortezomib-based regimens act more rapidly than IMiD-based regimens even in patients with severe RI. We conclude that bortezomib-based regimens are the preferred therapy for newly diagnosed myeloma patients with RI. Disclosures: Dimopoulos: Janssen-Cilag: Honoraria; Celgene: Honoraria; Millenium: Honoraria. Terpos:Janssen-Cilag: Honoraria; Celgene: Honoraria.

Improvement in Renal Function and Its Impact on Survival in Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3368-3368
Author(s):  
Wilson I Gonsalves ◽  
Nelson Leung ◽  
S. Vincent Rajkumar ◽  
Angela Dispenzieri ◽  
Francis Buadi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
High Risk ◽  
Renal Impairment ◽  
Induction Therapy ◽  
Response To Therapy ◽  
Older Age ◽  
Newly Diagnosed ◽  
Renal Response ◽  
Novel Agent

Abstract Background: Renal impairment is a common feature of multiple myeloma (MM) seen in over a quarter of newly diagnosed patients (pts). Studies have confirmed the presence of renal impairment (RI) as a strong predictor of inferior survival in MM. Some studies have also indicated that reversibility of RI is associated with improved survival. However, it is not clear if normalization of renal function improves the outcome to that expected for MM pts without RI at diagnosis. Methods: We evaluated 1,135 consecutive pts with newly diagnosed MM seen at the Mayo Clinic, Rochester between December 2002 and January 2011. Renal function was assessed by the estimated creatinine clearance (CrCl) which was calculated by the modified MDRD formula. We examined these pts for improvement in renal function based on their CrCl at diagnosis and their highest CrCl during their disease course. RI was defined as having a CrCl of < 60. Pts were categorized based on their renal function at diagnosis and response to therapy: Group 1- CrCl >60 at diagnosis, Group 2- CrCl <60 at diagnosis but improved to >60 after therapy and Group 3- CrCl <60 at diagnosis and remained <60 after therapy. The degree of restoration of renal function was evaluated according to the IMWG criteria. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log rank test. Results: The median age at diagnosis was 65 years (range; 22 - 93) and 682 (60%) were male. The median follow up for the entire group from diagnosis was 73 mos (95% CI; 69 - 77). At diagnosis, 123 (11%) pts had a CrCl < 30, 322 (28%) had a CrCl of 30-59 and 690 (61%) had a CrCl >60. Most pts (N=754, 67%) received novel agent induction (NAI) therapy. The median PCLI was 0.7 (range: 0 – 22) and 91 (21%) pts had high-risk cytogenetics by FISH. The median OS for the pts with CrCl at diagnosis of < 30, 30-59 and >60 were 41 mos, 60 mos and not reached respectively (P < 0.001). Of the 445 patients with RI, the median absolute creatinine and CrCl at diagnosis were 1.6 mg/dL (range: 1 – 11) and 44 (range: 4 – 59) respectively. Among pts with RI, any improvement in CrCl was seen in 295 (66%) with median time to highest CrCl of 5 months and 228 (51%) had complete reversal of their RI. The median OS for pts with RI at diagnosis receiving and not receiving NAI therapy was not reached (NR) vs. 46 mos (P < 0.001). The median OS for Groups 1, 2 and 3 were NR, 60 and 49 mos respectively (Figure 1, P < 0.001). At a 6 month landmark analysis, the median OS for Groups 1, 2 and 3 were NR, 67 and 62 mos respectively (P < 0.001). The complete renal response and no renal response rates for pts with RI at diagnosis receiving and not receiving NAI induction therapy was (57% vs. 44%, P=0.004) and (29% vs. 39%, P=0.04) respectively. In a univariable analysis, presence of RI at diagnosis, no NAI therapy, older age, ISS stage 3, high-risk FISH, elevated PCLI, diagnosis prior to 2007 and increased LDH were found to predict for worse OS; however only older age (P<0.001), high-risk FISH (P=0.037) and lack of NAI therapy (P=0.023) retained their negative prognostic significance in a multivariable analysis. Conclusion: MM pts with RI treated with novel agent induction therapy demonstrate improved responses in their renal function and OS. The results also demonstrate improved outcome for pts with improvement in renal function, but it remains inferior to pts with normal renal function at diagnosis. These results have implications for early treatment strategies for pts at risk of developing renal insufficiency. Figure 1: OS based on improvement in CrCl upon receiving treatment Figure 1:. OS based on improvement in CrCl upon receiving treatment Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Recovery of Renal Function and Independence from Dialysis in Newly Diagnosed and Relapsed Multiple Myeloma Patients - A Single Instituition Experience.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4847-4847
Author(s):  
Girish Ravindranathan ◽  
Tanya Indrakumar ◽  
Sohail Ahmad ◽  
Moez Dungarwalla ◽  
Pamela Kanagasabapathy ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Failure ◽  
Renal Function ◽  
Renal Impairment ◽  
Current Therapy ◽  
High Dose ◽  
Newly Diagnosed ◽  
Female Ratio ◽  
Male To Female ◽  
Relapsed Myeloma

