Bone Turnover In Multiple Myeloma: Impact Of Bortezomib-Based Induction Therapy, High-Dose Melphalan, and Lenalidomide Consolidation On Osteoblast and Osteoclast Function Within The GMMG-MM5 Trial

Abstract Introduction In multiple myeloma, initially, there are increased numbers of osteoclasts showing increased activity, but bone formation by osteoblasts is keeping step. In later stages, parts of the bone remodeling compartments are disrupted by the interaction with myeloma cells leading to increased bone resorption which can no longer be compensated (myeloma bone disease, uncoupling of bone formation and bone resorption). Lenalidomide and bortezomib have been shown to target both, myeloma cells and the microenvironment: lenalidomide inhibits osteoclastogenesis, bortezomib is also able to stimulate osteoblast differentiation leading to increased bone formation. Aim of this study is to evaluate the impact of bortezomib-based induction treatment, high-dose therapy, and lenalidomide consolidation on alterations of bone turnover, i.e. surrogates of osteoblast- (osteocalcin, OC) and osteoclast- (collagen type I fragments, CTX-I) function, and their induction by myeloma cells (DKK1-level). Methods Serum was collected during routine sampling within the GMMG-MM5 trial (EudraCT 2010-019173-16), and levels of CTX-I, OC, and DKK1 were assessed by ELISA in triplicates using commercially available assays according to the manufacturer’s instructions (RnD Systems and Immunodiagnostic Systems). The following time points were assessed: at inclusion (n=365), after induction therapy with either PAd (n=88) or VCD (n=84), stem cell mobilization using CAD (n=69), high-dose melphalan (n=92), and 2 months lenalidomide consolidation (n=92). Up to now, serum samples of 69 patients were measured sequentially at five time points in line with the GMMG-MM5 trial. DKK1 levels were correlated with the expression in CD138-purified myeloma cells (Affymetrix microarrays, n=365). Results Prior to treatment, CTX-I levels are increased, those of OC decreased compared to healthy donors (uncoupled bone turnover). DKK1 protein levels are increased and correlate with DKK1-expression in myeloma cells. After induction therapy, osteoclast activity (CTX-I) is decreased below normal values. PAd unlike VCD further decreases osteoblast activity (OC-levels); DKK1-levels are normalized. Subsequent treatment further decreases DKK1-levels below normal values and blocks osteoclast function. After 2 months lenalidomide consolidation, no normalization of osteoblast activity is found. Conclusion The main impact on bone turnover by bortezomib-based induction treatment is a reduction of osteoclast activity alongside a decrease in DKK1-levels. During the reported period, no normalization of decreased osteoblast function was observed. Disclosures: Seckinger: Novartis Pharma: Research Funding. Goldschmidt:Novartis Pharma: Research Funding. Hose:Novartis Pharma: Research Funding.

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Velcade, Intravenous Cyclophosphamide and Dexamethasone (VCD) Induction for Previously Untreated Multiple Myeloma (German DSMM XIa Trial).

Blood ◽

10.1182/blood.v114.22.131.131 ◽

2009 ◽

Vol 114 (22) ◽

pp. 131-131 ◽

Cited By ~ 20

Author(s):

Hermann Einsele ◽

Peter Liebisch ◽

Christian Langer ◽

Martin Kropff ◽

Hannes Wandt ◽

...

Keyword(s):

