Short Survival, Despite Promising Response Rates, after Bortezomib Treatment of Multiple Myeloma Patients with a 13q-Deletion.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 509-509 ◽  
Author(s):  
Johannes Drach ◽  
E. Kuenburg ◽  
Verena Sagaster ◽  
Niklas Zojer ◽  
Hannes Kaufmann ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Prognostic Factors ◽  
Serum Albumin ◽  
Single Agent ◽  
Remission Induction ◽  
High Dose ◽  
Minor Response ◽  
Bone Marrow Plasma ◽  
13Q Deletion

Abstract Presence of a chromosome 13q-deletion confers a poor prognosis to patients with multiple myeloma (MM) irrespective of the treatment modality (standard-dose chemotherapy, high-dose melphalan with autologous transplantation, allogeneic transplantation, thalidomide), which underlines the need for effective therapy in this high-risk MM patient population. Bortezomib (B) is the first compound of a new class of agents - the proteasome inhibitors - showing activitiy in relapsed and chemotherapy-refractory MM. Preliminary evidence suggests that B may also be active in MM with unfavorable standard prognostic factors. Therefore, the aim of our investigation was to study the activity of B in relapsed MM in the context of chromosomal aberrations (in particular deletion of chromosome 13q14 [del(13q14)] and 14q-translocations [t(14q32)]) as detected by interphase fluorescence in situ hybridization (FISH). Up to now, 52 patients with relapsed/refractory MM (47 after ≥2 lines of prior therapy) were treated with B (1.3 mg/m2 on days 1, 4, 8, 11; q21 days). Patients not achieving at least a minor response to single-agent B were treated with B plus dexamethasone (DEX; 8–20mg); subsequently, melphalan (10 mg/m2) or doxorubicin (9 mg/m2) was added to B/DEX treatment. To date 44 patients are evaluable for response, time to treatment failure (TTF), overall survival (OS), and association with prognostic factors. 23 evaluable patients (52%) experienced an objective response, with 8 patients (18%) achieving a CR/near-CR (>90% paraprotein reduction), 12 patients (27%) achieving a PR (50 – 90% paraprotein reduction), and 3 patients (75) showing a MR (25 – 50% paraprotein reduction). Median time to response was 3 weeks (range, 3 – 9 weeks). According to FISH, 22 patients (50%) had a del(13q14). B was effective for remission induction in both del(13q14) MM patients (18% CR/nearCR, 18% PR, 5% MR) and 13q-normal patients (18% CR/nearCR, 36% PR); however, median TTF (2.6 versus 6.7 months) and median OS (6.1 months versus not yet reached; P = .047) were shorter for del(13q14) patients compared to 13q-normal patients. Of note, failure to respond to B and short OS was observed in 2 patients with del(13q14) and concomitant amplification of CKS1B (1q21). Additional studies regarding 1q21 are in progress. Remission rates, TTF, and OS were similar in patients with and without a t(14q32). One patient with a t(4;14)(p16;q32) responded not only to single agent B with a remission lasting for 7 months, but later also responded to B/DEX and the B/DEX/chemotherapy combination with remissions lasting for several months each. On the other hand, only one of 5 patients with a t(11;14)(q13;q32) achieved a response (MR) to B. Beta-2-microglobulin did not influence treatment outcome after B. Significantly shortened OS following B treatment was noted in MM patients with serum albumin <3.5 g/dl (4.7 months versus median not yet reached) and bone marrow plasma cells >50% (6.4 months versus not yet reached). In conclusion, B is an effective salvage treatment for MM patients with relapsed/refractory MM, even in those with prognostically adverse cytogenetic features such as del(13q14). Due to the still short TTF and OS, MM patients with adverse prognostic indicators (unfavorable cytogenetics, low serum albumin, high bone marrow plasma cell infiltration) may derive a particular benefit from combining B with other anti-MM agents.

Rituximab in CD20 Positive Multiple Myeloma: A Prospective Study from the IFM Group.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3577-3577
Author(s):  
Philippe Moreau ◽  
Laurent Voillat ◽  
Lotfi Benboubker ◽  
Charles Dumontet ◽  
Claire Mathiot ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tumor Cells ◽  
Stable Disease ◽  
Plasma Cells ◽  
Single Agent ◽  
Stage I ◽  
Minor Response ◽  
Cd20 Expression ◽  
Anti Cd20

