The t(4;14)(p16.3;q32) is strongly associated with chromosome 13 abnormalities in both multiple myeloma and monoclonal gammopathy of undetermined significance.
Explore the source record for details and available documents.
Chromosome Aberrations↗
Biomedical subjects
P R Greipp
Publications and source records attributed to P R Greipp.
Eligibility for hematopoietic stem-cell transplantation for primary systemic amyloidosis is a favorable prognostic factor for survival.
PURPOSE: Based on the success of hematopoietic stem-cell transplantation (HSCT) for multiple myeloma, HSCT is being used to treat patients with primary systemic amyloidosis (AL). This article addresses the extent to which eligibility to undergo HSCT is a favorable prognostic feature and explores prognostic factors within the subset of eligible patients. PATIENTS AND METHODS: The Mayo Clinic amyloid database was queried for all patients with AL seen at the Mayo Clinic from 1983 through 1997 who would have been eligible for peripheral-blood stem-cell transplantation. Inclusion criteria included biopsy-proven amyloid, symptomatic disease, absence of a clinical diagnosis of multiple myeloma, age < or = 70 years, cardiac interventricular septal thickness < or = 15 mm, cardiac ejection fraction more than 55%, serum creatinine < or = 2 mg/dL, and direct bilirubin < or = 2.0 mg/dL. RESULTS: Median age was 56 years (range, 25 to 70) with 79 (34%) older than 60 years. One hundred patients had early cardiac involvement; 41, hepatic involvement; 167, renal involvement; and 39, nerve involvement. The 229 patients have had a median follow-up of 52 months, and 151 have died. The median survival was 42 months with 5- and 10-year survival rates of 36% and 15%, respectively. Important predictors of survival were size of M-component in 24-hour urine, number of involved organs, alkaline phosphatase, performance score, and weight loss. CONCLUSION: The same patients who are eligible for HSCT are a good-risk population who do relatively well with chemotherapy (median survival, 42 months), substantially better than the expected median survival of 18 months for all patients with AL. A randomized trial is needed to assess the true effect of HSCT.
Adult↗
Blood levels of immune cells predict survival in myeloma patients: results of an Eastern Cooperative Oncology Group phase 3 trial for newly diagnosed multiple myeloma patients.
Previously, it was reported that patients with multiple myeloma (MM) who have higher baseline levels of blood CD4(+) or CD19(+) cells have longer survival. This article extends the analysis of immune cell levels and survival in a large cohort (N = 504) of patients with MM entered on Eastern Cooperative Oncology Group (ECOG) phase 3 trial (9486). Newly diagnosed patients with MM received 2 cycles of vincristine, bischloroethylnitrosourea, melphalan, cytoxan, prednisone (VBMCP) and were treated on one of 3 randomized arms: VBMCP with either interferon or high-dose cyclophosphamide, or VBMCP alone. Blood immune cell levels were studied at trial entry (baseline), after 2 cycles of chemotherapy, after 2 years of therapy, and at relapse. Baseline CD3(+), CD4(+), CD8(+), CD19(+), and CD4(+) subset cell levels were all positively associated with survival (P =.0087 to P <.0001). A multivariate analysis incorporating CD4(+) and CD19(+) cell levels defined 3 separate groups of patients with MM to survival outcome. Higher CD19(+) blood levels were positively associated with MM-patient survival at entry to the study, at year 2, and at relapse (P <.0001 at all 3 timepoints). Patients with MM had evidence of immune cell reconstitution after 2 years of therapy, but the rate and extent of recovery was greater for CD8(+), which was greater than CD4(+), which was greater than CD19(+). This latter data affirms the positive relationship between the quantitative status of the blood immune system in MM and survival. In addition, the importance of the CD19(+) blood cells to survival is evident throughout the course of MM. Therapeutic efforts to maintain an intact immune system may be crucial in maximizing chemotherapeutic and/or immunotherapy efforts in this disease.
