High-Dose Treatment With Autologous Stem Cell Transplantation in Multiple Myeloma: Past, Present, and Future

doi:10.1053/j.seminhematol.2007.08.010

Seminars in Hematology

Volume 44, Issue 4, October 2007, Pages 227-233

https://doi.org/10.1053/j.seminhematol.2007.08.010 Get rights and content

High-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) has been used in the treatment of multiple myeloma since the early 1980s. Its present position as the backbone of first-line treatment in patients up to 60 to 65 years of age is the result of several controlled randomized trials, where its superiority over standard chemotherapy has been demonstrated. However, the method is not considered to have curative potential, with the possible exception of a small proportion of about 5% to 10% of patients with very long-standing complete remissions (CRs) of more than 8 years. Over the years, there have been several attempts to improve the technique, where, for example, tandem transplants and post-transplant maintenance treatment have been successful, at least in certain subgroups of patients, while others, such as graft purging, have been of no value. Treatment results need further improvement, particularly in poor-prognosis disease—based on abnormal karyotype and high β₂-microglobulin—and the future will show if the introduction of novel drugs like bortezomib, thalidomide, and lenalidomide will lead to longer survival and prolongation of disease control in multiple myeloma.

Section snippets

Prognostic Factors and Risk Factors

The EBMT myeloma registry has performed several analyses on factors of importance for the outcome after ASCT. In the most recent analysis of 4,322 patients transplanted from 1986 through 2000, favorable prognostic factors were lower age, response to chemotherapy before transplantation, only one line of primary induction treatment, Durie and Salmon stage I or II, and a low β₂-microglobulin value at diagnosis.³ However, despite the statistical significance, the actual difference in survival

ASCT Versus Standard Chemotherapy

Since the early 1990s, several studies have compared first-line treatment including ASCT versus standard combination chemotherapy (Table 1). Most trials have comprised patients of a younger age category, essentially up to the age of 65 years. The first randomized study to demonstrate the superiority of ASCT was the French IFM90 study on 200 patients, published in 1996: median OS and event-free survival (EFS) were 57 and 44 months, respectively, for patients who underwent ASCT, compared with 44

Tandem Transplants

The idea of further dose intensification by sequential cycles of high-dose treatment with ASCT emerged in the late 1980s, and its feasibility was demonstrated.³⁰ Double or tandem autotransplant programs as part of front-line therapy were then pursued during the 1990s in different centers,31, 32 in particular the “Total Therapy” program at the University of Little Rock, AR. In a retrospective case control study of 116 matched pairs, “Total Therapy” was superior to standard chemotherapy.²⁵ Single

ASCT in Elderly Patients

The initial study and most of the randomized studies on ASCT have consisted of myeloma patients in a younger age category, mainly up to the age of 60 to 65 years. The exception is the Italian study, which enrolled patients between 50 and 70 years.²⁴ The younger patient group is a minority within the myeloma patient community, since only about 15% of patients are under the age of 60.³⁸ The benefit of ASCT to older patients has been questioned: the treatment is less well tolerated by more elderly

Graft Purging in Multiple Myeloma

There is no doubt that autologous hematopoietic stem cell grafts from patients with multiple myeloma are always more or less contaminated with clonal myeloma cells in various steps of maturation,44, 45 and this forms the theoretical basis for graft purging to avoid or minimize the reinfusion of clonal malignant cells in the patient. The purging technique most widely used in clinical practice has been immunological separation of CD34-positive hematopoietic progenitor cells, which can reduce the

High-Dose Treatment Protocols

During recent years, melphalan at a dose of 200 mg/m² has been considered to be the standard high-dose preparative regimen before ASCT in multiple myeloma.²² In the 1980s and early 1990s, combinations with melphalan, usually at a dose of 140 mg/m², and total body irradiation (TBI) were frequently used, probably because of adoption from allogeneic transplant preparative protocols, and the fact that multiple myeloma is a radiosensitive disease. However, a retrospective EBMT registry study

Maintenance and Consolidation Treatment

Since HDT with ASCT does not cure multiple myeloma, and the disease in the vast majority of patients will progress with time, one obvious idea has been to augment the effect by some type of post-transplant maintenance or consolidation treatment, in order to prolong the duration of response. Alpha-interferon maintenance treatment, with doses of 9 to 15 million units weekly, has been demonstrated to be effective. In a randomized study of 84 patients, there was an initial survival advantage in the