Abstract Background: Renal impairment occurs in up to 30% of patients who present with multiple myeloma and in up tp 50% of patients at some stage of the illness. It is known that renal impairment can be reversed in a significant number of such patients by correction of precipitating factors and rehydration but that 3–12% patients will require dialysis or other major intervention. These patient have a worse prognosis largely due to an excess of early deaths, renal failure being the major cause of death in 14% of myeloma patients and contributing factor in a further 14%. (Drayson et al UK MRC MM trials 1980–2002) We have conducted a study to look into the clinical course and outcome of all patients with renal impairment sufficiently severe to be referred to the regional renal unit in South East England between 2000 and 2007 with either newly diagnosed multiple myeloma (MM) or relapsed disease to try to identify features which predict for better outcomes. Methods: 62 patients with MM and renal failure received treatment in our hospital over the last 8 years. Patients have been assessed for recovery of renal function and dialysis independence in two groups - newly diagnosed (n=47) and relapsed patients (n=15). They were analysed separately as the disease tends to be biologically different at presentation and relapse, and therapeutic options may be different. In addition relatively little data on relapsed myeloma with renal failure is available. Results: 14 patients in the newly diagnosed group and 4 in the relapsed group were deemed unsuitable for an active treatment approach and have been excluded from statistical analysis in this paper but will be analysed separately to try to identify factors which could improve the outcome for this group. The patients with newly diagnosed MM and actively treated had a mean age of 65.3±1.7 years (range 41.9–83.3), male to female ratio of 1.7:1 and a mean peak creatinine at presentation of 684.5±60.9 mmol/l (range 107–1820). Light chain myeloma was overrepresented and was seen in 57.5% of patients (n=19). 12 (36.3%) of 33 the new patients avoided dialysis. 21 required dialysis, of whom 8 patients (38.1%) recovered function to dialysis independence at 6 months. There were only 3 deaths at 6 months follow-up. The mean age of the relapsed patients was 61.8±3.5 years (range 34.9–80.7), male to female ratio of 2.6:1 and a mean peak creatinine at presentation of 824±118.4 mmol/l (range 231–1591). Majority of myeloma was IgA in 36.3% (n = 4). Among the 11 relapsed, 82% (n=9) required dialysis but a significant proportion, 88% (n=8), were dialysis independent at 6 months There was only one death within 6 months of a relapse. Treatments in the 2 groups varied but involved the use of regimes containing high dose steroids in most patients. Conclusions: Our data suggest that renal failure and dialysis dependence can be avoided or is reversible in a large number of newly diagnosed and relapsed myeloma patients. This study of an unselected group of patients receiving current therapy provides an important baseline against which to compare the effect of approaches involving the newer biological agents.

Improved Survival of Patients with Multiple Myeloma after the Introduction of Novel Agents and the Applicability of the International Staging System (ISS) An Analysis of the Greek Myeloma Study Group (GMSG)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 655-655
Author(s):  
Efstathios Kastritis ◽  
Konstantinos Zervas ◽  
Argiris Symeonidis ◽  
Evangelos Terpos ◽  
Sossana Delimpassi ◽  
...  
Keyword(s):  
Staging System ◽  
Stage I ◽  
High Dose ◽  
Agent Based ◽  
Novel Drugs ◽  
Group A ◽  
International Staging System ◽  
Group B ◽  
Novel Drug ◽  
Novel Agent