Abstract Multiple myeloma (MM) is a heterogenous disease. A strong association between small mature plasma cell morphology, t(11;14) and CD20 expression has been described in approximately 10% of the patients with MM (Robillard et al, Blood 2003). In this subgroup of patients with MM expressing CD20, rituximab (anti-CD20 chimeric monoclonal antibody) could target the antigen and could have a clinical impact. Thus we conducted a prospective phase II trial of 4 weekly IV infusions of 375 mg/m2 rituximab in patients with MM expressing CD20 on at least 33% of tumor cells. From 07/2004 to 02/2006, 14 consecutive patients, median age 65 years, with either stage I MM never pretreated (n = 7) or stage III MM in relapse or refractory after a median of 2 lines of therapy (n= 7) were treated. Immunophenotype using flow cytometry revealed that a median of 75% of tumor cells were expressing CD20 (range, 33–100%) at the onset of therapy. Responses were evaluated 3 months after therapy according to EBMT criteria. At the reference date of June 1st, 2006, a single patient, who had relapsed 8 months after a double autologous SCT, experienced a minor response, ongoing 18 months after rituximab therapy. At the time of rituximab therapy, 100% of its plasma cells were expressing CD20, and 3 months after treatment, bone marrow examination showed 0.6% of plasma cells, none of them expressing CD20. Five patients (1 with relapsed MM and 4 with stage I MM) experienced stable disease, ongoing for 3, 4, 4, 11 and 12 months, respectively. Three patients with stage I MM had stable disease but subsequently progressed 10, 11, and 15 months after therapy, respectively. The last 5 patients with relapsed MM did not respond to anti-CD20 therapy, despite partial clearance of CD20+ plasma cells in the bone marrow in 2 cases. Conversely in the 3 latter cases, the percentage of CD20+ plasma cells did not decrease despite rituximab therapy. Several factors have been described to explain resistance against rituximab in a variety of B-cell malignancies such as the level of CD20 expression, dissociated action of complement-dependent cytotoxicity and antibody-dependant cellular cytotoxicity, polymorphism in FcgammaRIIIA receptor, and may be inadequate dose schedule. These mechanisms could explain the marginal activity of rituximab as single-agent in CD20+ MM.

Improved Remission Induction Rate of Childhood AML: Preliminary Results of the AML02 Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 275-275 ◽  
Author(s):  
Jeffrey Rubnitz ◽  
Bassem Razzouk ◽  
Paul Bowman ◽  
Gary Dahl ◽  
Norman Lacayo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Low Dose ◽  
Single Agent ◽  
Remission Induction ◽  
Intrathecal Therapy ◽  
High Dose ◽  
Triple Combination Therapy ◽  
Cns Relapse ◽  
Low Dose Cytarabine ◽  
Bone Marrow Blasts

Abstract The multicenter AML02 trial randomly assigns patients to receive high-dose or low-dose cytarabine (A), daunorubicin (D), and etoposide (E) as Induction I; all subsequent therapy is risk-adapted. Pharmacokinetic, pharmacodynamic, and gene expression studies are performed after exposure to high-dose or low-dose cytarabine. Patients with no response (NR, ≥ 25% bone marrow blasts) to Induction I receive low-dose ADE + gemtuzumab ozogamicin (GO) as Induction II, whereas all others receive ADE. Minimal residual disease (MRD) is monitored by flow cytometry and is defined as ≥ 0.1% cells with leukemia-associated immunophenotypes among bone marrow mononuclear cells. Patients who are MRD+ after induction therapy receive GO as a single agent before consolidation chemotherapy or stem cell transplantation. Among the 112 patients enrolled since October 2002, 37 had -7, FAB M6 or M7, FLT3 internal tandem duplication (ITD), or MDS or treatment-related AML and were classified as high-risk (HR); 32 had AML1-ETO, CBFβ-MYH11, or MLL-AF9 (low-risk; LR); the remaining 43 were considered as standard-risk (SR). The rate of complete response (CR, <5% bone marrow blasts) was 84% after Induction I and 97% after Induction II. Of the 3 patients who did not attain CR, 2 had partial responses and 1 died of streptococcal sepsis during Induction II. CR rates differed according to risk group after Induction I (LR, 100%; SR, 91%, HR 61%) but not after Induction II (LR, 100%; SR, 98%, HR 94%). The association between risk groups and MRD (determined successfully in 95% of cases) was more striking: the rate of MRD negativity after Induction I was 88% in LR, 59% in SR, and 26% in HR patients; after Induction II, rates were 97%, 82%, and 53%, respectively. Response to initial therapy was particularly poor among patients with a FLT3-ITD: only 1 of 11 patients was MRD-negative after Induction I and only 3 were MRD-negative after Induction II. 5 of the 6 patients who had NR to Induction I attained CR after subsequent treatment with ADE + GO and all 6 had dramatic reductions in MRD levels (from a median of 26% to a median of 0.24%). An additional 14 patients with MRD levels 0.1% to 5.6% received GO at the beginning of consolidation: 9 became MRD-negative. Overall, there were 4 deaths from infection (2 bacterial, 1 fungal, 1 viral), which occurred during induction (1), consolidation (1), and after completion of chemotherapy (2). Because CNS relapse occurred in 3 of the first 33 patients treated, intrathecal therapy was changed from cytarabine alone to triple combination therapy with methotrexate, hydrocortisone, and cytarabine; none of the 79 subsequent patients has had a CNS relapse. The 1-year event-free and overall survival estimates are 76.8% (SE, 5.1%) and 89.1% (SE, 3.8%). In conclusion, AML02 therapy has produced a high overall remission rate and low treatment-related mortality, which we attribute to excellent supportive care and to the use of risk- and MRD-adapted therapy.

