Molecular monitoring of the tumor load predicts progressive disease in patients with multiple myeloma after high-dose therapy with autologous peripheral blood stem cell transplantation

Abstract Over the last years, high-dose (HD) chemotherapy followed by autologous peripheral blood stem cell transplantation (auto-PBSCT) has emerged as one very effective approach to improve the outcome in multiple myeloma (MM) patients (pts). HD- regimens in MM have been Busulfan and Cyclophosphamide (Bu/Cy) and HD-Melphalan (MEL), with or without total body irradiation (TBI). In this analysis, we analyzed the efficacy of different HD-regimens in consecutive MM (pts) receiving an auto-PBSCT at our institution between 8/1992 and 1/2005. Within these 12.5 years, 120 MM pts (68 male, 52 female) received an auto-PBSCT. Their median age was 56 (27–74) years. According to Durie &Salmon (DS), stage I, II and III disease prior to PBSCT were observed in 5 (4%), 30 (25%) and 85 pts (71%), respectively. Bu/Cy was used until 1997, TBI/MEL between 1997 and 1999, and MEL alone thereafter. The respective HD-regimens consisted of Bu/Cy (Bu 16mg/kg; Cy 120mg/kg) in 15 pts (12.3%), TBI/MEL (10 Gy; MEL 140 mg/m2) in 16 pts (13.1%) and MEL (200mg/m2) in 89 pts (73.0%). The median OS of all MM pts after auto-PBSCT in our analysis was 59.5 months. The therapy related mortality (d0 – d+100 after PBSCT) was 0% (0/15) for Bu/Cy, 3.4% (3/89) for MEL alone and 6.3% (1/16) for TBI/MEL. Main Bu/Cy side effects were infections (n=4), pulmonary fibrosis (n=2), renal failure (n=1) and VOD (n=1). Infections, mostly fever of unknown origin, were observed in the MEL and TBI/MEL group in 68/89 and 15/16 pts, respectively, however in none, pulmonary fibrosis, renal failure or VOD occurred. Comparing Bu/Cy- vs. MEL-conditioning in terms of OS, Bu/Cy prolonged OS in some pts (77.2 vs. 55.6 months, p=0.12), however, this difference failed to be of statistical significance. Our analysis on the influence of TBI on MEL-conditioning revealed no advantage for the combination-therapy (55.6 (+TBI) vs. 59.5 months (−TBI)), which confirms previous studies, also show no benefit for the addition of TBI. In conclusion, our data verify that comparable remission and OS rates can be obtained with less toxic conditioning regimens in MM, such as MEL200 alone, thereby significantly reducing therapy-related side effects. Since auto-PBSCT is an effective treatment option also for elderly and frail MM pts, choosing the best conditioning regimen is important and should improve the treatment outcome in MM further. Current studies are assessing the use of tandem-transplantations and novel anti-MM-agents, such as Bortezomib, Revlimid, Thalidomide and others, before, with and after high-dose regimens. These treatment concepts make highly effective but less toxic conditioning regimens imperative for auto- and allo-transplantations.

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Combination of Bortezomib and Dexamethasone (VD) or Bortezomib, Adriamycine and Dexamethasone (PAD) Followed by High Dose Therapy and Peripheral Blood Stem Cell Transplantation in First-Line Treatment of T(4;14) Multiple Myeloma : a Prospective Study of the MAG Group.

Blood ◽

10.1182/blood.v114.22.3408.3408 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3408-3408

Author(s):

Lionel Karlin ◽

David Ghez ◽

Marie-Olivia Chandesris ◽

Sylvain Choquet ◽

Margaret Macro ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Partial Response ◽