Abstract Since the 1960s the survival of patients with MM had remained rather stable, until the introduction of high-dose melphalan with autologous stem cell transplant (ASCT) in the early 90s which improved the survival of younger patients. In 1999, thalidomide was introduced in the treatment of relapsed/refractory MM, followed by two other novel drugs: bortezomib and lenalidomide. Clinical trials have indicated that novel agent-based treatment are associated with improvement of response and survival in both relapsed/refractory and newly diagnosed patients. A recent report from Mayo Clinic (Kumar et al Blood2008, 111, 1516–20) has indicated that the survival of patients with MM treated at this major referral center, has improved significantly over the last decade. The purpose of our analysis was to confirm this observation in a large number of unselected patients who were treated in several hospitals throughout Greece and to assess the current applicability of ISS, a staging system that has been developed from a large database of patients who were treated with conventional or high-dose therapy before the introduction of novel drugs. Therefore we compared the outcome of two patient cohorts who started treatment before or after the introduction of the first novel drug, thalidomide: since January 1985, 1376 patients were entered in to the database of GMSG: 859 patients started treatment before 31/12/1999 (Group A) and 517 patients after 1/1/2000 (Group B), when thalidomide became available in Greece. Patients in group A were younger (p<0.001), had less often hypercalcemia (p=0.039), less often anemia (p=0.095), lower levels of urine Bence Jones protein (p=0.027) and less bone marrow plasma cell infiltration (p=0.030). One hundred and sixty seven patients (32%) patients in Group B were treated upfront with novel-drug based regimens compared to only 2 (0.2%) in Group A (p<0.0001). At least partial response to first line treatment was significantly higher in Group B compared to Group A (67% vs 56%, p<0.001). Despite more favorable characteristics of patients in Group A, the median overall survival for patients in group A was 36 months and for patients in Group B 48 months (p<0.001). For patients ≤70 years of age, median survival has improved almost two-fold in group B (74 months vs 39 months in group A, p<0.001). For patients >70 years of age, median survival for groups A and B was 26 and 33 months respectively (p=0.27). Early death rates were similar among patients in Group A and B: 8% and 9% (p=0.65) of patients survived less than 3 months in each group respectively. We then validated the applicability of the International Staging System (ISS) in patients of Group B which included patients who could receive either upfront or at a later stage of their disease novel-drug based regimens: 34.5% of patients were rated as ISS stage I, 22.2% as ISS stage II and 43.3% as stage III. The 5-year survival rate was 66% for ISS stage I patients, 45% for ISS stage II patients and 18% for ISS III patients (p<0.001). When only the 169 patients who were actually treated upfront with novel agent-based were analyzed, the 4-year survival rate was 85%, 61% and 26% for ISS stage I, II and III patients respectively (p=0.001). In conclusion, we confirmed that the introduction of novel drugs in the treatment of a large number of unselected patients with MM has significantly improved the outcome of this disease. Our data indicate that the survival benefit was more pronounced in patients ≤70 years of age. The widely available and reproducible ISS is applicable in patients treated with novel agent-based regimens and can be used for the staging of such patients. Despite the improvement of the survival of myeloma patients over the last decade, the outcome of older patients and of those with ISS stage III remains unsatisfactory.

Upfront Treatment with Novel Agents Improves the Survival of Symptomatic Patients with Multiple Myeloma Who Are Older Than 65 Years

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1947-1947
Author(s):  
Meletios A. Dimopoulos ◽  
Efstathios Kastritis ◽  
Maria Roussou ◽  
Maria Gavriatopoulou ◽  
Magdalini Migkou ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
General Population ◽  
Renal Impairment ◽  
Performance Status ◽  
Novel Agents ◽  
Agent Based ◽  
Risk Of Death ◽  
Group A ◽  
Group B ◽  
Novel Agent