Actuarial Analysis↗
A high bone marrow plasma cell labeling index in stable plateau-phase multiple myeloma is a marker for early disease progression and death.
The plasma cell labeling index (PCLI) is a measure of plasma cell proliferative activity and is an important prognostic factor in newly diagnosed multiple myeloma (MM). Occasionally patients have been observed with stable, plateau phase MM with minimal numbers of residual light-chain-restricted monoclonal plasma cells, but a high PCLI. No data are available on the outcomes for such patients. Data from 57 patients with plateau phase MM and a marrow PCLI of more than 1.0% were compared with 105 matched control patients with MM with a marrow PCLI of less than 1.0%. All patients had less than 10% total plasma cells on marrow aspirate and biopsy. The median time to progression and overall survival were 8 months and 20 months, respectively, in the high PCLI group versus 39 months and 56 months, respectively, in the low PCLI group (P < .0001). These findings suggest that a high PCLI in patients with apparently stable, plateau phase MM is an adverse parameter that may predict a short time to disease progression and death.
Bone Marrow↗
Methods for estimation of bone marrow plasma cell involvement in myeloma: predictive value for response and survival in patients undergoing autologous stem cell transplantation.
In myeloma, the bone marrow plasma cell percentage (BMPC%) is usually estimated independently on the aspirate, core biopsy, and plasma cell labeling index (PCLI) samples. This study was done to determine which of the 3 individual estimates correlates best with complete response (CR) and survival. Seventy-five consecutive patients who underwent SCT for relapsed myeloma were studied. The median BMPC% on the marrow aspirate, core biopsy, and PCLI studies were 20, 25, and 20, respectively. There was a significant correlation between the three methods, rho > 0.65, P < 0.001. However, in 8% of patients the BMPC% was different by an absolute value of 50% between methods. No individual method was predictive for CR. However, the highest estimate of the BMPC% among the three methods was a significant predictor of CR (P = 0.02). Survival following SCT was longer among patients with a low BMPC% (< or =60) by the PCLI method compared to those with higher values, median survival 23 versus 7 months, respectively, P = 0.02. PFS was also different, with survival times of 11 and 5 months, respectively, P = 0.003. Similar results were obtained when the highest estimate of the BMPC% was used in survival analysis (P = 0.02 and 0.004, respectively). Statistical significance was lower when the BMPC% on the aspirate or biopsy used in survival analysis. Compared to any individual method of estimating BMPC%, the highest estimate of the BMPC% is the best predictor of CR in myeloma. It is also prognostic for poor survival and PFS following SCT for myeloma. We recommend that all three methods of estimating BMPC% be routinely performed and that the highest value be used for prognostic purposes.
Adult↗
Deletions of chromosome 13 in multiple myeloma identified by interphase FISH usually denote large deletions of the q arm or monosomy.
Deletions of the long arm of chromosome 13 (13q-) are observed in patients with multiple myeloma (MM), are rarely observed in the monoclonal gammopathy of undetermined significance (MGUS) and have been associated with a worsened prognosis in MM. However, no minimally deleted region in the 13q arm has been defined at 13q, and consequently no tumor suppressor genes have yet been identified that are important for disease pathogenesis. We attempted to characterize these chromosome 13q deletions at the molecular cytogenetic level. We studied 351 newly diagnosed patients, entered into the E9486/E9487 clinical study of the Eastern Cooperative Oncology Group. Fluorescent in situ hybridization (FISH) combined with immune fluorescent detection (cIg-FISH) of clonal plasma cells (PC) and cytomorphology were used to analyze interphase, bone marrow (BM) cell, cytospin slides. We simultaneously used DNA probes for the following locus specific probes (LSI); LSI 13 (Rb) and D13S319, which hybridize to 13q14. We subsequently studied distal deletions using the D13S25 probe (13q14.3) and a subtelomeric probe (13qSTP) for the 13q-arm (D13S327) in 40 cases with documented LSI 13 (Rb)/D13S319 deletion and 40 without deletion of these loci. Of 325 evaluable patients, we found 13q deletions in 176 (54%) using LSI 13 (Rb) and D13S319 probes. Of 40 patients with LSI 13 (Rb)/D13S319 deletions, 34 (85%) had coexistent deletion of both D13S25/13qSTP. These results indicate that chromosome 13 deletions in MM involve loss of most if not all of the 13q arm perhaps even indicating monosomy. In six cases the 13qSTP signal was conserved, but D13S25 was lost indicating large interstitial deletions involving 13q14. In 39 of the 40 cases without LSI 13 (Rb)/D13S319 deletions, the normal pattern of two pairs of signals was observed for D13S25/13qSTP. Deletions involving 13q14 are very common in MM as detected by cIg-FISH. These deletions appear to predominantly involve loss of large segments of the 13q arm or monosomy 13, and only occasionally represent an interstitial deletion.