Multiple Myeloma ◽

Induction Therapy ◽

Research Funding ◽

Response Rate ◽

Induction Treatment ◽

High Dose ◽

Prognostic Impact ◽

Short Period ◽

Grade 3 ◽

High Dose Melphalan

Abstract Abstract 131 Introduction. Autologous stem cell transplantation (ASCT) after cytoreductive induction is considered standard of care for younger patients (pts) with multiple myeloma (MM). The previous standard of induction, the Vincristin-Adriamycin-Dexamethasone (VAD) combination, achieves inferior results compared with induction regimens which combine the proteasome inhibitor Velcade (V = Bortezomib) with Dexamethasone (D)(=VD) and a cytostatic drug such as Doxorubicin (PAD = VD plus Doxorubicin). Velcade-based induction therapy was shown to translate into better myeloma control after high dose melphalan and to lead to prolonged progression-free survival. In order to find a more efficacious and safer drug combination for induction therapy in MM, we tested the combination of Velcade with Cyclophosphamide and Dexamethasone (VCD). Methods. This trial was designed as an open, prospective, multi-center, uncontrolled, combined phase II/III study. As previously reported (Kropff M et al., Ann Hematol 2009), in the first 30 pts the optimal dose of iv Cyclophosphamide in combination with V and D was defined as 900 mg/m2 on d1. Between 03/2006 and 03/2009 we enrolled an additional 370 pts up to 60 years of age with untreated MM to receive three 3-week cycles of induction treatment with V 1.3 mg/m2 iv d1,4,8,11; D 40 mg/d orally d1,2,4,5,8,9,11,12; and C 900mg/m2 iv d1 before scheduled high dose melphalan and ASCT. The primary endpoint of the study is response rate on day 63 after 3 cycles of VCD according to EBMT and IMWG criteria. Results. Final data from 400 pts from 39 German centers will be presented at the meeting. In the currently evaluable 300 pts (mean age 52.3 years; 1.7% stage I, 21.3% stage II, 77.0% stage III) molecular cytogenetic analysis showed a prevalence of 13q- in 38%, of t[4;14] in 13% and of 17p- in 12% of pts (no changes in 35%). All 300 pts (88.3% of whom completed three cycles) were included in the intent-to-treat analysis. Overall response rate (ORR = CR+PR) was 84%, with 10% CR and 74% PR, 5.7% MR, 7.3% NC and 2.3% PD. The negative prognostic impact of 13q- or t[4;14] was abrogated (ORR normal 87.3%, 13q- 83.7%, t[4;14] 90.0%), the unfavorable influence of p53 loss in the 17p- subgroup was still detectable (ORR 69.2%) but this did not reach statistical significance. VGPR rates will be reported at the meeting. Serious adverse events were documented in 78/300 (26.0%) patients. Death rate was remarkably low (1.3%, of which one was not related to the trial medication). 155/300 (52%) of pts experienced grade 3/4 non-serious AEs and of these leucopenia (93/300 pts= 31%), thrombocytopenia (7%), neutropenia (6%), anaemia (5%) were the most frequent events. 80 AEs grade 3 or 4 and 45 SAEs were of infectious origin and occurred in 47/300 pts. 80/130 SAEs (61.5%) were at least possibly related to Velcade. 101/300 pts (34%) developed episodes of peripheral neuropathy. PNP was grade 1 in 62/300 pt (20.7%), grade 2 in 31/300 pt (10.3%) and grade 3 in 7/300 pts (2.3%). Conclusion. This analysis demonstrates that proteasome inhibition by Velcade in combination with Dexamethasone and iv Cyclophosphamide (VCD) is an induction regimen for newly diagnosed MM which is highly effective in a short period of time, has a rather low toxicity profile and is feasible for administration in an outpatient setting. Based on these characteristics, VCD qualifies to become a new standard for MM induction therapy. Disclosures: Einsele: OrthioBiotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Bortezomib is licensed as monotherapy for use in relapsed/refractory MM and in combination with melphalan/Prednisone in the first-line treatment of MM pts ineligible for HD-MEL and ASCT. . Liebisch:OrthoBiotech: Consultancy, Honoraria. Langer:OrthoBiotech: Consultancy. Kropff:OrthoBiotech: Consultancy, Honoraria. Kröger:OrthoBiotech: Honoraria. Ostermann:OrthoBiotech: Honoraria. Mügge:OrthoBiotech: Honoraria. Wolf:OrthoBiotech: Honoraria. Gramatzki:OrthoBiotech: Consultancy, Honoraria. Maschmeyer:OrthoBiotech: Travel Grant. Sezer:OrthoBiotech: Consultancy, Honoraria. Heidemann:OrthoBiotech: Honoraria. Jäger:OrthoBiotech: Honoraria. Dechow:Celgene: Research Funding. Simon:OrthoBiotech: Honoraria. Straka:OrthoBiotech: Consultancy, Honoraria, Research Funding. Fingerle-Rowson:orthoBiotech: Employment. Knop:OrthoBiotech: Honoraria.

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Biochemical markers of bone turnover following high-dose chemotherapy and autografting in multiple myeloma

Blood ◽

10.1182/blood.v96.8.2697 ◽

2000 ◽

Vol 96 (8) ◽

pp. 2697-2702 ◽

Cited By ~ 34

Author(s):

Richard E. Clark ◽

Angela J. Flory ◽

Edwina M. Ion ◽

Barry E. Woodcock ◽

Brian H. Durham ◽

...

Keyword(s):

Bone Resorption ◽

Bone Turnover ◽

High Dose Chemotherapy ◽

Marrow Transplant ◽

High Dose ◽

Creatinine Concentration ◽

Bone Specific Alkaline Phosphatase ◽

Osteoblast Activity ◽

Markers Of Bone Turnover ◽

High Dose Melphalan

Abstract The effect of high-dose chemotherapy and autografting on bone turnover in myeloma is not known. A study of 32 myeloma patients undergoing blood or marrow transplant (BMT), conditioned with high-dose melphalan, was done. Bone resorption was assessed by urinary free pyridinoline (fPyr) and deoxypyridinoline (fDPyr), expressed as a ratio of the urinary creatinine concentration. Bone formation was assessed by serum concentration of procollagen 1 extension peptide (P1CP) and bone-specific alkaline phosphatase (BSAP). Eighteen cases had normal fPyr and fDPyr at transplant, and in all but one of these cases the level remained normal throughout subsequent follow-up. In contrast, in 14 cases urinary fPyr and fDPyr levels were increased at transplant. In these cases, both fPyr and fDPyr fell to normal levels over the next few months (P = .0009 and .0019, respectively). fPyr and fDPyr levels at transplant and their trends post-BMT were unrelated to the use of pre-BMT or post-BMT bisphosphonate or post-BMT interferon. Nine cases had elevated P1CP or BSAP at transplant, which rapidly normalized. In most patients there was an increase in P1CP and/or BSAP several months post-transplant. In conclusion, increased osteoclast activity may be present even in apparent plateau phase of myeloma. High-dose chemotherapy with autografting may normalize abnormal bone resorption, although the effect may take several weeks to emerge and may be paralleled by increased osteoblast activity. The findings provide biochemical evidence that autografting may help normalize the abnormal bone turnover characteristic of myeloma.

