Dispenzieri, Angela

Abstract Background: The measurement of monoclonal (M) protein in the serum and urine is critical for response assessment and disease evaluation in patients with multiple myeloma (MM). The serum free light chain (FLC) assay offers a new and sensitive method of assessing response to therapy. An important question that has not been adequately addressed is the correlation between 24 hour urine M protein levels and serum FLC measurements, and the extent to which response to therapy estimated using the FLC assay correlates with that assessed using the 24 hour urine M protein level. Methods: A total of 2194 sets of data, with simultaneous UPEP and serum FLC measurement, were studied. These included 752 unique patients, with individual patients having 1–23 paired assessments over time. FLC estimation was carried out using the serum FLC assay (Freelite; The Binding Site Limited, UK) performed on a Dade-Behring Nephelometer. Based on the established reference range, kappa/lambda FLC ratio <0.26 or >1.65 were defined as abnormal indicating the presence of monoclonal lambda and kappa FLC, respectively. The monoclonal light chain isotype was considered the involved FLC isotype, and the opposite light chain type as the uninvolved FLC type. The Urine M protein by UPEP was compared to the serum levels of the involved light chain using Spearman Rank Correlation. For comparisons in individual patients over time, those with at least 10 measurements each were studied. Results: The median involved FLC level in patients with an undetectable urine M protein was 2.3 mg/dl compared to 32.2 mg/dL among those with a detectable urine M protein (P<0.001). Among the 1676 points with an abnormal FLC ratio, only 75% had an M protein detected in the urine, P < 0.001. Conversely, among patients with a positive urine M-protein, 91% had an abnormal FLC ratio. When all the 2194 data points were considered together, there was a significant correlation between the urine M protein level and the FLC levels (FLC level calculated as the difference between involved and uninvolved levels), rho=0.763, P < 0.001. The correlation did not change when patients with a serum creatinine of over 2.5 were excluded. The correlation between FLC levels and urinary M protein can be affected by several factors such as renal function that will differ across patients. Therefore, we examined whether the correlation between the two variables is stronger when the variations introduced by inter-patient differences in the relationship between the two variables are eliminated. In order to do this, we studied individual patients on whom multiple data points over time were available. One patient who had the maximum number of paired assessments (23 pairs) of serum FLC level and urinary M protein; the correlation between the two variables over time was highly significant, rho 0.981, p<0.001. Similarly 26 other patients who had measurable urine M protein levels in whom 10 nor more paired observations over time were available, also showed significant correlations, rho, range 0.726–0.981, p<0.01. Conclusion: There is a significant correlation between urine M-protein and serum free light chain across patients and the correlation is stronger in individual patients in whom the effect of inter-patient variation in other confounding factors can be eliminated. These data if confirmed in a clinical trial setting would support the use of serum FLC levels instead of urinary M protein measurements to assess response to therapy.

Abstract INTRODUCTION Stem cell transplant has been increasingly used in the initial therapy of newly diagnosed systemic AL. Introduction of the free light chain assay has made it easier to quantify responses in patients with AL. It is unclear whether the goal of therapy should be a hematologic response or, as in multiple myeloma, a complete response. This paper addresses the impact of the degree of response on outcome. PATIENTS AND METHODS 282 consecutively transplanted patients are included in this analysis. None of the patients were excluded. There were 169 men (59%). 28% of the cohort have died. 69% had renal involvement, 51% cardiac involvement, 11% peripheral nerve involvement, 16% hepatic involvement. The median percentage of plasma cells at the time of transplant was 7. Echocardiographic analysis revealed a median septal thickness of 12 and a median ejection fraction of 65%. Patients ranged in age from 31 to 71 with a median of 57 years and were transplanted at a median of 4.2 months following histologic diagnosis of amyloidosis. 27% of patients received reduced intensity conditioning usually due to moderate cardiomyopathy or renal insufficiency. 201 patients achieved a hematologic response and 93 of these achieved a complete response. The criteria for response were reported in accord with the consensus definition for response established at The Xth International Symposium on Amyloid and Amyloidosis. A complete response required immunofixation negativity of serum and urine with a normal free light chain ratio. A hematologic objective response required a 50% reduction of serum and urine monoclonal protein with a 50% reduction in the free light chain value. Figure 1 shows the Kaplan Meier curves demonstrating the survival of all patients based on whether they achieved a complete response, partial response, or failed to achieve response. There were 93 CR, 108 PR, and 81 nonresponders. The differences in all three curves are significant at P<.001. Figure 2 demonstrates the same cohort of patients using a six month landmark analysis to exclude the effect of treatment related mortality on outcome. There were 86 CR, 91 PR, and 36 NR for a total of 213 patients. There was a difference in response rate based on conditioning intensity (p<0.01) and age (p=0.046). The median survival was only reached in the NR at 40.1 months and, in the landmark analysis the differences between all three survival curves were statistically significant. CONCLUSION Patients who achieve a hematologic complete response following sct for AL do better than other patients. Patients who achieve an objective response have a superior outcome than patients who fail to achieve a hematologic response, in a landmark analysis at six months. It is unclear if consolidation chemotherapy should be offered to partial responders in an attempt to convert them into CR’s. Figure Figure Figure Figure

