K. R. Desikan

Unique role of cytogenetics in the prognosis of patients with myeloma receiving high-dose therapy and autotransplants.

PURPOSE Although important predictors of survival in myeloma patients have been identified, it is well recognized that better prognostic factors for this disease are needed. Because cytogenetics play a dominant role in the outcome of patients with acute leukemia, their prognostic value was evaluated in a large group of newly diagnosed and previously treated myeloma patients receiving autotransplants. METHODS A total of 427 either newly diagnosed (26%) or previously treated patients (74%) received tandem transplants, supported by mobilized peripheral-blood stem cells. Numerous variables, including cytogenetics, were analyzed for their impact on complete remission, event-free survival (EFS), and overall survival (OS). RESULTS Abnormal karyotypes were detected in 37% of our patients and were very complex, irrespective of the duration of standard therapy before the first autotransplant. In addition to previously recognized unfavorable implications of partial or complete deletion of chromosome 13 and 11q abnormalities, we now observed that the presence of any translocation likewise portended poor outcome (unfavorable karyotypes). On multivariate analysis, the absence of an unfavorable karyotype was the most favorable variable for both EFS (P = .0001) and OS (P = .0001). Other favorable factors were duration of standard therapy and a low beta-2 microglobulin (B2M) level before the first autotransplant. A risk-based classification system was developed according to the number of these favorable variables present, showing highly significant differences in event-free and overall survival. CONCLUSION Cytogenetics play a dominant role in myeloma and were independent of previously recognized important prognostic factors, such as B2M and duration of prior standard therapy.

Comparable engraftment kinetics following peripheral-blood stem-cell infusion mobilized with granulocyte colony-stimulating factor with or without cyclophosphamide in multiple myeloma.

PURPOSE To compare, in the setting of tandem autotransplantations for multiple myeloma (MM), two established methods of peripheral-blood stem-cell (PBSC) procurement with chemotherapy or hematopoietic growth factor alone. PATIENTS AND METHODS Between June 1994 and July 1995, 44 patients with MM were randomized to PBSC mobilization with either granulocyte colony-stimulating factor (G-CSF) 16 microg/kg (group 1; n = 22) or high-dose cyclophosphamide (HDCTX) 6 g/m2 plus G-CSF 5 microg/kg (group 2; n = 22). All 44 patients received melphalan 200 mg/m2 with their first autograft and 32 patients proceeded to a second transplantation. RESULTS Group 2 required a significantly longer time interval for completion of PBSC collection than group 1 (median, 22 v 8 days; P = .0001), greater frequency of hospitalization (100% v 32%; P = .0001), and increased transfusion of platelets (86% v 18%; P = .0001) and packed RBCs (86% v 55%; P = .02). Likewise, the incidence of fever and pneumonia/sepsis were higher in group 2 (P = .02 and P = .04, respectively). Surprisingly, despite greater CD34 cell quantities infused in group 2, median recovery times of granulocytes (both > 500/microL and 2,500/microL) and platelets (both > 50,000/microL and > 100,000/microL) were similar (all P > .7). Posttransplant toxicities were also similar. CONCLUSION Compared with HDCTX plus G-CSF, high-dose G-CSF alone is associated with lower morbidity, shorter duration of PBSC mobilization, and comparable hematopoietic recovery after transplantation, which should result in significant cost reduction. Considering the relatively limited antitumor activity of HDCTX (10% with > or = 50% tumor cytoreduction), PBSC mobilization with HDCTX should be limited to selected patients with persistent MM despite induction chemotherapy.

Salvage autologous or allogeneic transplantation for multiple myeloma refractory to or relapsing after a first-line autograft?

Forty-two patients allografted for multiple myeloma after not having attained at least a partial remission (n = 19) or after having experienced disease progression (n = 23) following one autograft were compared with 42 pair-matched controls who underwent salvage autotransplantation under identical conditions. Autografted controls were matched closely for albumin, C-reactive protein, creatinine, disease sensitivity, duration of standard therapy prior to the first transplant, Ig isotype, karyotype, LDH, and response to the first transplant, but, in comparison to allografted patients, were older, had higher β2-microglobulin, and had a shorter interval between the two transplants. The complete remission rate was 41% after allogeneic and 33% after autologous transplantation (P = NS). The 3-year probability of event-free survival was comparable for the two groups (25 ± 8% after autografting and 20 ± 8% after allografting). The 3-year probability of survival was significantly higher after autologous transplantation (54 ± 8% vs 29 ± 9%; P = 0.01). Twenty-one patients in the autograft group were alive 11–59 months (median 32) following the second transplant, while 15 patients in the allograft group were alive at 10–53 months (median 20). The 3-year probability of disease progression was significantly lower after allogeneic transplantation (31 ± 10% vs 72 ± 9%, P = 0.03). The 1-year probability of transplant-related mortality was significantly higher after allografting (43 ± 8% vs 10 ± 5%; P = 0.0001). We conclude that while autografting appears to be superior to allografting for salvage therapy of myeloma persisting or relapsing after one previous autotransplant in terms of overall survival, event-free survival is comparable due to significantly lower disease progression after allografting. Reduction in allograft-related toxicity can potentially improve the results of allogeneic transplantation significantly.