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A Phase 2 Multi-Center, Open Label Study of Isatuximab Added to Standard Cybord Induction and Lenalidomide Maintenance Treatments in Newly Diagnosed, Transplant Eligible Multiple Myeloma

Blood ◽

10.1182/blood-2021-153632 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4767-4767

Author(s):

Rami Kotb ◽

Engin Gul ◽

Donna E. Reece

Keyword(s):

Stem Cell ◽

Sample Size ◽

Research Funding ◽

Response Rate ◽

Autologous Stem Cell Transplant ◽

Induction Treatment ◽

High Dose ◽

Cell Transplant ◽

Newly Diagnosed ◽

High Dose Melphalan

Abstract Background: Despite recent improvements, myeloma is still incurable. There is need to add new therapeutic tools. For young and fit patients, the current standard first-line therapy is a proteasome inhibitor (PI) containing induction, followed by stem cell collection, high dose Melphalan and autologous stem cell transplantation, followed by maintenance lenalidomide therapy in Canada. The anti-CD38 antibodies showed interesting activity in myeloma, and significant synergism with PI and IMiD based regimens. This CMRG-008 trial is designed to explore the benefit of adding Isatuximab to the current Canadian standard of care (CyBorD induction/Autologous SCT/Maintenance Len) in a single arm phase II trial. Design and Methods: Phase II study. Transplant eligible newly diagnosed myeloma patients (TE-NDMM) will receive Isatuximab added to four cycles of standard induction CyBorD chemotherapy (Cyclophosphamide 300 mg/m 2 PO, Bortezomib 1.5 mg/m 2 SC, and Dex 40 mg PO, all given on days 1, 8, 15 and 22 of 28-day cycles; Isatuximab 10 mg/kg IV days 1, 8, 15 and 22 of cycle 1; days 1 and 15 of cycles 2-4). After the completion of the induction treatment, subjects achieving at least stable disease will receive stem cell mobilization, collection of hematopoietic stem cells, high dose melphalan chemotherapy, and autologous stem cell transplantation. Maintenance treatment will start at 100 days (+/- 7 days) after the transplantation date (and to be continued until disease progression). The maintenance treatment will consist of Isatuximab administered in combination with Lenalidomide in 28-day cycles (Lenalidomide: 10 mg daily on days 1-21 of every cycle; Isatuximab: 10 mg/kg IV on days days 1, 8, 15 and 22 of cycle 1; days 1 & 15 of cycles 2-3; then day 1 of each subsequent cycle). The objectives: To evaluate the benefit of adding Isatuximab to CyBorD (induction = Isa + CyBorD) and Lenalidomide (maintenance = Isa + Lenalidomide) in transplant-eligible myeloma patients. Primary Endpoint: To determine the response rate (VGPR or better) defined by IMWG criteria at 100 days (+/- 7 days) after the autologous stem cell transplant (ASCT). Secondary Endpoints: A) To determine the response rate (VGPR or better) after induction treatment (before ASCT), and at 12 months, 24 months and 36 months. B) To evaluate additional efficacy outcomes including progression free survival (PFS), and overall survival (OS), time to response and duration of response. C) To confirm the feasibility, safety and tolerability of adding Isatuximab to CyBorD and to maintenance lenalidomide in transplant-eligible newly diagnosed myeloma patients. D) To determine the feasibility of autologous stem cell collection after Isa + CyBorD induction treatment. The key inclusion criteria are having a TE-NDMM with a measurable disease; adequate performance status; and adequate organ functions. The key exclusion criteria include previous exposure to anti-CD38 therapy, intolerance to CyBorD, adverse cardiac history, pulmonary disease, central nervous system disease, congenital or acquired immune suppression, and other concurrent severe or uncontrolled medical conditions. Statistics and Sample Size: Considering that the response rate (VGPR or better) after CyBorD induction therapy, high dose chemotherapy and autologous SCT is about 70-78%; and assuming a response rate (VGPR or better) to Isa-CyBorD induction and autologous stem cell transplant at 100 +/- 7 days of 88%; a sample size of 65 evaluable subjects will allow estimating the 95% confidence interval with a precision of +/- 7.9%. For the assumed rate and sample size, the lower bound of the confidence interval will be estimated to be larger than 80%. Assuming a 10% drop out rate, a total study size of 72 patients will be considered. This study is expected to open to recruitment in the third quarter of 2021. Clinicaltrials.gov #: NCT04786028. Disclosures Kotb: Janssen: Honoraria; Merck: Honoraria, Research Funding; Amgen: Honoraria; Akcea: Honoraria; Celgene: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria, Research Funding; Takeda: Honoraria; Karyopharm: Current holder of individual stocks in a privately-held company. Reece: BMS: Honoraria, Research Funding; GSK: Honoraria; Karyopharm: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Millennium: Research Funding; Sanofi: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

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Light Chain Deposition Disease: Impact of Stem Cell Tranplant on Hematological Response Achievement.