Prognostic Value of Bone Marrow Angiogenesis in Patients with Multiple Myeloma Undergoing High-Dose Therapy and Autologous Stem Cell Transplantation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3321-3321
Author(s):  
Olga Pokrovskaya ◽  
Larisa Mendeleeva ◽  
Irina Kaplanskaya ◽  
Elena Parovichnikova ◽  
Sergei Kulikov ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Stem Cell ◽  
Prognostic Factors ◽  
Stem Cell Mobilization ◽  
Control Group ◽  
High Dose ◽  
Newly Diagnosed ◽  
High Dose Therapy ◽  
Cell Mobilization

Abstract BACKGROUND. Angiogenesis is a constant hallmark of multiple myeloma (MM) progression. It has also been reported that bone marrow angiogenesis is a predictive factor of poor survival in newly diagnosed myeloma. The aim of the current study was to investigate the dynamics of bone marrow (BM) microvessel density (MVD) in patients undergoing high-dose therapy (HDT) and autologous stem cell transplantation (ASCT). PATIENTS AND METHODS. 36 patients with newly diagnosed MM (22 in stage II and 14 in stage III according to Salmon and Durie) were included in the study – 21 male and 15 female, median age – 51 ys (range 31–67). All patients underwent HDT that included 3–4 cycles of induction therapy (VAD), stem cell mobilization with cyclophosphamide 6 g/m2 and G-CSF 5 mcg/kg, EDAP and single or tandem ASCT with melphalan 200 mg/ m2. The BM biopsies for histological and immunohistochemical analysis were performed at the time of diagnosis, after induction, after stem cell mobilization before the 1st ASCT and after the end of therapy (5 times during the treatment). The Control group consisted of normal BM donors (7 male and 3 female, median age 29, (17–59)) who underwent BM biopsy during BM harvesting for alloBMT. Blood vessels were highlighted by immunostaining of endothelial cells with a monoclonal antibody to CD34 (Novocastra Lab Ltd). The MVD was calculated in 10 fields using an 40x objective and 16x ocular lens. RESULTS. At diagnosis in all MM pts, MVD was extremely high compared to normal donors (152±8 vs 74±4). A significant decrease of BM MVD was observed after each phase of therapy: after the induction therapy the MVD was 124±6; before the 1st ASCT – 109±5 and at the end of treatment – 97±3. There was a statistically significant increase of MVD after stem cell mobilization due to G-CSF (143±4). Although there was a marked decrease of BM MVD in MM pts with CR or VGPR, it nevertheless stayed significantly higher compared with control group (p<0,001). The analysis of probability of CR or VGPR duration after ASCT according to MVD at different phases of therapy showed that MVD at diagnosis and before the 1-st ASCT are important prognostic factors. Probability of duration of CR or VGPR was 63% in group with low MVD before the 1st ASCT compared with 15% in group with high MVD (p<0,02). MVD was revealed to be more powerful prognostic factor for progression free survival (PFS) then CR or VGPR achievement. CONCLUSION. BM angiogenesis is increased in patients with MM. BM MVD is decreased during and after treatment however even after the completion of HDT and ASCT, the MVD is higher then in the normal control group. There is a statistically significant increase of MVD after stem cell mobilization with cyclophosphamide and G-CSF. MVD at the time of diagnosis and before the 1-st ASCT are important prognostic factors for overall-survival and PFS after ASCT. MVD before the 1-st ASCT appears to be a more powerful prognostic factor for PFS then remission rate.

