Posttreatment nadir M-protein level is a stronger discriminator of survival following plateau attainment than is percent reduction in M-protein in patients with IgG myeloma

We conducted a retrospective study of patients with IgG or IgA myeloma who attained plateau to evaluate the relationships between survival and posttreatment nadir M-protein levels and between survival and the response to treatment evaluated by the percent reduction in M-protein. Of the 127 patients comprising 92 IgG and 35 IgA myeloma patients with disease stages II or III, 51 (40.2%) attained plateau. For IgG myeloma patients who attained plateau, survival time was not affected by the percent reduction in M-protein (median survival, 59.5 months for responding patients versus 54.4 months for nonresponding patients, P = .6910). Posttreatment nadir M-protein level, however, did affect survival time (median survival, 61.2 months for <3000 mg/dL versus 25.7 months for >3000 mg/dL, P = .0439). These findings suggest that the posttreatment nadir M-protein level is a stronger discriminator of survival following plateau attainment than the percent reduction of M-protein in patients with IgG myeloma.     

DAD,new intensive chemotherapy for patients with myeloma: a preliminary report

A new intensive chemotherapy regimen, DAD, composed of doxorubicin, melphalan and dexamethasone, was given to 17 patients with multiple myeloma. The end point of this regimen was to obtain a deep posttreatment nadir in the M-protein levels so as to increase the chance of plateau attainment which would be associated with prolonged survival in each patient. It was noteworthy that all the 17 evaluable patients achieved a partial response. Nine of the 17 (52.9%) attained a plateau. Ten of the 17 patients (58.8%) obtained a deep posttreatment nadir in their M-protein levels (IgG < 2,000 mg/dl, IgA < 1,000 mg/dl, BJP = 0 g/dl/day), and six of them reached a plateau phase, which was not significantly more frequent than those who did not obtain a deep posttreatment nadir in their M-protein levels (three of seven reached plateau phase). The median survival of the 17 patients (37.6 months) was significantly prolonged compared with that of patients treated with our previous chemotherapy regimens, VMCP (22.5 months) and MMPP (23.5 months), and was comparable to that of MMCP (29.5 months).     

Long-term survival in multiple myeloma: a Finnish Leukaemia Group study

The long-term survival of 324 multiple myeloma patients treated with conventional chemotherapy (CT) was analysed after at least 10 years follow-up. The unselected group of myeloma patients 70 years, as representative of the population, was derived from three prospective multicentre trials by the Finnish Leukaemia Group.
The median overall survival time (OS) was 49 months. At 10 years, 13% of the patients were alive. The significant single pre-treatment prognostic factors for long-term survival were age, Hb, platelet count, serum-creatinine and proportion of plasma cells in the bone marrow. Staging according to Hb level and plasma cell degree was more useful than that of the Durie and Salmon system in predicting long-term survival. The first-line chemotherapy combination and the level of response were unimportant in this respect. A long plateau phase after first response and response to salvage chemotherapy were important prognostic factors. Not only the salvage regimen but also the whole supportive treatment and adequate control of complications throughout the course of the disease are important.     

Second auto-SCT is safe and effective salvage therapy for relapsed multiple myeloma

Therapeutic options for patients with multiple myeloma whose disease has relapsed after a prior auto-SCT include novel biologic therapies, traditional chemotherapy or a second transplant, with no clear standard of care. Few published studies address the safety and efficacy of a second auto-SCT for relapsed disease. We reviewed the Abramson Cancer Center experience with salvage auto-SCT for relapsed multiple myeloma. Forty-one patients had received a salvage auto-SCT at our institution; the median time between transplants was 37 months (range 3-91). The overall response rate in assessable patients was 55%, and treatment-related mortality was 7%. With a median follow-up time of 15 months, the median PFS was 8.5 months and the median overall survival (OS) was 20.7 months. In a multivariate analysis of OS, independent prognostic factors were >or=5 prior lines of therapy and time to progression after initial auto-SCT of 相似文献   

Plateau phase in multiple myeloma: an analysis of long-term follow-up of 432 patients