Abstract Abstract 1947 The introduction of novel agents and improvements in supportive care over the last years resulted in a significant improvement of the overall survival (OS) of myeloma patients (Brenner et al Blood 2008, Kumar et al Blood 2008, Kastritis et al Leukemia 2009). However, these retrospective studies indicated that this survival benefit was more pronounced in younger patients while in older patients there was only a marginal improvement in outcome. Randomized studies have shown that upfront use of thalidomide with melphalan and prednisone (MPT) offers superior progression free survival (PFS) than MP alone, and in some of these studies there was also a survival advantage. Bortezomib with MP was also superior to MP in a randomized study, both in terms of PFS and OS. However, these studies included selected patients that may not be representative of the general population of elderly patients with myeloma. Thus, we analyzed our database in order to assess the effect of the upfront use of novel agents (thalidomide, bortezomib, lenalidomide) in consecutive patients older than 65 who were treated in a single center, in Athens, Greece. Many of these patients had been included in clinical trials; however, several patients who were ineligible because of poor performance status, significant renal impairment or comorbidities were also treated with novel agent-based regimens. Thus, these patients are more representative of the general myeloma population. We included patients who started treatment from January 1995 to January 2010, i.e patients who received similar supportive care. All patients were included in the analysis, regardless of performance status, infections, comorbidities etc. Patients were divided in two groups: those who were treated upfront with conventional regimens (group A, N=76) and those who were treated upfront with novel agent-based regimens (group B, N=115). Demographics of the two groups of patients, including gender and age were similar. Performance status at presentation was also similar among the two groups: 56% of those treated upfront with conventional agents and 57% of those treated upfront with novel agents had an ECOG performance status of 2 or higher. Thirty per cent of patients in group A and 44% of patients in group B were older than 75 years, respectively (p=0.07). The presence of osteolytic bone disease (p=0.313), anemia (Hb <10 g/dl, p=0.139), low platelets (<130,000/ml, p=0.949), albumin <3.5 g/dl (p=0.661), elevated LDH ≥300 IU/L (p=0.412), levels of Bence Jones proteinuria (p=0123), heavy (p=0.220) and light chain isotype (p=0.837) were similar among the two groups. However, patients treated upfront with novel agents presented more often with renal impairment (creatinine ≥2 mg/dl in 29% vs. 16%, p=0.044) and had more often elevated beta2-microglobulin levels (p=0.046) and ISS-3 disease (49% vs. 32%, p=0.1). Response to first line treatment was similar for the two groups: 73% for patients treated with novel agents vs. 67% for patients treated with conventional regimens (p=0.371). The median survival of the patients who were treated with novel agent-based regimens was 47 months while it was 34 months for those who received conventional regimens, but this was not statistically significant (p=0.271). Early death rates (<3 months from the initiation of treatment) were 8% for those treated upfront with novel agents and 11% for those treated with conventional regimens. After adjustment for adverse prognostic factors, such as elevated beta2-microglobulin, renal impairment and advanced age, upfront use of novel agents was associated with a significant reduction in the risk of death (HR=0.621, p=0.029). Subsequently, we performed a multivariate analysis which included established adverse prognostic factors and the upfront use of novel drugs. In this analysis, upfront treatment with novel agents was independently associated with superior outcome and a reduced risk of death (HR=0.626, p=0.033). Other factors independently associated with adverse outcome were ISS stage (ISS-3: HR=2.64, ISS-2: HR=1.25, p=0.032), elevated LDH ≥300 IU/L (HR=3.5, p=0.002) and low platelet counts <130,000/ml (HR=1.68, p=0.038) and age >75 years (HR=2, p=0.002). We conclude that in the general population of elderly patients with MM the upfront use of novel agents is associated with improved survival. Disclosures: Dimopoulos: Ortho-Biotech: Honoraria; Celgene: Honoraria; Millennium: Honoraria.

Reversibility of Renal Failure in Newly Diagnosed Patients with Multiple Myeloma Treated with High-Dose Dexamethasone Containing Regimens and the Impact of Novel Agents.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3586-3586 ◽  
Author(s):  
Efstathios Kastritis ◽  
Athanasios Anagnostopoulos ◽  
Aristotle Bamias ◽  
Maria Roussou ◽  
Dimitra Gika ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Serum Creatinine ◽  
Novel Agents ◽  
High Dose ◽  
Newly Diagnosed ◽  
High Dose Dexamethasone ◽  
Group A ◽  
Group B ◽  
The Impact ◽  
Bence Jones Proteinuria

Abstract Introduction: Approximately 20% of patients with multiple myeloma present with renal failure (RF). It has been reported that with supportive measures and with antimyeloma treatment RF is reversible in 25 to 58% of patients. However, the impact of specific antimyeloma therapies on RF reversibility has not been clarified. Because high dose dexamethasone containing regimens are associated with a rapid myeloma control we performed a study to assess the impact of such regimens on RF reversibility. Patients and methods: Over the last decade 41 patients with RF, defined as a serum creatinine ≥2 mg/dL at the time of diagnosis, received primary treatment with high dose dexamethasone-based regimens in our Department. All patients were eligible fore assessment of reversibility of RF which was defined as a sustained decrease of serum creatinine to <1.5 mg/dl. Patients were separated into two groups. Group A: 26 patients who received VAD, VAD like regimens, Melphalan-high dose Dexamethasone or high-dose Dexamethasone alone and Group B: 15 patients who received high-dose Dexamethasone with thalidomide, with bortezomib or both. Results: Patients characteristics included: median age of 65 years, creatinine ≥4 mg/dL in 44%, Bence-Jones proteinuria ≥2 gr/day in 34%, ISS stage III in 76%, light chain only myeloma in 37%. Dialysis was required at presentation in 24% of patients. Response to treatment (EBMT criteria) was documented in 46% of patients of Group A and in 64% of patients of group B. The toxicity profile of novel agents-Dexamethasone combinations was similar to that seen in patients without RF. RF was reversed in 73% of all patients, in 69% of patients in group A and in 80% of patients in group B. After treatment only two patients initially requiring dialysis remained on renal replacement therapy. Multiple variables were assessed for their impact in RF reversibility: serum Creatinine ≥4 mg/dL and Bence-Jones proteinuria≥2 gr/day were associated with significantly lower probability of RF reversal (56% and 54% respectively). RF reversibility rate was 85% in patients who responded to treatment versus 56% in those who did not respond (p=0.046). The median time to RF reversal was 1.9 months for all patients, 2 months for patients of group A and 0.8 months for patients of group B (p=0.005). Conclusions: RF can be reversed in the majority of patients with newly diagnosed MM when they are treated with high-dose dexamethasone based regimens. Furthermore, normalization of serum creatinine occurs in one half of patients who do not meet criteria for objective response. Novel agents such as thalidomide and bortezomib or both can be safely combined with high dose dexamethasone for the treatment of Myeloma patients who present with RF and are associated with rapid rate of RF reversal.

