Bortezomib-Thalidomide-Dexamethasone as Primary Induction Therapy for Newly Diagnosed Multiple Myeloma Significantly Decreases Bone Resorption While Sparing Bone Formation as Compared to Thalidomide-Dexamethasone

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5117-5117 ◽  
Author(s):  
Patrizia Tosi ◽  
Elena Zamagni ◽  
Paola Tacchetti ◽  
Giulia Perrone ◽  
Michela Ceccolini ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Bone Resorption ◽  
Bone Formation ◽  
Induction Therapy ◽  
Phase Iii ◽  
High Dose ◽  
Newly Diagnosed ◽  
Bone Formation Markers

Abstract Bone disease occurs in approximately 80% of patients with newly diagnosed multiple myeloma (MM) and is caused by the interaction of the neoplastic clone with bone marrow microenvironment, ultimately resulting in an altered balance between bone resorption and bone formation. It has been previously reported that therapies aimed at eradicating the myeloma clone could contribute to decrease bone resorption, even though bone formation remains impaired even in responding patients, due to the use of high-dose steroids. It has been recently demonstrated, both in vitro and in animal models, that Bortezomib improves bone formation by stimulating osteoblasts. In order to test whether this activity was retained also in vivo, we evaluated markers of bone resorption (serum crosslaps) and bone formation (serum osteocalcin-OC and bone alkaline phosphatase - BAP) in a series of patients who were enrolled in the “Bologna 2005” phase III clinical trial at our Center. By study design, after registration patients were randomized to receive three 21-days courses of induction therapy with either VTD (Bortezomib, 1.3 mg/sqm on d 1, 4, 8, and 11, plus Dexamethasone, 40 mg on each day of and after Bortezomib administration plus Thalidomide 200 mg/d from d 1 to 63.) or TD (Thalidomide as in VTD and Dexamethasone 40 mg/d on d 1–4 and 9–12 of every 21-d cycle), prior to stem cell collection and double autologous stem cell transplantation. As of January 2008, 27 patients (19 male and 8 female, median age = 57.5 yrs) entered the sub-study; of these, 15 and 12 patients were randomized in the VTD and TD arm, respectively. At diagnosis, both groups of patients showed a marked increase in serum crosslaps as compared to upper baseline limit (7321±1445pmol/L in the VTD arm and 11140±2576pmol/L in the TD arm) while both OC and BAP were reduced as compared to lower baseline limits. After completion of the induction therapy, serum crosslaps were significantly decreased in both treatment groups (2747±319pmol/L in VTD arm, p=0.007; 3686±1084pmol/L in the TD arm, p=0.0015). In the TD group a significant further reduction in bone formation markers was also observed (42% reduction in serum OC and 30% in BAP, p=0.03 and 0.04 as compared to pre-treatment values); on the contrary, in the VTD arm both OC and BAP were not significantly decreased as compared to baseline values (15% and 11% for OC and BAP, respectively). These data suggest that incorporation of Bortezomib into induction therapy counteracts the inhibitory effects of high-dose steroids on osteoblastogenesis, thus sparing bone formation.

High Dose Simvastatin Has No Beneficial Effect on Markers of Bone Turn-Over in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4824-4824
Author(s):  
Teis E. Sondergaard ◽  
Per T. Pedersen ◽  
Thomas L. Andersen ◽  
Thomas Lund ◽  
Patrick Garnero ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Pilot Study ◽  
Bone Resorption ◽  
Bone Formation ◽  
High Dose ◽  
Osteoclast Activity ◽  
Bone Formation Markers ◽  
Bone Degradation ◽  
Activity Trap