Data from an 8-year follow-up of 432 myeloma patients were analysed for incidence, duration and prognostic value of plateau phase and factors favouring its achievement. The first-line chemotherapy was melphalan and prednisolone in 121 cases, combination chemotherapy in 311 cases. The survival times were similar despite different response rates. Any response resulted in survival significantly ( P <0.001) better than in patients with progressive disease, but the level of response had no influence in this respect.   A plateau of at least 3 months was achieved in 81%, at least 6 months in 74%, at least 12 months in 59% and at least 24 months in 33%. Groups with significantly different ( P <0.001) survivals were identified: a plateau of <3 months, 3–11 months, 12–23 months, and 24 months or longer, with median survivals of 10, 27, 46 and 81 months, respectively.   In the multivariate analysis of pretreatment variables, only haemoglobin (Hb) ( P <0.001) and creatinine at 2 months ( P <0.01) were significant for a plateau >12 months. After inclusion of chemotherapy data, Hb and time taken to reach the best response were still significant ( P =0.002). The predictive power of high Hb and slow response for achieving a plateau of 6 or 12 months was 79%.   Accordingly, the criteria for response of treatment for multiple myeloma should include a stable period of at least 3 months; the criteria for a plateau a stable period of at least 12 months in order to have real prognostic significance.     

High serum lactate dehydrogenase level predicts short survival after vincristine-doxorubicin-dexamethasone (VAD) salvage for refractory multiple myeloma

We evaluated possible prognostic factors just before salvage therapy with vincristine, doxorubicin, and dexamethasone (VAD) for 36 patients with refractory multiple myeloma. The median duration from diagnosis to the first VAD salvage was 14 months (range 2-76 months). Among parameters that have been shown to be associated with poor survival, a high serum lactate dehydrogenase (LDH) level was the sole significant predictor of survival. The median survival of patients with high LDH levels was 4 months, whereas that of patients with low LDH levels was 20 months. A multivariate analysis identified high LDH and high age as independent prognostic factors. More aggressive therapies might be indicated for high-LDH patients with refractory myeloma.     

Plateau phase in multiple myeloma: an end-point of conventional-dose chemotherapy

BACKGROUND AND OBJECTIVE: In multiple myeloma (MM) patients treated with conventional chemotherapy, the attainment and duration of a plateau phase seems to affect survival more than the degree of response to initial treatment. The aims of this study are: 1) to analyze within a cohort of previously untreated MM patients the incidence and the duration of the plateau phase; 2) to correlate it with the presenting features; 3) to assess its impact on survival. DESIGN AND METHODS: A series of 146 consecutive MM patients treated with conventional chemotherapy were evaluated for this study. Of 146 patients, 102 responded (13 achieving complete response, 21 partial response, and 68 minimal response), and 44 showed less than minimal response or a progression. A plateau phase was documented in 115 patients (comprising all responders and 13 non responders. The median plateau phase duration was 21.6 months. The majority of patients received intermittent cycles of chemotherapy (melphalan or interferon) during the plateau phase. In multivariate analysis, lytic lesions, response, and time to the best response (TBR) correlated with the attainment of a plateau, while stage, response as a whole, and TBR showed a significant correlation with the duration. In contrast, the type of response did not correlate with either the attainment or the duration of plateau. To analyze the prognostic impact of presenting features, response to therapy and plateau we used a hierarchical model for survival. The analysis showed that the response to therapy and the duration of plateau significantly affect the survival. INTERPRETATION AND CONCLUSIONS: In multiple myeloma a plateau phase of at least 6 months' duration has a higher impact on survival than the degree of response to conventional chemotherapy so plateau duration could be used as target of therapeutic trials. The best way to maintain the plateau phase remains, however, undefined.     

Plateau phase in multiple myeloma: an analysis of long-term follow-up of 432 patients

Data from an 8-year follow-up of 432 myeloma patients were analysed for incidence, duration and prognostic value of plateau phase and factors favouring its achievement. The first-line chemotherapy was melphalan and prednisolone in 121 cases, combination chemotherapy in 311 cases. The survival times were similar despite different response rates. Any response resulted in survival significantly (P<0.001) better than in patients with progressive disease, but the level of response had no influence in this respect. A plateau of at least 3 months was achieved in 81%, at least 6 months in 74%, at least 12 months in 59% and at least 24 months in 33%. Groups with significantly different (P<0.001) survivals were identified: a plateau of <3 months, 3–11 months, 12–23 months, and 24 months or longer, with median survivals of 10, 27, 46 and 81 months, respectively. In the multivariate analysis of pretreatment variables, only haemoglobin (Hb) (P<0.001) and creatinine at 2 months (P<0.01) were significant for a plateau >12 months. After inclusion of chemotherapy data, Hb and time taken to reach the best response were still significant (P=0.002). The predictive power of high Hb and slow response for achieving a plateau of 6 or 12 months was 79%. Accordingly, the criteria for response of treatment for multiple myeloma should include a stable period of at least 3 months; the criteria for a plateau a stable period of at least 12 months in order to have real prognostic significance.     

