Prognostic value of bone marrow angiogenesis in patients with multiple myeloma undergoing high-dose therapy

Abstract Introduction Magnetic resonance imaging (MRI) of the spine and the pelvis is an important tool to evaluate bone disease in patients with symptomatic multiple myeloma (MM) at the time of diagnosis. In the context of high-dose therapy and autologous stem cell transplantation (ASCT), it has also been reported that the number of MRI focal lesions (> 7) and the presence of diffuse pattern correlate with inferior survival (Walker et al. J Clin Oncol; 25:1121-1128 2007). MRI might help in the better definition of complete response (CR). However, the high number of false positive results suggests that another imaging method, such as Positron emission tomography combined with computed tomography using fluoro-deoxy-glucose (PET-CT), might be of more value in this setting. Moreover, imaging techniques have rarely been compared to minimal residual disease (MRD) evaluated by flow cytometry from bone marrow aspiration in the context of frontline therapy including novel agents and ASCT. The goal of our study was to compare prospectively MRI and PET-CT at 3 different time-points, at diagnosis, after 3 cycles of triplet induction therapy and prior to maintenance therapy in a group of patients enrolled into IFM-DFCI 2009 trial comparing frontline or delayed ASCT. Patients and methods In the prospective IFM-DFCI 2009 trial, 700 patients with de novo symptomatic MM eligible for high-dose therapy have been randomized in France and Belgium to receive either 8 cycles of bortezomib-lenalidomide-dexamethasone (VRD) followed by 1-year maintenance with lenalidomide, or 3 cycles of VRD followed by high-dose therapy and ASCT plus 2 cycles of VRD consolidation and 1-year lenalidomide maintenance. 134 / 700 patients were also included in the IMAJEM trial (NCT01309334, also supported by STIC program granted by the French NCI) aimed at comparing in both arms of the IFM-DFCI 2009 study spine and pelvis MRI and whole-body PET-CT at diagnosis (number of lesions, primary end-point), after 3 cycles of VRD, and prior to maintenance (prognosis impact of imaging negativity, secondary end-point). PET-CT and MRI results before maintenance were also compared with MRD assessed by 8-color flow cytometry. MRI and PET-CT data were analyzed locally in each of the 15 participating centers, and systematically reviewed blindly by an independent committee consisting of 2 radiologists and 2 nuclear medicine physicians with extensive experience in MM field. Results At diagnosis, MRI was positive in 127/134 (94.7%), and PET-CT in 122/134 (91%) patients, respectively (McNemar test = 0.94, p-value = 0.33). MRI patterns of marrow involvement were the following: (1) normal in 7 cases (5%); (2) focal lesions (FL) in 46 cases (34%); (3) homogeneous diffuse infiltration in 41 cases (31%); (4) combined diffuse infiltration and FL in 35 cases (26%); and (5) variegated or "salt-and-pepper" pattern with inhomogeneous bone marrow with interposition of fat islands in 5 cases (4%). PET-CT patterns were the following: (1) normal in 12 cases (9%); (2) FL in 44 cases (33%); (3) diffuse infiltration in 12 cases (9%); (4) combined diffuse infiltration and FL in 66 cases (49%); (5) extramedullary disease in 10 cases (7.5%). The median number of FL assessed by PET-CT was 3. Conclusion MRI of the spine and pelvis and whole-body PET-CT are equally effective to detect bone involvement in symptomatic patients at diagnosis. The prognosis relevance of both MRI and PET-CT, and the comparison with MRD assessed by flow cytometry will be presented at the meeting. Disclosures Karlin: Janssen: Honoraria; celgene: Consultancy, Honoraria; Sandoz: Consultancy. Stoppa:Janssen: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hulin:Celgene Corporation: Honoraria. Marit:Celgene, Janssen: Congress expenses Other.

