Consolidation and maintenance therapy in multiple myeloma: randomized comparison of a new approach to therapy after initial response to treatment.

A randomized, controlled trial was initiated in 1977 to evaluate the impact of three alternative approaches to consolidation and maintenance therapy after initial maximal response for multiple myeloma. All patients were treated initially with BCNU, cyclophosphamide, and prednisone (BCP) until a designated level of response was achieved. Responders were randomly assigned to either melphalan and prednisone (MP); prednisone, Adriamycin (Adria Laboratories, Columbus, Ohio), azathioprine, and vincristine (PAIV), or no therapy until relapse, then treatment with BCP. Initial response rates were comparable with previous trials. A small number of incremental responses were observed with both MP and PAIV. Survival was the same for all three maintenance approaches and the same as that observed in our previous continuous BCP or MP therapy. Additional or consolidation/maintenance therapy of the type administered here appears to offer little advantage once an initial response has been achieved.

Splenectomy for Felty's syndrome. Clinicopathological study of 27 patients.

The major clinical and pathological features and the long-term follow-up of 27 patients with Felty's syndrome who were treated with splenectomy for sever granulocytpenia and for acute, chronic, or recurrent infection were studied. Granulocyte counts rose within days in most patients, although slow responses and transient granulocytopenia did occur; only 12% of the patients had persistent or recurrent granulocytopenia. Infections resolved promptly in 77% of the patients, more slowly in the remainder, and only one patient had new problems of infection after aplenectomy. Splenic enlargement, present in all but one case, was attributable to expansion of the sinusoidal pulp. The most substantial pathological features of immune stimulation included germinal center hyperplasia and prominent clusters of plasma and preplasma cells within sinuses.

Autologous marrow transplantation for patients with acute myelogenous leukemia--a preliminary report.

Twelve consecutive adult patients with acute myelogenous leukemia have been entered on a treatment protocol which examines the role of "remission-intensification" during maintenance using high-dose chemoradiotherapy and autologous remission marrow transplantation. Nine patients have achieved complete remission: 5/9 patients have had remission marrow stored followed by high-dose chemoradiotherapy and autologous marrow transfusion; two patients were removed from study because of excessive toxicity during remission-induction precluding high-dose therapy; two patients are currently ready for marrow storage; and two patients are receiving remission-induction therapy. Of the five transplanted patients, four experienced excellent return of blood counts and one patient has had prolonged pancytopenia and continues to require red cell and platelet transfusions. There have been no serious infectious or hemorrhagic problems associated with post-transplant period in any of the patients. Autologous remission bone marrow transplantation following lethal high-dose chemoradiotherapy results in effective restoration of normal hemopoiesis, is associated with acceptable toxicity and may be an effective means of increasing the numbers of acute leukemia patients having long-term complete remission.

Felty's syndrome without splenomegaly.

A woman with chronic rheumatoid arthritis and severe granulocytopenia but without splenic enlargement by physical examination or radionuclide scanning was studied for granulocyte-bound immunoglobulin G (IgG) and serum antigranulocyte antibodies. Prior to splenectomy 73 to 110 X 10(-14) g/cell of IgG were detected on the patient's granulocytes, a value in the range (20 to 220 X 10(-14) g) found in 16 patients with classic Felty's syndrome. Granulocyte-bound IgG in 21 patients with rheumatoid arthritis without Felty's syndrome was less than 20 X 10(-14) g. Following splenectomy, the patient had a partial correction of her peripheral granulocyte count, and granulocyte bound IgG was repeated less than 20 X 10(-14) g/cell. When paraformaldehyde-fixed granulocytes, obtained either from normal donors or from the patient after splenectomy, were incubated in the patient's serum obtained before splenectomy, more IgG was bound than with control serums from patients with rheumatoid arthritis. Similar results were obtained when serums from patients with classic Felty's syndrome were incubated with paraformaldehyde-fixed granulocytes. Thus, patients with rheumatoid arthritis without overt splenic enlargement may have pathophysiologic Felty's syndrome, and in vitro studies such as these may be used to define this process.

Effects of age on responses to treatment and survival of patients with multiple myeloma.

The elderly patient with malignancy is often considered a poor risk for treatment. To assess the effect of age on the treatment of one such disease, multiple myeloma (a disease with increased incidence in the elderly), a study was made of 280 patients treated with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), cyclophosphamide and prednisone on a Southeastern Cancer Study Group protocol. Initial response rates after six months of treatment were equivalent for the older compared with the younger age groups, with a slightly longer remission duration for those over 70. Likewise, survival was equivalent for the older patients. This was not the result of selection of older patients with less advanced disease, since the proportion with both good and poor risk factors are not significantly different in the various age groups. Moreover, for patients with each of the prognostic factors, older patients responded at least as well as younger patients. There were no significant differences among the age groups in gastrointestinal, skin, hair, or hematologic toxicity, although there was a slightly higher incidence of mild granulocyte and platelet toxicity in patients over 60. These findings are in contrast to the widely held belief that older patients cannot tolerate chemotherapy. On the contrary, they suggest that the elderly patient with myeloma may be expected to respond and survive, without excessive toxicity, at least as well as a younger counterpart with similar prognostic factors.