Abstract Background: Bone degradation in multiple myeloma (MM) is a result of increased bone degradation by osteoclasts that is not compensated for by bone forming osteoblasts. Ideally new drugs used for treatment of MM should target not only the myeloma cells but also the imbalance between bone resorption and bone formation. Statins have been shown to inhibit myeloma cell proliferation and induce apoptosis in vitro. Furthermore statins have been shown to stimulate osteoblasts and inhibit osteoclasts both in vitro and in animal models. Statins are normally used at doses around 20–80 mg/day, but in order to reach serum concentrations that can match the in vitro experiments MM patients were treated with 15 mg/kg/day of Simvastatin (HD-Sim) divided in two daily doses in this study. This high dose has previously been found to be safe for MM patients (Haematologica 2006, 91,542–545) Patients and methods: Six patients with advanced MM have been included in this pilot study, 4 males and 2 females with an average age of 68 years and an average duration of disease of 43 months. The patients were treated with 2 cycles of HD-Sim for seven days followed by a break of 21 days in a 4-weeks cycle. Two of the patients were treated with bisphosphonates during the study, and 4 had previously been treated with bisphosphonates. Endpoints are change in concentrations of markers of osteoclast activity (TRAP) or bone resorption (CTX, NTX, ICTP) or markers of bone formation (Osteocalcin and PINP). Cholesterol, OPG and DDK-1 were also measured. Results: Two patients completed the protocol with two cycles of HD-Sim at full dose, 2 patients were reduced to 7.5 mg/kg/day simvastatin in cycle 2 due to nausea and diarrhea and 2 patients left the protocol after 3 weeks (deaths not related to high dose simvastatin). All patients experienced gastrointestinal toxicity grade 1–2. Myalgia and other muscular symptoms grade 1–2 were reported by 5 patients but were not associated with an increase in creatin kinase. TRAP and NTX activity in serum increased for all 6 patients during the seven days of treatment with HD-Sim indicating that bone resorption may have been stimulated rather than inhibited. The other markers of bone resorption and the bone formation markers showed no change. All patients responded with a significantly reduced level of cholesterol in serum. None of the patients showed any reduction in free monoclonal light chains or monoclonal proteins in serum during treatment with HD-Sim and 2 of the 4 patients completing the protocol showed progression of diseases. Conclusion: This pilot study of HD-Sim in advanced MM has been terminated due to lack of response and evidence from two markers of osteoclast activity (TRAP) and bone resorption (NTX) that HD-Sim may be harmful rather than beneficial in MM.

scholarly journals Utilization of Autologous Stem Cell Transplantation in Older Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5701-5701
Author(s):  
Justin King ◽  
Mark A. Fiala ◽  
Scott R. Goldsmith ◽  
Keith E. Stockerl-Goldstein ◽  
Mark A. Schroeder ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Older Patients ◽  
Research Funding ◽  
Small Sample ◽  
Poor Performance Status ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Equity Ownership

Historically, high-dose therapy in combination with autologous stem cell transplants (ASCT) for multiple myeloma (MM) was reserved for younger patients. In more recent years, the use of ASCT has expanded in the older population. However, there is still limited data on the utilization and efficacy of ASCT in older patients, particularly those over the age of 75. To further evaluate this issue, we retrospectively analyzed all patients with newly diagnosed MM between the ages of 75-78, the institutional cutoff for ASCT eligibility, that were referred to the stem cell transplant unit at our institution for consultation from the years 2012-2018. Baseline characteristics, anti-myeloma treatments, and patient outcomes were abstracted through chart review. Seventy-five patients were referred to our institution. 71% were male, 29% female. 39% patients were considered ineligible for ASCT by the consulting transplant physician. Most patients were considered transplant ineligible due to comorbidities or poor performance status. Of the 46 patients eligible for ASCT, 52% underwent the procedure during their first-line therapy. The majority of those patients received reduced intensity melphalan (140 mg/m2) while 2 patients received conventional dosing (200 mg/m2). The other 22 patients eligible for ASCT declined or elected to defer the procedure and to be treated with conventional therapy. The characteristics of these three groups were similar and are detailed in Table 1. After a median follow-up of 30 months, 25% of the patients had expired. Estimated median overall survival (OS) was 71.3 months (unable to quantitate 95% CI) for all patients. Compared to transplant eligible patients, regardless of transplant receipt, those who were transplant ineligible had a 186% increase risk for death (HR 2.86; 95% CI 1.12-7.35; p = 0.029). There was also a notable trend for longer OS in those who underwent ASCT compared to those who were eligible but declined the procedure, but it was not statistically significant (HR 0.36; 95% CI 0.10-1.28; p = 0.114). At a transplant center, two-thirds of patients referred for newly diagnosed MM between the ages 75-78 were considered eligible for ASCT and one-third underwent the procedure. Outcomes were better for patients eligible for ASCT, regardless of whether they underwent the procedure. There was also a trend for better OS in patients who underwent the procedure compared to those who declined. While small sample sizes and the retrospective nature of the study limit our ability to draw conclusions, it appears that ASCT has an OS benefit among patients age 75-78. Disclosures Fiala: Incyte: Research Funding. Stockerl-Goldstein:AbbVie: Equity Ownership; Abbott: Equity Ownership. Vij:Genentech: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wildes:Janssen: Research Funding; Carevive: Consultancy.