Autologous Transplantation and Allogeneic Transplantation

In 1996, the EBMT published a retrospective case-matched registry study comparing ASCT with allogeneic bone marrow transplantation with full-dose, myeloablative conditioning, with 189 patients in each group.⁵⁹ Outcome was significantly better in the ASCT group, mainly because of a very high TRM of more than 40% in the allotransplant group. This TRM rate was improved in a later survey of allotransplant patients who were treated more recently, but was still high at more than 30%.⁶⁰ Therefore, the

Conclusions

Can HDT including ASCT cure multiple myeloma? The general opinion is probably no. However, in retrospective analyses of more than 10,000 transplanted patients from the EBMT myeloma registry³ and the University of Arkansas Total Therapy Program,⁶² the PFS curve forms a plateau on a 5% to 10% level from 7 to 8 years after transplantation and onwards. Furthermore, in the latter study, the analysis of the 515 patients who were followed for at least 5 years after transplantation showed no further

References (64)

T.J. McElwain et al.
High dose intravenous melphalan for plasma cell leukaemia and myeloma
Lancet
(1983)
B. Barlogie et al.
High-dose melphalan with autologous bone marrow transplantation for multiple myeloma
Blood
(1986)
B. Björkstrand et al.
Autologous stem cell transplantation in multiple myeloma—The 2000 EBMT registry update
Bone Marrow Transplant
(2001)
R. Desikan et al.
Results of high-dose therapy for 1000 patients with multiple myeloma: Durable complete remissions and superior survival in the absence of chromosome 13 abnormalities
Blood
(2000)
M. Attal et al.
Single versus double autologous stem-cell transplantation for multiple myeloma
N Engl J Med
(2003)
T. Facon et al.
Chromosome 13 abnormalities identified by FISH analysis and serum beta2-microglobulin produce a powerful myeloma staging system for patients receiving high-dose therapy
Blood
(2001)
A.B. Fassas et al.
Both hypodiploidy and deletion of chromosome 13 independently confer poor prognosis in multiple myeloma
Br J Haematol
(2002)
J. Shaughnessy et al.
Continuous absence of metaphase-defined cytogenetic abnormalities, especially of chromosome 13 and hypodiploidy, ensures long-term survival in multiple myeloma treated with Total Therapy I: Interpretation in the context of global gene expression
Blood
(2003)
J. Shaughnessy et al.
Prognostic impact of cytogenetic and interphase fluorescence in situ hybridization-defined chromosome 13 deletion in multiple myeloma: Early results of total therapy II
Br J Haematol
(2003)
F. Garban et al.
Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma
Blood
(2006)

M. Cavo et al.

Poor outcome with front-line autologous transplantation in t(4;14) multiple myeloma: Low complete remission rate and short duration of remission

J Clin Oncol

(2006)

B. Björkstrand et al.

Prognostic factors in autologous stem cell transplantation for multiple myeloma: An EBMT registry study

Leuk Lymphoma

(1994)

M. Attal et al.

A prospective randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma

N Engl J Med

(1996)

J.J. Lahuerta et al.

Remission status defined by immunofixation vs. electrophoresis after autologous transplantation has a major impact on the outcome of multiple myeloma patients

Br J Haematol

(2000)

R. Alexanian et al.

Impact of complete remission with intensive therapy in patients with responsive multiple myeloma

Bone Marrow Transplant

(2001)

D. O’Shea et al.

Predictive factors for survival in myeloma patients who undergo autologous stem cell transplantation: A single-centre experience in 211 patients

Bone Marrow Transplant

(2006)

B. Barlogie et al.

Total therapy 2 without thalidomide in comparison with total therapy 1: Role of intensified induction and posttransplantation consolidation therapies

Blood

(2006)

A. Badros et al.

Results of autologous stem cell transplant in multiple myeloma patients with renal failure

Br J Haematol

(2001)

B. Sirohi et al.

Glomerular filtration rate prior to high-dose melphalan 200 mg/m² as a surrogate marker of outcome in patients with myeloma

Br J Cancer

(2001)

K. Carlson

Melphalan 200 mg/m² with blood stem cell support as first-line myeloma therapy: impact of glomerular filtration rate on engraftment, transplantation-related toxicity and survival

Bone Marrow Transplant

(2005)

J.M. Bird et al.

