melphalan and Bone-Diseases

The clinical features, investigation, treatment and outcome of two adults with fibrogenesis imperfecta ossium are described. In this rare acquired disorder of bone, normal lamellar collagen is replaced by structurally unsound collagen-deficient tissue, which leads to extreme bone fragility and ununited fractures. Transmission microscopy and SEM showed striking ultrastructural changes in bone structure and mineralisation. Both patients had monoclonal IgG paraproteins in the plasma and one excreted monoclonal lambda light chains in the urine. No abnormal plasma cells were found in the bone marrow and there was no evidence of amyloid deposition in the tissues. In both patients initial treatment with 1 alpha-hydroxycholecalciferol appeared to be ineffective, but in one, repeated courses of melphalan and corticosteroids over three years together with 1 alpha-hydroxycholecalciferol produced striking clinical and histological improvement. The findings in these and other patients strongly suggest that paraproteinaemia is an integral feature of fibrogenesis imperfecta ossium, and this needs further investigation.

Topics: Adrenal Cortex Hormones; Adult; Aged; Bone and Bones; Bone Diseases; Child; Collagen; Collagen Diseases; Female; Fractures, Bone; Humans; Hydroxycholecalciferols; Male; Melphalan; Microscopy, Electron; Middle Aged; Paraproteinemias; Tendons

Patients with benign monoclonal gammopathy or smouldering multiple myeloma should not be treated. The plasma cell labelling index utilizing tritiated thymidine or a monoclonal antibody to 5-bromo-2-deoxyuridine is helpful in differentiating patients with benign monoclonal gammopathy or smouldering myeloma from those with overt myeloma. Although combinations of chemotherapeutic agents seem to produce a greater number of objective responses than does melphalan-prednisone, a significant difference in survival has not been proved. Possibilities for future treatment include chemotherapy with large intravenous doses of melphalan, very small doses of cyclophosphamide or melphalan, the administration of hydroxyurea before chemotherapy, combination of interferon with alkylating agents, autologous bone marrow transplantation, and improvement of the soft-agar colony-forming assay for myeloma cells. The therapeutic use of monoclonal antibodies to plasma cell antigens may be possible in the future. Much more needs to be learned about the biologic basis of myeloma before real progress can be made.

Topics: Acute Kidney Injury; Anemia; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Blood Viscosity; Bone Diseases; Bone Marrow Transplantation; Drug Resistance; Humans; Hypercalcemia; Kidney Failure, Chronic; Melphalan; Multiple Myeloma; Prednisone; Spinal Cord Compression; Time Factors

The basic pathologic process in multiple myeloma is the neoplastic proliferation of a single clone of plasma cells. Although the events which trigger autonomous cell growth are not well understood, the secretion of an M component, a serum or urinary immunoglobulin molecule or a light chain fragment by the vast majority of myeloma cells has provided a biologic marker which has greatly facilitated the study of this disease Some of the more recent clinical concepts which have evolved from studies on the plasma cell and the immunoglobulin molecule are discussed.

Topics: Alkylating Agents; Amyloidosis; Bacterial Infections; Blood Viscosity; Bone Diseases; Clone Cells; Hemostasis; Humans; Hypercalcemia; Kidney Failure, Chronic; Melphalan; Multiple Myeloma; Paraproteins

  Bone disease is a key presenting feature of myeloma. This post hoc analysis of the phase III VISTA trial of bortezomib plus melphalan-prednisone (VMP) vs. MP in previously untreated myeloma patients assessed clinical bone disease events and changes in alkaline phosphatase (ALP), a marker for osteoblast activation, and serum Dickkopf-1 (DKK-1), an inhibitor of osteoblast differentiation, during treatment..   Patients received nine 6-wk cycles of VMP (bortezomib 1.3 mg/m(2) , days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1-4, days 1, 8, 22, 29, cycles 5-9, plus melphalan 9mg/m(2) and prednisone 60mg/m(2) , days 1-4, cycles 1-9; N=344) or MP alone (N=338)..   Rates of bisphosphonates use during treatment (73% vs. 82%), progression because of worsening bone disease (3% vs. 11%), and requirement for subsequent radiotherapy (3% vs. 8%) were lower with VMP vs. MP. Median maximum ALP increase was significantly higher with VMP vs. MP overall (49.7% vs. 30.3%, P=0.029), and higher by response group (complete response [CR]: 68.7% vs. 43.9%; partial response [PR]: 41.5% vs. 31.2%). Greater maximum ALP increase was strongly associated with achievement of CR (P≤0.0001) and CR/PR (P≤0.01). Median DKK-1 decreased with VMP by 694.4pg/mL and increased with MP by 1273.3pg/mL from baseline to day 4 (P=0.0069). Available radiologic data revealed evidence of bone healing in 6/11 VMP-treated patients, who achieved best responses of three CR, one PR, and two stable disease..   These results suggest a positive effect of bortezomib on bone metabolism and potentially bone healing in myeloma.