Peripheral Blood Stem Cell ◽

Induction Treatment ◽

High Dose ◽

High Dose Therapy ◽

Free Survival ◽

Blood Stem Cell Transplantation

Abstract Abstract 3408 Poster Board III-296 The t(4;14)(p16.3;q32), leading to the ectopic expression of two potential oncogenes, the Multiple Myeloma Set Gene (MMSET) and the Fibroblast Growth Factor 3 (FGFR3), is found in 15% of patients with multiple myeloma (MM) and is associated with a very poor prognosis. We previously shown in patients under 65 years of age that High Dose Therapy followed by Peripheral Blood Stem Cell Transplantation (HDT-PBSCT) provides a high response rate (RR) but a very short median relapse-free survival of only 11 months. In addition, relapses are often aggressive and chemoresistant. Thus, more effective regimen is urgently needed. We prospectively studied 23 t(4;14) MM patients treated with 3 or 4 cycles of a combination of Bortezomib and Dexamethasone (VD) (n=4) or of Bortezomib, Adriamycine and Dexamethasone (PAD) (n=19) as induction treatment before HDT-PBSCT (Melphalan 200 mg/m2). T(4;14) was detected using real time quantitative PCR searching for IGH/MMSET and FGFR3 transcripts. RR, event-free survival (EFS) and overall survival (OS) were evaluated. Median age at diagnosis was 51 years (range, 33-64). Isotype was IgA in 12 (52%) patients. All patients had stage II or III MM. An elevated serum β2m level (>3.5 mg/L) was found in 14 (61%) patients, and a low haemoglobin (Hb) level (<10 g/dL) in 10. Four presented with renal failure and 5 with hypercalcemia. Three (16%) of 19 patients had a t(4;14) without expression of FGFR3. After induction treatment with VD or PAD, PBSC were successfully harvested with granulocyte-colony stimulating factor only (n=15) or following a cycle of high-dose cyclophosphamide (n= 7). RR after induction treatment was complete response (CR) in 6 (26%) patients, very good partial response (VGPR) in 9 (39%), partial response (PR) in 3. Five patients had refractory or progressive disease (PD), including 1 who died before stem cell mobilization. RR after HDT was CR in 11 (48%), VGPR in 4 (17%) and PR in 4 (overall RR of 82%). Three had PD. With a median follow-up of 18 months (range, 3-32), 9 (39%) patients are alive without relapse, including 4 with a 19, 27, 30 and 32 months follow-up respectively. Twelve (52%) patients relapsed. Two patients died in the first month post HDT from PD. We found a median EFS and OS from initiation of therapy of 14.7 and 30.9 months respectively. EFS was not influenced by Hb and/or serum β2m level. However, we found a significantly longer OS in patients with low β2m (median non reached) as compared to patients with high β2m (median=23.1 months, p=0.04). These preliminary results illustrate the heterogeneity of this disease and indicate that some t(4;14) MM patients seem to benefit from bortezomib containing regimen as induction treatment before HDT in term of EFS and OS. A larger series with a longer median time of follow up will be presented. Disclosures: No relevant conflicts of interest to declare.

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Bortezomib Plus Dexamethasone As Induction Treatment Followed by Autologous Peripheral Blood Stem Cell Transplantation in Patients with Multiple Myeloma: A Study From India

Blood ◽

10.1182/blood.v118.21.4584.4584 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4584-4584 ◽

Cited By ~ 1

Author(s):

Shyam Aggarwal ◽

Anshul Bhalla ◽

S.L Khatri ◽

Anand Simar S ◽

Manorama Bhargava ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Peripheral Blood ◽