Anti-myeloma activity of pamidronate in vivo

Two patients with progressive myeloma were treated with pamidronate disodium every 2‐4 weeks. Pamidronate therapy resulted in a significant reduction of marrow plasmacytosis and plasma cell labelling index (PCLI), together with durable (20 months) stabilization of immunoglobulin (Ig) levels and an increase in bone mineral density in the first patient and >50% reduction in Ig levels and bone marrow plasmacytosis in the second. This, to our knowledge, is the first report of an anti‐myeloma effect of bisphosphonates in humans and provides evidence that a therapeutic intervention largely directed at the myeloma microenvironment may alter the natural history of the disease.

Feasibility and cost-effectiveness of outpatient autotransplants in multiple myeloma

This report summarizes 2 years experience in performing 336 autotransplant procedures in 251 consecutive patients with multiple myeloma, using high-dose melphalan at 200 mg/m2 in the context of a tandem transplant program. A total of 91 patients received 118 transplants as outpatients while the remaining 160 patients received 218 transplants as inpatients. Outpatients were more often younger, with better stem cell products, normal serum albumin and β-2-microglobulin levels as well as chemotherapy-sensitive disease compared to inpatients. There were no differences in hematopoietic recovery and non-hematologic toxicities between outpatient and inpatient transplant recipients. Post-transplant febrile neutropenia and most other post-transplant toxicities were managed successfully in an ambulatory setting. Although liberal criteria were developed for hospitalization of outpatients, including clinical parameters as well as patient desire and physician/nurse judgment, only 21% of outpatients required admission after transplantation. Median hospital stay for these outpatients was 9 days, while inpatients were hospitalized for a median of 15 days (P = 0.0001). After adjusting for differences in disease and host features, our study showed outpatient management resulted in significant financial savings due to lower pharmacy (42%), hospitalization (50%) and pathology/laboratory charges (36%). We conclude that outpatient transplants should facilitate access to myeloablative therapy, thereby improving complete remission rates and survival of myeloma patients.

Melphalan plus total body irradiation (MEL-TBI) or cyclophosphamide (MEL-CY) as a conditioning regimen with second autotransplant in responding patients with myeloma is inferior compared to historical controls receiving tandem transplants with melphalan alone

The role of more intense conditioning for second transplant was evaluated in myeloma patients achieving at least partial remission (PR) after first transplant with melphalan at 200 mg/m2. Forty-three patients received more intensive conditioning for the second transplant. Nineteen patients received cyclophosphamide 120 mg/kg along with melphalan 200 g/m2 (MEL-CY; group 1) while 24 patients received total body irradiation (1125 cGy) in conjunction with melphalan 140 mg/m2 (MEL-TBI; group 2). Forty-three matched control patients were identified from 450 patients receiving melphalan alone for second transplant (MEL200; group 3). Engraftment and toxicities were comparable among the groups with the exception of increased treatment-related mortality of 8% in group 2 compared to none in groups 1 and 3 (P = 0.07). Despite identical CR rates of 74, 71 and 70%, respectively, in groups 1, 2 and 3 (P = 1.0), event-free survival (median: 27, 15 and 61; P < 0.0001) and overall survival (median: 39, 25 and 76 months; P = 0.003) were significantly decreased in patients receiving more intensive conditioning (groups 1 and 2). Lymphocyte recovery, evaluated as a surrogate for immune recovery, was inferior in more intensively treated patients (groups 1 and 2 compared to group 3). Our findings suggest that more intense conditioning appears to have no benefit in patients responding to their first cycle of high-dose therapy and may even be detrimental in this setting. Bone Marrow Transplantation (2000) 25, 483–487.

Incidence and Impact of Light Chain Associated (AL) Amyloidosis on the Prognosis of Patients with Multiple Myeloma Treated with Autologous Transplantation

Little is known about the incidence of clinically occult AL amyloid in patients with multiple myeloma and its impact on prognosis of these patients. To address these issues, subcutaneous fat pad aspirates (SAFA) and bone marrow biopsies were evaluated for the presence of amyloid in a cohort of newly diagnosed patients with multiple myeloma prior to enrollment on a phase II study including tandem transplants. Organ directed biopsies were performed when clinically indicated. Presence of amyloid at > or = 1 site was noted in 32 patients (38%). SAFA was positive in 25 (31%), bone marrow in 8 patients (10%) and other organ sites in 7 patients. Patients with and without amyloid did not differ in disease characteristics, in particular no lambda predominance was observed in patients with amyloid. Event free survival (59+ vs 52 months; p = .9) and overall survival (59+ vs 66+ months; p = .9) were similar in both groups. Even the seven patients with symptomatic organ involvement with AL amyloid had a median overall survival of 38+ months. In conclusion, AL amyloidosis occurs more often than previously reported, but its presence does not influence the outcome of these patients after transplantation.

