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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 8606-8606
    Abstract: 8606 Background: The rapidity of response to initial therapy in multiple myeloma (MM) depends on a variety of factors. There is limited data on its implications on long term outcomes in patients (pts) with newly diagnosed MM. Methods: We retrospectively examined the outcomes in a cohort of 454 pts with newly diagnosed MM between Jan 2000- Dec 2011 undergoing induction therapy. Results: The median age at diagnosis was 66 yrs (29-92). Pts had measurable serum M-spike ( 〉 = 1 g/dL), dFLC ( 〉 =10 mg/dl) or 24 hour urinary M protein excretion (UrM; 〉 =200 mg) in 70, 63 and 39% respectively. We first examined the relationship between the response to first cycle of therapy and overall survival (OS). We divided pts into quartiles based on their % reduction in the serum M spike, dFLC or UrM. The median OS (Table) was poorest for pts with the least reduction of serum M protein (P 〈 0.001) and of dFLC. The cutoffs for Q1 was 25, 40and 40% decrease for serum M spike, dFLC and 24 hr UrM respectively. Among various baseline characteristics only higher age was predictive of a poor (Q1) response. Given the trend toward worse OS among the Q 4 group (maximum decrease in serum M spike), we examined the relationship to cytogenetic risk. Among 232 pts with FISH data available, proportion of pts with high-risk disease was 27, 12, 22 and 31% respectively in quartiles 1 - 4). In a multivariate analysis, quartile 1 and 4 of serum M-protein response and the high-risk FISH were independent risk factors associated inferior OS. Conclusions: Both shallow and very deep response to therapy in cycle 1 is a strong indicator of eventual disease outcome and should be considered as marker of high-risk disease, likely through different mechanisms. For the shallow responders, prospective trials should assess if a change in therapeutic management will alter the outcome of these pts. The rapid deep responders also appear represent a different high-risk biology, emphasizing the fact that pts with high-risk disease often have excellent initial responses, but poor long term outcomes. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 36 ( 2013-12-20), p. 4529-4535
    Abstract: To study the impact of achieving stringent complete response (sCR), an increasingly attainable goal, after autologous stem-cell transplantation (ASCT) in patients with multiple myeloma (MM). Patients and Methods Maximal response rates were determined in 445 consecutive patients who underwent ASCT within 12 months of diagnosis of MM. The patients achieving varying degrees of complete response (CR) are the focus of our study. Results One hundred and nine patients (25%) achieved sCR after ASCT. The median overall survival (OS) rate from the time of transplantation for patients attaining sCR was not reached (NR), in contrast to those patients achieving conventional complete response (CR; n = 37; OS, 81 months) or near CR (nCR; n = 91; OS, 60 months; P 〈 .001). Five-year OS rates were 80%, 53%, and 47% for sCR, CR, and nCR, respectively. The median time to progression (TTP) from ASCT of patients achieving sCR was significantly longer (50 months) than TTP of patients achieving CR or nCR (20 months and 19 months, respectively). On multivariable analysis, post-ASCT response of sCR was an independent prognostic factor for survival (hazard ratio, 0.44; 95% CI, 0.25 to 0.80; versus CR; P = .008), in addition to proliferation rate, pre-ASCT cytogenetics, and performance status. OS rates of patients attaining sCR continued to remain superior at 2-year landmark (median, NR v 70 months for conventional CR group; P = .007). Conclusion Improved long-term outcome is seen after ASCT with achievement of sCR when compared with lesser degrees of responses. Myeloma trials reporting the response rates should identify patients achieving sCR and CR separately, owing to markedly disparate outcomes of the two categories.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
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  • 3
    In: Blood, American Society of Hematology, Vol. 122, No. 10 ( 2013-09-05), p. 1746-1749
    Abstract: A continued monoclonal protein response after ASCT in the absence of further therapy is prognostic in MM patients.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 2151-2151
