Light Chain–Induced Acute Renal Failure Can Be Reversed by Bortezomib-Doxorubicin-Dexamethasone in Multiple Myeloma: Results of a Phase II Study

Purpose To assess the efficacy of bortezomib-doxorubicin-dexamethasone (BDD) therapy in patients with multiple myeloma with light chain–induced acute renal failure. Patients and Methods Sixty-eight patients with light chain–induced acute renal failure and glomerular filtration rate (GFR) less than 50 mL/min received bortezomib (1.0 mg/m2 on days 1, 4, 8, and 11), doxorubicin (9 mg/m2 on days 1 and 4), and dexamethasone (40 mg on days 1, 4, 8, and 11); if well tolerated after two cycles, bortezomib could be increased to 1.3 mg/m2 and doxorubicin administered on days 1, 4, 8, and 11. Results By intent-to-treat analysis a myeloma response was obtained in 72% of 18 previously and 50 not previously treated patients (complete response [CR]/near CR [nCR], 38%; very good partial response [VGPR], 15%; partial response [PR], 13%; minor response [MR], 6%). Renal response was achieved in 62% of patients (renal CR, 31%; renal PR, 7%; renal MR, 24%). Median GFR increased from 20.5 to 48.4 mL/min. GFR improvement correlated with tumor response; the greatest increase to 59.6 mL/min was seen in the group of patients with CR/nCR/VGPR. Median progression-free survival was 12.1 months. One- and 2-year survival rates were 72% and 58%, respectively. Survival did not differ between patients with and without renal response but was inferior in previously treated patients (P < .001). In multivariate analysis, baseline GFR and tumor response correlated with renal response, and pretreatment status, lactate dehydrogenase, and myeloma response correlated with survival. The most common grade 3 or 4 toxicities were infection (19.1%), thrombocytopenia (14.7%), neutropenia (14.7%), fatigue/weakness (10.3%), and polyneuropathy (8.8%). Conclusion BDD induced a high rate of myeloma and renal responses, and treatment was well tolerated.

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Bortezomib-Doxorubicin-Dexamethasone (BDD) in Patients with Acute Light Chain Induced Renal Failure (ARF) in Multiple Myeloma (MM). Final Results of a Phase II Study.

Blood ◽

10.1182/blood.v114.22.3862.3862 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3862-3862 ◽

Cited By ~ 4

Author(s):

Heinz Ludwig ◽

Zdenek Adam ◽

Roman Hajek ◽

Richard Greil ◽

Elena Tóthová ◽

...

Keyword(s):