Adult↗
Thalidomide for previously untreated indolent or smoldering multiple myeloma.
We conducted a clinical trial of thalidomide as initial therapy for asymptomatic smoldering (SMM) or indolent multiple myeloma (IMM). Sixteen patients were studied. Thalidomide was given orally at a dose of 200 mg/day for 2 weeks, and then increased as tolerated by 200 mg/day every 2 weeks to a maximum dose of 800 mg/day. Bone marrow microvessel density (MVD) and angiogenesis grading were estimated using CD34 immunostaining. Six patients had a confirmed response to therapy with at least 50% or greater reduction in serum and urine monoclonal (M) protein. When minor responses (25-49%) decrease in M protein concentration) were included, 11 of 16 patients (69%) responded to therapy. Major grade 3-4 toxicities included two patients with somnolence, and one patient each with syncope and neutropenia. Pre-treatment MVD was not a significant predictor of response to therapy, median MVD 4 and 12 in responders and non-responders respectively, P = 0.09. We conclude that thalidomide has significant activity in the treatment of newly diagnosed SMM/IMM. However, we do not recommend treatment with thalidomide at this stage since some patients with SMM/IMM can be stable for several months or years without any therapy. Additional randomized trials are needed to determine if thalidomide will delay progression to active multiple myeloma.
Administration, Oral↗
Angiogenesis in multiple myeloma.
Explore the source record for details and available documents.
Antibodies, Monoclonal↗
Laboratory correlates in multiple myeloma: how useful for prognosis?
Explore the source record for details and available documents.
Clinical Laboratory Techniques↗
Smoldering, asymptomatic stage 1, and indolent myeloma.
Of patients presenting with multiple myeloma, 5% to 15% satisfy criteria for the diagnosis of multiple myeloma but have no or minimal symptoms and do not require chemotherapy (NRC). These patients are classified as having smoldering, asymptomatic stage 1, or indolent multiple myeloma in order of their increasing risk of progression. We avoid chemotherapy, especially with alkylating agents in such patients, and we either closely monitor them or use a nonchemotherapeutic intervention. If significant bone lesions, renal failure, or hypercalcemia occur, chemotherapy or transplant is recommended. Patients with mild anemia or with small or isolated bone lesions who are asymptomatic or minimally symptomatic because of anemia may be monitored and are classified as having indolent multiple myeloma. Unnecessary treatment with melphalan or cyclophosphamide probably has no benefit in multiple myeloma NRC and can cause significant risk. In long-term follow up, 25% of patients receiving alkylating agents develop myelodysplastic syndrome or acute leukemia. Patients who do not receive chemotherapy must be monitored closely to avoid complications of overt multiple myeloma, including anemia, bone lesions, renal failure, and hypercalcemia. We and others have begun to take a more active approach with the use of nonchemotherapeutic agents in selected patients. We use bisphosphonates in patients with bone lesions or osteoporosis or when there is a progressive rise in M-protein. We use dexamethasone alone in NRC multiple myeloma to reduce tumor burden in selected patients who do not yet have overt multiple myeloma or who are not candidates for chemotherapy. We use bisphosphonates to prevent osteoporosis in such patients. We use erythropoietin to correct anemia, and dexamethasone and erythropoietin together in patients with higher tumor burden (eg, indolent multiple myeloma). Future progress in treating multiple myeloma NRC depends on better identification of new therapeutic targets that control progression from the stable asymptomatic to the progressive symptomatic phase of multiple myeloma. We need to better understand the biologic target of new agents like thalidomide to design more effective treatment for this early phase of multiple myeloma. Although these approaches may delay chemotherapy, it is not known whether survival is prolonged. Nonchemotherapeutic approaches must be systematically studied in clinical trials in order to be put to better use.