Abstract Fluorescence in situ hybridization (FISH) is an effective alternative for the analysis of cytogenetic abnormalities of low proliferative entities such as Waldenström macroglobulinemia (WM) but, to date, no studies have been carried out to explore the potential impact of molecular cytogenetics on disease evolution. Deletion of the long arm of chromosome 6 (6q-) is the most frequent cytogenetic abnormality in WM. In this study we have analyzed the incidence of this aberration (using both conventional cytogenetics and FISH analysis) in 102 WM patients, and we have correlated it with disease characteristics. Deletion of 6q21 was detected in 6% of patients by conventional cytogenetics, while FISH studies increased this incidence up to 39%. Moreover, in those patients analyzed by cIgM-FISH, the incidence of 6q- was higher (54%). Interestingly, 6q- patients displayed features associated with adverse prognosis (higher levels of ESR, CRP and beta-2 microglobulin), and a greater tendency to display anemia and hypoalbuminemia. Other differentiating variables without reaching statistical significance were a tendency of displaying a higher bone marrow lymphoplasmacytoid infiltration and the amount of monoclonal component in 6q- patients (table). In addition, patients with 6q- displayed shorter survival from time of diagnose (log-rank; p=0.09). In summary, our results show that 6q deletion in WM patients is currently the most frequently found cytogenetic abnormality. Patients with this deletion also shows a trend towards an aggressive disease and poorer outcome in WM. Further studies should focus on possible tumor suppressor genes in the minimal area of deletion at 6q and to determine their role in disease progression. table del6q present del6q absent p-value n 40 (39%) 62 (61%) β2M ≥4mg/dL 48% 16% 0.005 CRP ≥3.5 mg/dL 47% 11% 0.006 Albumin <4mg/dL 86% 55% 0.006 ESR ≥100 mm/h 73% 44% 0.02 Hb <11 g/dL 63% 40% 0.02 serum IgM >20 g/L 86% 73% 0.10 BM infiltration >40% 44% 31% 0.20

Abstract AMD3100, a CXCR4 receptor antagonist, has been studied as a stem cell mobilization agent for the purpose of autologous stem cell transplantation (ASCT) in hematologic malignancies. Lymphocyte subset analysis of peripheral blood in patients treated with AMD3100 has been studied in healthy volunteers. To date, no reports exist describing the lymphocyte subsets of the autograft in patients undergoing AMD3100 stem cell mobilization for the purposes of ASCT in non-Hodgkin lymphoma (NHL). Considering our prior work demonstrating the significant impact of autograft lymphocyte content on clinical outcomes of patients undergoing ASCT for NHL we set out to profile autograft lymphocyte subsets of patients undergoing mobilization with AMD3100. Using flow cytometry, we analyzed aliquots of apheresis products in 7 patients with NHL undergoing AHSCT who received AMD3100 in addition to G-CSF as a part of their mobilization regimen. These results were compared to 29 patients with NHL who had undergone stem cell mobilization with G-CSF alone. There were no significant differences between these two groups of patients in terms of sex, age, performance status, histology, LDH, and number of pretransplant chemotherapeutic regimens. CD34+ cells collected at apheresis did not differ significantly between the groups. However, compared with G-CSF alone, patients that received AMD3100 had an approximate 5-fold increase in CD4+ cells (0.62 x 109 cells/kg vs. 0.12 x 109 cells/kg, p = 0.0004), a 3.5-fold increase in the absolute number of autograft CD3+ cells (1.21 x 109 cells/kg vs. 0.33 x 109 cells/kg, p = 0.0017), and a 2.5-fold increase in CD8+ cells (0.48 x 109 cells/kg vs 0.19 x 109 cells/kg, p = 0.215). A significant increase was also noted in CD4+25+ cell compartment (0.17 x 109 cells/kg vs. 0.006 x 109 cells/kg, p = 0.0001). No significant difference was noted in the absolute number of autograft CD16+56+ NK cells. Finally, an increase in the autograft total absolute lymphocyte count (41.6 x 109 cells/kg vs. 2.88 x 109 cells/kg, p < 0.001) as well as peripheral blood absolute lymphocyte count at day 15 after AHSCT was observed in those patients who had received AMD3100 (0.79 x 109 cells/kg vs. 0.58 x 109 cells/kg, p = 0.04). The increased lymphocyte content of the autograft (total and subset) would suggest the potential of positive impact on clinical outcomes in patients mobilized with AMD3100. Indeed, none of the patients who received AMD3100 had relapsed disease at one year post-transplant (although two of these patients are currently 9 months and 11 months post-transplant respectively), whereas 10 of the 29 control patients had relapsed disease at one year. Further studies are necessary to confirm these observations and ascertain their clinical significance.