Renal Failure ◽

Renal Function ◽

Renal Impairment ◽

Light Chain ◽

Tumor Response ◽

Safety Analysis ◽

Renal Response ◽

Previously Treated ◽

Grade 3 ◽

Intent To Treat

Abstract Abstract 3862 Poster Board III-798 Acute light chain (LC) induced renal failure (ARF) is a severe complication of progressive MM. Reversal of ARF can only be achieved by fast, substantial and continuous suppression of production of pathogenic LCs. Bortezomib is highly effective and well tolerated in myeloma patients (pts) with renal impairment, because its metabolism is independent of renal function. In this study we evaluated the efficacy of Bortezomib in combination with doxorubicin and dexamethasone (BDD) in restoring renal function and in achieving tumor control in pts with LC-induced renal failure. In total, 72 pts have been enrolled; 2 pts did not fulfil inclusion criteria, 2 pts had been excluded because kidney biopsy revealed renal amyloidosis as main cause of renal failure. Hence, 68 pts constituted the intent to treat population and 58 pts were evaluable per protocol (≥2 cycles of therapy). Age: median 65.8; range 41-79 years. Forty-six (79%) pts presented with de novo MM, and 12 (21%) with progressive, previously treated disease; median baseline GFR was 20.0 ml/min (range 3.7-49.5 ml/min). ARF was defined as decrease in GFR to <50ml/min due to LC nephropathy. Previously treated pts were required to have acute deterioration (< 4 weeks before inclusion) of formerly normal renal function (GFR „d60ml/min), and clear signs of progressive disease with increased LC excretion. Treatment regimen: Bortezomib (1.3mg/m2, d 1, 4, 8, 11 until the first safety analysis; thereafter 1.0mg/m2, d 1, 4, 8, 11), doxorubicin (9mg/m2, d 1, 4, 8, 11 until first safety analysis; thereafter 9mg/m2, d 1 and 4) and dexamethasone 40mg (d 1, 4, 8, 11). Cycles were repeated every 21 days. Renal response was defined as complete (CRrenal, with GFR ≥60 ml/min), partial (PRrenal with GFR increase >100%, from <15 ml/min to 30-<60 ml/min), or minor (MRrenal with GFR increase >50%, either from <15 ml/min to 15-<30 ml/min or from 15-<30 ml/min to 30-<60 ml/min). Twenty-six of 58 evaluable pts achieved CR/nCR (45%), 10 (17%) VGPR, 9 (16%) PR and 4 (7%) MR (CR-MR: 85%). Median time to best tumor response was 88 days. Twenty-one (36%) pts achieved CRrenal, and 19 (33%) pts PR/MRrenal, respectively, yielding an ORRrenal of 69%. Three of the 9 dialysis dependent pts became dialysis independent. Median GFR increased from 20.0 ml/min (range: 3.7 – 50.2 ml/min) to 48.4 ml/min (range 6.7 – 135.5 ml/min). Improvement of GFR correlated weakly with tumor response. The median of best GFR increased to 60.0 ml/min (14.7-131.3 ml/min) in the 36 pts with CR/nCR/VGPR, to 38.9 ml/min (14.7 – 135.5 ml/min) in the 13 pts with PR/MR, and to 16.8 ml/min (6.7 – 57.9 ml/min) in 9 the pts with SD/PD, respectively. Overall survival (OS) was 72% @ 1 and 60% @ 2 years in the intent to treat and 84% @ 1 and 70% @ 2 years in the evaluable population. OS was similar in pts with and without complete renal response (p= 0.9267). Univariate analysis revealed a significant association between both, treatment status (previously treated vs. not previously treated), and LDH with survival (p<0.0003, and p<0.0232, respectively), while in multivariate analysis (Cox regression) treatment status only was found to correlate with survival (p=0.0211). Leukopenia, thrombopenia, and anemia of grade 3&4 were seen in 12%, 14% and 48%, respectively. Other common grade 3&4 toxicities were weakness/fatigue (12%) and polyneuropathy (10%), infection (7%), herpes reactivation (7%) and nausea/vomiting (5%). In conclusion, the BDD regimen resulted in high tumor (CR/nCR/VGPR: 62%, ORR: 85%) and renal response rates (CRrenal 36%, ORRrenal 69%). Improvement of renal function was more often seen in pts with significant tumor response and CRrenal was more likely in pts with less severe renal impairment. Treatment was well tolerated after dose adjustment. Disclosures: Ludwig: Celgene: Honoraria; Mundipharma: Honoraria; AMGEN: Honoraria; Ortho-Biotech : Honoraria; Janssen-Cilag: Research Funding; Roche: Honoraria. Hajek:Janssen-Cilag: Honoraria.

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

Blood ◽

10.1182/blood.v112.11.1725.1725 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1725-1725 ◽

Cited By ~ 1

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) < 50 mL/min. Median CrCl was 23 mL/min (range 6 to 48), 34 (74%) had a CrCl<30 ml/min and 9 patients required renal dialysis. Sixteen patients (35%) had light chain only myeloma, elevated LDH>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 >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: <30 mL/min, stage III 30–59 mL/min) but with a post treatment CrCl < 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 <30 ml/min (47% vs. 33% for ClCr 330 ml/min, p=0.410), age>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.

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Autologous haematopoietic stem cell transplantation in patients with multiple myeloma complicated by dialysis-dependent renal failure

Terapevticheskii arkhiv ◽

10.26442/00403660.2020.07.000777 ◽

2020 ◽

Vol 92 (7) ◽

pp. 70-76

Author(s):

M. V. Firsova ◽

L. P. Mendeleeva ◽

M. V. Solovev ◽

I. G. Rekhtina ◽

O. S. Pokrovskaya ◽

...

Keyword(s):