Blood ◽

10.1182/blood.v116.21.4600.4600 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4600-4600 ◽

Cited By ~ 1

Author(s):

Victor H Jimenez-Zepeda ◽

Norman Franke ◽

Andrew Winter ◽

Donna E. Reece ◽

Suzanne Trudel ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Induction Therapy ◽

Research Funding ◽

Elevated Serum ◽

High Dose ◽

Light Chain Deposition Disease ◽

Monoclonal Protein ◽

Light Chain Deposition ◽

High Dose Melphalan

Abstract Abstract 4600 Light chain deposition disease (LCDD) is a systemic disorder characterized by deposition of monoclonal light chains (LC) in different organs. A single clone of plasma cells is responsible for the overproduction of either kappa or rarely lambda LC. Renal dysfunction generally is the main feature but many organs could be affected. The treatment of LCDD has not been standardized and remains controversial because of the small number of patients reported in the literature. However, as LCDD is associated with plasma cell dyscrasias, patients have typically been treated with regimens used for multiple myeloma, most commonly melphalan (mel) and prednisone and VAD (Vincristine, Adriamycin and Dexamethasone). Here, we report our experience using High Dose Melphalan (HDM) with Autologous Stem Cell Transplant (ASCT) in five patients (pts) with LCDD. In addition, we report the use of Velcade (vel) as induction therapy in two patients before undergoing ASCT. Patients and Methods We retrospectively reviewed the records of all pts treated with HDM/ASCT at Princess Margaret Hospital between January 2004 and December 2009 and identified five pts with LCDD. Pretreatment evaluation included staging investigations: 1) complete blood cell counts, 2) complete biochemistry panel, 3) albumin and β2-microglobulin, 4) Blood and Urinary Monoclonal protein assessment including Free LC Assay; 5) skeletal survey. 6) Bone marrow aspirate and biopsy. Pts with LCDD and concurrent multiple myeloma were excluded. LCDD was diagnosed by renal biopsy in all pts with histology confirming characteristic linear monoclonal LC deposits along the tubular membrane staining for kappa and lambda chains on inmunofluorescence. All pts received induction therapy prior to consolidation with HDM/ASCT [dexamethasone (n=3) and vel plus dexamethasone (n=2)]. Assessment of hematologic response (HR) to treatment was based on modified EORTC consensus criteria. Results Pts characteristics are shown in Table 1. Two pts were male subjects; the median age was 55 (range 45–65). All five pts, had elevated serum FLC and an abnormal κ-to- λ ratio. All of the pts presented with kidney involvement. The monoclonal protein deposited in the kidney consisted of free κ-LC in four pts and free lambda LC in 1. Two pts received vel and dexamethasone (3 cycles) induction therapy achieving PR after 6 weeks of therapy and three received dexamethasone alone: 1 pt achieving a PR and 2 SD. All of them received a conditioning regimen of mel 200 mg/m2. Complete HR was seen in 3 pts and PR in 1 patient (ORR 80%, CR 60%). Transplanted pts had a median time to ANC ≥0.5 ×109/L of 12d (Range 12–13) and time to platelets ≥ 20 ×109/L was 14 days (Range 12–17). Median time to discharge was 17 days (range 13–30) and no pts exhibited engraftment syndrome. There was no mortality related to transplant. The most common grade 3/4 adverse events included: neutropenic fever (n=5); mucositis (n=2); and transient worsening in kidney function (n=1). All pts are alive and progression-free at a median follow-up of 20 months (range 7–37) from transplant. As kidney dysfunction represents the most prominent morbidity in LCDD, it is important to emphasize that the elevated serum creatinine was ameliorated in these pts after ASCT Conclusions LCDD is a rare condition and its management is controversial. In a few small series, investigators have reported that high-dose melphalan (HDM) followed by ASCT can be associated with beneficial results whereas toxicity remains acceptable in this group of pts. We report our experience using HDM and ASCT in pts with LCDD without concurrent myeloma, demonstrating feasibility and tolerability. Disclosures: Reece: Celgene: Honoraria, Research Funding. Chen:Celgene Corporation: Consultancy, Honoraria, Research Funding. Kukreti:Celgene: Honoraria.