Alkylating Agents↗
Delayed stem cell transplantation for the management of relapsed or refractory multiple myeloma.
The optimal timing of stem cell transplantation for multiple myeloma is controversial. Late stem cell collection is undesirable because of the inability to mobilize stem cells. We report on 64 recipients of stem cells collected within 1 year after diagnosis, none of whom had transplantation in plateau phase of their disease. Patients seen within 12 months after diagnosis received four cycles of standard vincristine, doxorubicin, and dexamethasone (VAD) chemotherapy and then had stem cells mobilized. Patients were then placed on maintenance vincristine, BCNU, melphalan, cyclophosphamide, and prednisone or melphalan and prednisone chemotherapy for 12 cycles. At the sign of first progression, transplantation occurred. Fourteen patients were refractory to VAD chemotherapy, 20 relapsed on maintenance chemotherapy, and 30 relapsed off chemotherapy. The time to platelet engraftment was not affected by the duration of stem cell cryopreservation or extent of chemotherapy exposure after mobilization. The complete response rate was 34%. The actuarial median survival from initial diagnosis, from transplant day 0, and post-transplant progression-free survival was 51, 20 and 11.4 months, respectively. The patient status at transplantation and percentage of plasma cells circulating in the blood at apheresis influenced post-transplant survival; circulating plasma cells, status at transplantation and plasma cell labeling index influenced progression-free survival. Response duration was shorter in patients relapsing on chemotherapy.
Adult↗
Effect of complete response on outcome following autologous stem cell transplantation for myeloma.
We studied the effect of complete response (CR) among 126 consecutive patients who underwent stem cell transplantation (SCT) for myeloma. The CR rate with SCT was 33%. Median overall survival (OS) from diagnosis of myeloma was 56 months. OS following SCT was 22 months. Progression-free survival (PFS) was 12 months. OS was not different between patients who achieved CR and those who did not, median survival 25 vs 24 months, P = 0.5. Corresponding median times for PFS were 15 and 11 months, P = 0.2. The plasma cell labeling index (PCLI) was high (> or = 1%) in 36% (high risk group) and was associated with poor OS and PFS (P < 0.001). Achieving CR did not influence OS or PFS in either the high or the low risk group. In contrast, OS and PFS were significantly influenced by high PCLI both in patients who achieved CR and those who did not. OS was poor (< 30 months) in high risk patients regardless of CR status and in low risk patients who did not achieve CR, compared to low risk patients achieving CR (57 months), making them candidates for novel post-transplant treatment options. Outcome following SCT is dependent more on biological variables such as the PCLI than on CR status.
Antineoplastic Combined Chemotherapy Protocols↗
Waldenström's macroglobulinaemia: a prospective study comparing daily with intermittent oral chlorambucil.