Multiple Myeloma ◽

Renal Failure ◽

Stem Cell ◽

Partial Response ◽

Stem Cell Transplantation ◽

Haematopoietic Stem Cell Transplantation ◽

Complete Response ◽

Haematopoietic Stem Cell ◽

Renal Response ◽

Good Partial Response

Aim.To assess the safety and efficacy of autologous haematopoietic stem cell transplantation (auto-HSCT) in multiple myeloma (MM) patients with dialysis-dependent renal failure. Materials and methods.During a period from May 2010 to December 2016 fourteen MM patients with dialysis-dependent renal failure aged 48 to 65 years underwent auto-HSCT. After the induction therapy complete response, very good partial response, partial response were documented in 64, 29, 7% of patients, respectively. In no case was a renal response achieved. Haematopoietic stem cell mobilization in most patients (13/14) was performed according to the scheme: G-CSF 10 g/kg. Melphalan in 3 dosages was used as pre-transplant conditioning: 100, 140 and 200 mg/m2; 13 patients underwent a single and in one case underwent a tandem auto-HSCT against the background of hemodialysis. Evaluation of the antitumor and renal response was assessed on the 100th day after auto-HSCT. Subsequently, against the background of programmed hemodialysis and in the setting of high-dosed melphalan (100200 mg/m2), 13 patients underwent a single and one patient underwent a tandem auto-HSCT. At +100 days after auto-HSCT, an antitumor response and renal response were assessed. Results.The period of agranulocytosis after auto-HSCT was from 5 to 12 days (median 8,5) and was accompanied by infectious complications, cardiac and neurological dysfunctions. At +100 days after auto-HSCT, the complete response was confirmed in 71% patients and very good partial response was confirmed in 29% patients. The minimal renal response was registered in 2 patients (14%), hemodialysis was stopped. The transplant-related mortality was absent. After a median follow-up of 53 months 5-year progression-free survival was 59%, and overall survival was 93%. Conclusion.Carrying out auto-HSCT in patients with dialysis-dependent renal failure contributed to the achievement of a minimal renal response in 14% of cases, which allowed these patients to stop hemodialysis. Patients whose conditioning regimen was performed using melphalan at a dose of 200 mg/m2showed more frequent complications in the early post-transplant period compared to patients who received a lower dose of melphalan (100140 mg/m2). Auto-HSCT in MM patients with dialysis-dependent renal failure is a feasible and effective treatment method, which in some cases contributes to independence from hemodialysis.

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Combined Bendamustine, Prednisone and Bortezomib (BPV) In Patients With Relapsed Or Refractory Multiple Myeloma and Light Chain Induced Renal Failure

Blood ◽

10.1182/blood.v122.21.3203.3203 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3203-3203 ◽

Cited By ~ 1

Author(s):

Wolfram Pönisch ◽

Barbara Moll ◽

Dietger Niederwieser

Keyword(s):

Multiple Myeloma ◽

Renal Failure ◽

Renal Dysfunction ◽

Light Chain ◽

Severe Side Effect ◽

Renal Response ◽

Group A ◽

Severe Renal Dysfunction ◽

Grade 3 ◽

Group B

Abstract Introduction Serious renal failure represents a main complication of Multiple Myeloma (MM). An estimated 25% to 50% of patients are affected during the course of their disease. These patients are at increased risk for infections and have a significantly worse prognosis. Small phase I/II studies suggest that treatment with chemotherapy and/or new substances results in recovery of renal function in more than 25%. The window of opportunity for reversal of renal impairment is rather small making an immediate and highly active treatment strategy mandatory. Bortezomib and bendamustine have turned out to be quickly acting and effective drugs in the treatment of MM. Methods Between March 2005 and March 2013, 36 patients (median age 64; range 32-81 years) with relapsed/refractory MM and light chain induced renal failure (creatinine clearance <60ml/min) were treated with bendamustine 60mg/qm on day 1 and 2, bortezomib 1.3mg/qm on day 1, 4, 8 and 11, and prednisone 100mg on day 1, 2, 4, 8 and 11. Cycles were repeated every 21 days. Patients were divided into two groups: group A (n=20) consisted of patients with moderate or severe renal dysfunction (eGFR 15-59ml/min) and group B (n=16) of patients with renal failure/dialysis (eGFR <15ml/min). Results The median number of the BPV-treatment was 2 (1-7) cycles. 24 patients (67%) responded after at least one cycle of chemotherapy with 3 CR, 3 nCR, 6 VGPR, and 12 PR. Six patients had MR, 2 patients stable disease and 4 patients had a progress. With a median follow up of 22 months of the surviving patients, median PFS and OS for patients with moderate or severe renal dysfunction (group A) were 10 months and 25 months, respectively. Outcome for these patients was significantly better compared to patients with renal failure/dialysis (group B) with a median PFS and OS of 3 months and 7 months, respectively (p<0.02). Eleven patients showed a CRrenal, 5 patients a PRrenal and 15 patients a MRrenal. Median time to first renal response and best renal response were 21 days and 42 days, respectively. The most common severe side effect was grade 3-4 thrombocytopenia in 81% of the patients. Grade 3-4 neutropenia was observed in 50% of the patients. Moderate to severe infections were seen in 13 patients. Summary These results indicate that the combination of bortezomib, bendamustine and prednisone is effective and well tolerated in patients with relapsed/refractory MM and light chain induced renal failure. Disclosures: No relevant conflicts of interest to declare.