Bortezomib–Melphalan–Prednisone (VMP) in Newly Diagnosed Multiple Myeloma Patients with Impaired Renal Function: Cohort Analysis of the Phase III VISTA Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1727-1727 ◽  
Author(s):  
Meletios A Dimopoulos ◽  
Paul Richardson ◽  
Rudolf Schlag ◽  
Nuriet K Khuageva ◽  
Ofer Shpilberg ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Adverse Events ◽  
Renal Impairment ◽  
Cohort Analysis ◽  
Phase Iii ◽  
High Dose ◽  
Newly Diagnosed ◽  
Kaplan Meier ◽  
Number Of Patients

Abstract Renal impairment is a major complication of multiple myeloma (MM) and is associated with poor prognosis. Early effective treatment can lead to improvement in renal function, which is associated with better outcomes. Bortezomib (VELCADE®) is approved by the US FDA for the treatment of MM based on the results of the large, international, phase III VISTA study in previously untreated MM patients ineligible for high-dose therapy, in which bortezomib plus melphalan–prednisone (VMP, N=344) was superior to melphalan–prednisone (MP, N=338) across all efficacy end points, including response rates, time to progression (TTP), and overall survival (OS). Previous studies have shown bortezomib to be active and well tolerated in MM patients with renal impairment, including those requiring dialysis, and bortezomib pharmacokinetics are not influenced by degree of renal impairment (US label). In this analysis we assessed the efficacy and safety of VMP and MP in VISTA in patients with renal impairment. We also evaluated reversal of renal impairment after treatment. Treatment comprised nine 6-week cycles of VMP (bortezomib 1.3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32, cycles 1–4, and days 1, 8, 22, and 29, cycles 5–9, plus melphalan 9 mg/m2 and prednisone 60 mg/m2 on days 1–4, cycles 1–9) or MP alone. Patients with serum creatinine &gt;2 mg/dL were excluded. At baseline, 19 (6%), 162 (48%), and 159 (47%) VMP patients, and 15 (4%), 168 (50%), and 154 (46%) MP patients, had creatinine clearance (CrCl) ≤30, 31–60, and &gt;60 mL/min, respectively. Efficacy of VMP was not affected by CrCl; complete response rate (28% vs 32%), TTP, and OS were not significantly different among patients with baseline CrCl ≤60 vs &gt;60 mL/min. Safety profiles were comparable among patients with CrCl of 31–60 and &gt;60 mL/min for both VMP and MP. In the VMP arm, rates of serious adverse events (SAEs; 42% vs 47%), grade 3 (52% vs 55%), 4 (28% vs 27%), and 5 (8% vs 8%) adverse events (AEs), and discontinuations due to AEs (13% vs 17%) were similar between the groups. Rates of SAEs (63%) and grade 4 AEs (42%) appeared somewhat higher in the small group of patients with CrCl ≤30 mL/min, but rate of discontinuations due to AEs (11%) was similar. Similar trends were seen in the MP arm, with rates of grade 4 and 5 AEs and discontinuations due to AEs appearing higher in patients with CrCl ≤30 mL/min, suggesting an effect independent of addition of bortezomib. Reversal of renal impairment, defined as an improvement in CrCl from &lt;50 mL/min at baseline to &gt;60 mL/min on treatment, was seen in 49/111 (44%) VMP patients vs 40/116 (34%) MP patients. Time to reversal in all patients with baseline CrCl &lt;50 mL/min was significantly shorter with VMP (Figure; hazard ratio 1.586, p=0.03). Among patients achieving renal impairment reversal, median time to reversal was 2.1 months (range 0.2–11.8) with VMP and 2.4 months (range 0.2–13.6) with MP. By multivariate analysis, rate of reversal was significantly higher in younger patients (49% vs 30%, age &lt;75 vs ≥75 years, p=0.006) and those with less severe renal impairment (42% vs 24%, CrCl ≥30 vs &lt;30 mL/min, p=0.027), and showed a trend towards significance for VMP vs MP (odds ratio 1.50, p=0.07). Patients treated with VMP who achieved renal impairment reversal had a trend for longer OS (1-year rate: 90% vs 81%) and a better safety profile (lower rates of SAEs, grade 5 AEs, and discontinuations due to AEs) than those who did not. In conclusion, VMP represents a feasible, active, and well-tolerated treatment option for newly diagnosed MM patients with renal impairment, and results in reversal of renal impairment in a significant number of patients. Figure. Kaplan-Meier analysis of time to reversal of renal impairment in patients with baseline CrCl &lt;50 mL/min Figure. Kaplan-Meier analysis of time to reversal of renal impairment in patients with baseline CrCl &lt;50 mL/min