Topics: Aged; Aged, 80 and over; Alkaline Phosphatase; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Bone Diseases; Bone Remodeling; Boronic Acids; Bortezomib; Cell Differentiation; Female; Humans; Intercellular Signaling Peptides and Proteins; Male; Melphalan; Middle Aged; Multiple Myeloma; Osteoblasts; Prednisone; Pyrazines; Radiotherapy, Adjuvant

We conducted a prospective pilot study to assess the feasibility and safety of high-dose busulfan/melphalan as conditioning therapy prior to autologous PBPC transplantation in pediatric patients with high-risk solid tumors. From January 1995 to January 1999, 30 patients aged 2-21 years (median 8) were entered into the study. There were 14 females and 16 males. Diagnoses included neuroblastoma in 10 patients; Ewing's sarcoma and peripheral neuroectodermal tumor (PNET) in 15 patients and rhabdomyosarcoma in five patients. Treatment consisted of busulfan 16 mg/kg, orally over 4 days (from days -5 to -2) in 6 hourly divided doses, and melphalan at a dose of 140 mg/m2 given by intravenous infusion over 5 min on day -1. G-CSF mobilized PBPC were used as autologous stem-cell rescue. One patient developed a single generalized convulsion during busulfan therapy. The most relevant non-hematologic toxicity was gastrointestinal, manifesting as grade 2-3 mucositis and diarrhea in 12 patients. Two patients died of procedure-related complications, one from veno-occlusive disease of liver and multiorgan failure and the other from adult respiratory distress syndrome. Probability of treatment-related mortality was 6.6 +/- 4.5%. With a median follow-up of 18 months (range, 1-48), 19 patients are alive and disease-free, the actuarial EFS at 4 years being 55 +/- 12% for the whole group. We conclude that high-dose busulfan/melphalan for autologous transplantation in children with solid tumors is feasible even in small patients. It is well-tolerated, with an acceptable transplant-related mortality and has proven antitumor activity.

Topics: Adolescent; Adult; Antigens, CD34; Antineoplastic Agents, Alkylating; Blood Cell Count; Bone Diseases; Bone Neoplasms; Busulfan; Child; Child, Preschool; Clonazepam; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Melphalan; Neoplasms; Neuroblastoma; Pilot Projects; Retrospective Studies; Rhabdomyosarcoma; Sarcoma, Ewing; Survival Rate; Transplantation Conditioning; Transplantation, Autologous

In order to study whether oral bisphosphonate therapy might prevent or reduce skeletal-related morbidity in patients with newly diagnosed multiple myeloma who required chemotherapy, 300 patients were included in a randomized multi-centre trial. Patients were given oral pamidronate at a dose of 300 mg daily, or placebo, in addition to conventional intermittent melphalan/prednisolone (and in some cases alpha-interferon) treatment. With a median treatment duration of about 550d, no statistically significant reduction in skeletal-related morbidity (defined as bone fracture, related surgery, vertebral collapse, or increase in number and/or size of bone lesions) could be demonstrated. Pamidronate treatment also did not have any influence on patient survival or on the frequency of hypercalcaemia. However, in patients treated with pamidronate there were fewer episodes of severe pain (P=0.02) and a decreased reduction of body height of 1.5 cm (P= 0.02). The overall negative result of the study is attributed to the very low absorption of orally administered bisphosphonates in general.

Topics: Administration, Oral; Aged; Anti-Inflammatory Agents; Antineoplastic Combined Chemotherapy Protocols; Body Height; Bone Diseases; Diphosphonates; Double-Blind Method; Female; Fractures, Bone; Humans; Hypercalcemia; Male; Melphalan; Multiple Myeloma; Pain; Pamidronate; Prednisolone; Treatment Failure