VRd versus VCd as induction therapy for newly diagnosed multiple myeloma: A Phase III, randomized study

2019 ◽  
Vol 19 (10) ◽  
pp. e361
Author(s):  
Lalit Kumar ◽  
Santosh kumar Chellapuram ◽  
Ranjit Sahoo ◽  
Ritu Gupta
Keyword(s):  
Multiple Myeloma ◽  
Induction Therapy ◽  
Randomized Study ◽  
Phase Iii ◽  
Newly Diagnosed

scholarly journals Stem-cell transplantation in multiple myeloma: how far have we come?

2019 ◽  
Vol 10 ◽  
pp. 204062071988811 ◽  
Author(s):  
Cinnie Y. Soekojo ◽  
Shaji K. Kumar
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Residual Disease ◽  
Phase Iii ◽  
Novel Agents ◽  
Optimal Timing ◽  
High Dose ◽  
Phase Iii Trials

High-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) has historically been an essential part of multiple myeloma (MM) management since early studies demonstrated its efficacy in relapsed disease, and subsequent phase III trials demonstrated better responses and improved survival with this modality compared with standard chemotherapy. With further advances in the MM treatment landscape, including the development of potent novel agents, there has been an increasing debate around various aspects of ASCT, including the optimal timing, role of single versus tandem ASCT, and the practice of consolidation and maintenance therapy post-ASCT. Routine incorporation of the novel agents at each of the treatment phases, induction, consolidation when used, and maintenance has led to better responses as reflected by increasing rates of minimal residual disease (MRD) negativity, longer progression-free survival (PFS) with improvement in overall survival (OS) and in some of the trials. The phase III trials over the last decade have provided significant clarity on the current approach, and have raised important questions regarding the applicability of this modality in all patients. This review aims to summarize the latest literature in the field and discusses how these findings impact the practice of ASCT today.

Long-Term Follow-Up of a Randomized Phase III Multicenter Study Comparing a Standard Versus an Intensified Conditioning Regimen for High-Dose Chemotherapy in Patients with Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 945-945
Author(s):  
Roland Fenk ◽  
Peter Schneider ◽  
Martin Kropff ◽  
Ali-Nuri Huenerlituerkoglu ◽  
Ulrich Steidl ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Conditioning Regimen ◽  
High Dose Chemotherapy ◽  
Phase Iii ◽  
Study Endpoint ◽  
Primary Study ◽  
High Dose ◽  
Significant Difference

Abstract High-dose chemotherapy (HDT) improves the outcome of patients with multiple myeloma (MM) in comparison to conventional chemotherapy. Dose-escalating strategies including tandem HDT are currently evaluated to further improve remission rates and survival of patients. Therefore we conducted a randomized multicenter trial to compare an intensified conditioning regimen with the current standard high-dose melphalan. The primary study endpoint was response rate, with overall survival (OS), event-free survival (EFS) and toxicity analysed as secondary endpoints. Between 1997 and 1999 a total of 56 patients with stage II and III disease, who were matched for age (median 56 years), number of previous therapies (median time from diagnosis to transplant 7 months) and different risk factors (beta2-microglobulin, LDH, CRP, cytogentic abnormalities, chemoresistant disease, IgA-subtype, renal impairment), were randomized. All patients received 2 courses of oral idarubicine/dexamethasone and 2 courses of intravenous cyclophosphamide/adriamycine in combination with G-CSF followed by peripheral stem cell collection. Thirty patients were treated with melphalan 200mg/m2 (HD-M) whereas 26 patients received idarubicine 42mg/m2, melphalan 200mg/m2 and cyclophosphamide 120mg/kg (HD-IMC) followed by autologous blood stem cell transplantation. Acute toxicity was higher with HD-IMC, including 5 (20%) treatment-related deaths due to infections versus none (0%) in the HD-M group. This lead to early termination of the study. Severity of mucositis (grade III-IV 19 vs. 8 pts., p=0.001), CRP (20 vs. 7 mg/dl, p<0.001), days of fever (11 vs. 3, p<0.001), days with iv-antibiotics (13 vs. 4, p<0.001), number of erythrocyte-transfusions (6 vs. 2, p<0.001), number of platelet-transfusions (16 vs. 4, p<0.001) and days to granulocyte engraftment (18 vs. 11, p=0.007) were significantly higher after HD-IMC. After a follow-up of 5 years analysis restricted to patients surviving the first 30 days after HDT showed a trend to higher response rates (CR+vgPR: 47% (95%CI 24–72%) vs. 35% (95%CI 18–56%), PR 37% (95%CI 17–63%) vs. 48% (95%CI 29–68%) and time-to-progression (median 31 vs. 15 months, p=0.1) in the HD-IMC treatment arm in comparison to HD-M, but there was no significant difference in EFS and OS (median 22 vs. 30, p= 0.31 and 66 vs. 66 months, p=0.8, respectively). Univariate analysis demonstrated that LDH levels > 200 U/L (p=0.04) and chemoresistant disease (p=0.05) were a bad prognostic factor for EFS. Beta2-Microglobulin levels > 5mg/dl (p=0.01), abnormal conventional cytogenetics (p=0.02) and LDH levels > 200 U/L (p=0.03) were predictive for an inferior OS. In conclusion intensified conditioning for HDT had an intolerable high treatment-related mortality and did not improve EFS and OS in patients with multiple myeloma.