Abstract Background: While the therapeutic armamentarium for plasma cell disorders have expanded recently with introduction of thalidomide, lenalidomide and bortezomib, these diseases are still incurable and more agents are needed. We have previously demonstrated expression of CD 52 on plasma cells in MM, MGUS and AL amyloidosis. Based on this data we conducted a Phase II Study of Campath (Alemtuzumab; Monoclonal Anti-CD52 Antibody) in Primary Systemic Amyloidosis and Relapsed or Refractory Multiple Myeloma. Methods: The study was an IRB approved, Phase II protocol, with a two stage design and interim analysis at 14 patients, to assess the efficacy and toxicity of Alemtuzumab. The regimen involved a dose escalation during week one (Day I 3 mg SQ; Day II 10 mg SQ; Day III 30 mg SQ; then 30 mg SQ three times a week for a planned total of 17 additional weeks). All patients received concurrent Co-Trimoxazole, Fluconazole and Valacyclovir prophylaxis. The planned accrual was 32 patients. Results: A total of 14 patients were accrued, 8 patients with MM and 6 patients with AL. There were 8 females and 6 males in the study. The median age was 62 years (range: 50–78) years. The patients were heavily pretreated with the median number of treatments being 4. There were 5 grade 3–4 toxicities (CMV viremia (2 pts), skin rash (2 pts), and febrile neutropenia (1 pt)). Seven patients had evidence of disease progression and were removed from study. One patient completed the treatments with a mixed response. One patient had a sudden death while on study. The median duration of therapy was 6 weeks (range 3 weeks to 17 weeks). The accrual was stopped after 14 patients when the interim analysis showed a lack of anti-tumor efficacy and significant toxicity. Conclusion: This phase II study in patients with relapsed / refractory myeloma or amyloidosis demonstrated no evidence of clinical activity with use of Campath. In addition it was also associated with significant toxicity in this population. We do not recommend use of campath as a primary treatment modality in these patients. The lack of efficacy despite demonstrated expression of CD52 on clonal plasma cells once again highlights the need for combining treatments with multiple mechanisms in order to improve the response and outcome in these patients. Whether it can synergize with other therapies at lower doses without significant toxicity remains unknown.