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Evaluation of the kinetics of the bone marrow tumor load in the course of sequential high-dose therapy assessed by quantitative PCR as a predictive parameter in patients with multiple myeloma

Bone Marrow Transplantation ◽

10.1038/sj.bmt.1702628 ◽

2000 ◽

Vol 26 (8) ◽

pp. 851-858 ◽

Cited By ~ 15

Author(s):

FW Cremer ◽

E Ehrbrecht ◽

K Kiel ◽

A Benner ◽

U Hegenbart ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Quantitative Pcr ◽

High Dose ◽

High Dose Therapy ◽

Dose Therapy ◽

Tumor Load ◽

Kinetics Of

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Meta-analysis to Evaluate High-Dose Therapy Followed by Stem Cell Transplant in Patients With Multiple Myeloma

JAMA Oncology ◽

10.1001/jamaoncol.2018.3483 ◽

2018 ◽

Vol 4 (11) ◽

pp. 1617 ◽

Cited By ~ 1

Author(s):

Brian Claggett ◽

Lu Tian ◽

Lee-Jen Wei

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Stem Cell Transplant ◽

Meta Analysis ◽

High Dose ◽

Cell Transplant ◽

High Dose Therapy ◽

Dose Therapy

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High dose therapy (autologus transplant)

Oxford Handbook of Cancer Nursing ◽

10.1093/med/9780198569244.003.0020 ◽

2007 ◽

pp. 261-268

Keyword(s):

Bone Marrow ◽

Bone Marrow Suppression ◽

Limiting Factor ◽

High Dose ◽

Cure Rate ◽

High Dose Therapy ◽

Dose Therapy ◽

Normal Tissues ◽

Higher Doses

Principles and uses 262 Conditioning 264 Nursing issues of high dose therapy 266 Many haematological cancers are treated more effectively by higher doses of chemotherapy and radiotherapy than by lower doses. Continuing to escalate the dose given will theoretically increase the cure rate. However, the dose-limiting factor is the toxicity to normal tissues. The first tissue to be seriously affected is the bone marrow. Bone marrow suppression results in:...

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Total Therapy With Tandem Transplants for Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v93.1.55 ◽

1999 ◽

Vol 93 (1) ◽

pp. 55-65 ◽

Cited By ~ 436

Author(s):

B. Barlogie ◽

S. Jagannath ◽

K.R. Desikan ◽

S. Mattox ◽

D. Vesole ◽

...

Keyword(s):

Multiple Myeloma ◽

Remission Induction ◽

Comprehensive Treatment ◽

High Dose ◽

Newly Diagnosed ◽

High Dose Therapy ◽

Dose Therapy ◽

Total Therapy ◽

Macrophage Colony ◽

Intent To Treat

Abstract Between August 1990 and August 1995, 231 patients (median age 51, 53% Durie-Salmon stage III, median serum β-2-microglobulin 3.1 g/L, median C-reactive protein 4 g/L) with symptomatic multiple myeloma were enrolled in a program that used a series of induction regimens and two cycles of high-dose therapy (“Total Therapy”). Remission induction utilized non–cross-resistant regimens (vincristine-doxorubicin-dexamethasone [VAD], high-dose cyclophosphamide and granulocyte-macrophage colony-stimulating factor with peripheral blood stem cell collection, and etoposide-dexamethasone-cytarabine-cisplatin). The first high-dose treatment comprised melphalan 200 mg/m2 and was repeated if complete (CR) or partial (PR) remission was maintained after the first transplant; in case of less than PR, total body irradiation or cyclophosphamide was added. Interferon--2b maintenance was used after the second autotransplant. Fourteen patients with HLA-compatible donors underwent an allograft as their second high-dose therapy cycle. Eighty-eight percent completed induction therapy whereas first and second transplants were performed in 84% and 71% (the majority within 8 and 15 months, respectively). Eight patients (3%) died of toxicity during induction, and 2 (1%) and 6 (4%) during the two transplants. True CR and at least a PR (PR plus CR) were obtained in 5% (34%) after VAD, 15% (65%) at the end of induction, and 26% (75%) after the first and 41% (83%) after the second transplants (intent-to-treat). Median overall (OS) and event-free (EFS) survival durations were 68 and 43 months, respectively. Actuarial 5-year OS and EFS rates were 58% and 42%, respectively. The median time to disease progression or relapse was 52 months. Among the 94 patients achieving CR, the median CR duration was 50 months. On multivariate analysis, superior EFS and OS were observed in the absence of unfavorable karyotypes (11q breakpoint abnormalities, -13 or 13-q) and with low β-2-microglobulin at diagnosis. CR duration was significantly longer with early onset of CR and favorable karyotypes. Time-dependent covariate analysis suggested that timely application of a second transplant extended both EFS and OS significantly, independent of cytogenetics and β-2-microglobulin. Total Therapy represents a comprehensive treatment approach for newly diagnosed myeloma patients, using multi-regimen induction and tandem transplantation followed by interferon maintenance. As a result, the proportion of patients attaining CR increased progressively with continuing therapy. This observation is particularly important because CR is a sine qua non for long-term disease control and, eventually, cure.