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Mature Results From ECOG Study E1405 – A Phase II Study of VcR-CVAD with Maintenance Rituximab for Previously Untreated Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v120.21.153.153 ◽

2012 ◽

Vol 120 (21) ◽

pp. 153-153 ◽

Cited By ~ 5

Author(s):

Brad S. Kahl ◽

Hailun Li ◽

Mitchell R Smith ◽

Randy D. Gascoyne ◽

David T. Yang ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Induction Therapy ◽

Research Funding ◽

Cell Lymphoma ◽

Treatment Plan ◽

Induction Treatment ◽

High Dose ◽

Group Setting ◽

Mantle Cell ◽

Grade 3

Abstract Abstract 153 Introduction Modified R-hyperCVAD is a well-tolerated induction regimen with a high response rate in MCL. We hypothesized that the incorporation of bortezomib (Velcadea) into this regimen would enhance the complete response rates. We further hypothesized that the addition of maintenance rituximab (MR) would improve remission duration. The new regimen, VcR-CVAD with MR, was tested for safety and efficacy in the Eastern Cooperative Oncology Group. Methods Eligible patients had histologically confirmed, previously untreated MCL, PS 0–2, and adequate end organ function. The treatment plan included: bortezomib 1.3 mg/m2 days 1 and 4, rituximab 375 mg/m2 IV day 1, cyclophosphamide 300 mg/m2 IV over 3 hrs q 12 hrs × 6 doses days 1–3, doxorubicin 50 mg/m2 continuous infusion over 48 hrs days 1–2, vincristine 1 mg IV day 3, dexamethasone 40 mg po days 1–4. Cycles were repeated every 21 days for 6 cycles and all patients received G-CSF support. Patients achieving SD, PR, or CR received MR administered as 4 weekly treatments every 6 months for 2 years (protocol therapy). Patients could elect to receive high dose chemotherapy and autologous stem cell transplantation (SCT) off protocol rather than MR. The primary endpoint of the trial was the CR rate, defined as PET-negative, marrow-negative, to VcR-CVAD induction therapy. Results Seventy-five eligible patients were enrolled between 5/07 and 10/08. Baseline characteristics include median age 62 (40–76), 58M:17F, 92% stage III/IV, and 40% with elevated LDH. MIPI risk distribution included 37% low, 36% intermediate, 19% high, 8% unknown. Sixty-eight patients (91%) completed VcR-CVAD induction therapy. Reasons for treatment discontinuation included PD (1), toxicity (4), and patient preference (2). The ORR was 97% (73/75), CR rate 68% (51/75) and PR rate 29% (22/75). Of the 22 PR patients, 11 were so coded due to no bone marrow evaluation and/or PET imaging post therapy. The CR rate in the 64 completely restaged patients was 80%. Forty-four patients proceeded to protocol planned MR while 22 patients received SCT consolidation off protocol. With a median follow up of 3.6 years, the 3-yr PFS for the MR cohort (n = 44) and entire cohort (n = 75) are 73% and 74%, respectively. OS at 3-yrs is 88%, with no difference between MR and SCT patients. The major toxicity of the induction treatment regimen was expected myelosuppression. Grade 3–4 non-hematologic toxicities were rare. No patients developed grade 3–4 neuropathy. There were no serious toxicities during MR. There were no treatment related deaths. Conclusion The VcR-CVAD induction produced high overall OR (97%) and CR rates (68%) in a representative MCL patient population treated in a cooperative group setting. The 3-yr PFS (74%) and OS (88%) are highly encouraging. Remissions in patients receiving MR were as durable as patients receiving SCT consolidation. The value of bortezomib, when added to conventional chemotherapy, is currently being tested in a randomized intergroup trial (E1411). Disclosures: Kahl: Genentech: Consultancy, Research Funding; Roche: Consultancy; Millennium: Consultancy, Research Funding. Off Label Use: Bortezomib as frontline treatment of mantle cell lymphoma. Smith:Millennium: Research Funding. Advani:Genentech: Research Funding. Horning:Genentech: Employment; Roche: Equity Ownership.

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GMMG MM5 Trial In Newly Diagnosed Multiple Myeloma To Evaluate PAd Vs VCD Induction Prior To High Dose Treatment Followed By Lenalidomide Consolidation and Maintenance – Final Analysis On Induction Therapy

Blood ◽

10.1182/blood.v122.21.3369.3369 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3369-3369 ◽

Cited By ~ 2

Author(s):

Hartmut Goldschmidt ◽

Jan Duerig ◽

Uta Bertsch ◽

Christina Kunz ◽

Thomas Hielscher ◽

...

Keyword(s):