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Favorable kidney recovery by extracorporeal light chain removal and anti-myeloma treatments in patients with newly diagnosed multiple myeloma and acute renal failure

Saudi Journal of Kidney Diseases and Transplantation ◽

10.4103/1319-2442.308370 ◽

2020 ◽

Vol 31 (6) ◽

pp. 1445

Author(s):

Pasquale Niscola ◽

Giorgio Silvestrini ◽

Paola Tatangelo ◽

Laura Scaramucci ◽

Germana Sfara ◽

...

Keyword(s):

Multiple Myeloma ◽

Renal Failure ◽

Acute Renal Failure ◽

Light Chain ◽

Newly Diagnosed

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Light chain muscle deposition caused rhabdomyolysis and acute renal failure in patient with multiple myeloma

Clinical Nephrology ◽

10.5414/cnp63050 ◽

2005 ◽

Vol 63 (01) ◽

pp. 50-53 ◽

Cited By ~ 3

Author(s):

R. Farah ◽

M. Kolin ◽

H. Cohen ◽

B. Kristal

Keyword(s):

Multiple Myeloma ◽

Renal Failure ◽

Acute Renal Failure ◽

Light Chain

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Bortezomib-Doxorubicin-Dexamethasone (BDD) for Reversal of Acute Light Chain Induced Renal Failure (ARF) in Multiple Myeloma (MM). Results from a Phase II Study

Blood ◽

10.1182/blood.v112.11.3682.3682 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3682-3682 ◽

Cited By ~ 2

Author(s):

Heinz Ludwig ◽

Zdenek Adam ◽

Roman Hajek ◽

Richard Greil ◽

Felix Keil ◽

...

Keyword(s):

Renal Failure ◽

Renal Function ◽

Light Chain ◽

Tumor Response ◽

Safety Analysis ◽

Tumor Control ◽

Newly Diagnosed ◽

Renal Response ◽

Grade 3 ◽

Intent To Treat

Abstract Acute light chain induced renal failure (ARF) is a severe complication of progressive MM, leading to permanent renal dysfunction and dependence on chronic hemodialysis in a substantial proportion of patients (pts). Reversal of kidney failure can only be achieved by fast and substantial suppression of pathogenic light-chains with effective anti-MM therapy. Bortezomib in combination with doxorubicin and dexamethasone has been shown to be highly effective in newly diagnosed pts. In addition, bortezomib is well tolerated in pts with reduced glomerular filtration rate (GFR) and its half life is independent of renal function. In this study we aimed to evaluate the efficacy of the BDD regimen in restoring renal function and in achieving tumor control in pts with light chain-induced renal failure. Up to now 67 of 70 planned pts have been enrolled. Documentation is available for 55 pts for intent to treat analysis and for 47 evaluable for renal and tumor response (age: median 66 years, range 41–79 years, ISS stage I: 2%, II: 13%, III: 85%. 37 (79%) of pts presented with de novo MM, and 10 (21%) with progressive disease; baseline median GFR 19.8 ml/min (range 3.7–49.9ml/min). ARF was defined in newly diagnosed pts as reduction of GFR to <50ml/min due to MM nephropathy, and in previously treated pts with signs of tumor progression and a GFR of ≥60ml/min within the last 4 weeks before enrolment as a reduction of GFR by >25% to <50ml/min. Treatment regimen: Bortezomib (1.3mg/m2, d 1, 4, 8, 11 until the first safety analysis; thereafter 1.0mg/m2 d 1, 4, 8, 11), doxorubicin (9mg/m2, d 1, 4, 8, 11 until first safety analysis; thereafter 9mg/m2, d 1 and 4) and dexamethasone 40mg (d 1, 4, 8, 11). Cycles were repeated every 21 days. 47 pts have completed at least 2 cycles and are evaluable for response as yet. 23 pts achieved CR/nCR (50%), 3 (6%) VGPR, 6 (13%) PR and 5 (11%) MR (CR-MR: 90%). Median time to response was 108 days. Median GFR increased from 19.8 ml/min (range: 3.7 – 49.9 ml/min) to 46.1ml/min (range 6.7 – 106 ml/min). Improvement of GFR correlated weakly with tumor response. In 26 pts with CR/nCR/VGPR, median GFR increased to 62 ml/min (10–106 ml/min). Best median GFR was 25 ml/min (11 – 106 ml/min) in 11 pts with PR/MR, and 22 ml/min (7 – 51 ml/min) in 10 pts with SD/PD. When renal response was defined either as complete (CRrenal: GFR≥60 ml/min), partial (PRrenal: increase from GFR <15 ml/min to 30–59 ml/min), or minor (MRrenal: increase in GFR either from < 15 ml/min to 15–29 ml/min or from 15–29 ml/min to 30–59 ml/min), a total of 15 (32%), and 14 (30%) pts achieved a CRrenal, or a PR/MRrenal, respectively, yielding an ORRrenal in 29 (62%) of pts (Table 1). Three of 8 dialysis dependent pts became dialysis independent. Table 1 Stage of renal failure at baseline (GFR) Number of pts Best renal response (number of pts, percentage) CRrenal PRrenal MRrenal Stage III 30–59ml/min 11 6 (55%) - - Stage IV 15–29ml/min 23 8 (35%) 8 (35%) - Stage V <15ml/min 13 1 (8%) 3 (23%) 3 (23%) Overall survival (OS) was 72% @ 2 years in the intent to treat and 78% @ 2 years in the evaluable population. OS was 76% @ 2 years in pts without CRrenal, and 86% in pts with CRrenal. Leucopenia, thrombopenia, and anemia of grade 3&4 were seen in 15%, 6% and 6%, respectively. Other common grade 3&4 toxicities were infection (4%), nausea/vomiting (6%), weakness/fatigue (11%) and polyneuropathy (8%). In conclusion, the BDD regimen resulted in high tumor (CR/VGPR 56%, ORR: 90%) and renal response rates (CRrenal 32%, ORRrenal 62%). Improvement of renal function was more often seen in pts with significant tumor response and CRrenal was more likely in pts with less severe renal impairment. Treatment was well tolerated after dose adjustment.