Clinical response to the treatment of multiple myeloma

Between 1971 and 1985, 133 patients were diagnosed as symptomatic multiple myeloma. Recently the number and percentage of patients, who were older (70 years old) and type of diffuse proliferation, were remarkably increased. In 132 previously untreated patients who received chemotherapy, the 50% Survival time was 32 months; thirty-nine (29%) survived more than five years after treatment and 4 of them (3%) survived more than ten years. Among the prognostic factors related to survival time, serum albumin level, M-protein type, bone marrow plasma cell (%), clinical stage and classification according to tumor distribution were considered to be significantly important. Clinical responses were evaluated in 120 patients who received combination chemotherapy for at least 3 months. A 50% or more reduction of M-protein was obtained in 58% and a marked improvement in bone pain or motor-disturbance was found in 54%. Overall response rate evaluated by the effects of both objective and subjective symptoms was 43%. New criteria for response defined by the level of serum albumin and M-protein after treatment were proposed.     

Cytoreduction and stem cell mobilization with a regimen of paclitaxel, etoposide and cyclophosphamide followed by autologous transplantation using a preparative regimen of busulfan, etoposide and cyclophosphamide for patients with advanced lymphoma

Forty-one patients with advanced Hodgkin's disease or intermediate or high-grade lymphoma, after having received standard salvage chemotherapy, were treated with a nonablative high-dose regimen of paclitaxel, etoposide and cyclophosphamide (D-TEC) to optimally cytoreduce their disease and simultaneously mobilize peripheral blood stem cells. This regimen produced a response rate of 78% (35% complete and 43.2% partial response) and mobilized sufficient peripheral blood stem cells in 94% of the patients. Thirty-two of these patients then underwent autologous progenitor cell transplantation after ablative conditioning with busulfan, etoposide and cyclophosphamide. Actuarial overall survival at 61 months was 71.9% with an event-free survival (EFS) of 65.6%. Median EFS was 24.4 months. EFS of patients responsive to salvage chemotherapy was 75% at 61 months, compared to 33.3% at 51.4 months in patients resistant to salvage chemotherapy. EFS of patients with disease sensitive to D-TEC was 75% at 61 months compared to 0% at 13.1 months in patients resistant to D-TEC. In a multivariate analysis, the only significant parameter for transplant outcome was sensitivity to D-TEC (p = 0.016), but not sensitivity to standard salvage chemotherapy. Aggressive cytoreduction may permit even those patients who are resistant to standard salvage chemotherapy to become successful transplant candidates.     

Plasma cell leukemia: an evaluation of response to therapy

Forty-three patients with plasma cell leukemia were seen at the Mayo Clinic. Twenty-five (58 percent) had primary plasma cell leukemia (diagnosis first made in the leukemic phase) and 18 (42 percent) had secondary plasma cell leukemia (leukemic transformation of a previously diagnosed multiple myeloma). Patients with secondary plasma cell leukemia were older, had a greater incidence of lytic bone lesions, had a lower platelet count, and had a larger M-protein in the serum than did patients with primary plasma cell leukemia. The median survival was 6.8 months for patients with primary plasma cell leukemia and 1.3 months for patients with secondary plasma cell leukemia. In patients with primary plasma cell leukemia, multiple alkylating agents produced a higher response rate than did melphalan, but the median time from treatment to progression or death was not significantly improved with such therapy. Review of the literature also suggests that the response rate is higher with combination chemotherapy than with single alkylating agents. Patients with secondary plasma cell leukemia usually show resistance to any type of chemotherapy and have a short survival.     