scholarly journals Impact on Survival Outcomes of Bone Marrow Plasma Cells Percentage and Morphology Evaluation By Conventional Microscopy in Multiple Myeloma after High Dose Therapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3396-3396
Author(s):  
Camille Claracq ◽  
Murielle Roussel ◽  
Benjamin Hébraud ◽  
Michel Attal ◽  
Herve Avet Loiseau ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Survival Outcomes ◽  
High Dose ◽  
High Dose Therapy ◽  
Impact On Survival ◽  
Bone Marrow Plasma ◽  
Conventional Microscopy

Abstract Impact on Survival Outcomes of Bone Marrow Plasma Cells Percentage and Morphology Evaluation by Conventional Microscopy in Multiple Myeloma after High Dose Therapy. Background: The achievement of at least CR is a crucial step for a long-lasting response and prolonged survival after autologous stem cell transplantation (ASCT) in patients (pts) with multiple myeloma (MM). The current definition of complete remission (CR) or better in MM requires a negative serum and urine immunofixation (IF) and <5% bone marrow plasma cells (BMPCs). Additional prognostic tools are related to sFLC ratio, immunophenotypic and molecular evaluations, when possible. As BMPCs levels could differ if evaluated by BM biopsy or aspirate (the latter supposed to underestimate BMPCs count), we aim to determine a new threshold for PCs in BM aspirate and to determine whether it could be, in association with PCs morphology by standard microscopic evaluation, an easy and cheap surrogate marker for outcome, in the absence of sFLC assay and/or phenotypical-molecular analysis for MRD. Material and Methods: 191 de novo MM pts treated between 2003-2010 in Toulouse's myeloma and BMT center with adequate clinical and biological data were retrospectively studied. Responses were evaluated at day 100 after ASCT in all pts according to IMWG criteria. BM examination comprised PCs count, BM cellularity, and the presence of PCs dysmorphy. Progression free survival (PFS) was calculated from the start of therapy until progression, death or last follow-up. Overall survival (OS) was calculated from the start of therapy until death or last follow-up. The Kaplan-Meier method was used to estimate the survival distribution. Results: Baseline demographics and initial disease characteristics are summarized in table 1. Median follow-up is 6 years. At the completion of ASCT, 49 pts (26%) achieved CR, 89 (47%) VGPR and 41 (21%) PR; 57 pts (30%) had a negative serum IF (sIF). Overall, 151 pts relapsed and 68 died with median PFS and OS of 36 and 99 months, respectively. At D100, median PCs count was 1% (range 0-23%): 1% (0-3%) in CR pts, 1% (0-23%) in VGPR pts, and 1.5% (0-7%) in PR pts. Only 1 pt with negative sIF had 5% BMPCs and a positive urine IF, and was assessed as VGPR. Overall, 55 negative sIF pts had 2% or less BMPCs. The number of 2% of BMPCs was found to be predictive, irrespective of response. Median PFS was 39 vs 21 months if BMPCs is > 2% (p<.001) and median OS was 99 months vs 66 (ns). We further aimed to evaluate the impact of PCs dystrophy on survival outcomes in 176 evaluable pts. PCs dysmorphy was reported in 29 pts including 3 pts in CR, 9 VGPR and 13 PR, respectively. All except 2 pts relapsed, with a median PFS of 26 mo (vs 39, p=.002). Nineteen died with a median OS of 60 mo (vs 101, p=.003). For pts at least in VGPR, median PFS was 26 mo in case of PCs dysmorphy vs 40 mo (p=.004) and median OS was 59 mo vs not reached (p=.005). (see figures) Conclusion: conventional microscopy of BM aspirate is a useful and rapid tool to evaluate the percentage of PCs and their morphology as a first step to assess the residual tumor mass in patients with MM after ASCT, and it constitutes a good predictor for disease progression and survival outcome. These findings have to be confirmed and the exact threshold of PCs remains to be determinate in a large prospective study. Table Characteristics n=191 Sex: M/F, n 109/82 Median age, y (range) 57 (31–68) Isotype, n (%) IgG, IgA, LC 123 (64), 35 (18), 28 (15) ISS stage, n (%) n= 158 I, II, III 85 (54), 40 (25), 33 (21) Median bone marrow plasma cells, % (range) 23 (1-96) Median b2-microglobulin, mg/L (range) 3.1 (1.3–19.4) Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Bortezomib in Combination with High-Dose Dexamethasone and Continuous Low-Dose Oral Cyclophosphamide for Relapsed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2549-2549 ◽  
Author(s):  
Martin Kropff ◽  
Guido Bisping ◽  
Peter Liebisch ◽  
Orhan Sezer ◽  
Hermann Einsele ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Low Dose ◽  
Response Rate ◽  
Single Agent ◽  
Median Number ◽  
High Dose ◽  
Oral Cyclophosphamide ◽  
Minor Response ◽  
Chromosome 13 ◽  
Dose Oral