Reversibility of Renal Impairment of Multiple Myeloma Patients Treated with Bortezomib-Based Regimens: Identification of Predictive Factors.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1725-1725 ◽  
Author(s):  
Meletios A. Dimopoulos ◽  
Maria Roussou ◽  
Efstathios Kastritis ◽  
Maria Gavriatopoulou ◽  
Flora Zagouri ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Failure ◽  
Renal Function ◽  
Partial Response ◽  
Renal Impairment ◽  
Creatinine Clearance ◽  
Light Chain ◽  
Management Problem ◽  
Newly Diagnosed ◽  
Renal Response

Abstract Renal impairment (RI) is a frequent complication of multiple myeloma (MM) and a major management problem. Previous studies have shown that bortezomib is active and well tolerated in MM patients with RI and can be associated with improvement of renal function. The purpose of our analysis was to identify factors that may predict for renal impairment reversal in patients treated with bortezomib-based regimens. Over the last 5 years, 149 either newly diagnosed or relapsed/refractory MM patients received bortezomib-based regimens in our center. Our analysis is based on 46 consecutive patients with newly diagnosed (n=10) or relapsed/refractory (n=36) MM who presented with RI defined as creatinine clearance (CrCl) &lt; 50 mL/min. Median CrCl was 23 mL/min (range 6 to 48), 34 (74%) had a CrCl&lt;30 ml/min and 9 patients required renal dialysis. Sixteen patients (35%) had light chain only myeloma, elevated LDH&gt;300 IU/L was found in 24%, more than 2 gr/day of Bence Jones protein in 20 (44%) and kappa to lambda free light chain ratio was ≥8 or ≤0.125 in 25%. Patients received bortezomib (B) at standard dose and schedule, plus dexamethasone (D) (16 patients, 35%), or BD in combination with other agents such as thalidomide, doxorubicin or melphalan (30 patients, 65%). Renal complete response (RCR) was defined as a sustained increase of CrCl to &gt;60 mL/min after treatment. Renal partial response (RPR) was defined as an increase of CrCl by 50% and with improvement of renal function by at least one stage (stage IV: &lt;30 mL/min, stage III 30–59 mL/min) but with a post treatment CrCl &lt; 60 mL/min. RCR was documented in 22% of patients and RPR in 22% of patients. Thus, renal response (RCR + RPR) occurred in 20 patients (44%). The median time to renal response was 11 days (range 8 to 41). Among 9 patients who required dialysis 2 patients became independent of this procedure after the second cycle of treatment. The objective response rate (at least partial response) of the myeloma was 63%. Toxicities were similar to those seen in myeloma patients without renal failure who were treated with bortezomib-based regimens. Previously untreated patients (80% vs 33% for pretreated patients, p=0.012) and those with light chain only myeloma (69% vs 30%, p=0.012) had a higher probability to achieve renal response. Response of MM to treatment was also associated with higher rate of renal response (55% vs. 24% for non-responders, p=0.037). Creatinine clearance &lt;30 ml/min (47% vs. 33% for ClCr 330 ml/min, p=0.410), age&gt;75 years (p=0.309), corrected serum calcium ≥10,5 mg/dl (p=0.428), Bence Jones proteinuria ≥2g/day (p=0.167) or type of bortezomib regimen (BD or BD plus other agents, p=0.222) did not significantly affect the probability of renal response. Seventeen percent of patients presenting with RI died within the first 3 months after initiation of treatment. Patients with renal response had a trend for longer survival compared to those who did not achieve a renal response (79% vs 54% alive at 1 year, p=0.150). We conclude that when bortezomib-based regimens are administered to MM patients with RI, they are associated with a clinically meaningful renal response in 44% of them. Renal response is very rapid and occurred within 2 months in all patients. Previously untreated patients and those with light chain only myeloma may have a higher probability of renal response. Moreover, patients who achieved at least a partial response of their myeloma reversed RI more frequently than non-responders. Our data were derived from an unselected patient population with severe renal failure in more than two-thirds and with 20% of patients on dialysis. They provide further evidence that bortezomib-based regimens have a unique role in patients with RI.

