For establishing the true effect of different response categories in patients with multiple myeloma (MM) treated with autologous stem cell transplantation, we evaluated, after a median follow-up of ...153 months, 344 patients with MM who received a transplant between 1989 and 1998. Overall survival (OS) at 12 years was 35% in complete response (CR) patients, 22% in near complete response (nCR), 16% in very good partial response (VGPR), and 16% in partial response (PR) groups. Significant differences in OS and progression-free survival were found between CR and nCR groups (P = .01 and P = .002, respectively), between CR and VGPR groups (P = .0001 and P = .003), or between CR and PR groups (P = .003 and P = < 10−5); no differences were observed between the nCR and VGPR groups (P = .2 and P = .9) or between these groups and the PR group (P = .1 and P = .8). A landmark study found a plateau phase in OS after 11 years; 35% patients in the CR group and 11% in the nCR+VGPR+PR group are alive at 17 years; 2 cases had relapsed in the nCR+VGPR+PR group. In conclusion, MM achieving CR after autologous stem cell transplantation is a central prognostic factor. The relapse rate is low in patients with > 11 years of follow-up, possibly signifying a cure for patients in CR.
Complete response (CR) is considered an important goal in most hematologic malignancies. However, in multiple myeloma (MM), there is no consensus regarding whether immunofixation (IF)-negative CR, ...IF-positive near-CR (nCR), and partial response (PR) are associated with different survivals. We evaluated the prognostic influence on event-free survival (EFS) and overall survival (OS) of these responses pre- and post-transplantation in newly diagnosed patients with MM.
We analyzed 632 patients from the prospective Grupo Español de Mieloma 2000 protocol who were uniformly treated with vincristine, carmustine, cyclophosphamide, melphalan, and predisone/vincristine, carmustine, adryamcine, and dexamethasone induction followed by high-dose therapy and autologous stem-cell transplantation.
Post-transplantation response markedly influenced outcomes. Patients achieving CR had significantly longer EFS (median, 61 v 40 months; P < 10(-5)) and OS (medians not reached; P = .01) versus patients achieving nCR, who likewise had somewhat better outcomes compared with patients achieving PR (median EFS, 34 months, P = .07 v nCR; median OS, 61 months, P = .04). EFS and OS and influence of response were similar among older (age 65 to 70 years) and younger (age < 65 years) patients. Similar findings were observed with pretransplantation response, with trends toward EFS (P = .1; P = .05) and OS (P = .1; P = .07) benefit in patients achieving CR versus nCR and PR, respectively. Post-transplantation response was markedly influenced by pretransplantation response; improvements in response were associated with prolonged survival.
Quality of response post-transplantation, notably CR, is significantly associated with EFS and OS prolongation in newly diagnosed patients with MM. There were trends toward similar associations with pretransplantation response status.
To investigate the impact of immunophenotypic response (IR) versus complete response (CR) and CR plus normal serum free light chain (sFLC) ratio (stringent CR) in elderly patients with multiple ...myeloma (MM) treated with novel agents.
From a total of 260 elderly patients newly diagnosed with MM included in the GEM05>65y trial, 102 patients achieving at least a partial response with ≥ 70% reduction in M-component after the six planned induction cycles were simultaneously analyzed by immunofixation, sFLC, and multiparameter flow cytometry (MFC) immunophenotyping; this population is the focus of this study.
Forty-three percent of patients achieved CR, 30% achieved stringent CR, and 30% achieved IR. Patients in stringent CR showed no significant survival advantage compared with those in CR, whereas patients in IR showed significantly increased progression-free survival (PFS) and time to progression (TTP) compared with those in stringent CR or CR; this was confirmed by multivariate analysis (hazard ratio, 4.1; P = .01 for PFS). Discrepancies between the three techniques were relatively common. Notably, in all seven patients achieving IR but remaining immunofixation positive, the M-component disappeared in follow-up analysis. In contrast, MFC-positive patients who were immunofixation negative (n = 20) showed a tendency toward early reappearance of the M-component (median, 3 months). Similarly, in five of 11 stringent CR but MFC-positive patients, symptomatic disease progression was recorded at a median of 13 months after induction.
Achieving an IR translates into superior PFS and TTP compared with conventional CR or stringent CR. These techniques provide complementary information and thus, an effort should be made to refine response criteria in MM.