Abstract Single agent bortezomib treatment yields ≥ partial responses (PR) in 24% of patients with relapsed, refractory multiple myeloma (MM) and 38% of patients who had received 1 – 3 previous therapies. Dexamethasone (DEX) adds to anti-myeloma activity of bortezomib. The present phase II trial was intitiated to study bortezomib combined with DEX and continuous low-dose oral cyclophosphamide (CY). 50 patients with advanced MM were scheduled to receive bortezomib 1.3 mg/m2 IV days 1, 4, 8, and 11 q 3 weeks for 8 cycles in combination with DEX 20 mg PO on the day of bortezomib injection and the day thereafter, and CY 50 mg PO daily; followed by 3 cycles bortezomib 1.3 mg/m2 IV days 1, 8, 15, and 22 q 5 weeks in combination with corresponding DEX and CY schedules. Patient characteristics included median age 63 years; B2M &gt; 3,0 mg/L, 64%; CRP &gt; 3,0 mg/L, 25%; deletion of chromosome 13, 46%; median number of prior regimens, 2 (range 1 – 9), and prior standard therapy &gt; 12 mo, 94 %. 78% of patients had relapsed after high-dose melphalan. The EBMT criteria were used for definition of response. Five patients (10%) achieved a complete response, 33 (66%) a PR, and 6 (12%) a minor response (MR) resulting in an overall response rate (≥MR) of 88%. On an intention-to-treat basis, median event-free survival (EFS) with this combination was 10 months. After a median follow-up of 10 months, median overall survival has not been reached. Notably, chromosome 13 deletion was predictive of a favorable outcome (higher response rate, longer EFS) in this setting. The median number or treatment cycles given was 6. 56% of the patients terminated study treatment prematurely, mainly for disease progression (10%) or adverse events (34%). Grade 4 neutropenia during at least one treatment cycle occurred in one patient (2%), grade 4 thrombocytopenia in 17%; one thrombocytopenic bleeding. Grade 3/4 non-hematologic toxicities requiring dose or schedule modifications included infections (26%), peripheral neuropathy (25%), fatigue (15%), herpes zoster (13%), and cardiovascular events (11%). One patient succumbed to infection without predisposing neutropenia. Bortezomib in combination with DEX and CY appears to be a highly active regimen without increased toxicity compared to a single agent treatment with bortezomib. Maintenance treatment might be required for prolonged EFS.

Bortezomib in Combination with Dexamethasone for Relapsed Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4923-4923
Author(s):  
Martin H. Kropff ◽  
Guido Bisping ◽  
Doris Wenning ◽  
Wolfgang E. Berdel ◽  
Joachim Kienast
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Adverse Events ◽  
Disease Progression ◽  
Remission Rate ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Minor Response ◽  
Chromosome 13 ◽  
Grade 3

Abstract Single agent bortezomib treatment at the dosage and schedule published by Richardson (2003) stabilizes disease in nearly 60% of patients with relapsed, refractory multiple myeloma (MM). However, only 35% of patients achieve an objective (≥ minor) response (MR). Dexamethasone adds to clinical anti-myeloma activity of bortezomib by inducing 18% responses in patients with either stable or progressive disease on bortezomib alone. In an attempt to improve disease response, we evaluated a primary bortezomib/dexamethasone combination in patients with multiple myeloma in ≥ 2nd untreated or refractory relapse. Eligible patients were 18–80 years old, had an ECOG performance status of 0 – 2 and adequate renal, hepatic, pulmonary and cardiac function. Pre-existing peripheral neuropathy ≥ grade 2 or neuropathic pain of any grade were exclusion criteria. However, we made no restrictions in terms of pretreatment blood counts. Fifteen consecutive patients with relapsed multiple myeloma (9/15 with ≥ 2nd untreated and 6/15 with refractory relapse; 71% with a chromosome 13 deletion) were scheduled to receive bortezomib 1.3 mg/m² IV days 1, 4, 8, 11 q 3 weeks for up to 8 cycles in combination with dexamethasone 20 mg PO once daily on the day of bortezomib injection and the day thereafter. Treatment was withheld for nonhematologic adverse events (AE) ≥ grade 3 and reinitiated at a 25% lower dose after resolution. Treatment was not stopped for myelosuppression of any grade if interim response evaluations precluded myeloma progression as the cause of cytopenia. One patient (7%) achieved a complete response, 10 (67%) a partial response, and 1 (7%) a MR resulting in an overall response rate (≥ MR) of 80% (9/9 with ≥ 2nd untreated and 3/6 with refractory relapse; EBMT/IBMTR/ABMTR criteria). Responses occurred after a median of 3 weeks and were independent of conventional prognostic parameters. Importantly, 8/10 patients with a chromosome 13 deletion achieved a ≥ PR. Adverse events, mainly myelosuppression (34% grade 3/4 neutropenia; 47% grade 3/4 thrombocytopenia), neuropathy (grade 2/3/4 20%/7%/0%) and fatigue (grade 2/3/4 20%/13%/20%), were manageable. There was no case of neutropenic infection or thrombocytopenic bleeding. Two patients suffered herpes zoster. The percentage of transfusion dependent patients decreased from 44% during the 1st treatment cycle to 23% and 11% after the 2nd and 3rd treatment cycles, respectively. Even non-responders did not experience cumulative hematologic toxicity. After a median follow-up of 5 months, median event free and overall survival were not reached. Five out of 15 patients were non-responders (n=1) or had experienced disease progression (n=4). Notably, 2 patients with sustained paraprotein and bone marrow remission (confirmed by biopsy) had extramedullary disease progression, pointing to a bone marrow restricted response to bortezomib in MM. This study indicates that bortezomib can be given safely even in patients with poor bone marrow reserve, who would not have been candidates for the SUMMIT trial. Though the remission rate was high, remissions often were not durable. This fact underlines the need for consolidating treatment and evaluation of bortezomib combinations with other anti-myeloma agents.