The Impact of Different Pre-Transplant Regimens Including Novel Agents On Peripheral Blood Mobilization, Harvest, Response and Survival in Patients Undergoing ASCT for Multiple Myeloma. A Single-Center Experience in 210 Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2279-2279
Author(s):  
Evangelos Eleutherakis-Papaiakovou ◽  
Dimitrios Christoulas ◽  
Magdalini Migkou ◽  
Maria Gavriatopoulou ◽  
Maria Roussou ◽  
...  
Keyword(s):  
Induction Therapy ◽  
Response Rate ◽  
Novel Agents ◽  
High Dose ◽  
Agent Based ◽  
Cd34 Cells ◽  
Group A ◽  
Group B ◽  
The Impact ◽  
Novel Agent

Abstract Abstract 2279 Poster Board II-256 High dose therapy (HDT) with autologous stem cell transplantation (ASCT) has become the standard of care for eligible patients with multiple myeloma (MM) younger than 65 years. Induction therapy with combination regimens such as VAD or single agent dexamethasone has little impact on SC mobilization and offers a PFS of 12-18 months post-ASCT. Recently, novel agents (IMiDs and bortezomib) are used in the induction regimens prior to ASCT. The aim of this study was to assess the impact of conventional and novel agent-based induction regimens on SC harvest, response and survival among patients with MM treated in the Department of Clinical Therapeutics of the University of Athens, Greece. From January 1996 to June 2009, 210 consecutive patients who underwent ASCT were classified according to the induction regimens to: those who had received conventional chemotherapy (CC) only (MP, CD or VAD) (group A); those who were treated with CC followed by novel agent-based regimens (dexamethasone plus an IMiD and/or bortezomib; group B); and patients who were treated with novel agent-based regimens only prior to SC collection (group C). Stem cells were mobilized with G-CSF alone or with cyclophosphamide and G-CSF. Group A included 102 (49%) patients, group B 72 (34%) and group C 33 (16%) patients. Induction with novel agents only (group C) yielded a significantly greater SC collection compared to induction with CC only (group A) or CC followed by novel agent-based therapies (group B) (p=0.006 and p=0.038, respectively). The mean number of collected CD34+ cells/kg was 10×106 (range 2-43.2×106), 10.4×106 (range 2-49×106) and 15.1×106 (range 2-65×106) for groups A, B and C, respectively. The probability to collect a number of at least 5×106 CD34+ cells/kg was significantly higher in patients who received novel agents only when compared to those of groups A and B (78.8% vs. 57.5%, p=0.021). Among patients of group A, those who received induction with VAD had a significantly greater SC collection when compared to MP or CD (mean CD34+ cells/kg collected: 12.2×106vs. 7.56×106 /kg; p=0.031). Moreover, SC yield did not differ between patients who received VAD only or novel agent-based regimens only, as induction therapy (p=0.155). Engraftment data were comparable between the three groups. Age >55 years (p=0.039) and prior radiation therapy (p<0.0001) negatively influenced SC collection. The administration of novel agent-based regimens alone was associated with superior response rate prior to ASCT compared to CC alone as induction therapy (objective response (OR) 87.5% vs. 61.7%, p=0.007; at least vgPR 27.2% vs. 18.9%, p=0.032, for groups C and A, respectively). However, post-ASCT, patients of groups A and C achieved similar response rates (OR: 94.6% vs. 92.9%, p=0.736 and at least vgPR: 53.6% vs. 46.7%, p=0.526). The median OS, from the date of ASCT, in all patients was 74 months. Factors associated with longer OS included the achievement of CR or sCR post-ASCT (p=0.027), ISS-1 and -2 vs. ISS-3 (p=0.007), low beta2-microglobulin (<3.5 mg/mL) prior to ASCT (p=0.023), low marrow infiltration by plasma cells (<5%) prior to ASCT (p=0.016) and normal MRI pattern at diagnosis (vs. focal and diffuse, p=0.027). The use of novel agent-based regimens in induction therapy was associated with a probability of 4-year OS of 88% compared to 54% in patients of group A. There was a trend in favor of novel agent-based regimens as induction therapy in terms of OS (median 89 vs. 62 months, for patients of groups B+C and A, respectively; p=0.144). Furthermore, patients of group C had superior EFS post-ASCT compared to patients of group A (median 84 vs. 27 months; p=0.046). Other variables like mobilization regimen before HDT (cyclo 4g/m2+G-CSF vs. cyclo 2.5 g/m2+G-CSF vs. G-CSF only), high dose therapy dosage (melphalan 200 mg/m2vs. 180 mg/m2vs. 140mg/m2 or less), and the interval from diagnosis to ASCT (more or less than one year) did not correlate with OS or PFS. In conclusion, our study demonstrates that patients who received induction therapy with novel agents only prior to ASCT had a higher number of CD34+ cells collected when compared to induction with CC followed by novel agent-based regimens or CC alone. Furthermore, these patients achieved a higher response rate and a better quality of response before HDT, compared to patients who received CC only, but this did not correspond to a higher response rate post-ASCT. Further follow-up is needed to fully assess the impact of novel agent induction on patient's OS. Disclosures: No relevant conflicts of interest to declare.