In 1989, a prospective randomized multicenter study was initiated in order to determine the safety and efficacy of oral clodronate in myeloma patients. The primary objective of this long-term trial is to evaluate whether supportive clodronate is able to prevent or retard the progression of bone disease and reduce the occurrence of characteristic complications: pain, pathologic fractures, and hypercalcemia. We now report first results as an interim analysis, including data obtained from 26 patients (total number of Tübingen patients n = 36) who entered the study at the Medizinische Universitätsklinik Tübingen. Patients were randomized to receive either chemotherapy alone (melphalan 15 mg/m2 i.v. on day 1 and prednisolone 60 mg/m2 orally on days 1-4 every 4 weeks (control group) or in combination with 1600 mg clodronate/day orally as a single dose for a period of at least 1 year. Repeated radiologic examinations in addition to hematologic and biochemical analysis were performed in order to evaluate the skeletal status with respect to lytic bone lesions and osteoporosis and the course of serum M protein and light chain excretion into urine. Clodronate treatment resulted in a significant decrease of serum calcium concentrations and of biochemical indices for bone resorption. No clodronate-related toxicity or hypocalcemia was observed. In patients treated with chemotherapy alone, this effect was less marked and discontinuous. Clodronate-treated patients developed fewer progressive bone lesions (significant for lytic, not for osteoporotic lesions). No hypercalcemic episodes occurred in the clodronate-treated patients, but there were six episodes in the control group. Whereas the number of vertebral fractures was evidently less is clodronate-treated patients, three of those patients suffered from multiple fractures of long bones and ribs. All together, 12 pathologic fractures occurred in five clodronate-treated patients, whereas in the control group 23 pathologic fractures occurred in the same number of patients during the whole observation period. The final analysis of all multicenter included patients should clarify these findings. There was a significant finding that clodronate proved to have an analgesic effect.

Topics: Adult; Aged; Analgesia; Bone Diseases; Bone Resorption; Calcium; Clodronic Acid; Female; Fractures, Bone; Humans; Hypercalcemia; Male; Melphalan; Middle Aged; Multiple Myeloma; Osteoporosis; Prednisolone; Prospective Studies

A randomized double-blind study was carried out in 26 patients with multiple myeloma to compare the therapeutic effect of sodium fluoride (50 mg twice daily) plus calcium carbonate (1 g four times daily) and placebo. All patients also received melphalan and prednisone for one week every six weeks. Bone biopsies for microradiography and histology, and videodensitometry as well as conventional roentgenograms, 99mTc-polyphosphate bone scans, and bone densitometry of the mid and distal radius, were done initially and one year after therapy. Microradiography and videodensitometry studies revealed significant increases in bone formation (P less than 0.01) and bone mass (P less than 0.005) in the fluoride-calcium group. Bone trabeculae appeared thickened on roentgenograms of six of 13 fluoride-calcium-treated patients (P less than 0.02). Technetium bone scans and bone densitometry determinations proved insensitive for detection of skeletal changes. Fluoride calcium should be considered a useful adjunct in the treatment for multiple myeloma.

Topics: Bone and Bones; Bone Diseases; Calcium Carbonate; Clinical Trials as Topic; Fluorides; Humans; Melphalan; Multiple Myeloma; Osteosclerosis; Prednisone; Prospective Studies

Topics: Adult; Bone Diseases; Combined Modality Therapy; Diagnosis, Differential; Diffusion Magnetic Resonance Imaging; Female; Femur; Humans; Infarction; Melphalan; Multiple Myeloma; Osteosclerosis; Pelvic Bones; Severity of Illness Index; Stem Cell Transplantation; Thoracic Vertebrae; Treatment Outcome

A 74-year-old woman with refractory IgG-κ multiple myeloma developed massive melena caused by hemorrhagic submucosal tumors in the duodenum and middle jejunum. A biopsy revealed the tumor to be marked AL amyloid deposition. Treatment with bortezomib did not improve the melena or the underlying disease. The patient also developed multiple amyloidomas in the bilateral femoral heads, which caused a fracture in the left femoral head. Treatment with lenalidomide, as the final therapeutic option, resolved the intractable melena and improved both the intestinal lesions and myeloma. This case shows that successful treatment of multiple myeloma leads to marked improvement of accompanying AL amyloidosis.

Topics: Aged; Amyloid; Amyloidosis; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Bone Diseases; Boronic Acids; Bortezomib; Carpal Tunnel Syndrome; Dexamethasone; Disease Progression; Doxorubicin; Duodenal Diseases; Female; Femur Head; Fractures, Spontaneous; Gastrointestinal Hemorrhage; Hip Fractures; Humans; Jejunal Diseases; Lenalidomide; Melphalan; Multiple Myeloma; Osteolysis; Prednisolone; Pyrazines; Thalidomide; Vincristine

Major advances continue apace in therapy and in understanding its molecular pathogenesis.