High-dose therapy/autologous stem cell transplantation in patients with chemosensitive multiple myeloma: predictors of complete remission

High-dose therapy (HDT) followed by autologous stem cell support is widely used as intensification treatment in patients with multiple myeloma (MM) responsive to the initial chemotherapy. However, there is growing evidence that only the subset of patients who achieve complete remission (CR) actually benefit from this approach. The aim of this study was to identify pretransplant predictors of CR in responding myeloma patients intensified with HDT. A total of 59 patients with chemosensitive disease received myeloablative therapy. The intensification regimen consisted of MEL-200 (23), MEL-140/TBI 12 Gy (21) or busulfan-based regimens (15). Serum and urine negative immunofixation were required for CR. After HDT, the CR rate increased from 8 to 37%. For the overall series, the median event-free survival (EFS) and overall survival (OS) from the initiation of therapy were 41 and 68 months, respectively. Patients who achieved CR had an EFS (median 47 vs 36 months; P=0.023) as well as an OS (median not reached vs 60 months; P=0.006) significantly longer than those attaining a lower degree of response. Finally, the pretransplant features significantly associated to CR were a low M-protein size (serum 相似文献   

High serum lactate dehydrogenase level as a marker for drug resistance and short survival in multiple myeloma

OBJECTIVE: To evaluate serum lactate dehydrogenase (LDH) as a prognostic factor in previously untreated patients with multiple myeloma. DESIGN: Study of 391 consecutive patients with uniformly treated multiple myeloma, followed until death in 63% of patients. SETTING: Tertiary, referral cancer center. PATIENTS: A total of 391 consecutive, previously untreated, symptomatic patients with various stages of multiple myeloma. INTERVENTION: Various chemotherapy regimens that included doxorubicin or glucocorticoids, or both, with a consistent response rate (53%). MEASUREMENTS: Outcomes included clinical response based on a 75% reduction of calculated tumor load and survival time from treatment. Univariate and multivariate analyses were used. MAIN RESULTS: Eleven percent of patients showed a high serum LDH level of more than 5.0 mukat/L (300 U/L). An elevated LDH level was seen more frequently with a rise in the tumor load; an increased level was present in 26% of patients with high tumor mass. A high LDH level was associated with plasma cell leukemia or lymphoma-like clinical features (43%) and with plasma cell hypodiploidy (17%). Only 20% of patients with elevated LDH levels responded to chemotherapy compared with a response rate of 57% for patients with low levels of LDH. Using multivariate analysis, LDH was a significant independent predictor of response (P = 0.001), with an odds ratio of 0.25 (95% Cl, 0.11 to 0.57). A high LDH level was associated with a short median survival (9 months) and showed the highest relative risk (2.63; Cl, 1.75 to 3.95; P = 0.001). CONCLUSIONS: Elevation of the LDH level suggests the presence of occult extraosseous disease and high tumor mass. The LDH level is a predictor of a poor prognosis in selected patients who should be considered for early intensive treatment.     

Autologous transplantation in multiple myeloma: a GITMO retrospective analysis on 290 patients. Gruppo Italiano Trapianti di Midollo Osseo.

BACKGROUND AND OBJECTIVE: Autologous transplantation is a better treatment for multiple myeloma (MM) than chemotherapy, but uncertainty remains about patient selection, optimal timing of autograft, conditioning regimen, need for a second autograft, and role of maintenance. To provide partial answers to these questions we assessed the results of autologous transplantation in a large cohort of patients whose data were reported to the GITMO registry. DESIGN AND METHODS: We retrospectively analyzed data from 290 patients with MM (M = 150; F = 140; median age 52 years, range 19-70; stage I = 34, stage II = 75, stage III = 167) reported to the GITMO. At the time of autograft, 20% were in CR, 66% in PR, while the remaining had non-responsive or progressive disease. Median time between diagnosis and transplant was 16 months (1-90). Seventy-two patients (26%) had been planned to receive a double autograft, but this was actually done in only 35 (12%). The conditioning was chemotherapy in 90%. Peripheral blood was the only source of stem cells in 94%, and purging was applied in 10% of cases. For statistical analysis of data, differences between patient subsets were analyzed using the chi-square test, while the Kaplan-Meier method was used to estimate event-free survival (EFS) and survival (OS) probabilities. The Cox model was used for multivariate analysis. RESULTS: Following the autograft, 116 patients (40%) were in CR, 144 (50%) in PR, 24 (8%) did not respond or progressed and 6 (2%) died before response evaluation. Transplant-related mortality occurred in 3%. At a median follow-up of 23 months, 223 (77%) patients are alive, 71 (24%) of them in CR, and 67 (23%) patients have died at a median time of 20 months (0-70). OS and EFS at 6 years are 47% and 28%, respectively, but the EFS curve shows no plateau. In multivariate analysis, age, beta2-microglobulin level and status at transplant emerged as significant prognostic factors for both OS and EFS, while time from diagnosis to transplant showed borderline significance. INTERPRETATION AND CONCLUSIONS: Based on the prognostic factors identified in multivariate analysis, we were able to assess the weight of a single prognostic factor or their combinations on transplant outcome. We also calculated the probability of OS and EFS by the number of factors at the time of autograft. Autologous transplantation is a safe and effective procedure, not only in sensitive patients, but also in resistant cases, provided they are <55 years of age and have low beta2-microglobulin. It should be applied early after the diagnosis of multiple myeloma, following the delivery of brief primary chemotherapy.     