Renal Impairment Is Not An Independent Adverse Prognostic Factor In Multiple Myeloma Patients Who Are Treated Upfront with Novel Agent-Based Regimens

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3033-3033 ◽  
Author(s):  
Meletios A. Dimopoulos ◽  
Efstathios Kastritis ◽  
Maria Roussou ◽  
Maria Gavriatopoulou ◽  
Magdalini Migkou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Renal Function ◽  
Kidney Disease ◽  
Renal Impairment ◽  
Renal Disease ◽  
Renal Dysfunction ◽  
Prognostic Impact ◽  
Agent Based ◽  
Stage 1 ◽  
Novel Agent

Abstract Abstract 3033 The adverse prognosis of renal impairment in patients with multiple myeloma (MM) has been reported in several series. However, the prognostic impact of renal dysfunction on the survival of MM patients who are treated upfront with novel agents has not been clearly defined. To address this question we studied 180 consecutive patients who received upfront novel agent (thalidomide, bortezomib or lenalidomide)-based regimens, in a single center in Athens, Greece. Many of these patients had been included in clinical trials; however, several patients who were ineligible because of poor performance status, significant renal impairment or comorbidities were also treated with novel agent-based regimens. Thus, these patients are more representative of the general myeloma population. Renal function, estimated by the glomelural filtration rate (eGFR) was assessed using the simplified Modification of Diet in Renal Disease (MDRD) formula (eGFR in mL/min/1.73 m2 = 186 × (Serum Creatinine)−1.154 × (Age)−0.203 × (0.742 if female) × (1.212 if African-American). Patients were divided into 5 groups according to the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (KDOQI) chronic kidney disease (CKD) classification. According to this classification, stage 1 includes patients with eGFR ≥90 ml/min, while stage 2 includes patients with eGFR between 60–89 ml/min, stage 3 with eGFR between 30–59 ml/min, stage 4 with eGFR between 15–29 ml/min and stage 5 includes patients with eGFR below 15 ml/min or patients who undergo dialysis. Eighty-five patients (47%) had stage 3–5 CKD and 95 (53%) had stage 1 or 2 CKD. One half of our patients (51%) were 70 years of age or older. Advanced age (p=0.001), anemia (p<0.001), low serum albumin (p=0.017), hypercalcemia (p<0.001), elevated beta2-microglobulin (p<0.001) and Bence Jones proteinuria >2 g/day (p<0.001) were associated with stage 3–5 CKD. The majority of patients with International Scoring System (ISS)-3 myeloma had advanced renal disease (stage 3–5 CKD in 76%) in comparison with ISS-2 (33%) or ISS-1 (10.5%) patients (p<0.001). Eighty-one percent of our patients received upfront an IMiD-based therapy, while 19% received bortezomib-based regimens. The dose of lenalidomide was adjusted according to renal function. The frequency of advanced CKD was similar among patients treated with IMiDs- or bortezomib-based regimens (47% vs. 48.5%, p=0.843). Response to primary treatment was similar between patients with stage 3–5 CKD and patients with stage 1 or 2 CKD (72.6% vs. 78.7%, respectively; p=0.343). In the univariate analysis, variables associated with worse survival were: stage 3–5 CKD (median survival 39 months vs. not reached in stage 1 or 2 CKD; p=0.001), age ≥70 years (p<0.001), anemia (p=0.005), hypercalcemia (p=0.012), ISS stage (p<0.001) and LDH ≥300 IU/L (p=0.007). However, in the multivariate analysis, the presence of renal dysfunction (stage 3–5 CKD) or the degree of renal dysfunction (evaluating each CKD stage separately) was not independently associated with survival. Age >70 years (p<0.001), corrected serum calcium ≥11.5 mg/dl (p=0.04) and elevated LDH ≥300 IU/L (p=0.001) were the only independent factors associated with worse survival. The same results were obtained when we assessed renal function as a continuous variable. We also evaluated the effect of CKD staging on the survival of patients within each ISS stage and we did not find any statistically significant correlation. We conclude that the presence °r the degree of renal dysfunction has no independent prognostic impact on the survival of multiple myeloma patients who are treated upfront with novel agent-based regimens. Disclosures: No relevant conflicts of interest to declare.

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