The clinical outcome and toxicity of high-dose chemotherapy and autologous stem cell transplantation in patients with myeloma or amyloid and severe renal impairment: A British Society of Blood and Marrow Transplantation study

Br J Haematol

(2006)

J.L. Harousseau et al.

High-dose therapy in multiple myeloma

Hematol J

(2003)

J.A. Child et al.

High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma

N Engl J Med

(2003)

A. Palumbo et al.

Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: Results of a randomized controlled trial

Blood

(2004)

B. Barlogie et al.

Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma

Blood

(1997)

S. Lenhoff et al.

Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma: A population-based study

Blood

(2000)

J.P. Fermand et al.

High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: Long-term results of a randomized control trial from the Group Myelome-Autogreffe

J Clin Oncol

(2005)

J. Blade et al.

High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: Long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA

Blood

(2005)

B. Barlogie et al.

Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: Final results of phase III US Intergroup Trial S9321

J Clin Oncol

(2006)

J.L. Harousseau et al.

High dose melphalan and autologous bone marrow transplantation in high risk myeloma

Br J Haematol

(1987)

D.H. Vesole et al.

High-dose therapy for refractory multiple myeloma: Improved prognosis with better supportive care and double transplants

Blood

(1994)

B. Björkstrand et al.

Double high-dose chemo-radiotherapy with autologous stem cell transplantation can induce molecular remissions in multiple myeloma

Bone Marrow Transplant

(1995)

Cited by (27)