Prognostic Factors and Outcome of Older Patients with Symptomatic Multiple Myeloma: A Study of the Greek Myeloma Study Group (GMSG).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4847-4847
Author(s):  
Athanasios Anagnostopoulos ◽  
Dimitra Gika ◽  
Argiris Symeonidis ◽  
Konstantinos Zervas ◽  
Anastasia Pouli ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Prognostic Factors ◽  
Median Survival ◽  
Older Patients ◽  
Elevated Serum ◽  
Primary Treatment ◽  
High Dose ◽  
Younger Patients ◽  
Cox Regression Analysis

Abstract Introduction: Prospective randomized trials have shown that high dose therapy with autologous stem cell transplantation may improve the survival of patients with multiple myeloma (MM). This procedure is usually applied to patients ≤70 years of age. Nevertheless, many patients with MM are diagnosed at an older age and are usually treated with conventional chemotherapy. We performed a retrospective analysis in order to compare the prognostic factors and outcome of younger patients with myeloma (≤ 70 years) with those of older patients (&gt;70 years). We also applied the recently proposed International Staging System (ISS) for multiple myeloma in the two groups of patients. Patients and Methods: Since 1987, 1162 patients with symptomatic myeloma requiring treatment have been included in the data base of GMSG. Patients with asymptomatic myeloma were not included. 357 patients (31%) were &gt; 70 years at the time of initial treatment. Multiple clinical and laboratory variables were evaluated in patients &gt;70 years of age and in younger patients. Furthermore, the same variables were assessed for possible correlation with prognosis in patients &gt;70 years of age. Results: The only variable that was different between the two groups of patients was the ISS with older patients presenting more often with advanced ISS (p=0.02). Older patients received more often primary treatment with standard alkylating agents - corticosteroid combinations whereas younger patients received more often primary treatment based on high dose pulse dexamethasone (VAD etc) (p=0.001). Response to treatment was similar but patients ≤ 70 years had a median survival of 40 months versus 29 months for older patients (p&lt;0.001). Variables associated with shorter survival for the group of older patients were: anemia, thrombocytopenia, hypercalcemia, renal impairment, more extensive bone marrow plasmacytosis, elevated serum LDH and advanced ISS (2+3). A Cox regression analysis showed, that adjusting for the effects of other factors, elevated LDH, bone marrow plasmacytosis and advanced ISS retained prognostic significance in this group of older patients (median survival of 12 months, 22 months and 21 months respectively). However patients &gt;70 years of age with ISS 1 had a relatively long median survival of 55 months. Conclusions: The clinical and laboratory characteristics of older patients with MM are similar to those of younger patients but older patients tend to present with more advanced ISS. The survival of older patients is shorter than that of younger patients. Elevated serum LDH, advanced ISS, and increased bone marrow plasmacytosis may identify older patients with particularly bad prognosis. Older patients with poor prognosis should be entered into clinical trials in order to see if treatment with new agents or combinations would prolong their survival. The application of ISS in patients &gt;70 years of age permitted the identification at diagnosis of a subgroup of patients with ISS 1 who had a relatively good prognosis.