    Abstract: Acquired factor X (FX) deficiency is associated with immunoglobulin light chain (AL) amyloidosis and may be accompanied by hemorrhage. There are limited data on the effects of autologous stem cell transplant (ASCT) on FX deficiency. We reviewed hemorrhagic complications and the effect of high dose melphalan (HDM) and ASCT on FX levels in AL amyloidosis patients with FX deficiency. Methods We conducted a retrospective chart review of patients with AL amyloid with FX levels below 60%, not on chronic anti-coagulation who underwent HDM/ASCT at the Mayo Clinic, Rochester, MN between 1995 and 2011. Results Forty-one of 358 patients (11%) met our study criteria. Median pre-ASCT FX was 45% (range: 2%, 59%). The most common bleeding complication was central line associated n=15 (37%) followed by gastrointestinal n=10 (24%) and genitourinary n=9 (22%). The most frequent and severe bleeding complications occurred in patients with FX levels less than 10%. Four patients required emergent splenectomy owing to splenic rupture; one of these patients died from hemorrhagic shock. Periprocedural prophylaxis included activated recombinant Factor VII (rFVIIa) infusions, fresh frozen plasma (FFP) infusions and platelet transfusions. rFVIIa was efficacious in controlling bleeding during splenectomy (n=5) and, in conjunction with arterial embolization, for retroperitoneal bleed (n=1). Elective splenectomy for FX deficiency (n=1) resulted in only transient improvement in FX level. No relationship between the degree of pre-ASCT FX deficiency and other laboratory values (alkaline phosphatase, AST, total bilirubin, serum albumin, total serum protein, serum creatinine, total urine protein, beta2 microglobulin, troponin T) was found. Post-ASCT FX levels were determined in seventeen patients. In four of these patients, post-ASCT FX levels were determined in the acute/subacute phase of ASCT before steady state FX levels could be achieved; the median change in FX for these patients was -6.5% (range: -19%, 3%). In the remaining thirteen patients, who were between 99 and 1920 days from ASCT, FX improved by median 26% (range: -15%, 92%). Overall post-ASCT FX increased in twelve of thirteen (92%) patients. The improvement in FX correlated with improvement in the degree of proteinuria (p = 0.04) and showed a trend towards significant correlation with improvement in serum alkaline phosphatase (p = 0.06). Conclusions Hemorrhagic complications are most frequent and severe for FX levels below 10%. rFVIIa infusions, FFP and platelets were effective prophylactic agents. In the single patient who underwent elective splenectomy, a transient improvement in FX level was seen. Splenectomy was otherwise reserved for patients with splenic rupture/hematoma. Post-ASCT FX levels increased in twelve (92.3%) of the remaining thirteen patients; five of the patients (38.5%) were no longer FX deficient after ASCT. The degree of improvement in FX levels was correlated with improvement in markers of renal or hepatic involvement by amyloid. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 5
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 1979-1979
    Abstract: Pomalidomide (POM) is the newest Immunomodulatory agent (IMiDs) that has shown clinical efficacy in relapsed multiple myeloma (MM) refractory to lenalidomide (LEN) and thalidomide (THAL). Studies of MM cell microenvironment suggest that tumor subclones compete for dominance during changes in drug therapy. It was previously observed that a minor clonal population increased in prominence of MM cells after 1 year of treatment with LEN. We examined whether the patients having THAL or LEN as the most recent prior-line therapy affects response to POM. Methods We studied 208 patients enrolled in a phase II trial of POM / dexamethasone between November 2007 and March 2012 at Mayo Clinic, Rochester. We reviewed the immediate prior-line therapy before enrollment in our trial. Comparison of treatment duration of POM and response rates were conducted between patients who had either THAL or LEN as latest prior-line therapy, and patients who were treated with non-IMiDs immediate before enrollment in POM trial. Treatment duration of POM was estimated using Kaplan Meier method and the survival curves were compared using log-rank test. We used univariate Cox proportional hazard models to estimate the prognostic impact of different variables. Results The median age of patients was 63 (range from 32 to 88). 68 % were males. 