Partial Response ◽

Induction Therapy ◽

Research Funding ◽

Treatment Strategies ◽

Response Rates ◽

Complete Response ◽

Disease Stage ◽

Induction Treatment ◽

High Dose ◽

Good Partial Response

Abstract Background The MM5 phase III trial of the German-Speaking Myeloma Multicenter Group (GMMG) was designed to address two independent primary objectives: 1.) demonstration of non-inferiority of VCD (bortezomib, cyclophosphamide, dexamethasone) induction compared to PAd (bortezomib, adriamycin, dexamethasone) induction therapy with respect to response rate (very good partial response or better). 2.) determination of the best of four treatment strategies with respect to progression-free survival (PFS). The four treatment strategies were defined by PAd vs. VCD induction treatment, high dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) as well as consolidation and maintenance treatment with lenalidomide for 2 years vs. lenalidomide until complete response (CR). Methods 504 patients were included in the trial between July 2010 and October 2012. A non-inferiority analysis of VCD compared to PAd with respect to response rates after induction treatment with a non-inferiority margin of 10% for the difference in response rates (VGPR and better; first primary endpoint) and a safety analysis were performed. During the induction phase the patients were treated with 3 cycles of PAd or VCD. PAd was dosed as bortezomib 1.3 mg/m2, days 1, 4, 8, 11, doxorubicin 9 mg/m2, days 1-4, dexamethasone 20 mg, days 1-4, 9-12, 17-20 (repeated every 28 days). VCD consisted of bortezomib 1.3 mg/m2, days 1, 4, 8, 11, cyclophosphamide 900 mg/m2 day 1, dexamethasone 40 mg, days 1-2, 4-5, 8-9, 11-12 (repeated every 21 days). The route of administration for bortezomib was changed from intravenously to subcutaneously in all study arms by a protocol amendment in February 2012 after inclusion of 314 patients. The non-inferiority analysis was based on intention-to-treat (ITT) population (502 evaluable patients) and per-protocol (PP) population (473 evaluable patients). Responses were assessed according to the response criteria of the International Myeloma Working Group (IMWG). Results In the ITT population, patients treated with PAd or VCD were equally distributed for ISS and Durie-Salmon disease stage, LDH, kidney function and the cytogenetic abnormalities translocation t(4;14), deletion 17p13 and gain 1q21. In the PAd group, the median age of the patients was higher (59.4 vs. 58.7, p=0.04). 229 of 251 patients (91.2%) in the PAd group and 241 of 251 patients (96.0%) in the VCD group completed induction treatment. Observed response rates (PAd vs. VCD) were 4.4% vs 8.4% for complete response, 34.3% vs. 37.0% for ≥ very good partial response and 72.1% vs. 78.1% for ≥ partial response. Non-inferiority of VCD compared to PAd was shown (two-sided p=0.0026). Similar results were obtained in the PP analysis. The proportion of patients with any adverse event (AEs) was comparable in PAd vs. VCD (61.3% vs. 64.0%, p=0.58), but more serious adverse events (SAEs) were observed during PAd induction (32.7% vs. 24.0%, p=0.037). VCD led to a significantly higher proportion of leukopenia and neutropenia CTCAE grade 3 and 4 (PAd: 11.3% vs. VCD: 35.2%; p<0.001). There was no significant difference in the number of infections (≥ CTCAE grade 2) during PAd induction compared to VCD induction (24.6% vs. 22.4%; p=0.60). Interestingly, compared to the infection rate (≥ CTCAE grade 2) of 49% during PAD (dexamethasone 40 mg days 1-4, 9-12, 17-20) in the HOVON65/GMMG-HD4-trial, a reduction in MM5 during induction was observed. In the PAd arm more deaths were observed compared to the VCD arm (6 vs. 1). Conclusion PAd and VCD are well tolerated with more than 90% of the patients receiving all three planned induction cycles. Non-inferiority of VCD compared to PAd was shown in ITT and PP analysis. In conclusion, VCD was found to be a valid alternative to PAd with comparable efficacy and a favourable toxicity profile. Disclosures: Goldschmidt: Celgene: Consultancy, Honoraria, Research Funding; Chugai: Research Funding; Janssen Cilag: Consultancy, Honoraria, Research Funding. Duerig:Janssen Cilag: Honoraria; Celgene: Honoraria. Schmidt-Wolf:Janssen: Honoraria; Novartis: Honoraria. Weisel:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Scheid:Janssen Cilag: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Salwender:Janssen Cilag: Honoraria; Celgene: Honoraria.

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Addition of Bortezomib to High Dose Melphalan As Conditioning Regimen for Autologous Stem Cell Transplantation Improves the Response Rate in Newly Diagnosed Multiple Myeloma Patients

Blood ◽

10.1182/blood.v128.22.4647.4647 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4647-4647 ◽

Cited By ~ 1

Author(s):

Benedetta Dalla Palma ◽

Lucia Prezioso ◽

Fabrizio Accardi ◽

Stefano Bisbano ◽

Federica De Luca ◽

...

Keyword(s):

