Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management.

Monoclonal gammopathy of undetermined significance (MGUS) was identified in 3.2% of 21 463 residents of Olmsted County, Minnesota, 50 years of age or older. The risk of progression to multiple myeloma, Waldenstrom's macroglobulinemia, AL amyloidosis or a lymphoproliferative disorder is approximately 1% per year. Low-risk MGUS is characterized by having an M protein <15 g/l, IgG type and a normal free light chain (FLC) ratio. Patients should be followed with serum protein electrophoresis at six months and, if stable, can be followed every 2-3 years or when symptoms suggestive of a plasma cell malignancy arise. Patients with intermediate and high-risk MGUS should be followed in 6 months and then annually for life. The risk of smoldering (asymptomatic) multiple myeloma (SMM) progressing to multiple myeloma or a related disorder is 10% per year for the first 5 years, 3% per year for the next 5 years and 1-2% per year for the next 10 years. Testing should be done 2-3 months after the initial recognition of SMM. If the results are stable, the patient should be followed every 4-6 months for 1 year and, if stable, every 6-12 months.

Is the International Staging System superior to the Durie-Salmon staging system? A comparison in multiple myeloma patients undergoing autologous transplant.

The international staging system (ISS) for multiple myeloma (MM) is a validated alternative to the Durie-Salmon staging system (DSS) for predicting survival at diagnosis. We compared these staging systems for predicting outcomes after upfront autologous stem cell transplantation by analyzing the outcomes of 729 patients between 1995 and 2002. With a median follow-up of 56 months, the univariate probabilities (95% CI) of non-relapse mortality (NRM), relapse, progression-free survival (PFS) and overall survival (OS) at 5 years were 7, 68, 25 and 52%, respectively. The median OS for stages I, II, III by DSS and ISS were 82, 68, 50 and 64, 68, 45 months, respectively. The concordance between the two staging systems was only 36%. Staging systems were formally compared using Cox models fit with DSS and ISS stages. The relative risks of PFS and OS were significantly different for stages I vs II and II vs III for DSS, but only for stages II vs III for ISS. Although both systems were predictive of PFS and OS, the DSS was superior in formal statistical comparison using Brier score. However, neither system was strongly predictive of outcomes, indicating the need for newer schemes incorporating other prognostic markers.

Second malignancy risk associated with treatment of Hodgkin's lymphoma: meta-analysis of the randomised trials.

BACKGROUND: Despite several investigations, second malignancy risks (SMR) following radiotherapy alone (RT), chemotherapy alone (CT) and combined chemoradiotherapy (CRT) for Hodgkin's lymphoma (HL) remain controversial. PATIENTS AND METHODS: We sought individual patient data from randomised trials comparing RT versus CRT, CT versus CRT, RT versus CT or involved-field (IF) versus extended-field (EF) RT for untreated HL. Overall SMR (including effects of salvage treatment) were compared using Peto's method. RESULTS: Data for between 53% and 69% of patients were obtained for the four comparisons. (i) RT versus CRT (15 trials, 3343 patients): SMR were lower with CRT than with RT as initial treatment (odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.62-0.98 and P = 0.03). (ii) CT versus CRT (16 trials, 2861 patients): SMR were marginally higher with CRT than with CT as initial treatment (OR = 1.38, CI 1.00-1.89 and P = 0.05). (iii) IF-RT versus EF-RT (19 trials, 3221 patients): no significant difference in SMR (P = 0.28) although more breast cancers occurred with EF-RT (P = 0.04 and OR = 3.25). CONCLUSIONS: Administration of CT in addition to RT as initial therapy for HL decreases overall SMR by reducing relapse and need for salvage therapy. Administration of RT additional to CT marginally increases overall SMR in advanced stages. Breast cancer risk (but not SMR in general) was substantially higher after EF-RT. Caution is needed in applying these findings to current therapies.

Autologous stem cell transplantation in multiple myeloma patients <60 vs >/=60 years of age.