Multiple myeloma cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation
2018, Biochemical and Biophysical Research Communications
Citation Excerpt :
Multiple myeloma (MM) is a malignant neoplasm of plasma cells that is characterized by clonal proliferation of neoplastic plasma cells, production of M-proteins, and associated organ damage including bone fractures, renal failure, anemia, and hypercalcemia. The recent introduction of new molecular targeting agents such as proteasome inhibitors and immunomodulatory drugs, and autologous stem cell transplantation has improved the outcomes of MM patients [1,2]. However, MM remains incurable, and new molecular targeting agents are continually being developed as understanding of the pathogenesis of this disease increases [3–5].
The emergence of new molecular targeting agents has improved the prognosis of patients with multiple myeloma (MM). However, MM remains incurable because MM stem cells are likely resistant to these agents. Thus, it is important to further investigate the biology of MM stem cells, which reside in the hypoxic bone marrow niche. In this study, we established and investigated the characteristics of hypoxia-adapted MM (HA-MM) cells, which could proliferate for more than six months under hypoxic conditions (1% O₂). The G0 fraction of HA-MM cells was larger than that of parental MM cells under normoxic conditions (20% O₂). HA-MM cells possess enhanced tumorigenicity in primary and secondary transplantation studies. HA-MM cells also exhibited increased mRNA levels of stem cell markers and an enhanced self-renewal ability, and thus demonstrated characteristics of MM stem cells. These cells overexpressed phosphorylated Smad2, and treatment with a transforming growth factor (TGF)-β/Smad signaling inhibitor decreased their clonogenicity in a replating assay. In conclusion, MM cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation.
CG13250, a novel bromodomain inhibitor, suppresses proliferation of multiple myeloma cells in an orthotopic mouse model
2017, Biochemical and Biophysical Research Communications
Citation Excerpt :
Multiple myeloma (MM) is a malignant neoplasm of plasma cells that is characterized by clonal proliferation of neoplastic plasma cells, production of M-proteins, and associated organ damage including bone fractures, renal failure, anemia, and hypercalcemia. Due to the availability of new molecular targeting agents such as proteasome inhibitors and immunomodulatory drugs, and the introduction of autologous stem cell transplantation, the outcomes for MM patients have recently improved [1–3]. However, it remains incurable at present [1], and new molecular targeting agents are continually being sought and developed in step with better understanding of the pathogenesis underlying MM [1,4–6].
Multiple myeloma (MM) is characterized by the clonal proliferation of neoplastic plasma cells. Despite a stream of new molecular targets based on better understanding of the disease, MM remains incurable. Epigenomic abnormalities contribute to the pathogenesis of MM. bromodomain 4 (BRD4), a member of the bromodomain and extraterminal (BET) family, binds to acetylated histones during M/G1 transition in the cell cycle promoting progression to S phase. In this study, we investigated the effects of a novel BET inhibitor CG13250 on MM cells. CG13250 inhibited ligand binding to BRD4 in a dose-dependent manner and with an IC₅₀ value of 1.1 μM. It inhibited MM proliferation in a dose-dependent manner and arrested cells in G1, resulting in the induction of apoptosis through caspase activation. CG13250 inhibited the binding of BRD4 to c-MYC promoter regions suppressing the transcription of the c-MYC gene. Administered in vivo, CG13250 significantly prolonged survival of an orthotopic MM-bearing mice. In conclusion, CG13250 is a novel bromodomain inhibitor that is a promising molecular targeting agent against MM.
The effects of cold atmospheric plasma on cell adhesion, differentiation, migration, apoptosis and drug sensitivity of multiple myeloma
2016, Biochemical and Biophysical Research Communications
Cold atmospheric plasma was shown to induce cell apoptosis in numerous tumor cells. Recently, some other biological effects, such as induction of membrane permeation and suppression of migration, were discovered by plasma treatment in some types of tumor cells. In this study, we investigated the biological effects of plasma treatment on multiple myeloma cells. We detected the detachment of adherent myeloma cells by plasma, and the detachment area was correlated with higher density of hydroxyl radical in the gas phase of the plasma. Meanwhile, plasma could promote myeloma differentiation by up-regulating Blimp-1 and XBP-1 expression. The migration ability was suppressed by plasma treatment through decreasing of MMP-2 and MMP-9 secretion. In addition, plasma could increase bortezomib sensitivity and induce myeloma cell apoptosis. Taking together, combination with plasma treatment may enhance current chemotherapy and probably improve the outcomes.
Efficacy and Outcome of Allogeneic Transplantation in IgD and Nonsecretory Myeloma. A Report on Behalf of the Myeloma Subcommittee of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation
2015, Biology of Blood and Marrow Transplantation
Citation Excerpt :
The number of patients who could be evaluated for each parameter was noted and the proportions of evaluable patients are included in the results. Factors known to affect transplantation outcomes from previous EBMT studies were also analyzed [5]. Response criteria were those used by the centers that were in current use at the time of reporting.