80 patients (38.5%) had THAL or LEN immediate prior to POM. Median prior-line therapies were 3. Patients who received THAL or LEN immediately prior to POM had a lower response rate than those who had non-IMiDs as latest therapy (29% vs 44%, p 0.04) and shorter median duration of POM treatment (5.7 months vs 7.3 months, p 0.02). In 190 (91%) patients who were previously treated with LEN and THAL at any time, median time between the end of LEN or THAL treatment and the initiation of POM was higher for POM responders than non-responders (10 months vs 3 months, p 0.0008). Patients responded to POM had a shorter duration of prior LEN or THAL treatment compared to non-responders (9 months vs 15 months, p 0.001). Conclusion THAL or LEN as an immediate prior-line therapy to POM is associated with a lower response rate and shorter effective treatment duration. Longer interval between prior immunomodulatory compounds and POM, and shorter exposure to previous immunomodulatory compounds are associated with better POM treatment response. Disclosures: Gertz: Celgene: Honoraria. Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Novartis: Research Funding; Genzyme: Research Funding. Lacy:Celgene Corporation: Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
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  • 6
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 3209-3209
    Abstract: Lenalidomide is an immunomodulatory drug that is active in newly diagnosed as well as relapsed multiple myeloma (MM). The goal of this study is to describe patients with newly diagnosed MM remaining on lenalidomide for more than 3 years (long term responders) as well as patients that after discontinuing lenalidomide were able to maintain disease control while only on observation (LenO group). Methods We retrospectively reviewed 283 patients with newly diagnosed MM that were treated with lenalidomide between January 2003 and January 2011. We excluded patients that underwent early autologous stem cell transplant (n=102) or had less than 3 years of follow-up (n=6), leaving 175 patients for the current analysis. Results Long term responders Thirty-three patients (19%) received lenalidomide for more than 3 years. When compared to patients receiving lenalidomide for less than 3 years, at baseline, long term responders were more likely to have standard risk disease (64% versus 44%, p=0.03) and less likely to have high risk disease (18% versus 4%, p=0.04). They were more likely to have achieved a deeper response (VGPR versus PR, p 〈 0.001) and had a longer median time to best response (6 versus 4 months, p 〈 0.001). When considering the 12 patients who received lenalidomide for more than 5 years, this group was more likely to have achieved a deeper response (CR versus PR, p 〈 0.0001) and had a longer median time to achieving best response (9 versus 4 months, p 〈 0.0001) than those 163 patients who remained on lenalidomide for fewer than 5 years. Observation group Thirty-three patients (19%) discontinued lenalidomide for reasons other than progression and were observed without receiving further treatment (LenO group). Prior to moving to observation, five patients had received lenalidomide for more than three years. Indications for stopping in the LenO group included: prolonged disease stability (n= 20); and toxicity (n=13). The only differences in baseline characteristics between the LenO group and patients that were not observed off any treatment was depth of response, with 61% (n=20) of LenO in VGPR or better versus 23% (n=23) in the remainder, p=0.0003. Median PFS from the time of discontinuing lenalidomide was significantly longer in those patients who took lenalidomide for more than 1 year (n=24) when compared to patients taking it for less than one year (n=9) (median PFS off therapy was 38.5 months versus, 14.9 months log rank 0.08; Wilcoxon p 〈 0.05), figure 1a; PFS for those treated for 1-2 years (n=11) as compared to 2 years or greater (n= 13) were comparable to each other (data not shown). Among those taking lenalidomide for at least a year, PFS from time of discontinuing lenalidomide was superior in patients who had achieved a VGPR/CR (n=20) as compared to those who achieved only a PR (n=13) (Median 48.4 months versus 14.8 months, log-rank p 〈 0.05; Wilcoxon p=0.01), figure 1b. Conclusion Approximately one out of five patients with newly diagnosed MM can achieve responses lasting more than three years while on treatment with lenalidomide. Patients with standard risk FISH and those achieving at least VGPR are more likely be long-term responders. Furthermore, long-term responders were more likely to be slow responders. We also demonstrate that suspension of lenalidomide therapy after 1 year among those patients achieving a VGPR or better can result in long-term disease control and can be considered as a therapeutic strategy. Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Gertz:Celgene: Honoraria. Lacy:Celgene: Honoraria. Dispenzieri:Celgene: Research dollars Other.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 7
    In: Blood, American Society of Hematology, Vol. 122, No. 26 ( 2013-12-19), p. 4172-4181