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Significance of detection of occult non-Hodgkin's lymphoma in histologically uninvolved bone marrow by a culture technique

Blood ◽

10.1182/blood.v79.4.1074.1074 ◽

1992 ◽

Vol 79 (4) ◽

pp. 1074-1080 ◽

Cited By ~ 1

Author(s):

JG Sharp ◽

SS Joshi ◽

JO Armitage ◽

P Bierman ◽

PF Coccia ◽

...

Keyword(s):

Bone Marrow ◽

Hodgkin’S Lymphoma ◽

Culture Technique ◽

Hodgkin's Lymphoma ◽

High Dose ◽

High Dose Therapy ◽

Lymphoma Cells ◽

Dose Therapy ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma

Abstract Prolonged disease-free survival of patients with recurrent or resistant non-Hodgkin's lymphoma (NHL) has been achieved with high-dose therapy followed by autologous bone marrow transplantation (ABMT). A concern with the use of ABMT is that the marrow that is reinfused may contain undetected NHL cells with the potential to reestablish metastatic disease in the recipient. Using a culture technique that is sensitive for detecting occult lymphoma cells in BM, we analyzed histologically normal marrow harvests from 59 consecutive patients with intermediate- or high-grade NHL who were candidates for high-dose therapy and ABMT. The culture results indicated that 22 of the patients had occult lymphoma in their marrow. Forty-three patients underwent high-dose therapy followed by ABMT. Twenty-four achieved a complete clinical remission. Those with occult lymphoma in their harvests (11 patients) continued to relapse for up to 3 years, whereas no relapses were observed beyond 8 months in 13 patients receiving marrow that did not contain detectable lymphoma cells using the culture technique. The relapses in the patients who achieved a complete remission occurred at sites of prior bulky disease rather than at new sites, suggesting that the ability to detect occult lymphoma cells in marrow is a marker of biologic aggressiveness and/or resistance to therapy, or that the reinfused cells could only grow in previously involved sites. The detection of lymphoma cells in marrow used for ABMT is an important adverse prognostic factor, and appears to be independent of other clinical predictors of outcome such as sensitivity or resistance of disease to prior chemotherapy.

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An Interim Report Experience on Acute Leukemia and High Dose Therapy in Jehovah’s Witnesses Treated in a Single Institution.

Blood ◽

10.1182/blood.v104.11.5021.5021 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5021-5021

Author(s):

Patrizio P. Mazza ◽

Giulia G. Palazzo ◽

Barbara B. Amurri ◽

Giovanni G. Pisapia ◽

Giancarla G. Pricolo ◽

...

Keyword(s):