We have recently reported on the outcome of autologous transplantation in the rare myelomas (IgD, IgE, IgM, and nonsecretory [NS]) but there is no real information on the outcome of these conditions after allogeneic transplantation. We used the European Group for Blood and Marrow Transplantation myeloma database to compare the outcomes after allogeneic transplantation of 1354 common myelomas (IgG, IgA, and light chain myeloma) with the outcome in 26 IgD myelomas and 52 NS myelomas. There was little difference between common and the IgD and NS myeloma patients with respect to prognostic factors although the IgD group had a higher beta 2 microglobulin at diagnosis, shorter time to transplantation, and more T cell depletion. IgD and NS patients had a significantly greater achievement of complete remission at conditioning but this did not translate into equivalent progression-free survival and overall survival for the IgD patients although the NS outcome was very similar to that of common myeloma. The PFS and OS of IgD, common, and NS myelomas appear similar after allogeneic transplantation, despite a tendency for higher early relapse rate in IgD myeloma. Allogeneic transplantation may, therefore, be an option to investigate in prospective observational studies.
Second Autologous Stem Cell Transplant: An Effective Therapy for Relapsed Multiple Myeloma
2015, Biology of Blood and Marrow Transplantation
Therapeutic options for patients with multiple myeloma (MM) whose disease has relapsed after a prior autologous stem cell transplant (ASCT) include an expanding armamentarium of novel agents, often combined with traditional chemotherapy, or a second ASCT, with no clear standard of care. We retrospectively analyzed the outcomes of 75 patients who underwent salvage melphalan-based ASCT for relapsed MM at Memorial Sloan-Kettering Cancer Center between 1995 and 2012. Conditioning was performed with melphalan 200 mg/m² (n = 43), 180 mg/m² (n = 1), 140 mg/m² (n = 22), and 100 mg/m² (n = 9). The median age at second ASCT was 59 years (range, 36 to 75), and 58% (n = 35) were men. Of those with available data, 19% had high-risk cytogenetics (including t (4;14), p53 loss, or del 13q by karyotype) at the time of second ASCT. Median interval between first and salvage ASCT was 37.5 months (range, 6.9 to 111.4). Of 72 assessable patients, 57% had chemotherapy-sensitive disease before to salvage ASCT and 43% were chemoresistant. Four patients died within 100 days of ASCT. Response was assessed at 2 to 3 months post-ASCT, and of 71 assessable patients, 82% achieved at least a partial response, 15% had stable disease, and 3% progressed despite salvage ASCT. After salvage ASCT, 38 patients received maintenance therapy and 14 went on to allogeneic ASCT. The median progression-free survival (PFS) after second autograft was 10.1 months (95% confidence interval [CI], 7.6 to 13.4) and median overall survival (OS) 22.7 months (95% CI, 19.2 to 41.2). Patients with chemosensitive relapse had a trend toward better PFS (hazard ratio [HR], .60 [95% CI, .36 to 1.02]; P = .058) and significantly longer OS (HR, .49 [95% CI, .27 to .88]; P = .017) than patients with resistant relapse. Those with high-risk cytogenetics at the time of second ASCT had higher risk of death (HR, 2.98 [95% CI, 1.28 to 6.97]; P = .012) compared with patients with standard-risk cytogenetics. Salvage ASCT is an effective strategy for relapsed MM with chemosensitive disease and results in comparable PFS and OS to other salvage strategies.
Selective Purging of Human Multiple Myeloma Cells from Autologous Stem Cell Transplantation Grafts using Oncolytic Myxoma Virus
2012, Biology of Blood and Marrow Transplantation
Citation Excerpt :
In North America alone, ASCT is used to treat approximately 5,000 patients with MM annually. This treatment results in improved rates of disease remission as well as significantly prolonged event-free survival time compared with patients treated with conventional chemotherapy [4,5]. However, despite the improved prognosis associated with myeloablative chemotherapy followed by ASCT, the treatment is generally not curative, and a large majority of all patients with MM will suffer from relapsed disease.
Autologous stem cell transplantation and novel therapies have improved overall survival of patients with multiple myeloma; however, most patients relapse and eventually succumb to their disease. Evidence indicates that residual cancer cells contaminate autologous grafts and may contribute to early relapses after autologous stem cell transplantation. Here, we demonstrate that ex vivo treatment with an oncolytic poxvirus called myxoma virus results in specific elimination of human myeloma cells by inducing rapid cellular apoptosis while fully sparing normal hematopoietic stem and progenitor cells. The specificity of this elimination is based on strong binding of the virus to myeloma cells coupled with an inability of the virus to bind or infect CD34⁺ hematopoietic stem and progenitor cells. These 2 features allow myxoma to readily identify and distinguish even low levels of myeloma cells in complex mixtures. This ex vivo rabbit-specific oncolytic poxvirus called myxoma virus treatment also effectively inhibits systemic in vivo engraftment of human myeloma cells into immunodeficient mice and results in efficient elimination of primary CD138⁺ myeloma cells contaminating patient hematopoietic cell products. We conclude that ex vivo myxoma treatment represents a safe and effective method to selectively eliminate myeloma cells from hematopoietic autografts before reinfusion.