    Abstract: Smoldering multiple myeloma (SMM) bridges the gap between monoclonal gammopathy of undetermined significance (a mostly premalignant disorder) and active multiple myeloma (MM). Until recently, no interventional study in patients with SMM showed improved overall survival (OS) with therapy as compared with observation. A report from the PETHEMA-GEM (Programa Español de Tratamientos en Hematologica) group described both fewer myeloma-related events and better OS among patients with high-risk SMM who were treated with lenalidomide and dexamethasone. This unique study prompted us to review current knowledge about SMM and address the following questions: (1) Are there patients currently defined as SMM who should be treated routinely? (2) Should the definitions of SMM and MM be reconsidered? (3) Has the time come when not treating is more dangerous than treating? (4) Could unintended medical harm result from overzealous intervention? Our conclusion is that those patients with the highest-risk SMM (extreme bone marrow plasmacytosis, extremely abnormal serum immunoglobulin free light chain ratio, and multiple bone lesions detected only by modern imaging) should be reclassified as active MM so that they can receive MM-appropriate therapy and the paradigm of careful observation for patients with SMM can be preserved.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 8
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 3095-3095
    Abstract: The use of soluble cardiac biomarkers such as NT-proBNP and troponin has revolutionized prognostication for patients with AL amyloidosis and led to their use in the Mayo 2004 and 2012 staging systems. Novel soluble markers with different phenotypic targets may further improve this approach. Soluble ST2 (sST2), which is the circulating form of the IL-33 receptor, has been shown to be a marker of cardiac remodelling and fibrosis, is predictive of mortality in patients with congestive heart failure, and is predictive of risk of GVHD and GVHD mortality. Samples of blood of patients with AL amyloidosis collected and frozen at -20C under a biobank IRB protocol were retrieved and sST2 measured. Patients were eligible for present study if they had a research sample collected within 90 days of their AL amyloidosis diagnosis. We have validated that values do not change significantly with storage at -20C over a 90 day period. Concentrations of sST2 were determined using a novel high-sensitivity sandwich immunoassay (Presagew ST2; Critical Diagnostics, San Diego, CA, USA). The sST2 assay had within-run and total coefficients of variation of 〈 7.5% and 13.0% across its measurement range. Samples from 273 consecutive patients meeting diagnostic criteria for AL amyloidosis seen at our institution from 1/9/2010 to 12/22/2011 were evaluated. Median age was 63. 58% were male. One hundred and thirty have died over 33.9 months. Correlation between sST2 and the other biomarkers was modest with correlation coefficients of 0.48 and 0.20 for NT-proBNP and Troponin T, respectively. Patients with sST2 above and below the median of 27.2 ng/mL (6.3-596) had significant differences in 2 year overall survival: 71.2% to 39% (figure). In multivariate modeling sST2’s prognostic value was independent of the Mayo 2004 and the Mayo 2012 cardiac biomarker staging systems, the latter of which also includes prognostic information relating to plasma cell burden. In these multivariate models, sST2 median had a RR of 2.4, (95%CI 1.6, 3.6 p 〈 0.001) with the Mayo 2004 Staging system (RR of 2.9, 95%CI 2.1, 4.1p 〈 0.001); and sST2 median had a RR of 2.2 (95%CI 1.5, 3.4, p 〈 0.001) with the Mayo 2012 staging system (RR 1.9, 95%CI 1.6, 2.3, p 〈 0.001). A larger cohort including patients with longer follow up will be presented at the meeting as will gender specific cut off values and a comparison of our values with those previously used to prognosticate in patients with heart failure. sST2 appears to be a novel powerful prognostic factor for patients with AL amyloidosis. Because sST2 functions as a decoy receptor, which neutralizes the benefits of IL-33, it may play a role in the deleterious phenotype seen in patients with AL, i.e. myocardial hypertrophy and reduction of contractility. Disclosures: Saenger: Critical Diagnostics : Research Funding; Roche: Research Funding. Jaffe:Critical Diagnostics: Consultancy, Research Funding; Roche: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
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  • 9
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 8587-8587