This prospective study compared continuous and intermittent chlorambucil therapy of untreated Waldenström's macroglobulinaemia. The diagnosis was established by the presence of an IgM monoclonal (M-) protein in the serum, an infiltrate of lymphocytes and plasma cells in the bone marrow, anaemia or other laboratory abnormalities, physical findings or constitutional symptoms. Patients were randomized to receive chlorambucil 0.1 mg/kg/d or chlorambucil 0.3 mg/kg/d orally for 7 d, repeated every 6 weeks. Criteria for response included 50% or more reduction of serum M-protein, increase in haemoglobin level of 2 g/dl without transfusion, >/= 50% decrease of urine M-protein, or a reduction of 2 cm in the size of the liver, spleen or lymph nodes. Forty-six patients were randomized to continuous chlorambucil (n = 24) or to intermittent chlorambucil (n = 22). Nineteen (79%) (95% CI = 58-93) of the 24 patients given continuous therapy had an objective improvement by either reduction of serum M-protein or increase in haemoglobin. Fifteen (68%) (95% CI = 45-86) of the 22 patients given chlorambucil intermittently had an objective response. The size of the liver decreased by >/= 2 cm in 55% of patients, and the size of the spleen decreased >/= 2 cm in 67%. Lymphadenopathy decreased in 71%. Acute leukaemia or refractory anaemia developed in four patients. The median duration of survival was 5.4 years, and there was no difference between the regimens. Chlorambucil is effective for the treatment of Waldenström's macroglobulinaemia. Patients must be treated for at least 6 months before therapy is abandoned because response is slow. Chlorambucil is an effective agent and should be compared with purine analogues or rituxan (Rituximab) in a prospective study.
Aged↗
Prognostic value of serum markers of bone metabolism in untreated multiple myeloma patients.
Bone involvement is a central feature of multiple myeloma (MM). We investigated whether serum markers of osteoblastic and osteoclastic activity correlate with the presence of bone disease and survival in 313 MM patients enrolled in a phase III trial (E9486). Five markers were measured, including osteocalcin (OC), carboxy-terminal propeptide of type I collagen (PICP), bone alkaline phosphatase (BAP), carboxy-terminal telopeptide of type I collagen (ICTP) and tartrate-resistant acid phosphatase (TRAP). We analysed the relationship between serum levels of these markers and the presence of bone manifestations, and survival. Serum levels of ICTP and BAP correlated significantly with bone pain, lesions and fractures. Serum level of ICTP was also higher in stage II-III compared with stage I disease. The serum level of ICTP was significantly associated with shortened survival in the univariate analysis. The median survival times were 4.1 and 3.5 years for low and high ICTP respectively (P = 0.02). There was a strong relationship between ICTP and beta-2-micrgolobulin (B2M). ICTP stands out as a significant marker of bone disease. Incorporation of these markers into clinical trials assessing the use of bisphosphonates in MM is needed to determine whether they might serve as indicators of effectiveness of these agents.
Acid Phosphatase↗
The (11;14)(q13;q32) translocation in multiple myeloma. A morphologic and immunohistochemical study.
We identified 24 cases of multiple myeloma with the t(11;14)(q13;q32). In 22 cases, the t(11;14)(q13;q32) was part of a complex karyotype, and in 2 cases it was an isolated abnormality. All patients had clinical and laboratory features consistent with multiple myeloma. The median degree of plasma cell involvement in the bone marrow was 60%, and in 10 cases, the plasma cells had a lymphoplasmacytoid appearance. Of the 24 cases, 21 had intermediate or high proliferative rates based on labeling index studies. Immunohistochemical studies performed on all bone marrow biopsy specimens showed strong cyclin D1 nuclear positivity in 19 cases. There also was strong cyclin D1 nuclear positivity found in 6 of 30 additional cases without the t(11;14)(q13;q32) demonstrated by routine cytogenetics. The t(11;14)(q13;q32) in multiple myeloma results in overexpression of the cyclin D1 protein, which can be demonstrated by immunohistochemical stain. The cyclin D1 stain results in the additional cases of multiple myeloma suggest that the t(11;14)(q13;q32) may be more common than previously thought and may be missed by routine cytogenetics, particularly if the proliferative rate is low.
Adult↗
Fish demonstrates treatment-related chromosome damage in myeloid but not plasma cells in primary systemic amyloidosis.