Early harvest and late transplantation as an effective therapeutic strategy in multiple myeloma

Transplantation after high-dose chemotherapy prolongs survival in patients with multiple myeloma compared with standard therapy. It is unclear whether the optimal timing of transplantation is immediately after induction chemotherapy or whether stem cells may be cryopreserved for transplantation at subsequent progression or relapse. In this study, stem cells were collected within 6 months of diagnosis, followed by transplantation only at progression of myeloma. One hundred and eighteen patients with multiple myeloma had stem cells collected and cryopreserved. Eleven had transplants early in the disease after they demonstrated failure to respond to primary therapy. The remaining 107 were eligible for transplants when there was evidence of progressive disease. Of the 118 patients, 67 had transplants, nine died of progressive disease before transplantation, and 42 remain alive in plateau phase. The median survival of the group is 58.5 months; 67 are alive. Serum beta2-microglobulin, bone marrow labeling index (S phase), and hemoglobin level predicted overall survival (P < 0.006, P < 0.001, and P < 0.01, respectively). We conclude that early cryopreservation of blood stem cells followed by transplantation at progression is a feasible approach to therapy in patients with myeloma. The underlying biology of the disease has a greater impact on survival than the timing of transplantation. A prospective randomized trial is required to answer definitively the question of the optimal timing of blood cell transplantation.     

Extended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the APEX trial

Initial analysis of the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of relapsed multiple myeloma patients showed significantly longer time to progression, higher response rate, and improved survival with single-agent bortezomib versus high-dose dexamethasone. In this updated analysis (median follow-up: 22 months), survival was assessed in both arms, and efficacy updated for the bortezomib arm. Median survival was 29.8 months for bortezomib versus 23.7 months for dexamethasone, a 6-month benefit, despite substantial crossover from dexamethasone to bortezomib. Overall and complete response rates with bortezomib were 43% and 9%, respectively; among responding patients, 56% improved response with longer therapy beyond initial response, leading to continued improvement in overall quality of response. Higher response quality (100% M-protein reduction) was associated with longer response duration; response duration was not associated with time to response. These data confirm the activity of bortezomib and support extended treatment in relapsed multiple myeloma patients tolerating therapy.     

Smoldering multiple myeloma: natural history and recognition of an evolving type

Patients with smoldering multiple myeloma (SMM) meet the diagnostic criteria of multiple myeloma (MM) but are asymptomatic. Between January 1978 and July 2001, 53 patients (median age 63 years) were diagnosed with SMM. The median serum M-protein and proportion of bone marrow plasma cells were 36 g/l and 27% respectively. Two subsets of SMM were identified: (i) evolving SMM (n = 22), characterized by a progressive increase in serum M-protein, a previously recognized monoclonal gammopathy of undetermined significance (MGUS) and a significant higher proportion of IgA type and (ii) non-evolving SMM (n = 26) with stable M-protein that abruptly increases when symptomatic MM develops. Thirty-four patients developed symptomatic MM. The median time to progression in the overall series was 3.2 years and the only feature associated with a shorter time to progression was the evolving versus non-evolving type (1.3 vs. 3.9 years respectively, P = 0.007). The pattern of progression consisted of anaemia, lytic bone lesions or both, without renal failure, hypercalcaemia or extramedullary plasmacytomas. Fifty-seven per cent of patients that required chemotherapy showed no or minimal response. The median survival from diagnosis and from progression was 8.2 and 3.5 years respectively.     