    Abstract: 8587 Background: Patients (pts) undergoing an auto-transplant (ASCT) for multiple myeloma (MM) have disease assessment approximately 100 days later. This result may direct decisions of further therapy versus observation. However, some pts continue to experience a decline in their serum or urine monoclonal (M) - protein after day 100 without more therapy. Little is known about the prevalence and significance of this phenomenon. Methods: We identified 903 MM pts who underwent ASCT within 12 months (mos) of diagnosis (Dx) at our institution. Their day 100 post-ASCT M-protein from serum and urine electrophoresis with immunofixation as well as serum free light chains were compared to subsequent values during follow-up. The IMWG criteria were used to evaluate response. Results: Of the pts included, 510 (56%) were male and median age at ASCT was 59 (range 28-76). Median follow up from Dx and ASCT was 82 mos (95% CI; 75 - 86) and 74 mos (95% CI; 70 - 79) respectively. There were 453 (50%) pts seen in follow-up who had not achieved a CR at Day 100 nor initiated on maintenance therapy. Of these pts, 167 (37%) had a further decrease in their M-protein after day 100 at a median of 9.4 mos (95% CI; 8 – 10) post-ASCT. Given the time taken for maximal response, we assessed patients’ clinical response at one year post-ASCT. Compared to patients who did not have further clinical response between day 100 and 1 year, pts experiencing further response had a longer time to next therapy (TTNT) (43 mos vs. 17 mos, P 〈 0.001) as well as overall survival (OS) (96 mos vs. 62 mos, P 〈 0.001). Positive predictors for continued response included having an IgG isotype, evolution from a pre-existing MGUS, smoldering myeloma or solitary plasmacytoma and a Day 100 bone marrow plasma cell 〈 3%. In a multivariate analysis, elevated creatinine at Dx and lack of continued response predicted for shorter TTNT and OS post-ASCT. Older age and high-risk MM by FISH also predicted a shorter OS. Conclusions: In MM pts undergoing ASCT, continued M - protein response was seen in a third of the pts lacking a CR at day 100. This phenomenon appears prognostic and must be considered when interpreting studies evaluating post-ASCT response and the need for further therapy.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
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  • 10
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 8600-8600
    Abstract: 8600 Background: The combination of bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide and etoposide (VDTPACE) was developed as an intense regimen for disease control prior to tandem transplantation for multiple myeloma (MM) in total therapy protocols. The regimen is very effective in this setting, and since has also been used in the relapsed setting. We examined the outcomes of a set of patients undergoing VDTPACE therapy for relapsed MM at our institution. Methods: We identified 71 patients who received VDTPACE for relapsed MM, at Mayo Clinic from 7/2006 to 7/2012. Plasma cell leukemia was excluded. All data was extracted from clinical records. Results: The median age of patients was 59 years (range, 39-80); 48 (67.6%) were male. The median time from diagnosis to initiation of VDTPACE was 38.2 months (range, 2-125). The median number of cycles given was 1 (range, 1-9). The overall response rate after one cycle was 57.1% (14.3% VGPR, 22.2% PR and 20.6% MR) in the 63 patients in whom the response was evaluable. The median overall survival (OS) post-VDTPACE was 8.2 months (95% CI, 5.7-10.9). Eighteen (25.4%) patients went on to autologous stem cell transplantation (SCT), and 7 (9.9%) received matched allogeneic SCT following VDTPACE, and the median OS post-VDTPACE was significantly longer for these groups compared to those who were not transplanted (15.3 and 20.5 months, respectively vs 5 months, p-value 〈 0.001). Thirty eight of 66 (57.6%) patients were rehospitalized after initial admission for infusion therapy for a median duration of 6 days (range, 1-26). The median platelet and red cell transfusions were 4 (range, 0-21) and 5 (range, 0-22) units, respectively. Renal toxicity was seen in 13/62 (21%) patients and 27/65 (41.5%) patients developed neutropenic fever. The median duration to absolute neutrophil and platelet count recovery was 18 (range 12-42) and 27 (range, 12-42) days, respectively. Three (4.2%) patients died within 30 days and 11 (15.5%) within 8 weeks of initiating VDTPACE. Conclusions: VDTPACE is an effective therapy in relapsed MM but is associated with significant morbidity and short-term mortality. It appears to be more effective when followed by an autologous or allogeneic SCT.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
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