The role of autologous stem cell transplantation (AuSCT) in older multiple myeloma patients is unclear. Using data from the Autologous Blood and Marrow Transplant Registry, we compared the outcome of 110 patients >/=the age of 60 (median 63; range 60-73) years, undergoing AuSCT with that of 382 patients <60 (median 52; range 30-59) years. The two groups were similar except that older patients had a higher beta(2)-microglobulin level at diagnosis (P=0.016) and fewer had lytic lesions (P=0.007). Day 100 mortality was 6% (95% confidence interval 4-9) and 1-year treatment-related mortality (TRM) was 9% (6-13) in patients <60 years, compared with 5% (2-10) and 8% (4-14), respectively, in patients >/=60 years. The relapse rate, progression-free survival (PFS) and overall survival (OS) in the two groups were also similar. Multivariate analysis of all patients identified only an interval from diagnosis to AuSCT >12 months and the use of two prior chemotherapy regimens within 6 months of AuSCT as adverse prognostic factors. Our results indicate that AuSCT can be safely performed in selected older patients: the best results were observed in patients undergoing AuSCT relatively early in their disease course.

Valacyclovir prophylaxis for the prevention of Herpes simplex virus reactivation in recipients of progenitor cells transplantation.

HSV can cause oral lesions that exacerbate chemotherapy-related mucositis. Intravenous acyclovir is effective in preventing HSV reactivations, but expensive. Valacyclovir has good bioavailability and has not been studied for prophylaxis of HSV among PCT patients. We compared the efficacy and costs of valacyclovir in preventing HSV reactivation among HSV seropositive autologous progenitor cell transplantation (APCT) patients with historical controls in whom intravenous acyclovir or no HSV prophylaxis were used. Valacyclovir group: From October 1997 to April 1999 108 adult patients received valacyclovir 500 mg twice daily from day -3 of APCT until neutropenia recovery or day +30. Valacyclovir was switched to intravenous acyclovir in cases of oral intolerance (17 patients) or suspected HSV reactivation (five patients). Intravenous acyclovir group: From January 1996 to October 1997 43 patients received 5 mg/kg twice-daily intravenous acyclovir from day -3 until recovery from neutropenia. No prophylaxis group: 38 patients from January 1996 to October 1997 did not receive HSV prophylaxis. HSV reactivations were seen in 2.7%, 2% and 45% of patients in the valacyclovir, intravenous acyclovir, and no prophylaxis groups, respectively. Valacyclovir was well tolerated and was the least expensive strategy. Oral valacyclovir was as effective as intravenous acyclovir for the prophylaxis of HSV reactivation in APCT patients.

Use of GnRH analogs for functional protection of the ovary and preservation of fertility during cancer treatment in adolescents: a preliminary report.

OBJECTIVE: Recent success in polychemotherapy (PCT) in adolescent female cancer patients has become a source of concern for specialists who also strive to preserve fertility. We studied whether gonadotropin-releasing hormone (GnRH) analogs could prevent the early onset of ovarian insufficiency postchemotherapy and protect fertility. METHODS: The patients were divided into three groups: Control group 1 (Group A), premenarchal patients aged 3 to 7.5 years (n = 5), were not given GnRH analogs administered prior to PCT. Postmenarchal patients (Group B), aged 14.7 to 20 years (n = 12) with normal menstrual rhythm and ovulatory cycles, received treatment with GnRH analogs prior to PCT. Control group 2 (Group C), postmenarchal patients aged 15.9 to 20 years (n = 4), received PCT but no GnRH analog protection. All groups received the PCT regimens CAVPE, CVPP, ABVD, TAMO, ARA-C, and MTT. In group B, leuprolide acetate inhibition was obtained with a depot injection administered each month before and during treatment with PCT. To accelerate the timing of ovarian regression, a subcutaneous injection (0.2 mg) was administered simultaneously. RESULTS: In Group A, patients had spontaneous menarche between the ages of 12 and 17.9 years, followed by normal menstruation and ovulatory cycles. Three patients became pregnant. After GnRH analog withdrawal, Group B patients continued with normal ovulatory cycles. Two patients became pregnant. Group C patients presented hypergonadotrophic hypoestrogenic amenorrhea. CONCLUSION: GnRH analog treatment before and during PCT enhances ovarian function and preserves adolescent fertility. The results must be confirmed in a larger study.