1 Hospital Universitario de Salamanca;
2 Hospital General de Segovia
3 Hospital Universitario de Canarias
4 Hospital Lozano Blesa de Zaragoza
5 Hospital Virgen Blanca de León
6 Hospital Clínico ...Universitario San Carlos de Madrid
7 Hospital 12 de Octubre de Madrid
8 Hospital La Fe de Valencia
9 Hospital Clinico Universitario de Valencia
10 Hospital Santa Creu i Sant Pau de Barcelona
11 Hospital Sont Llatzer de Palma de Mallorca
12 Hospital Dr Pesset de Alicante
13 Hospital la Princesa de Madrid
14 Hospital Morales Messeguer de Murcia
15 Hospital Germans Trials I Pujol de Badalona
16 Hospital Central de Asturias
17 Hospital Ramón y Cajal de Madrid
18 Hospital Clinic. IDIBAPS. Barcelona, Spain
19 Clínica Universitaria de Navarra
* PETHEMA/GEM (Grupo Español de MM), Spain
+ University Hospital, CIC/CSIC Salamanca, Spain
20 Millennium Pharmaceuticals, Inc., Cambridge, MA, USA and
21 Johnson & Johnson Pharmaceutical Research & Development, Beerse, Belgium
Correspondence: Jesús F. San Miguel, Paseo San Vicente 58-182, 37007 Salamanca, Spain. E-mail: sanmigiz{at}usal.es
Background: New treatment options offering enhanced activity in elderly, newly diagnosed patients with multiple myeloma are required. One strategy is to combine melphalan and prednisone with novel agents. We previously reported an 89% response rate, including 32% complete responses and 11% near complete responses, in our phase 1/2 study of bortezomib plus melphalan and prednisone (VMP) in 60 newly diagnosed multiple myeloma patients with a median age of 75 years. Here, we report updated time-to-events data and the impact of poor prognosis factors on outcome.
Design and Methods: Updated analyses of time to biochemical progression and overall survival with VMP were conducted, and compared with those of historical controls treated with melphalan and prednisone. A univariate analysis was performed to evaluate the influence of known prognostic factors on the time to progression.
Results: After a median follow-up of 26 months, the median time to progression with VMP was 27.2 months, compared with 20.0 months with melphalan plus prednisone. The median overall survival with VMP was not reached versus 26 months with melphalan and prednisone; the survival rate at 38 months was 85% versus 38%, respectively. Time to progression was not significantly affected by elevated β 2 -microglobulin or lactate dehydrogenase levels, advanced age, or cytogenetic abnormalities, but was shorter in patients with albumin <3 g/dL, Karnofsky performance status 70%, bone marrow plasma cell infiltration 40%, and, particularly, high plasma cell proliferative activity ( 2.5% S-phase cells).
Conclusions: VMP is highly active and well tolerated in elderly patients with newly diagnosed muktiple myeloma, with 85% of patients alive at 3 years. Moreover, VMP may overcome the poor prognostic impact of various factors, particularly cytogenetic abnormalities.
Key words: multiple myeloma, bortezomib, melphalan, prednisone, elderly, clinical trial, first-line.