Amplification of 1q21 Is Associated with Poor Outcome after Treatment with Bortezomib in Relapsed/Refractory Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3398-3398 ◽  
Author(s):  
Johannes Drach ◽  
Verena Sagaster ◽  
Victoria Odelga ◽  
Hannes Kaufmann ◽  
Jutta Ackermann ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Risk Factor ◽  
Treatment Outcome ◽  
Prognostic Factor ◽  
Serum Albumin ◽  
Single Agent ◽  
High Dose ◽  
Low Serum ◽  
Chromosome 1Q21

Abstract Bortezomib is an active agent for treatment of multiple myeloma (MM) and may even be effective in patients (pts) with adverse prognostic factors including unfavorable cytogenetic abnormalities. However, it is unknown whether or not bortezomib may overcome the negative prognostic impact of a CKS1B gene amplification at chromosome 1q21 (amp1q21), which has recently been reported as a negative prognostic factor even in the setting of a total therapy approach. We therefore evaluated chromosome 1q21 among other abnormalities in 46 pts with relapsed/refractory MM who were treated with single-agent bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11 every 3 weeks). Median age of pts was 63 years (range, 40 – 82 ) and median time to bortezomib therapy was 40 months (median number of prior therapies: 3; 96% of pts had high-dose pulsed dexamethasone, 61% thalidomide, 85% alkylating agents, and 41% high-dose melphalan). A response to bortezomib was noted in 45% of pts, with 17% of pts achieving a CR/near CR. Amp1q21 as determined by interphase FISH was observed in 20 of the 46 pts (43.5%). Treatment outcome after bortezomib was negatively affected by presence of amp1q21: The overall response rate was 30% (versus 58% in pts with normal 1q21; P = .06) and the CR/near-CR rate was 10% (versus 23%). Moreover, amp1q21 was associated with shortened time to treatment failure (median, 2.4 versus 6.6 months; P = .043) and overall survival (OS) (median, 4.4 versus 19.8 months; P = .003) compared to pts with normal 1q21. Beta-2-microglobulin and 14q32 translocations were unrelated to treatment outcome with bortezomib. In contrast, median OS was short in the presence of low serum albumin (4.8 versus 17.8 months; P = .036) and deletion of 13q14 (6.7 months versus median not yet reached; P = .06). Using amp1q21, low serum albumin, and deletion of 13q14 as risk factors, patients with significantly different median OS after bortezomib treatment were discriminated: Pts with ≥ 2 risk factors had a median OS of only 4.9 months as opposed to pts with 1 risk factor (median OS 16.5 months) or without any risk factor (median OS not yet reached) (P = .004). In conclusion, FISH-defined amp1q21 is a strong adverse prognostic factor for pts with relapsed/refractory MM treated with single-agent bortezomib. We are currently investigating whether or not bortezomib combinations may be more effective in MM pts with amp1q21.

Outcomes Among High Risk and Standard Risk Multiple Myeloma Patients Treated With High Dose Therapy and Autologous Hematopoietic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3358-3358
Author(s):  
Maliha Nusrat ◽  
Syed M. Kazmi ◽  
Amanda Megan Cornelison ◽  
Partow Kebriaei ◽  
Yago Nieto ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Chromosomal Abnormalities ◽  
Poor Response ◽  
Chromosome 1 ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Bone Marrow Plasma ◽  
Standard Risk