Preceding chemotherapy, tumour load and age influence engraftment in multiple myeloma patients mobilized with granulocyte colony-stimulating factor alone

Haematopoietic growth factors, especially granulocyte colony‐stimulating factor (G‐CSF), are frequently utilized alone for peripheral blood stem cell (PBSC) procurement to avoid the morbidity associated with high‐dose chemotherapy (HDT). Moreover, the cytotoxic agents used may not be the most optimal therapy for the malignancy. It also makes scheduling of apheresis easier. Factors having an impact on PBSC procurement and engraftment after HDT were analysed in 117 multiple myeloma patients mobilized with G‐CSF (10–16 µg/kg, median 12 µg/kg) alone using Cox regression analysis. A median of 6·2 × 106 CD34 cells/kg (range 0·6–34·1) were procured during leukapheresis and a median of 2·5 × 106 CD34 cells was infused after the first HDT (range 0·3–23·9). The only factor significantly affecting optimal PBSC procurement was duration of preceding conventional chemotherapy (P = 0·002). Granulocyte recovery was prompt in almost all patients, 75% of whom attained a granulocyte count of 0·5 × 109/l by day 13 (median 11, range 7–19). However, platelet recovery to both 20 × 109/l (median 12 d, range 8–50+) and 50 × 109/l (median 20 d, range 7–205+) varied widely. On univariate analysis, factors influencing platelet recovery were the number of CD34 cells/kg infused, age, β2‐microglobulin levels, response to preceding therapy, bone marrow plasmacytosis and duration of prior therapy. Factors attaining significance on multivariate analysis included number of CD34 cells/kg infused (P = 0·007), β2‐microglobulin levels (P = 0·0001), most probably representing disease load, and age (P = 0·002). Patients with high tumour burden, i.e. β2‐microglobulin levels > 2·5 mg/l, probably benefit from chemotherapy for mobilization both in terms of cytoreduction and adequate stem cell mobilization resulting in accelerated engraftment.

Tumour lysis syndrome complicating high‐dose treatment in patients with multiple myeloma

Tumour lysis syndrome (TLS), because of its low proliferative activity, is thought to only rarely complicate the treatment of patients with multiple myeloma. However, as more aggressive therapeutic approaches are increasingly used in the management of this disease, it is conceivable that clinicians will encounter this complication more frequently.

Collection of More Hematopoietic Progenitor Cells with Large Volume Leukapheresis in Patients with Multiple Myeloma

Reinfusion of mobilized peripheral blood stem cells (PBSC) after high dose chemotherapy accelerates hematopoietic recovery. Because of the relatively low content of hematopoietic progenitors in the peripheral blood even after mobilization, multiple leukapheresis procedures are necessary to reach the required target number of CD34 cells to ensure prompt engraftment post-transplantation. Our previous studies have shown that the highest proportions of hematopoietic progenitors cells (CD34) are collected during the first three days of apheresis, whereas peak levels of myeloma cells are observed during subsequent days. Therefore, large volume leukapheresis (LVL), defined as processing of greater than 3 blood volumes or a total of at least 15 liters, was explored in 23 myeloma patients, undergoing 91 procedures; 14 patients were mobilized with high dose cyclophosphamide (6g/m2) and hematopoietic growth factors and 9 with G-CSF only. CD34 yields were measured separately for the first and last two hours of collection. We observed no decrease in CD34 cells/kg during the last two hours of collection and when the LVL collections were compared to historical matched controls, mobilized with the same regimen, the median quantity of CD34 cells/kg/liter collected remained equivalent during all days of apheresis. When compared to G-CSF only, mobilization with high dose cyclophosphamide appeared to result in superior hematopoietic stem cell collections. Interestingly, the G-CSF group experienced a progressive decrease in platelets during consecutive days of LVL, while the opposite was seen in the cyclophosphamide group. LVL procedures were not associated with a higher complication rate than standard volume apheresis. We conclude that LVL procedures allow collection of more CD34 cell per session while not jeopardizing progenitor cell collections during subsequent sessions. Since more CD34 cells are collected, fewer days are required to attain the optimal target of progenitor cells. This should result in PBSC grafts with less tumor contamination.