Summary Background Bortezomib plus melphalan and prednisone (VMP) is significantly better than melphalan plus prednisone alone for elderly patients with untreated multiple myeloma; however, toxic ...effects are high. We investigated a novel and less intensive bortezomib-based regimen to maintain efficacy and to reduce toxic effects. Methods Between March, 2006, and October, 2008, 260 patients with untreated multiple myeloma, 65 years and older, from 63 Spanish centres, were randomly assigned to receive six cycles of VMP (n=130) or bortezomib plus thalidomide and prednisone (VTP; n=130) as induction therapy, consisting of one cycle of bortezomib twice per week for 6 weeks (1·3 mg/m2 on days 1, 4, 8, 11, 22, 25, 29, and 32), plus either melphalan (9 mg/m2 on days 1–4) or daily thalidomide (100 mg), and prednisone (60 mg/m2 on days 1–4). The first cycle was followed by five cycles of bortezomib once per week for 5 weeks (1·3 mg/m2 on days 1, 8, 15, and 22) plus the same doses of melphalan plus prednisone and thalidomide plus prednisone. 178 patients completed the six induction cycles and were randomly assigned to maintenance therapy with bortezomib plus prednisone (n=87) or bortezomib plus thalidomide (n=91), consisting of one conventional cycle of bortezomib for 3 weeks (1·3 mg/m2 on days 1, 4, 8, and 11) every 3 months, plus either prednisone (50 mg every other day) or thalidomide (50 mg per day), for up to 3 years. Treatment codes were generated with a computerised random number generator, and neither participants nor study personnel were masked to treatment. The primary endpoint was response rate in induction and maintenance phases. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00443235. Findings In the induction phase, 105 (81%) patients in the VTP group and 104 (80%) in the VMP group achieved partial responses or better (p=0·9), including 36 (28%) and 26 (20%) complete remissions, respectively (p=0·2). Treatment with VTP resulted in more serious adverse events (40 31% vs 20 15%, p=0·01) and discontinuations (22 17% vs 15 12%, p=0·03) than did treatment with VMP. The most common toxicities (grade 3 or worse) were infections (one 1% in the VTP group vs nine 7% in the VMP group), cardiac events (11 8% vs 0), and peripheral neuropathy (nine 7% vs 12 9%). After maintenance therapy, the complete remission rate was 42% (40 44% patients in complete remission in the bortezomib plus thalidomide group, 34 39% in the bortezomib plus prednisone group). No grade 3 or worse haematological toxicities were recorded during maintenance therapy; two (2%) patients in the bortezomib plus prednisone group and six (7%) in the bortezomib plus thalidomide group developed peripheral neuropathy. Interpretation Reduced-intensity induction with a bortezomib-based regimen, followed by maintenance, is a safe and effective treatment for elderly patients with multiple myeloma. Funding Pethema (Spanish Program for the Treatment of Hematologic Diseases).
Summary
This study aimed to standardize a simple molecular method for evaluating the response to treatment in multiple myeloma (MM) patients after high dose chemotherapy. Fifty three patients ...enrolled in the GEM2000 protocol were studied for minimal residual disease (MRD) using both fluorescent‐polymerase chain reaction (F‐PCR) and flow cytometry. Most patients had achieved complete remission or very good response after autologous stem cell transplantation. The molecular analysis of immunoglobulin gene rearrangements at diagnosis and during the follow‐up was carried out by F‐PCR according to the Biomed‐2 protocols. F‐PCR could be used in 91% of the patients and the results were similar to flow cytometry. F‐PCR was able to identify a group of patients with a better prognosis progression‐free survival (PFS) 67·86% in patients with negative F‐PCR vs. 28%; P = 0·001, even amongst patients who achieved a complete response with negative immunofixation (PFS 75% vs. 25%; P = 0·002). Multivariate analysis identified the F‐PCR result as the only variable to show a prognostic value when PFS was analysed. F‐PCR of DHJ and light chain rearrangements of immunoglobulin genes is a feasible method for evaluating MRD in MM patients after intensive therapy. Achieving molecular response by F‐PCR shows prognostic value.
The aim of the present randomized trial was to compare high-dose therapy (HDT) with continued conventional chemotherapy in patients with multiple myeloma (MM) who responded to the initial treatment. ...From May 1994 to October 1999, 216 patients (122 men/94 women; stage II or III; Eastern Cooperative Oncology Group ECOG score less than 3) entered the study. Initial chemotherapy consisted of 4 cycles of alternating vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, Adriamycin, dexamethasone (VBMCP/VBAD). Responding patients were randomly assigned to receive 8 additional cycles of VBMCP/VBAD, intensification with melphalan 200 mg/m2, or melphalan 140 mg/m2 plus 12 Gy fractionated total body irradiation (TBI). One-hundred sixty-four patients were randomly assigned, 83 to continued chemotherapy and 81 to HDT. The complete remission (CR) rate was significantly higher with HDT (30% vs 11%; P = .002). However, progression-free survival (PFS) was not significantly different between HDT and conventional therapy (median, 42 vs 33 months; P = not significant NS), and overall survival (OS) was similar in both groups (median, 61 vs 66 months). Finally, survival after relapse was identical in the 2 arms (15.9 vs 16.4 months). In conclusion, these results show that HDT intensification, when given to myeloma patients who have responded to the initial chemotherapy, significantly increases the CR rate but has no significant impact on PFS or OS.