Autotransplants for Hodgkin's disease in first relapse or second remission: a report from the autologous blood and marrow transplant registry (ABMTR).

Although patients with relapsed Hodgkin's disease have a poor prognosis with conventional therapies, high-dose chemotherapy and autologous hematopoietic stem cell transplantation (autotransplantation) may provide long-term progression-free survival. We reviewed data from the Autologous Blood and Marrow Transplant Registry (ABMTR) to determine relapse, disease-free survival, overall survival, and prognostic factors in this group of patients. Detailed records from the ABMTR on 414 patients with Hodgkin's disease in first relapse (n = 295) or second complete remission (CR) (n = 119) receiving an autotransplant from 1989 to 1995 were reviewed. Median age was 29 (range, 7-64) years. Median time from diagnosis to relapse was 18 (range, 6-219) months; median time from relapse to transplant was 5 (range, <1-215) months. Most patients received high-dose chemotherapy without total body irradiation for conditioning (n = 370). The most frequently used high-dose regimen was cyclophosphamide, BCNU, VP-16 (CBV) (n = 240). The graft consisted of bone marrow (n = 246), blood stem cells (n = 112), or both (n = 56). Median follow-up was 46 (range, 5-96) months. One hundred-day mortality (95% confidence interval) was 7 (5-9)%. One hundred and sixty-five of 295 patients (56%) transplanted in relapse achieved CR after autotransplantation. Of these, 61 (37%) recurred. Twenty-four of 119 patients (20%) transplanted in CR recurred. The probability of disease-free survival at 3 years was 46 (40-52)% for transplants in first relapse and 64 (53-72)% for those in second remission (P < 0.001). Overall survival at 3 years was 58 (52-64)% after transplantation in first relapse and 75 (66-83)% after transplantation in second CR (P < 0.001). In multivariate analysis, Karnofsky performance score <90% at transplant, abnormal serum LDH at transplant, and chemotherapy resistance were adverse prognostic factors for outcome. Progression of Hodgkin's disease accounted for 69% of all deaths. Autotransplantation should be considered for patients with Hodgkin's disease in first relapse or second remission. Future investigations should focus on strategies designed to decrease relapse after autotransplantation, particularly in patients at high risk for relapse.

Autologous transplantation for diffuse aggressive non-Hodgkin's lymphoma in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry.

PURPOSE: To evaluate the results of high-dose chemotherapy and autologous hematopoietic stem-cell transplantation (autotransplants) in patients with diffuse aggressive non-Hodgkin's lymphoma (NHL) who never achieve a complete remission with conventional chemotherapy. PATIENTS AND METHODS: Detailed records from the Autologous Blood and Marrow Transplant Registry (ABMTR) on 184 patients with diffuse aggressive NHL who never achieved a complete remission with conventional chemotherapy and subsequently received an autotransplant were evaluated. Transplants were performed between 1989 and 1995 and were reported to the ABMTR by 48 centers in North and South America. RESULTS: Seventy-nine (44%) of 184 patients achieved a complete remission or a complete remission with residual imaging abnormalities of unknown significance after autotransplantation. Thirty-four (19%) of 184 had a partial remission and 55 (31%) of 184 had no response or progressive disease. Eleven patients (6%) were not assessable for response because of early death. The probabilities of progression-free and overall survival at 5 years after transplantation were 31% (95% confidence interval [CI], 24% to 38%) and 37% (95% CI, 30% to 45%), respectively. In multivariate analysis, chemotherapy resistance, Karnofsky performance status score less than 80 at transplantation, age > or = 55 years at transplantation, receiving three or more prior chemotherapy regimens, and not receiving pre- or posttransplant involved-field irradiation therapy were adverse prognostic factors for overall survival. CONCLUSION: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation should be considered for patients with diffuse aggressive NHL who never achieve a complete remission but who are still chemotherapy-sensitive and are otherwise transplant candidates.

[Eight years of experience in a single institution in hematopoietic stem cell autologous transplantation in malignant hematological diseases and in solid tumors]. / Ocho años de experiencia en una sola institucion en trasplante autólogo de células progenitoras hematopoyéticas en enfermedades hematológicas malignas y en tumores solidos.