Abstract Background: We reported a high response rate with the combination of lenalidomide plus dexamethasone (Rev/Dex) as initial therapy for newly diagnosed multiple myeloma (Blood2005;106:4050–3). We now present new data on time to progression (TTP), progression free survival (PFS), and overall survival (OS) from this phase II trial, and also include updated response data. Patients and Methods: 34 patients (23 male and 11 female) were enrolled. Lenalidomide was given orally 25 mg daily on days 1–21 of a 28-day cycle. Dexamethasone was given orally at a dose of 40 mg daily on days 1–4, 9–12, 17–20 of each cycle. Patients were allowed to go off treatment after 4 cycles of therapy to pursue autologous stem cell transplantation (SCT), but treatment beyond four cycles was permitted at the physician’s discretion. For patients continuing therapy beyond 4 months, the dose of dexamethasone was reduced to 40 mg on days 1–4 of each cycle. Response was assessed by modified EBMT/International Myeloma Working Group Uniform Response criteria. All patients received aspirin (81 mg or 325 mg daily) as prophylaxis against DVT. Results: The median age was 64 years (range, 32–78). All patients were evaluable for response and toxicity. Median follow up is 21 months. Thirteen patients proceeded to SCT following initial therapy with Rev/Dex and were censored at that time point for purposes of calculation of response, TTP and PFS. Patients who discontinued therapy to proceed to SCT received a median of 4 cycles of therapy (range, 4–13), while those staying on Rev/Dex (n=21) received a median of 19 cycles of therapy (range, 2–30). Thirty-one of 34 patients (91%) achieved an objective response to therapy; including 6 patients (18%) achieving a complete response (CR) and 13 patients (38%) achieving very good partial response for a CR+VGPR rate of 56%. The CR+VGPR rate among the 21 patients staying on Rev/Dex as primary therapy without SCT was 67% (CR 24%, VGPR 43%). Median TTP, PFS, and OS have not been reached (Figure). By Kaplan-Meier method, the estimated 2 year progression rate was 18%. The 2-year PFS rate and OS rate were 74% and 91%, respectively. Fifty-five percent of patients experienced grade 3 or higher non-hematologic toxicity at any point during therapy, most commonly fatigue (21%), neutropenia (21%), anxiety (6%), pneumonitis (6%), muscle weakness (6%), and rash (6%). Two patients died on study: one attributed to infection unrelated to therapy, the patient had stopped all therapy for over a month before the fatal infection occurred; the other death was due to infection felt possibly related to therapy. One patient developed a pulmonary embolism (grade 4 toxicity), but recovered with therapy; no other patient developed deep vein thrombosis or pulmonary embolism. Conclusion: Rev/Dex is highly active and well tolerated in the treatment of newly diagnosed multiple myeloma with a high CR+VGPR rate of 56% for the trial, and 67% among the subset of patients receiving this regimen as primary therapy. Responses are durable with a low progression rate at 2 years.

Abstract Introduction: Stem cell transplant is an increasingly widely applied technique for managing amyloidosis. As in multiple myeloma, the treatment would not be expected to be curative and patients would be expected to relapse in most instances. In addition, approximately one-third of patients fail to respond to initial therapy. The role of second transplantation in treatment failures or patients who relapse is reviewed. Patients: Of 242 patients undergoing high dose conditioning and stem cell transplantation for amyloidosis (AL) at the Mayo Clinic, 6 subsequently underwent a second transplant. Results: Patient 1, who had single organ renal amyloid nephrotic syndrome responded and relapsed at 73 months, received a second stem cell transplant achieving a hematologic complete response with normalization of a markedly elevated pre transplant free light chain (59 to 1.9 mg/dL) and is alive at 12 months. Patient 2 relapsed 42 months after transplant for single organ renal amyloidosis; the second stem cell transplant, has normalized his free light chain ratio reduced his urinary protein loss from 5450 to 1482 mg/day and he is alive 21 months following his second transplant (63 months overall). Patient 3 relapsed 34 months after a response of renal and cardiac amyloidosis. After transplant two, he failed to achieve a 50% reduction in his free light chain, began hemodialysis 7 months post transplant and died one year post transplant. Patient 4 with single organ cardiac involvement relapsed 30 months following his first transplant and died on day +5 of his second transplant of an acute pulmonary embolus. Patient 5 was a response failure after his first transplant, had a second transplant 35 months later, having failed Dexamethasone followed by Melphalan/Dexamethasone therapy, and died 3 months later of progressive disease. Patient 6 had single organ vascular involvement manifest by calf and thigh claudication and failed to respond with his first transplant with a persistently elevated free light chain. The second transplant was performed six months after the first without further free light chain reduction and persistent claudication at 11 months. Conclusion: Patients who failed to achieve a hematologic response after a first transplant appear not to benefit from a second course of high dose therapy. Among 4 patients who were previously responsive and relapsed, one achieved a hematologic complete response, one achieved a hematologic partial response, and two died. The two patients achieving a second hematologic response had the longest response duration (73 and 42 months) following their first transplant, and the second response presumably reflects favorable (indolent; non proliferative) biology of the underlying plasma cell dyscrasia. High dose therapy and stem cell transplant may be an effective salvage regimen for patients who responded to a first transplant and whose response lasted greater than 36 months.