Abstract Background Chromosomal analysis using conventional cytogenetics (CC) and interphase fluorescence in situ hybridization (FISH) identifies a high risk multiple myeloma population (HR-MM) characterized by poor response to chemotherapy and shorter survival. The objective of this study was to compare outcomes of autologous hematopoietic stem cell transplantation (ASCT) at our institution in HR-MM and standard risk MM (SR-MM) patients (pts) identified through CC and FISH. Methods Metaphase CC and FISH data was collected from medical records of MM pts who underwent ASCT at our institution between Jan 2005 to Dec 2009. HR-MM pts were defined if CC revealed deletion (del) of chromosome 13/13q, del17/17p, t(4;14), t(14;16), hypoploidy (<45 chromosomes excluding –Y), or chromosome 1 abnormalities [+1, -1, t(1;x)] in at least 2 metaphases; or if FISH showed del 17p, t(4;14). Kaplan & Meier method was used for assessing progression free survival (PFS) and overall survival (OS); log-rank test was used to evaluate the difference between pt groups and Cox proportional hazards models were fitted for multivariate analysis. Results Out of 670 MM pts who received ASCT during the specified time, 74 (11%) had HR-MM while 596 (89%) had SR-MM. Table 1 summarizes baseline characteristics and outcomes of HR- and SR-MM pts. In HR-MM pts, chromosome 1 aberrations were most common and seen in 53 (76%) pts while del13/13q, hypodiploidy, del17/17p and t(4;14) was found in 48 (65%), 27 (37%), 16 (22%) and 5 (9%) pts, respectively. Concurrence of high-risk chromosomal abnormalities (i.e. >1) occurred in 58% of HR-MM pts. As compared to SR-MM pts, HR-MM pts were more commonly male (72 vs. 56%), had a significantly higher bone marrow plasma cell burden at diagnosis (52 vs. 29%. p<0.001) or at time of ASCT (5 vs. 2%. p<0.000) and were refractory to treatment before undergoing ASCT (34 vs. 22%; p0.01). Melphalan 200mg/m2 was the most common conditioning regimen used and there was no difference in time to bone marrow engraftment and platelet recovery. With median follow up of 39.8 months after ASCT, HR-MM pts, as compared to SR-MM pts, had significantly lower rates of >/= PR (74 vs. 84%; p <0.01), median PFS (10.3 vs. 32.4 months p<0.001) and OS (28 vs. not reached, p<0.001). On multivariate analysis of the HR-MM pts, having only 1-high-risk cytogenetic abnormality or achieving at least very-good-partial-response (VGPR) after ASCT were factors independently associated with improved OS (p<0.002). In contrast, induction chemotherapy with bortezomib, myeloma status at time of ASCT and post-ASCT maintenance chemotherapy did not significantly affect PFS or OS. Conclusion HR-MM pts are characterized by higher bone marrow plasma cell burden, concurrence of high-risk chromosomal abnormalities, and poor response to induction or high dose chemotherapy followed by ASCT as compared to SR-MM pts. In HR-MM pts, having only 1-high risk cytogenetic abnormality or achieving at least VGPR with ASCT are independent factors associated with improved survival. Disclosures: No relevant conflicts of interest to declare.

Phase I/II dose-escalation study of daratumumab in patients with relapsed or refractory multiple myeloma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8512-8512 ◽  
Author(s):  
Henk M Lokhorst ◽  
Torben Plesner ◽  
Peter Gimsing ◽  
Hareth Nahi ◽  
Monique Minnema ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Dose Escalation ◽  
Plasma Cells ◽  
Single Agent ◽  
Safety Data ◽  
Efficacy Data ◽  
Dose Escalation Study ◽  
Safety And Efficacy ◽  
Bone Marrow Plasma

8512^ Background: Daratumumab (DARA) is a human CD38 monoclonal antibody (mAb) with broad-spectrum killing activity. Preliminary safety and efficacy data from this first-in-human dose-escalation study of DARA in pts with relapsed or refractory (RR) multiple myeloma (MM) have previously been published. Here, we present safety and efficacy data from the finalized part 1 and preliminary safety data from the ongoing part 2 of the study. Methods: Pts ≥18 years requiring systemic therapy and considered RR to at least 2 prior lines of therapy and ineligible for ASCT were enrolled. In part 1, a 3+3 dose-escalation design was applied and DARA was administered over a 9-week period as 2 pre- and 7 full doses. The phase II dose was determined to 8mg/kg and these pts receive DARA weekly for 8 weeks followed by dosing every 2nd week for 16 weeks and every 4th week until disease progression, toxicity or for max. 24 months. Results: Data from 32 pts included in part 1 are presented. In part 2, 7/16 pts have been recruited: all available data will be presented at the meeting. In part 1, the median number of prior treatment lines was 6. PK analysis showed plasma peak levels as expected but relatively rapid clearance at low dose levels. At doses ≥4mg/kg, observed PK values approximated model-predicted values. Efficacy evaluation from part 1 was based on IMWG guidelines. In the ≥4mg/kg groups (n=12), 5 PRs and 3 MRs were observed. 7 of these pts had a 50-100% concomitant reduction in bone marrow plasma cells. Median PFS in the ≥4mg/kg dose groups was not reached (median follow-up at data cut-off was 3.8mths (range: 0-9.6mths). No ADA responses were detected. In part 1, the most common adverse events reported were infusion related (IRE) which occurred predominantly during the first full infusion. 44% of subjects across all dose groups had IREs grade 1-3, of which 2 were grade 3. Six related SAEs (1 anemia, 1 thrombocytopenia, 2 bronchospasm, 1 cytokine release, 1 AST increase) were reported. Conclusions: DARA induced a marked reduction in paraprotein and bone marrow plasma cells at doses ≥4mg/kg in heavily pretreated RR MM pts. In addition, high response rates and encouraging PFS data were observed. This is unprecedented for single-agent mAb treatment of MM. Clinical trial information: NCT00574288.

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