Between August 1991 and December 1998, 400 patients (lymphomas: 197; acute leukemia: 86; multiple myeloma: 70 and solid tumors: 47) were admitted for autologous transplantation. All patients were mobilized with chemotherapy plus G-CSF. The hematological recovery was similar in all disease groups. Patients with acute leukemias and multiple myeloma had a slower platelet recovery. Treatment-related death was 4.5%. The status of the disease at diagnosis was the most significant prognostic factor. With a median follow-up of 23 months the probability of event-free survival at 60 months was 46% for low grade lymphoma, 44% for intermediate and high grade lymphoma, 58% for Hodgkin's disease, 45% for acute myeloblastic leukemia, 38% for solid tumors and 15% for multiple myeloma. The probability of survival at 60 months was 67% for low grade lymphoma, 47% for intermediate and high grade lymphoma, 75% for Hodgkin's disease, 52% for acute myeloblastic leukemia, 54% for solid tumors and 25% for multiple myeloma. It can be concluded that autologous progenitor cell transplantation induces a complete and faster hematological recovery in all groups of patients without any late graft failure. Results are similar to those published in the literature. The treatment-related death was low and acceptable.

Ocho años de experiencia en una sola institucion en trasplante autólogo de células progenitoras hematopoyéticas en enfermedades hematológicas malignas y en tumores solidos. / [Eight years of experience in a single institution in hematopoietic stem cell autologous transplantation in malignant hematological diseases and in solid tumors]

Between August 1991 and December 1998, 400 patients (lymphomas: 197; acute leukemia: 86; multiple myeloma: 70 and solid tumors: 47) were admitted for autologous transplantation. All patients were mobilized with chemotherapy plus G-CSF. The hematological recovery was similar in all disease groups. Patients with acute leukemias and multiple myeloma had a slower platelet recovery. Treatment-related death was 4.5

. The status of the disease at diagnosis was the most significant prognostic factor. With a median follow-up of 23 months the probability of event-free survival at 60 months was 46

for low grade lymphoma, 44

for intermediate and high grade lymphoma, 58

for Hodgkins disease, 45

for acute myeloblastic leukemia, 38

for solid tumors and 15

for multiple myeloma. The probability of survival at 60 months was 67

for low grade lymphoma, 47

for intermediate and high grade lymphoma, 75

for Hodgkins disease, 52

for acute myeloblastic leukemia, 54

for solid tumors and 25

for multiple myeloma. It can be concluded that autologous progenitor cell transplantation induces a complete and faster hematological recovery in all groups of patients without any late graft failure. Results are similar to those published in the literature. The treatment-related death was low and acceptable.

Ceftriaxone plus once daily aminoglycoside with filgrastim for treatment of febrile neutropenia: early hospital discharge vs. Standard In-patient care.

BACKGROUND: In febrile neutropenic patients, ceftriaxone plus an aminoglycoside is effective for the treatment of infection, while filgrastim reduces the extent and duration of neutropenia. Because the once daily dosing regimen of this combination permits ambulatory treatment, there is a need to test criteria for early hospital discharge. METHODS: Hospitalized adult patients with febrile neutropenia (following chemotherapy) considered to be potentially treatable on a follow-up out-patient basis were entered into this open-label, multinational study. Patients received a once daily combination of ceftriaxone for > or =5 days, aminoglycoside for > or =2 days, and filgrastim until the absolute neutrophil count was > or =1.0x10(9)/l for 2 days. Those initially responding to therapy (reduction of fever by > or =1 degrees C within 72 h, and clinical improvement) were randomized into standard in-patient or follow-up out-patient treatment groups, the latter patients being discharged from hospital early, after meeting defined criteria. RESULTS: 105 patients were enrolled, of whom 21 initial non-responders were not randomized. Efficacy was evaluable in 80 patients. Success (resolution of fever and symptoms, maintained for 7 days after cessation of therapy, and eradication of infecting pathogens) was similar among in-patients (40/42, 95%) and out-patients (34/38, 89%). The duration of hospitalization was shorter for out-patients than in-patients (median of 4 vs. 6 days, respectively). No hospital readmissions were necessary in out-patients. All other efficacy parameters assessed were comparable in both groups, as was tolerability/safety. One potentially drug-related death was reported. CONCLUSIONS: Patients who satisfy prospectively defined criteria for early discharge can be treated safely on an out-patient basis with a regimen of once daily ceftriaxone plus an aminoglycoside with filgrastim. In addition to reducing healthcare costs, it may improve patients' quality of life.