Conventional cytogenetic analysis is limited in the evaluation of plasma cell disorders because, relative to normal hematopoietic elements, plasma cells divide slowly. Moreover, it is difficult to know whether abnormal metaphases originate from malignant plasma cells or myeloid cells harboring other abnormalities. We studied a patient with primary systemic amyloidosis who had previously been treated with an alkylating agent. Bone marrow cells were analyzed by cytoplasmic-immunoglobulin fluorescent staining combined with fluorescent in situ hybridization (cIg-FISH). Both chromosome enumeration probes for chromosome 1 and 7 and loci-specific probes for the short and long arm of chromosome 7 were used. Cytogenetic analysis disclosed the following abnormality: +der(1;7)(q10;p10). On cIg-FISH, the myeloid cells had fusion signals between chromosome enumeration probes for chromosomes 1 and 7, whereas plasma cells had the normal appearance of two pairs of signals. There was a second clone of abnormal myeloid cells with monosomy of chromosome 7. The bone marrow did not show any evidence of myelodysplasia. Interphase cIg-FISH is a useful technique for assigning the lineage of chromosomal abnormalities in plasma cell disorders.
Amyloidosis↗
A prospective study of CD38/45 flow cytometry and immunofluorescence microscopy to detect blood plasma cells in patients with plasma cell proliferative disorders.
Malignant plasma cells can be detected in the blood of patients with multiple myeloma (MM) using flow cytometry (FC), immunofluorescence microscopy (IM), or a variety of molecular techniques. Increased numbers of light chain-restricted blood plasma cells as detected by IM is associated with a diagnosis of overt MM and a decreased overall survival. The IM technique is time consuming; therefore, a prospective study was designed to test whether CD38 CD45 FC could simplify the procedure. Blood samples from 769 patients with plasma cell proliferative disorders were studied prospectively by FC and IM over a one-year period. The FC technique was performed on 1 ml of whole blood after ammonium chloride red blood cell lysis and utilized anti-CD38PE and anti-CD45PerCP. The number of CD38+ 45- events were enumerated and compared to the number of light chain-restricted plasma cells detected by the standard IM technique. In 46% (353/769) of cases > or = 1 CD38+ CD45- events were detected by FC whereas IM was positive for light chain restricted plasma cells in 33%; there was concordance between FC and IM in 73% of cases. In 20% of cases FC was positive and IM was negative; however, in 7% of cases FC was negative yet light chain-restricted plasma cells were detected by IM. FC was positive in 88% (134/153) of cases where the IM technique showed a high number of circulating plasma cells. This study demonstrates that two-color CD38/45 FC identifies most cases with a high IM result and reduces the workload in the clinical laboratory. The prognostic implications of a positive FC screen but a negative IM will require long-term patient follow-up.
ADP-ribosyl Cyclase↗
Thalidomide in the treatment of relapsed multiple myeloma.
OBJECTIVE: To describe the efficacy of therapy with thalidomide, a drug that has antiangiogenic properties, in patients with relapsed multiple myeloma. PATIENTS AND METHODS: We studied 16 patients (median age, 64 years) who received thalidomide for relapsed myeloma at the Mayo Clinic in Rochester, Minn, between November 1998 and August 1999. Treatment consisted of thalidomide given orally at a dose of 200 mg/d for 2 weeks, then increased by 200 mg/d every 2 weeks, up to a maximal dose of 800 mg/d. RESULTS: The stage of myeloma at treatment was Durie-Salmon IIIA in 9 patients (56%) and IIIB in 7 (44%). The median time from myeloma diagnosis to initiation of thalidomide therapy was 32 months. In 4 patients (25%) prior stem cell transplantation had failed, and 14 (88%) had received 2 or more prior chemotherapeutic regimens before institution of thalidomide. All patients were evaluable for response. Four (25%) achieved a partial response to therapy, with a greater than 50% reduction in the serum or urine M protein level. Responses lasted 2, 4+, 8, and 10+ months. Major adverse effects included constipation, sedation, rash, and peripheral neuropathy. CONCLUSION: Thalidomide is an active agent in the treatment of patients with advanced myeloma.
Administration, Oral↗