View all citing articles on Scopus

: Supported by the Swedish Cancer Society and the Stockholm Cancer Society.

View full text

Seminars in Hematology

High-Dose Treatment With Autologous Stem Cell Transplantation in Multiple Myeloma: Past, Present, and Future

Section snippets

Prognostic Factors and Risk Factors

ASCT Versus Standard Chemotherapy

Tandem Transplants

ASCT in Elderly Patients

Graft Purging in Multiple Myeloma

High-Dose Treatment Protocols

Maintenance and Consolidation Treatment

Autologous Transplantation and Allogeneic Transplantation

Conclusions

High dose intravenous melphalan for plasma cell leukaemia and myeloma

Lancet

High-dose melphalan with autologous bone marrow transplantation for multiple myeloma

Blood

Autologous stem cell transplantation in multiple myeloma—The 2000 EBMT registry update

Bone Marrow Transplant

Results of high-dose therapy for 1000 patients with multiple myeloma: Durable complete remissions and superior survival in the absence of chromosome 13 abnormalities

Blood

Single versus double autologous stem-cell transplantation for multiple myeloma

N Engl J Med

Chromosome 13 abnormalities identified by FISH analysis and serum beta2-microglobulin produce a powerful myeloma staging system for patients receiving high-dose therapy

Blood

Both hypodiploidy and deletion of chromosome 13 independently confer poor prognosis in multiple myeloma

Br J Haematol

Continuous absence of metaphase-defined cytogenetic abnormalities, especially of chromosome 13 and hypodiploidy, ensures long-term survival in multiple myeloma treated with Total Therapy I: Interpretation in the context of global gene expression

Blood

Prognostic impact of cytogenetic and interphase fluorescence in situ hybridization-defined chromosome 13 deletion in multiple myeloma: Early results of total therapy II

Br J Haematol

Prospective comparison of autologous stem cell transplantation followed by dose-reduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma

Blood

Poor outcome with front-line autologous transplantation in t(4;14) multiple myeloma: Low complete remission rate and short duration of remission

J Clin Oncol

Prognostic factors in autologous stem cell transplantation for multiple myeloma: An EBMT registry study

Leuk Lymphoma

A prospective randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma

N Engl J Med

Remission status defined by immunofixation vs. electrophoresis after autologous transplantation has a major impact on the outcome of multiple myeloma patients

Br J Haematol

Impact of complete remission with intensive therapy in patients with responsive multiple myeloma

Bone Marrow Transplant

Predictive factors for survival in myeloma patients who undergo autologous stem cell transplantation: A single-centre experience in 211 patients

Bone Marrow Transplant

Total therapy 2 without thalidomide in comparison with total therapy 1: Role of intensified induction and posttransplantation consolidation therapies

Blood

Results of autologous stem cell transplant in multiple myeloma patients with renal failure

Br J Haematol

Glomerular filtration rate prior to high-dose melphalan 200 mg/m2 as a surrogate marker of outcome in patients with myeloma

Br J Cancer

Melphalan 200 mg/m2 with blood stem cell support as first-line myeloma therapy: impact of glomerular filtration rate on engraftment, transplantation-related toxicity and survival

Bone Marrow Transplant

The clinical outcome and toxicity of high-dose chemotherapy and autologous stem cell transplantation in patients with myeloma or amyloid and severe renal impairment: A British Society of Blood and Marrow Transplantation study

Br J Haematol

High-dose therapy in multiple myeloma

Hematol J

High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma

N Engl J Med

Intermediate-dose melphalan improves survival of myeloma patients aged 50 to 70: Results of a randomized controlled trial

Blood

Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma

Blood

Impact on survival of high-dose therapy with autologous stem cell support in patients younger than 60 years with newly diagnosed multiple myeloma: A population-based study

Blood

High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: Long-term results of a randomized control trial from the Group Myelome-Autogreffe

J Clin Oncol

High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: Long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA

Blood

Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: Final results of phase III US Intergroup Trial S9321

J Clin Oncol

High dose melphalan and autologous bone marrow transplantation in high risk myeloma

Br J Haematol

High-dose therapy for refractory multiple myeloma: Improved prognosis with better supportive care and double transplants

Blood

Double high-dose chemo-radiotherapy with autologous stem cell transplantation can induce molecular remissions in multiple myeloma

Bone Marrow Transplant

Multiple myeloma cells adapted to long-exposure of hypoxia exhibit stem cell characters with TGF-β/Smad pathway activation

CG13250, a novel bromodomain inhibitor, suppresses proliferation of multiple myeloma cells in an orthotopic mouse model

The effects of cold atmospheric plasma on cell adhesion, differentiation, migration, apoptosis and drug sensitivity of multiple myeloma

Efficacy and Outcome of Allogeneic Transplantation in IgD and Nonsecretory Myeloma. A Report on Behalf of the Myeloma Subcommittee of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation

Glomerular filtration rate prior to high-dose melphalan 200 mg/m² as a surrogate marker of outcome in patients with myeloma

Melphalan 200 mg/m² with blood stem cell support as first-line myeloma therapy: impact of glomerular filtration rate on engraftment, transplantation-related toxicity and survival