Protección funcional ovárica con análogos de GnRH y preservación de la fertilidad en adolescentes durante la terapéutica oncológica / Protection of the ovarian function with GnRH analogs and preservation of fertility during cancer therapy

Objetivos: Investigar si los análogos de GnRH pueden evitar la falla ovárica precoz post-quimioterapia antineoplásica y tener así un efecto protector de la fertilidad. Diseño del Estudio: Veintiún pacientes oncológicas fueron divididas en dos grupos y seguidas a lo largo de 18 años. A: premenarca, 3-7,5 años (n:5) recibió poliquimioterapia (PCT). B: post-menarca, 14,7 - 20 años (N:12), ciclos menstruales ovulatorios normales, recibieron análogos de GnRH antes de la PCT.B1 (n:5) trasplante de médula ósea previo (BMT) a la PCY.B2 (n:7) recibió PCT y cobaltoterapia supradiafragmática. C: post-menarca, 15,9 - 20 años (n:4) recibió PCT y fue sometida a BMT. La inhibición se obtuvo mediante la administración de acetato de Leuprolide de depósito en dosis mensuales antes y durante la poliquimioterapia. Resultados: A: menarca espontánea (12.17.8 años), ciclos menstruales ovulatorios normales, cinco embarazos normales. B: ciclos ovulatorios normales desde la supresión del análogo de GnRH, tres embarazos. C: amenorrea hipergonadotrófica hipoestrogénica. Conclusiones: El seguimiento de estas pacientes demostró que la administración de análogos de GnRH antes y durante la poliquimioterapia protege la función ovárica y preserva la fertilidad futura de las adolescentes

Protección funcional ovárica con análogos de GnRH y preservación de la fertilidad en adolescentes durante la terapéutica oncológica / Protection of the ovarian function with GnRH analogs and preservation of fertility during cancer therapy

Objetivos: Investigar si los análogos de GnRH pueden evitar la falla ovárica precoz post-quimioterapia antineoplásica y tener así un efecto protector de la fertilidad. Diseño del Estudio: Veintiún pacientes oncológicas fueron divididas en dos grupos y seguidas a lo largo de 18 años. A: premenarca, 3-7,5 años (n:5) recibió poliquimioterapia (PCT). B: post-menarca, 14,7 - 20 años (N:12), ciclos menstruales ovulatorios normales, recibieron análogos de GnRH antes de la PCT.B1 (n:5) trasplante de médula ósea previo (BMT) a la PCY.B2 (n:7) recibió PCT y cobaltoterapia supradiafragmática. C: post-menarca, 15,9 - 20 años (n:4) recibió PCT y fue sometida a BMT. La inhibición se obtuvo mediante la administración de acetato de Leuprolide de depósito en dosis mensuales antes y durante la poliquimioterapia. Resultados: A: menarca espontánea (12.17.8 años), ciclos menstruales ovulatorios normales, cinco embarazos normales. B: ciclos ovulatorios normales desde la supresión del análogo de GnRH, tres embarazos. C: amenorrea hipergonadotrófica hipoestrogénica. Conclusiones: El seguimiento de estas pacientes demostró que la administración de análogos de GnRH antes y durante la poliquimioterapia protege la función ovárica y preserva la fertilidad futura de las adolescentes (AU)

IgG1-kappa biclonal gammopathy associated with multiple myeloma suggests a regulatory mechanism.