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Pulsed Cyclophoshamide, Thalidomide and Dexamethasone (CTD) Regimen for Previously Treated Patients with Multiple Myeloma: Long Term Follow up and Disease Control after Subsequent Treatments.

Blood ◽

10.1182/blood.v108.11.3565.3565 ◽

2006 ◽

Vol 108 (11) ◽

pp. 3565-3565

Author(s):

Maria Roussou ◽

Athanasios Anagnostopoulos ◽

Efstathios Kastrtis ◽

Charis Matsouka ◽

Despina Barmparoussi ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Progression Free Survival ◽

Conventional Chemotherapy ◽

Free Survival ◽

Long Term Follow Up ◽

Previously Treated Patients ◽

Previously Treated

Abstract Introduction: The effectiveness of thalidomide based regimens in patients with relapsed/refractory multiple myeloma is well established. However, there is still limited data regarding the long term follow up after such regimens and the outcome of patients when they progress and they receive further treatment. In order to answer these questions we reassessed our original series of 43 patients with previously treated multiple myeloma who were treated with a pulsed, oral CTD regimen between December 2000 and April 2002 (Dimopoulos MA, Hematol J2004;5:112). The CTD regimen consisted of oral cyclophosphamide 150 mg/m2 every 12 hours before meals on days 1 to 5, thalidomide 400 mg p.o. in the evening on days 1 to 5 and 14 to 18 and dexamethasone 20 mg/m2 in the morning after breakfast on days 1 to 5 and 14 to 18. The CTD combination was repeated every 28 days for three courses. Subsequently, responding patients were scheduled to receive maintenance treatment with monthly courses of CTD administered only for the first five days of each month. Patients and Methods: Progression free survival after initiation of CTD was updated in June 2006,ie more than 4 years after inclusion of the last patient. Type of treatment at the time of progression after CTD, response to this treatment and progression free survival were recorded for each patient. Results: Among the 43 patients, 14 had not responded to CTD and 29 (67%) had achieved at least a partial response. The median PFS for all patients was 10 months. As of June 2006, 3 patients remain off treatment and without progression for 55+, 55+ and 56+ months respectively. Thus, 40 patients were analyzed for further treatment and outcome. Ten patients (25%) died before receiving further treatment, 9 patients(23%) received conventional chemotherapy and 21 patients (52%) received continuous thalidomide and dexamethasone(15 patients), melphalan-bortezomib-dexamethasone and intermittent thalidomide (3 patients) or lenalidomide with dexamethasone (3patients). Among the 21 latter patients,6(28%)achieved at least partial response. A response was documented in 31% of CTD-sensitive patients (ie patients who had responded to CTD and then progressed) and in 20% of CTD-resistant patients (ie patients who had not responded to CTD). The median progression free survival of the 21 patients who received retreatment with novel agents plus dexamethosone was 5,3 months and the median survival was 10 months. Among the 9 patients who received conventional chemotherapy only one patient responded and the progression free survival was 2,8 months. Conclusions: After an oral pulsed CTD regimen 7% of patients remain without treatment and free of progression for more than 4 years. Further control of myeloma was achieved in one-third of patients who progressed after CTD and who received further treatment which included a novel agent.

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