Abstract Background: Overall prognosis in CMML is unfavorable. The only curative option is ASCT, yet the limited data available from the largest reported series, reports 2 year overall (OS) and disease free (DFS) survival of only 21% and 18%, respectively [Kroger et al, BJH 2002, 118: 67]. Data on DLI for CMML are generally restricted to case reports. We retrospectively reviewed our experience of ASCT and DLI for adults with CMML. Patients: Seventeen consecutive patients (11 males) with CMML underwent ASCT from 1992 to 2004. At transplant, median (range) age was 50 years (26–60), duration of disease 7 months (2.5–44), and bone marrow (BM) blast count 6% (1–58%). Prior to transplant, 11 had evolved into acute myeloid leukemia (AML). Of these, 10 received standard induction chemotherapy but only one achieved complete remission (CR); 5 had persistent CMML and 4 refractory AML. Karyotype at transplant was either normal (n=9) or revealed isolated monosomy 7 (n=4), complex (n=1), or single, nonrecurrent abnormalities. ASCT: Conditioning was Cytoxan/Total Body Irradiation in all but one who received a non-myeloablative (NMA) regimen (cladrabine/ATG/thiotepa). Stem cell source was HLA-identical sibling in 14 patients and unrelated in 3 peripheral blood (PB) in 7, BM in 8, or both in 2. Median BM mononuclear cell/kg dose was 2.3 (1.7–4.15) x 108 and PB CD34 cell/kg was 5.12 (0.94–7.29) x 106. Graft versus host disease (GVHD) prophylaxis was cyclosporin alone (n=3), with methotrexate (n=12), or prednisone (n=1) or was tacrolimus/methotrexate (n=1). Post-transplant course: All but one patient who died on day 11 of sepsis engrafted (sustained ANC > 500) at a median of 19.5 days (13–31). CR was documented in 13 (76%) post-ASCT. Acute GVHD was grade II-IV (75%) and III-IV (37.5%) and chronic GVHD was extensive (n=37.5%). Seven (41%) demonstrated relapse or persistent disease at a median of 6 months (3–55.5) and 13 (76%) have died due to disease (n=6) or transplant related mortality (n=7). DLI: Six patients underwent DLI for morphologic (4 recurrent/persistent CMML, 1 early AML with extramedullary disease) or cytogenetic relapse (n=1), at a median of 19.5 days (6–52) post-relapse. Median BM blast count at DLI was 3% (1–22%). The median CD3+ cell dose infused was 30.45 x 107 cells/kg (11.2–45.5), given in a median of 3 infusions (range: 1–3). Four did not respond, but two (one with cytogenetic and one with morphologic relapse) achieved a durable CR of 15 months each, both had extensive CGVHD, from which one died of complications. The other relapsed but failed to respond to a second DLI and died of disease. Survival: For the entire cohort, median DFS and OS were 6 months and 7 months, respectively. At last follow up, 4 remain alive, 3 in continuous CR (18%), at 12, 29 (treated with the NMA regimen) and 116 months, respectively. Of the 3 patients surviving in remission, all had transformed to AML prior to ASCT and only one had achieved CR following induction chemotherapy. Multivariate analysis failed to demonstrate any significant effect of age, duration of disease, BM blast %, karyotype or induction chemotherapy on RFS or OS, likely reflecting the small numbers available for analysis. Conclusion: The current study demonstrates anti-CMML activity of both ASCT and DLI although overall outcome is less than encouraging and unpredictable. Novel approaches are needed.