Multiclonal gammopathies associated with multiple myeloma may result either from a neoplastic transformation of a cell clone undergoing immunoglobulin class switching or from independent transforming events yielding proliferation of unrelated plasma cell clones. The simultaneous presence of more than one neoplastic clone may possess regulatory implications in terms of cell proliferation, clonal expansion, secretion of M-components or response to chemotherapy. We report a patient, diagnosed with multiple myeloma stage IIIa, who presented with two well-defined homogeneous IgG1-kappa components in the serum (designated WER-1 and WER-2) with striking differences in their plasma concentration and response to the classic melphalan/prednisone treatment. Immunochemical characterization and amino terminal sequence analysis of both the heavy and light chains of each M-component undoubtedly determined their biclonal origin. WER-1 was identified as IgG1(VHII)-kappaI while WER-2 was classified as IgG1(VHIII)-kappaIII. The plateau phase was characterized by very low or undetectable levels of WER-2, a high, almost constant, concentration of WER-1 and the absence of Bence Jones proteinuria, whereas these parameters were completely reversed during the escape phase with levels resembling those observed at the time of diagnosis. The statistically significant negative correlation between the biclonal components and the different susceptibility to the treatment clearly suggests regulatory interactions between the clones WER-1 and WER-2.

Autologous peripheral blood progenitor cell transplantation mobilized with high-dose cytarabine in acute myeloid leukemia in first complete remission.

BACKGROUND: The aim of this study was to increase disease-free survival (DFS) in AML in CR1 using a high-dose cytarabine consolidation plus G-CSF as in vivo purging and mobilization of CD34+ cells before ablative therapy and peripheral blood autograft. PATIENTS AND METHODS: Fifty-six consecutive AML patients (pts) (including 11 children < 15 years), with a median age of 32 years, were analyzed. After achievement of CR with cytarabine-mitoxantrone (7 + 3) in adults and a BFM-like protocol in children, pts were intensified with cytarabine 2 g/m2 x six doses plus mitoxantrone for adults, or, 3 g/m2 x six doses plus etoposide for children, followed by G-CSF 5 micrograms/kg SC daily. The ablative regimens used were busulfan and cyclophosphamide (Bu/Cy) in standard-risk pts plus etoposide (2400 mg/m2) for high-risk pts. RESULTS: For the 54 pts who underwent autologous transplant, the median time to reach > 1.0 x 10(9)/l neutrophils was 13 days (8-48), and to reach platelets > 25 x 10(9)/l 32 days (8-364), and the median numbers of red blood cell and platelet units transfused were 3 and 5, respectively. Six pts had treatment-related deaths (11%). The disease-free survival and overall survival at 30 months (mos) for the 56 eligible pts were 61% and 62%, respectively. Only two relapses were observed after 21 mos, while there were 12 relapses within 12 mos. CONCLUSIONS: The above treatment results in a similar DFS rate as does rescue with bone marrow cells, with faster neutrophil and platelet recovery.

Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin's disease. International Database on Hodgkin's Disease Overview Study Group.

DESIGN: To perform a meta-analysis of all randomized trials that compared chemotherapy (CT) alone versus combined modality treatment (CT + radiotherapy [RT]) for which individual patient data could be made available. PATIENTS AND METHODS: Data on 1,740 patients treated on 14 different trials that included 16 relevant comparisons have been analysed. Eight comparisons were designed to evaluate the benefit of additional RT after the same CT (CT1 v CT1 + RT; additional RT design). Eight comparisons were designed to evaluate whether RT in a combined modality setting can be substituted by CT using either more cycles of the same CT or regimens that contain additional drugs (CT1 + CT2 v CT1 + RT or CT1 v CT2 + RT; parallel RT/CT design). RESULTS: Additional RT showed an 11% overall improvement in tumor control rate after 10 years (P = .0001; 95% confidence interval [CI], 4% to 18%). No difference could be detected with respect to overall survival (P = .57; 95% CI, -10% to 4%). In contrast, when combined modality treatment was compared with CT alone in the parallel-design trials, no difference could be detected in tumor control rates (P = .43; 95% CI, -6% to 9%), but overall survival was significantly better after 10 years in the group that did not receive RT (P = .045; 8% difference; 95% CI, 1% to 15%). There were significantly fewer fatal events among patients in continuous complete remission (relative risk [RR], 1.73; 95% CI, 1.17 to 2.53; P = .005) if no RT was given. CONCLUSION: Combined modality treatment in patients with advanced-stage Hodgkin's disease overall has a significantly inferior long-term survival outcome than CT alone if CT is given over an appropriate number of cycles. The role of RT in this setting is limited to specific indications.