Topics: Antineoplastic Agents, Alkylating; Bone Diseases; Boronic Acids; Bortezomib; Diphosphonates; Humans; Immunosuppressive Agents; Medical Oncology; Melphalan; Multiple Myeloma; Protease Inhibitors; Pyrazines; Stem Cell Transplantation; Thalidomide; Treatment Outcome

Fibrogenesis imperfecta ossium (FIO) is an extremely rare, acquired, metabolic bone disease related to a collagen defect in bone matrix inducing spontaneous fractures. Among the 17 cases of FIO reported to date, four patients exhibited a monoclonal gammopathy (MCG) and one, treated with melphalan, was the first patient to present clinical and histological remission of the bone and plasma cell manifestations. We report the case of a 56-year-old woman who suffered spontaneous fractures of both patellae and olecranons. Skeletal X-rays showed generalized coarse, ill-defined trabeculae. The following biological parameters were abnormal: ESR: 50 mm/hour, alkaline phosphatase (AP) 256 IU/liter [normal (N): 40-110], serum IgG kappa light chain 11 g/liter, bone marrow aspirate 9% atypical plasma cells. Iliac crest biopsy showed the features of FIO including evidence of osteomalacia and nonbirefringent osteoid seams under polarized light. Eroded surfaces were increased, and trabecular bone volume was decreased. Melphalan (4 mg/day) was given in 1988 and was interrupted 1 year later because of leucopenia. Clinical status worsened. A second bone biopsy in 1989 showed identical features of FIO. In November 1990, an X-ray film showed several fractures, and coarser trabeculae. The patient died in December 1991. Regarding the prevalence of MCG and FIO, their association is unlikely accidental. The collagen defect might be related to a plasma cell-induced osteoblast impairment.

Topics: Aged; Antineoplastic Agents, Alkylating; Bone and Bones; Bone Diseases; Female; Humans; Melphalan; Radiography; Syndrome

Topics: Adult; Amyloidosis; Bone Diseases; Colchicine; Diagnosis, Differential; Drug Therapy, Combination; Female; Femoral Neck Fractures; Fractures, Spontaneous; Humans; Male; Melphalan; Middle Aged; Prednisolone

The osteoid of a patient with Fibrogenesis Imperfecta Ossium is described. Three iliac crest biopsies were taken; firstly before treatment, secondly after calcitriol therapy and finally after successful treatment with melphalan and prednisolone. In the pretreatment biopsy the osteoid was greatly enlarged, showed complete absence of the birefringence characteristic of oriented collagen fibers, and at ultrastructural level was shown to be composed of abnormal collagen fibrils. The fibrils were often curved and were extremely variable in thickness. Calcification within the osteoid took the form of calcospherites and spread of calcification from these to collagen fibrils was greatly delayed. In the second biopsy two aspects of osteoid ultrastructure were noted; some samples resembled the first biopsy, but others had a different organization. The osteoid of these samples had two regions: an inner region containing abnormal collagen fibrils and an outer region composed of moderately electron-dense amorphous material. The osteoblasts associated with this region were clearly highly biosynthetically active. The third biopsy, after treatment with Melphalan and prednisolone, showed a reversion to more normal bone ultrastructure with uniform, oriented collagen fibrils and prompt mineralization resulting in narrow osteoid seams. Remnants of the original abnormal osteoid were present in the marrow space as calcified debris. Reasons for the success of this therapeutic regime are unclear; however, some speculation is made as to the possible roles of the cytotoxic drug and the glucocorticoid in the regression of this condition.

Topics: Biopsy; Bone and Bones; Bone Diseases; Calcification, Physiologic; Calcitriol; Collagen; Humans; Male; Melphalan; Microscopy, Electron; Middle Aged; Pain; Prednisolone

Topics: Acute Disease; Antineoplastic Combined Chemotherapy Protocols; Bone Diseases; Drug Resistance; Humans; Leukemia; Melphalan; Multiple Myeloma; Pain Management; Prednisone

The experience of a solo practitioner suggests that the incidence of multiple myeloma is higher than the widely reported figure of 2.7/100,000. Only by early recognition and treatment will the survival rate be increased. Measurement of the sedimentation rate may be helpful in spotting the disease, for a rapid rate in patients with bone pain and anemia suggests multiple myeloma.

Topics: Adult; Anemia; Blood Sedimentation; Bone Diseases; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Pain; Prednisone

Topics: Blood Viscosity; Bone Diseases; Cyclophosphamide; Fluorides; Humans; Hypercalcemia; Melphalan; Multiple Myeloma; Myeloma Proteins; Pain; Phosphates; Plasmapheresis; Prednisolone; Procarbazine; Vincristine

Topics: Adult; Alkaline Phosphatase; Bone Diseases; Chemistry, Clinical; Chloramphenicol; Fenclonine; Humans; Liver Diseases; Melphalan; Neoplasms; Phenylalanine; Phenylketonurias; Stereoisomerism

Topics: Bone Diseases; Bone Neoplasms; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Neurologic Manifestations; Prednisone; Urethane

Topics: Bone Diseases; Calcium; Female; Humans; Male; Melphalan; Myeloproliferative Disorders; Nitrogen Mustard Compounds; Pain