Progressive Disease ◽

Peripheral Blood Stem Cell ◽

Blood Stem Cell ◽

Induction Regimen ◽

Stem Cell Collection ◽

Blood Stem Cell Transplantation

Abstract Abstract 4584 Background and Objectives – Multiple myeloma (MM) is an incurable hematological malignancy, afflicting 25000 patients each year in India. Complete remission in myeloma is a surrogate marker for improved survival. The objective of induction regimen, using novel agents such a bortezomib, and Autologous Peripheral Blood Stem Cell Transplantation (APBSCT) is to increase the number of patients achieving CR. Here, we report a retrospective evaluation of the efficacy and response rates of induction with Bortezomib (Velcade) plus Dexamethasone (VD Regimen) followed by APBSCT and its effect on stem cell collection and final outcome of the transplant. Methods – Ten patients with symptomatic MM who had received VD induction before stem cell collection were evaluated. VD Induction comprised of Bortezomib (1.3 mg/m2) and Dexamethasone (40 mg) administered on days 1, 4, 8, 11 for four 21-day cycles. Peripheral blood stem cell collection technique involved administration of granulocyte stimulating factor (G-CSF); 300 mg/kg administered twice daily for 5 days. Adequate number of stem cells was collected in nine patients by a single harvest. One patient required apharesis twice for adequate stem cell collection. These cells were cryo-preserved. High dose Melphalan (200 mg/m2) was given followed by stem cell transfusion. Results – The median CD34-positive stem cell count was 5.6 × 106/kg. All the patients engrafted post transplant. The median time for engraftment i.e. Absolute Neutrophil Count (ANC) > 500/mL was 10 days and Platelet Count > 50000/mL was 16 days. The median length of hospital stay was 21 days. They were successfully managed for fever and infections with antibiotics, antifungals and supportive treatment. Irradiated blood (median - 4 units) and platelet apharesis (median – 3 units) were given. Response was assessed according to International Myeloma Working Group uniform response criteria. After induction with VD protocol, the overall response rate (ORR) was 90%. 2 patients (20%) had a complete response (CR), 7 patients (70%) had very good partial response (VGPR) and 1 patient (10%) had progressive disease. Post – APBSCT, the patient with progressive disease achieved VGPR and 6 out of 7 patients (85.7%) with VGPR achieved CR making the total responses as 8 CRs and 2 VGPRs. Thus, ORR was 100%, including 80% CR rate and 20% VGPR rate. All patients were put on maintenance therapy, 6 patients were on thalidomide (50 mg/day) and 4 patients received lenalidomide (10 mg/day) therapy. In the analysis, the median progression-free survival (PFS) was not reached at 22 months. The median overall survival (OS) was not reached after a median follow-up of 25 months, and the 2-year OS rate was 70%. Three patients (30%) had a relapse post-APBSCT, after 5 months, 9 months and 18 months respectively. Two patients (20%) expired, one due to myeloma and the other due to unrelated cause. All three patients with renal insufficiency experienced improvement in renal function and did not require dialysis post-APBSCT. Two patients (20%) developed neuropathy and two patients (20%) developed Herpes Zoster infection due to bortezomib therapy. Conclusions – The induction regimen of bortezomib plus dexamethasone is effective and well tolerated in symptomatic myeloma patients. It significantly improves post-induction and post-transplantation CR and VGPR rates and does not affect stem cell mobilization and collection procedure. Disclosures: No relevant conflicts of interest to declare.

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Idiotype Vaccination Using Dendritic Cells After Autologous Peripheral Blood Stem Cell Transplantation for Multiple Myeloma—A Feasibility Study

Blood ◽

10.1182/blood.v93.7.2411.407a24_2411_2419 ◽

1999 ◽

Vol 93 (7) ◽

pp. 2411-2419 ◽

Cited By ~ 3

Author(s):

Volker L. Reichardt ◽

Craig Y. Okada ◽

Arcangelo Liso ◽

Claudia J. Benike ◽

Keith E. Stockerl-Goldstein ◽

...

Keyword(s):

Multiple Myeloma ◽

Immune Response ◽

Dendritic Cells ◽

Stem Cell ◽

Immune Responses ◽

Peripheral Blood Stem Cell ◽

High Dose ◽

High Dose Therapy ◽

Dose Therapy ◽

Blood Stem Cell Transplantation

The idiotype (Id) determinant on the multiple myeloma (MM) protein can be regarded as a tumor-specific marker. Immunotherapy directed at the MM Id may stem the progression of this disease. We report here on the first 12 MM patients treated at our institution with high-dose therapy and peripheral blood stem cell transplantation (PBSCT) followed by Id immunizations. MM patients received PBSCT to eradicate the majority of the disease. PBSCT produced a complete response in 2 patients, a partial response in 9 patients and stable disease in 1 patient. Three to 7 months after high-dose therapy, patients received a series of monthly immunizations that consisted of two intravenous infusions of Id-pulsed autologous dendritic cells (DC) followed by five subcutaneous boosts of Id/keyhole limpet hemocyanin (KLH) administered with adjuvant. Between 1 and 11 × 106 DC were obtained by leukapheresis in all patients even after PBSCT. The administration of Id-pulsed DC and Id/KLH vaccines were well tolerated with patients experiencing only minor and transient side effects. Two of 12 patients developed an Id-specific, cellular proliferative immune response and one of three patients studied developed a transient but Id-specific cytotoxic T-cell (CTL) response. Eleven of the 12 patients generated strong KLH-specific cellular proliferative immune responses showing the patients’ immunocompetence at the time of vaccination. The two patients who developed a cellular Id-specific immune response remain in complete remission. Of the 12 treated patients, 9 are currently alive after autologous transplantation with a minimum follow-up of 16 months, 2 patients died because of recurrent MM and 1 patient succumbed to acute leukemia. These studies show that patients make strong anti-KLH responses despite recent high-dose therapy and that DC-based Id vaccination is feasible after PBSCT and can induce Id-specific T-cell responses. Further vaccine development is necessary to increase the proportion of patients that make Id-specific immune responses. The clinical benefits of Id vaccination in MM remain to be determined.

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