Stem Cell ◽

Induction Therapy ◽

Research Funding ◽

Response Rate ◽

Conditioning Regimen ◽

Median Number ◽

High Dose ◽

Newly Diagnosed ◽

Significant Difference ◽

High Dose Melphalan

Abstract High-dose Melphalan (HDM) is the most commonly used conditioning regimen for autologous stem cell transplantation (ASCT) in newly diagnosed transplant-eligible Multiple Myeloma (MM) patients. Recent evidence suggests that the depth of response after induction therapy influences progression free survival (PFS) and, in most studies, overall survival (OS). Actually the effect of the inclusion of new drugs in the conditioning regimen for ASCT is still unknown. Phase I-II clinical study showed that the addition of Bortezomib (Bor) to HDM is safe and a promising conditioning regimen. Thus, in this study we analyzed a single center experience on the use of Bor in combination with HDM (Bor-HDM) as conditioning regimen before ASCT as frontline treatment in MM patients in order to evaluate the safety and the response rates of this combination regimen. We analyzed a total cohort of 48 newly diagnosed MM patients (25 females and 23 males; median age 60 years, range 42-70) admitted consecutively to our Bone Marrow Transplantation Center from 2008 to 2014. Regarding prognostic stratification, 25% of patients were classified as stage III according to International Staging System (ISS), and 12% exhibited high-risk cytogenetic features (defined by presence of del(17p) and/or t(4;14) and/or t(14;16)). All patients with the exception of three underwent to 3-drugs Bor-based induction therapy including Bor (median cumulative dose: 28.9 mg/m2), Thalidomide and Dexamethasone (VTD). After induction therapy and stem cell collection 28 out of 48 patients were treated with Bor-HDM, whereas 20 patients with HDM alone as conditioning regimen before ASCT. HDM was administered on day -2 (median dose: 200 mg/m2), and a single-dose Bortezomib at the dosage of 1.3 mg/m2 was administered on day -1 in the Bor-HDM group. Stem cells were reinfused on day 0 (median number of CD34+ infused: 3.3x106/Kg, range 1.86-6x106/Kg). Responses were evaluated at day 100 after ASCT, and definitions of response were used according to the International Myeloma Working Group (IMWG) Uniform Response Criteria for MM. Quantitative variables were compared by non-parametric Kruskal-Wallis and Mann-Whitney tests as appropriate and categorical variables were analyzed by Chi-square and Fisher's exact test. pvalue of <0.05 was considered significant. Any significant difference was not observed between Bor-HDM group vs HDM group, regarding age at diagnosis (p=0.77), sex (p=0.24), cumulative induction dose of Bortezomib (p=0.42), dose of Melphalan used for conditioning (p=0.16) and the median number of CD34+ cells infused (p=0.12). Distribution of ISS stage was similar in the two groups (p=0.14), as well as that of high-risk cytogenetic (p=0.14). Moreover the response rates after the induction therapy was not statistically different in the two groups of patients analyzed (sCR + CR: 19% in Bor-HDM group vs 26% in HDM group; VGPR: 33% vs 48%; PR: 48% vs 26%, p=0.22). Any significant difference on hematopoietic recovery rates was not observed in Bor-HDM as compared to HDM alone with a mean time to neutrophil recovery of 12 days (range 9-18) and to platelet recovery of 12 days (range 9-21) in both groups. Bor-HDM conditioning was well tolerated, without increase of neuropathy occurrence. Then we analyzed the response rate after ASCT, showing that the overall response rate (ORR) was significantly higher in Bor-HDM group as compared to HDM (sCR+CR: 56% in Bor-HDM vs 17% in HDM; VGPR 30% vs 28%; PR: 15% vs 56%, p=0.0072) with a higher number of "good quality" response (sCR + CR + VGPR: 86% vs 45%; p=0.0075). The number of sCR was also significantly higher in Bor-HDM as compared to HDM alone (23% vs 0%, p=0.067). Moreover an improvement of the response rate after ABMT was seen more frequently in the Bor-HDM group as compared to the HDM group (p=0.0063). We then observed that the number of patients that underwent tandem ASCT was higher in the HDM group (66% vs 41%), even not reaching a statistical significance. In conclusion, this retrospective analysis suggests that BOR-HDM is safe as conditioning regimen with a higher response rate after ASCT as compared to the standard HDM regimen giving the rational design for randomized studies needed to assess whether this conditioning regimen is superior to HDM alone. Disclosures Giuliani: Celgene: Research Funding; Janssen: Research Funding.

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Biochemical markers of bone turnover following high-dose chemotherapy and autografting in multiple myeloma

Blood ◽

10.1182/blood.v96.8.2697.h8002697_2697_2702 ◽

2000 ◽

Vol 96 (8) ◽

pp. 2697-2702

Author(s):

Richard E. Clark ◽

Angela J. Flory ◽

Edwina M. Ion ◽

Barry E. Woodcock ◽

Brian H. Durham ◽

...

Keyword(s):

Bone Resorption ◽

Bone Turnover ◽

High Dose Chemotherapy ◽

Marrow Transplant ◽

High Dose ◽

Creatinine Concentration ◽

Bone Specific Alkaline Phosphatase ◽

Osteoblast Activity ◽

Markers Of Bone Turnover ◽

High Dose Melphalan

The effect of high-dose chemotherapy and autografting on bone turnover in myeloma is not known. A study of 32 myeloma patients undergoing blood or marrow transplant (BMT), conditioned with high-dose melphalan, was done. Bone resorption was assessed by urinary free pyridinoline (fPyr) and deoxypyridinoline (fDPyr), expressed as a ratio of the urinary creatinine concentration. Bone formation was assessed by serum concentration of procollagen 1 extension peptide (P1CP) and bone-specific alkaline phosphatase (BSAP). Eighteen cases had normal fPyr and fDPyr at transplant, and in all but one of these cases the level remained normal throughout subsequent follow-up. In contrast, in 14 cases urinary fPyr and fDPyr levels were increased at transplant. In these cases, both fPyr and fDPyr fell to normal levels over the next few months (P = .0009 and .0019, respectively). fPyr and fDPyr levels at transplant and their trends post-BMT were unrelated to the use of pre-BMT or post-BMT bisphosphonate or post-BMT interferon. Nine cases had elevated P1CP or BSAP at transplant, which rapidly normalized. In most patients there was an increase in P1CP and/or BSAP several months post-transplant. In conclusion, increased osteoclast activity may be present even in apparent plateau phase of myeloma. High-dose chemotherapy with autografting may normalize abnormal bone resorption, although the effect may take several weeks to emerge and may be paralleled by increased osteoblast activity. The findings provide biochemical evidence that autografting may help normalize the abnormal bone turnover characteristic of myeloma.