High‐dose chemoradiotherapy conditioning regimens for autologous stem cell transplantation (ASCT) are generally held to give similar results in multiple myeloma (MM), but no specific comparative ...study has been published. We addressed this issue by comparing the main high‐dose chemoradiotherapy regimens used in the Spanish Registry. Patient cohorts included 315 cases treated with 200 mg/m2 melphalan (MEL200), 127 patients with 140 mg/m2 melphalan plus total body irradiation (MEL140 + TBI) and 121 cases with 12 mg/kg busulphan plus 140 mg/m2 melphalan (BUMEL). After ASCT, granulocyte and platelet recovery time was similar in all conditioning groups. There were no differences in transplant‐related mortality. All regimens yielded a similar response in reference to pre‐ASCT MM status, although BUMEL produced a slightly better overall response when compared with the other regimens (97% vs. 89% and 92%, P = 0·003). The 5‐year overall survival (OS) with BUMEL was 47% 95% confidence interval (CI) 26–68 compared with 43% (CI 31–54) for MEL140 + TBI and 37% (CI: 18–56) for MEL200. The median survival for the BUMEL group was 64 months compared with 45 and 37 months for the MEL200 and MEL140 + TBI groups respectively. These differences were non‐significant (P = 0·2). The median event‐free survival (EFS) was better for BUMEL (32 months) than for MEL200 (22 months) or for MEL140 + TBI (20 months). The differences in EFS between BUMEL and the other conditioning regimens reached statistical significance (P = 0·01). Nevertheless, the adjusted multivariate analysis for OS and EFS revealed that the conditioning regimens had no independent prognostic value. We concluded that three different conditioning regimens, commonly used for ASCT in MM, have a similar antimyeloma effect. However, the trend for better results observed in our series with BUMEL requires a prospective trial.
The transfusion of erythrocytes that have been stored for long periods of time can produce visceral ischemia and favor the acquisition of postsurgical infections. To estimate the role of the duration ...of storage of erythrocytes on morbidity in cardiac surgery, we performed an observational study.
All patients (n = 897) undergoing cardiac surgery during three consecutive years were included. Morbidity (main outcome measure) was evaluated by means of four surrogate measures: duration of stay in the intensive care unit longer than 4 days, mechanical ventilation time longer than 1 day, perioperative myocardial infarction rate, and severe postoperative infection rate. The mean duration of storage of all erythrocytes transfused and the duration of storage of the oldest unit transfused were used as storage variables.
After considering multiple confounding variables related to patient severity, illness, and surgical difficulty, the duration of storage of erythrocytes was found to be associated neither with a more prolonged stay in the intensive care unit or mechanical ventilation time nor with increased rates of perioperative infarction, mediastinitis, or sepsis. However, each day of storage of the oldest unit was associated with an increment of the risk of pneumonia of 6% (95% confidence interval, 1-11; P = 0.018). The cutoff point of maximum sensitivity and specificity (54.8 and 66.9%) associated with a greater risk for pneumonia corresponded to 28 days of storage for the oldest unit (odds ratio, 2.74; 95% confidence interval, 1.18-6.36; P = 0.019).
Prolonged storage of erythrocytes does not increase morbidity in cardiac surgery. However, storage for longer than 28 days could be a risk factor for the acquisition of nosocomial pneumonia.
Despite improvement in the treatment of advanced classical Hodgkin lymphoma, approximately 30% of patients relapse or die as result of the disease. Current predictive systems, determined by clinical ...and analytical parameters, fail to identify these high-risk patients accurately. We took a multistep approach to design a quantitative reverse-transcription polymerase chain reaction assay to be applied to routine formalin-fixed paraffin-embedded samples, integrating genes expressed by the tumor cells and their microenvironment. The significance of 30 genes chosen on the basis of previously published data was evaluated in 282 samples (divided into estimation and validation sets) to build a molecular risk score to predict failure. Adequate reverse-transcription polymerase chain reaction profiles were obtained from 262 of 282 cases (92.9%). Best predictor genes were integrated into an 11-gene model, including 4 functional pathways (cell cycle, apoptosis, macrophage activation, and interferon regulatory factor 4) able to identify low- and high-risk patients with different rates of 5-year failure-free survival: 74% versus 44.1% in the estimation set (P < .001) and 67.5% versus 45.0% in the validation set (P = .022). This model can be combined with stage IV into a final predictive model able to identify a group of patients with very bad outcome (5-year failure-free survival probability, 25.2%).
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