Abstract Patients with multiple myeloma (MM) who undergo high dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) and achieve a complete response (CR) have a superior overall survival (OS) and time to progression (TTP). Thus achieving a CR is an important goal of therapy with ASCT. Cyclophosphamide has significant activity against MM and is often used in high doses prior to ASCT for mobilization of hematopoietic stem cells. We hypothesized that high dose cyclophosphamide (HDC) may further improve CR rates in patients undergoing ASCT. Methods: The Mayo Clinic myeloma transplant database was searched for patients without circulating myeloma cells who had stem cell mobilization with hematopoietic growth factor (HGF) alone or HDC followed by HGF. Relevant demographic, clinical and laboratory characteristics were abstracted. The main outcome studied was the impact of HDC on CR rates and time to progression (TTP) to myeloma. Results: We identified 201 patients without circulating myeloma cells. Of these, 127 were mobilized with HDC and HGF and 74 with HGF alone. The two cohorts were similar with respect to age, gender, isotype, B2M, plasma cell labeling index, cytogenetics, conditioning regimen, disease status at time of transplant with no statistically significant differences between the two cohorts. CR rates were 37.4 and 41.3% (p=0.6115) for patients mobilized with HDC/HGF and HGF respectively. TTP was 19.9 and 17.6 months (p=0.6039) respectively. The median number of collection sessions for patients mobilized with HDC/HGF was 2 (1–10) and those mobilized with HGF was 4 (1–10) (p<0.0001). In a multivariate analysis for TTP, cytogenetics and achieving a CR were the only independent variables (p=0.0012 and p<0.0001). Conclusion: HDC for autologous hematopoietic stem cell collection reduces the number of collections necessary to support HDT/ASCT. However, HDC does not increase CR rates or improve on TTP for patients undergoing ASCT.

Abstract Smoldering multiple myeloma (SMM) is characterized by a serum M protein ≥ 3g/dL and/or 10% or more of plasma cells in the bone marrow. However, the definition is not standardized, and it is not known whether both serum M protein levels and bone marrow plasma cell counts are necessary for diagnosis or if one parameter is sufficient. We reviewed the medical records and bone marrows of all patients from Mayo Clinic seen within 30 days of recognition of an IgG or IgA M protein ≥ 3g/dL or a bone marrow containing ≥ 10% plasma cells from 1970 to 1995. This allows for a minimum potential follow-up of 10 years. Patients with end-organ damage at baseline from plasma cell proliferation, including active multiple myeloma (MM) and primary amyloidosis (AL) and those who had received chemotherapy were excluded. A differential of the bone marrow aspirate coupled with the bone marrow biopsy morphology and immunohistochemistry using antibodies directed against CD138, MUM-1 and Cyclin D1 were evaluated in every case in order to estimate the plasma cell content. In all, 301 patients fulfilled either of the criteria for SMM. Their median age was 64 years and only 3% were less than 40 years of age; 60% were male. The median hemoglobin value was 12.9 g/dL; 7% were less than 10 g/dL, but the anemia was unrelated to plasma cell proliferation. IgG accounted for 75%, IgA 22%, and biclonal proteins were found in 3%. The serum light-chain was κ in 67% and λ in 33%. The median serum M spike was 2.9 g/dL; 11% were at least 4.0 g/dL. Uninvolved serum immunoglobulins were reduced in 81%; only 1 immunoglobulin was reduced in 31% and both were decreased in 50%. The urine contained a monoclonal κ protein in 36% and λ in 18% and 46% were negative. The median size of the urine M spike was 0.04 g/24h; only 5 (3%) were > 1 g/24h. The median bone marrow plasma cell content was 15 – 19%; 10% had less than 10% plasma cells, while 10% had at least 50% plasma cells in the bone marrow. Cyclin D-1 was expressed in 17%. Patients were categorized into 3 groups: Group 1, serum M protein ≥ 3g/dL and bone marrow containing ≥ 10% plasma cells (n= 113, 38%); Group 2, bone marrow plasma cells ≥ 10% but serum M protein < 3g/dL (n= 158, 52%); Group 3, serum M protein ≥ 3g/dL but bone marrow plasma cells < 10% (n= 30, 10%). During 2,204 cumulative years of follow-up 85% died (median follow-up of those still living 10.8 years), 155 (51%) developed MM, while 7 (2%) developed AL. The overall rate of progression at 10 years was 62%; median time to progression was 5.5 yrs. The median time to progression was 2.4, 9.2, and 19 years in groups 1, 2, and 3 respectively; correspondingly at 10 years, progression occurred in 76%, 59%, and 32% respectively. Significant risk factors for progression with univariate analysis were serum M spike ≥ 4g/dL (p < 0.001), presence of IgA (p = 0.003), presence of urine light chain (p = 0.006), presence of λ urinary light chain (p = 0.002), bone marrow plasma cells ≥ 20% (p < 0.001) and reduction of uninvolved immunoglobulins (p < 0.001). The hemoglobin value, gender, serum albumin, and expression of cyclin D-1 were not of prognostic importance. On multivariate analysis, the percentage of bone marrow plasma cells was the only significant factor predicting progression to MM or AL.