Amyloidosis complicating hairy cell leukemia.

A patient development renal failure following a ten-year affliction with hairy cell leukemia. Renal biopsy showed amyloidosis, characterized by the presence of potassium permagnate-sensitive congophilia in deposits within glomeruli and renal blood vessels. Electron microscopy demonstrated amyloid fibrils. Immunohistochemical technics showed the deposits were composed of AA Protein. These Congo red staining properties, and the presence of AA Protein are characteristic of deposits in secondary amyloidosis. Secondary amyloidosis is a known complication of many chronic illnesses. This report shows it may concur with hairy cell leukemia, and that amyloidosis should be considered in the differential diagnosis of renal failure in patients with hairy cell leukemia.

Mitomycin-induced hemolytic-uremic syndrome.

Four patients who took the antitumor agent mitomycin manifested microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. At autopsy, kidneys from all four patients had a microangiopathy typical of the hemolytic-uremic syndrome (HUS), with thromboses in glomerular capillaries and arterioles, fibrin deposition in mesangium, and prominent cellular intimal proliferation of the interlobular arteries. Development of the HUS was an important factor contributing to death in all four patients. From a review of the literature and our initial results of a randomized chemotherapy protocol for metastatic adenocarcinoma of the colorectum, it appears that mitomycin was the most likely cause for the development of the HUS in these patients. As more patients are being treated with mitomycin, particular care must be taken to monitor them for development of a drug-induced HUS.

Approach to oncologic emergencies in the elderly.

Until now there has not been a treatise summarizing the management of oncologic emergencies in the aged. All of the well-described acute complications of malignancy occur in the elderly. Such clinical events are best labeled urgent rather than emergent, and some may be less well tolerated in the older patient because of normal physiologic changes of aging. However, all should be recognized as early as possible and can be treated, when it is appropriate to do so, as has been detailed for 14 problems discussed in this article. The authors also address two important topics, the quality of life and the use of intensive care units, both germane to the difficult question of whom and when to treat.

Comparison of two long-term chemotherapy regimens, with or without agents to modify skeletal repair, in multiple myeloma.

A randomized controlled trial was initiated in 1972 to compare two chemotherapeutic regimens [1-3-bis (2-chloroethyl) 1-nitrosourea (BCNU), cyclophosphamide, and prednisone versus melphalan and prednisone], to determine whether the two regimens are cross-resistant, and to evaluate the effectiveness of sodium fluoride, vitamin D, calcium gluconate, and fluoxymesterone in the promotion of bone healing. Initial responses (50%) and survival (36 mo median) for patients treated with the two chemotherapeutic regimens were the same. Patients on either regimen who failed to respond after 6 mo had a very low response rate to the alternative regimen (approximately 10%). Initially responding patients were randomly assigned to either an active drug regimen (sodium fluoride, vitamin D, calcium gluconate, fluoxymesterone) or placebo tablets. There was no significant difference in the low percentage of patients demonstrating bone improvement. Thus, the BCNU, cyclophosphamide, prednisone regimen is as effective as melphalan and prednisone. Fluoride, calcium, vitamin D, and androgenic steroids should not be routinely recommended in myeloma, as they seem to add little to effective chemotherapy and may contribute to morbidity.

Assessment of myeloma maintenance regimen of prednisone. Adriamycin, imuran, and vincristine in a murine plasmacytoma model.

A current southeastern cancer study group protocol for the treatment of multiple myeloma involves induction with BCNU, cyclophosphamide, and prednisone (BCP) and maintenance with either melphalan and prednisone (MP), prednisone, Adriamycin, imuran, and vincristine (PAIV), or delayed treatment of relapsed cases following induction. These combinations of drugs are used as induction regimens to establish their chemotherapeutic effects and hematological toxicity in the murine MOPC 104E plasmacytoma model. The three combinations of drugs produce rapid, reliable, and reproducible tumor regressions. However, MP is the only combination which consistently gives long-term disease-free survivors. This particular regimen has least toxicity and is considered to be most effective. BCP produces complete remission with no relapses; however, long-term survivors are not observed with this combination due to early deaths because of drug toxicity. Most of the mice on the PAIV regimen die due to drug toxicity. This combination is considered least effective. With the different drug regimens, toxic events and regressions are noted to occur at different time periods, indicating that perhaps tumor cells in different stages are being destroyed. Toxic events as measured by hematocrit and body weight changes always precede regression by several days. This disparity between rapid drug effects on the host and a delayed effect on the tumor remains unexplained but may possibly be used to advantage in designing future trials.