Sequential VAD (Vincristine, Adriamycin, Dexamethasone) and VTD (VELCADE®, Thalidomide, Dexamethasone) Induction Followed by High-Dose Therapy with Autologous Stem Cell Transplantation and Maintenance Treatment with VELCADE for Newly Diagnosed Multiple Myeloma: Interim Results of Phase II Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 952-952 ◽  
Author(s):  
Sung-Soo Yoon ◽  
Hye Jin Kim ◽  
Dong Soon Lee ◽  
Hyeon Seok Eom ◽  
Jun Ho Jang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Maintenance Treatment ◽  
Response Rate ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Newly Diagnosed

Abstract Introduction Effective reduction of myeloma before autologous stem cell transplantation (ASCT) prolongs survival in multiple myeloma patients. Recently, incorporation of novel agents resulted in improved response rate and reduced side effect in newly diagnosed multiple myeloma. Method: Patients are planned to receive 2 cycles of VAD (vincristine 0.4mg D1-4, adriamycin 9mg/m2 D1-4, dexamethasone 40mg D1-4, 9–12 every 3 weeks), and VTD (bortezomib 1.3mg/m2 D1, 4, 8, 11, thalidomide 100mg daily, dexamethasone 40mg D1-4, 9–12 every 3 weeks). High dose melphalan (200mg/m2) is used as a conditioning regimen for ASCT. Bortezomib (1.3mg/m2) as a maintenance treatment is administered weekly x 4 times every 6 weeks for 4 cycles after ASCT. Response was assessed by EBMT criteria, with additional category of nCR. Adverse events were graded by the NCI-CTCAE, Version 3.0. Result: At this interim analysis, 60 patients have been entered into the ongoing trial, and efficacy could be assessed in 53 patients. After 2 cycles of VAD, response rate was 70%. After VTD, two patients showed further improvement with additional CR, and an overall response was 97% with 14% CR. Especially, patients with poor prognostic cytogenetics (n=6) all responded after VTD. So far, autologous stem cells were successfully collected in all 28 patients with a median CD34+ count of 7.8 x 106/kg (range, 2.17–44.7 x 106/kg). In 24 patients who underwent autologous stem cell transplantation, five patients gained additional CR. There was no progression in patients completed bortezomib maintenance (n=9, CR 77%). The median follow-up duration was 6 months, median time to response was 1.4 months, and median overall survival was not reached. Grade 3,4 hematologic toxicity was more frequently observed after VAD than VTD (anemia 15.8%, 4.6%, neutropenia 7.9%, 3.5%), and incidence of grade 2,3 peripheral neuropathy was low (VAD 3.5%, VTD 7%). Conclusion: Sequential VAD and VTD induction therapy in newly diagnosed multiple myeloma was highly effective, even in patients with poor prognostic cytogenetics, and did not prejudice stem cell collection. VTD could have contributed to increased RR and minimized side effects. An updated results will be presented at the ASH meeting. *Protocol Number: KMM51-NCT00378755.