Bone Marrow ◽

Acute Leukaemia ◽

Phase 1 ◽

High Dose ◽

Blood Products ◽

High Dose Therapy ◽

Jehovah’S Witnesses ◽

Jehovah's Witnesses ◽

Dose Therapy ◽

Autologous Pbsct

Abstract The major difficulty in the treatment of Jehovah’s Witnesses with haematological malignancies is the deny to the transfusion of blood products as support to chemo-radiotherapy; since the use of any form of bone marrow transplantation it is instead not precluded, this may be an alternative. From 1997 to July 2004 we treated 9 Jehovah’s Witnesses with de novo acute leukaemia without transfusions of blood products; in the same period 10 Jehovah’s Witnesses with various malignancies received high-dose therapy as conditioning to autologous PBSCT or allogeneic BMT. Acute leukaemia consisted of FAB-M3 4 patients (pts), FAB-M4 1 pt, FAB-L1 1 pt, FAB-L2 2 pts, FAB-L3 1 pt. Hb at diagnosis was 10.3g/dL mean (5.5–14.0 range), PLT at diagnosis were 40x10^3/μL mean (5–197 range). The mean age of pts was 26.2 years (2–49 range). The treatment consisted of protocols in use in our Institution at the time of diagnosis. The nadir of Hb was 5.3g/dL mean (1.3–8.3 range) and it was reached 10 days mean from start of therapy (1–16 days range); the nadir of PLT was 16x10^3/μL mean (0–70 range) and was reached 6 days mean from start of therapy (1–13 days range). The results to therapy show that 8/9 pts reached a CR and 1 died for anaemia during induction when the Hb was 1.3g/dL; at the follow-up 2 pts relapsed 3 and 8 months, respectively and died for disease progression, 6 pts are alive and in CR 12–60 months following the end of therapy. The patients undergoing high-dose therapy included NHL 1 pt, ALL 2 pts, CLL 1 pt, Breast Cancer 1 pt, CML chronic phase 1 pt, CML blastic phase 1 pt, MDS 1 pt, MM 1 pt and AML 1 pt; 6 of them received autologous PBSCT and 4 allogeneic BMT. Three pts were in CR following first-line therapy, 5 in relapse and 2 with progressive untreated disease. High-dose therapy consisted of classic Thiotepa and Melphalan, CTX and TBI, BEAM and Melphalan alone depending the disease. Hb before high-dose therapy was 12.2g/dL mean (6.2–14.0 range) and PLT were 186x10^3/μL mean (10–328 range). The nadir of Hb was 7.2g/dL mean (2.0–11.0 range) and that of PLT 6.0x10^3/μL (1–14 range). The recovery of reticulocytes (>20x10^3/μL) was reached at 12 days from HDT mean (7–22 range) and PLT (>20x10^3/μL) at 13 days mean (8–27 range). None of patients occurred major bleeding or complications due to anaemia. One pt died for acute GVHD 2 months following TMO, 3 pts died for disease progression and 6 pts are alive in CR 2–48 months following HDT. In conclusion this study demonstrates that therapy for acute leukaemia and high-dose therapy as conditioning to bone marrow transplant are feasible in patients refusing transfusions of blood products and the results are almost similar to comparable patients accepting blood transfusions.

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High-Dose Therapy and Autologous Peripheral Blood Stem Cell Transplantation in Multiple Myeloma: Up-front or Rescue Treatment? Results of a Multicenter Sequential Randomized Clinical Trial

Blood ◽

10.1182/blood.v92.9.3131.421k30_3131_3136 ◽

1998 ◽

Vol 92 (9) ◽

pp. 3131-3136 ◽

Cited By ~ 19

Author(s):

Jean-Paul Fermand ◽

Philippe Ravaud ◽

Sylvie Chevret ◽

Marine Divine ◽

Véronique Leblond ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Peripheral Blood ◽

Peripheral Blood Stem Cell ◽

Blood Stem Cell ◽

High Dose ◽

High Dose Therapy ◽

Dose Therapy ◽

Rescue Treatment ◽

Late Group

Results to date indicate that high-dose therapy (HDT) with autologous stem cell support improves survival of patients with symptomatic multiple myeloma (MM). We performed a multicenter, sequential, randomized trial designed to assess the optimal timing of HDT and autotransplantation. Among 202 enrolled patients who were up to 56 years old, 185 were randomly assigned to receive HDT and peripheral blood stem cell (PBSC) autotransplantation (early HDT group, n = 91) or a conventional-dose chemotherapy (CCT) regimen (late HDT group, n = 94). In the late HDT group, HDT and transplantation were performed as rescue treament, in case of primary resistance to CCT or at relapse in responders. PBSC were collected before randomization, after mobilization by chemotherapy, and, in the two groups, HDT was preceded by three or four treatments with vincristine, doxorubicin, and methylprednisolone. Data were analyzed on an intent-to-treat basis using a sequential design. Within a median follow-up of 58 months, estimated median overall survival (OS) was 64.6 months in the early HDT group and 64 months in the late group. Survival curves were not different (P = .92, log-rank test). Median event-free survival (EFS) was 39 months in the early HDT group whereas median time between randomization and CCT failure was 13 months in the late group. Average time without symptoms, treatment, and treatment toxicity (TWiSTT) were 27.8 months (95% confidence interval [CI]; range, 23.8 to 31.8) and 22.3 months (range, 16.0 to 28.6) in the two groups, respectively. HDT with PBSC transplantation obtained a median OS exceeding 5 years in young patients with symptomatic MM, whether performed early, as first-line therapy, or late, as rescue treatment. Early HDT may be preferred because it is associated with a shorter period of chemotherapy. © 1998 by The American Society of Hematology.

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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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