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The Prognosis of PR Patients after Induction Therapy Was Not Inferior to CR in ASCT-Eligible NDMM Patient.

Blood ◽

10.1182/blood.v128.22.5682.5682 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5682-5682

Author(s):

Anna Takahashi ◽

Yuko Mishima ◽

Norihito Inoue ◽

Yoshiharu Kusano ◽

Hirofumi Yamauchi ◽

...

Keyword(s):

Stem Cells ◽

Multiple Myeloma ◽

Stem Cell ◽

Induction Therapy ◽

Research Funding ◽

Residual Disease ◽

High Dose ◽

Myeloma Cells ◽

Ecog Ps ◽

Cell Harvest

Abstract Introduction: Autologous stem cell transplantation (ASCT) is standard therapy for newly diagnosed multiple myeloma (NDMM) patients who are younger than 70 years old. In the IFM 90 trial, 5-year OS was 52% in the ASCT group compared to 12% in the initial chemotherapy group (p=0.03). 5-year EFS was 28% in the ASCT group compared to 10% in the chemotherapy only group (p=0.01). MRC Ⅳ trial also showed a higher rate of OS (p=0.04) and PFS (p<0.001) in the ASCT group. However, there was no result about the differences of the prognosis between CR and PR before ASCT. In this study, we studied the response level before ASCT to understand if it is related to the prognosis after ASCT. Methods: We studied 25 NDMM patients who received ASCT in our hospital from 2005 to 2015. Induction therapies were VRD, VCD, VAD, VD, Rd or VTD-PACE. Stem cells were collected using G-CSF or cyclophosphamide plus G-CSF. After stem cell harvest, all patients underwent high dose melpharan (200mg/m2) before ASCT. The responses according to the IMWG guidelines were performed at the point of 4-6 weeks after ASCT. Statistical analyses were performed using a software, EZR version 1. Results: The total number of NDMM patients was 25. The median age was 55 years (range 33-62), the median follow-up period was 1,375 days (range 340-3,763). Male were 16 (64%), 11 patients (44%) were ISS Ⅱor more and 20 (80%) were D&S stageⅡor more. ECOG PS 2 was 4 patients (8%) and one (4%) is ECOG PS 3. Before ASCT, 21 patients (84%) received 1 regimen and 4 (16%) received 2 regimens. In the 1 regimen group, 9 patients (43%) were treated by VCD with 2-4 cycles, 9 received VD with 4-5 cycles and 5 (24%) were received VAD with 3 cycles before ASCT. In the 2 regimens group, details of induction therapy were VD with BCD, VCD with Rd, VCD with VRD and VCD with VTD-PACE. In all patients, 3-year OS was 91.6% (95% CI, 70-98%) and 3-year PFS was 56% (95% CI, 34-74%). After induction therapy, CR was achieved in 11 (44%), VGPR was 2 (8%), PR was 11 (44%) and MR was 1 (4%). After ASCT, CR was achieved in 18 (72%), VGPR was 2 (8%), PR was 4 (16%) and PD was 1 (4%). 4 patients (16%) died for progression of multiple myeloma. There were no statistical differences in 3-year OS and PFS between CR group and VGPR + PR group after induction therapy (3-year OS; 100% vs 92%, p=0.11, 3-year PFS; 70% vs 50%, p=0.26). There were also no differences between the two groups CR group and PR without VGPR group (3-year OS; 100% vs 90%, p=0.18a, 3-year PFS; 70% vs 60%, p=0.4). As sub-analysis, the achievement time until normalization of FLC and disappearance of serum or urine M-protein in IFE did not affect 3-year OS and PFS. Discussion and Conclusions: When MM patients having residual disease did the stem-cell harvest, it has been possible to contaminate of myeloma cells in their collected stem cells. Several literatures described the contamination of myeloma cells in the stem cells induced inferior prognosis after ASCT. However our limited data suggested that the prognosis of patients who had residual disease after induction therapy, if they had achieved better than PR, were not inferior to CR group. This is reasonable data for recommendation of ASCT to MM patients getting PR after induction therapy. Disclosures Mishima: Chugai: Consultancy. Nishimura:Chugai: Consultancy. Yokoyama:Chugai: Consultancy. Terui:Yanssen: Honoraria. Hatake:Chugai: Research Funding; Otsuka: Consultancy; Kyowa Kirin: Honoraria, Research Funding; Meiji-Seika: Consultancy.

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