Aggressive combination chemotherapy in multiple myeloma. A multicentre trial

A one-armed multicentre trial was conducted in Finland during the period from Jan. 1979 to Feb. 1980 to document the possible beneficial effect of aggressive combination chemotherapy MOCCA on the remission induction and survival in multiple myeloma. The regimen MOCCA consisted of vincristine, methylprednisolone and 3 alkylating agents. Of the 50 patients eligible for the for study, 39 (78%) achieved at least a 50% response. 27 (54%) achieved an excellent response. The median survival time for all patients was 49 months from the initiation of the treatment, but 23 of the 33 patients whose myeloma protein had shown a ≥ or ≧ 75% reduction were still alive at 4 yr. Advanced clinical stage and irreversible renal damage had a negative prognostic value. After 12 months on regimen MOCCA the patients with a ≧ or ≥ 75% reduction in myeloma protein were allocated at random to receive MOCCA courses bimonthly or no further chemotherapy. The maintenance chemotherapy did not prolong remission or survival.     

Expansion of the growth fraction in multiple myeloma with alkylating agents

Patients with IgG multiple myeloma underwent serial studies of tumor cell kinetics including (1) estimation of the total body myeloma cell number (TBMC), (2) measurement of the myeloma cell tritiated thymidine labeling index (LI), and (3) calculation of the total number of myeloma cells undergoing DNA synthesis. Intermittent courses of chemotherapy with cycle-non-specific agents such as melphalan resulted in a marked increase in the LI of myeloma cells in patients who had a 75% reduction in TBMC. The long "plateau" phase of partial remission of myeloma in these patients was associated with a continued high LI: this suggests that the plateau resulted from a balance between the cytoreductive effects of chemotherapy and expansion of the growth fraction (GF) of the tumor. Preliminary attempts to capitalize therapeutically on this expansion of the GF in several patients included administration of the cycle-active agents vincristine and cytosine arabinoside. Vincristine appeared to induce a further reduction in tumor in several patients, although cytosine arabinoside appeared to be ineffective despite clear evidence of its inhibition of DNA synthesis in myeloma cells in vivo. Further clinical studies of the effects of cycle-active drugs on myeloma appear to be warranted; however, successful exploitation of the dynamic change in myeloma cell kinetics with chemotherapy will require the use of cycle-active agents with marked selective toxicity for myeloma cells.     

Low-dose thalidomide plus dexamethasone is an effective salvage therapy for advanced myeloma

BACKGROUND AND OBJECTIVES: The immunomodulatory drug thalidomide can inhibit angiogenesis and induce apoptosis in experimental models. It can also induce marked and durable response in advanced myeloma patients. Thalidomide has been used at doses ranging from 200 to 800 mg with significant toxicity. No data are available on the impact of low-dose thalidomide plus dexamethasone as salvage therapy for relapsed patients. DESIGN AND METHODS: To address this issue, myeloma patients were treated with 100 mg/day thalidomide continuously and dexamethasone 40 mg, days 1-4, every month. Between June 1999 and August 2000, 77 patients (median age 65 years) who had relapsed or were refractory to chemotherapy were treated with thalidomide plus dexamethasone. RESULTS: After a minimum of 3 months of treatment, 14 patients (18%) showed a myeloma protein reduction of 75%-100%, 18 patients (23%) showed a response of 50-75%, 19 patients (25%) a response of 25-50% and 26 patients (34%) a response of < 25% or disease progression. After a median follow-up of 8 months, median progression-free survival was 12 months. Thalidomide was well tolerated. Constipation (12%) and sedation (6%) were mild. Tingling or numbness were present in 17% of patients, discontinuation of treatment was required in 10% of patients. INTERPRETATION AND CONCLUSIONS: The association of low-dose thalidomide plus dexamethasone is active against advanced myeloma. A significant proportion of patients benefit from this treatment as a salvage therapy postponing the delivery of chemotherapy.