A Phase III Study of Enoxaparin Versus Low-Dose Warfarin Versus Aspirin as Thromboprophylaxis for Patients with Newly Diagnosed Multiple Myeloma Treated up-Front with Thalidomide-Containing Regimens

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3017-3017 ◽  
Author(s):  
Michele Cavo ◽  
Antonio Palumbo ◽  
Sara Bringhen ◽  
Antonietta Falcone ◽  
Pellegrino Musto ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Induction Therapy ◽  
Cardiovascular Events ◽  
Low Dose ◽  
Phase Iii ◽  
Bleeding Complications ◽  
Newly Diagnosed ◽  
P Values ◽  
Dose Warfarin ◽  
To Receive

Abstract Thalidomide-containing regimens are currently being used as standard initial therapy for both younger and elderly pts with multiple myeloma (MM), but are associated with an increased risk of venous thromboembolism (VTE) which necessitates routine thromboprophylaxis. Controversies exist concerning the best thromboprophylactic regimen to be used in these pts. To address this issue, the Italian Myeloma Network GIMEMA designed a phase III sub-study aimed at prospectively investigating the efficacy and safety of low molecular weight heparin (LMWH) or fixed low-dose warfarin (WAR) or low-dose aspirin (ASA) as prophylaxis against VTE in newly diagnosed MM pts who were randomized to receive primary induction therapy with thalidomide-containing regimens in the context of 2 phase III studies conducted by the same group. In one of these studies, pts with ≤65 years of age were randomly assigned to receive Velcade-Thalidomide-Dexamethasone (VTD) or Thalidomide-Dexamethasone (TD) before autologous transplantation. In the other study, Velcade-Melphalan-Prednisone (VMP) was compared with VMP plus thalidomide (VMPT) for elderly patients aged &gt;65 years. The daily dose of Thalidomide was 200 mg in both VTD and TD, and 50 mg in VMPT. Pts randomized to VTD or TD received a total Dexamethasone dose of 320 mg/cycle, while those assigned to VMP or VMPT were given a total Prednisone dose of 240 mg/m2/cycle. By sub-study design, pts treated on VTD or TD or VMPT were randomly assigned to receive thromboprophylaxis with LMWH (Enoxaparin, 40 mg/d) or WAR (1.25 mg/d) or ASA (100 mg/d) for the duration of induction therapy. At the opposite, pts randomized to VMP did not receive any prophylaxis and were used as controls. Sub-study end points included incidence of VTE, acute cardiovascular events, sudden death, bleeding and any other serious adverse events. At the time of the present analysis, 703 pts who received at least 3 cycles of induction therapy were evaluated. Of these pts, 164 treated on VMP were the control group, while the remaining 539 pts (of whom, 209 treated on VTD, 211 on TD and 119 on VMPT) were randomized to receive either LMWH (n=178) or WAR (n=180) or ASA (n=181). Baseline pts characteristics and risk factors for VTE were comparable in all sub-groups. Overall, the risk of VTE was 3.9% with WAR vs 4.5% with LMWH vs 5.5% with ASA (P values not significant for comparisons between different sub-groups), whereas it was 1.8% among the controls. Median times to onset of VTE for pts treated on LMWH or WAR or ASA were 2.66 vs 2.96 vs 2.10 months, respectively. Pts receiving Velcade-containing regimens (VTD or VMPT) had a VTE frequency in the range of approximately 3%, as compared to 5.8% for pts on TD (P value not significant). The rates of cardiovascular events were 0.6% in each of sub-groups including LMWH, WAR and controls, vs 1.1% for pts treated on ASA. No sudden deaths were reported. The incidence of all grades bleeding was 0.6% with LMWH vs 1.1% with WAR vs 3.3% with ASA (P values not significant for comparisons between different sub-groups), while it was 3.7% among the controls. In conclusion, results of the present analysis show that the overall risk of VTE among sub-groups of pts treated with different thalidomide-containing regimens was not superior to that expected during the natural course of MM. No significant relationship was found between the frequency of VTE and thromboprophylactic regimens, induction treatments (e.g. containing or not Velcade) and age of pts (e.g. young vs elderly). In comparison with LMWH and WAR, there was a higher, albeit marginal, risk of VTE and bleeding complications associated with ASA prophylaxis. Finally, a finding not previously well recognized, fixed low-dose WAR was not inferior to LMWH in reducing the risk of VTE among newly diagnosed MM pts receiving thalidomide-containing regimens. For these pts, LMWH, WAR and ASA are likely to be effective thromboprophylactic regimens.

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