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Bryostatin 1, a macrocyclic lactone isolated from the marine bryozoan Bugula neritina, is a protein kinase C (PKC) modulator which has shown both preclinical and clinical activity in lymphoid malignancies. We conducted a phase II trial of bryostatin 1 administered at a dose of 120 microg/m2 by 72-h continuous infusion every 2 weeks in patients with relapsed multiple myeloma. Treatment was well tolerated with myalgias constituting the primaray toxicity. There were no responses in nine evaluable patients. The preclinical anti-lymphoid activity is strong enough to support further exploration of bryostatin 1 in different schedules and in combination therapy for multiple myeloma.

Advances in the understanding of the cellular and molecular derangements involved in the initiation and progression of multiple myeloma are beginning to be translated into novel therapeutic approaches. The myeloma stem cell has been under intense scrutiny regarding its normal B-cell counterpart. Oncogenes, tumor-suppressor genes, and cell-survival genes have all been found to be dysregulated in some myeloma patients. Growth factors, especially interleukin-6, appear to be critical for disease progression, and interruption of autocrine and paracrine loops has been achieved with resultant inhibition of myeloma cell growth. Mechanisms of drug resistance and the implications of the multidrug resistance phenotype are just beginning to be understood. High-dose therapeutic regimens with autologous peripheral blood stem cell or allogeneic bone marrow rescue are rigorously being studied with an emphasis on exploiting the graft-versus-myeloma effect. Pamidronate, a second-generation bisphosponate, has been shown to be effective at decreasing adverse skeletal events in patients with advanced myeloma. The topoisomerase 1 inhibitor, topotecan, has shown activity in an initial study.

We performed a multicenter comparative analysis of autologous peripheral blood stem cell transplantation (PBSCT) and allogeneic bone marrow transplantation (alloBMT) in multiple myeloma. Forty-eight consecutive patients received either PBSCT (24 patients) or alloBMT (24 patients) at one of three institutions in the study group. Preparatory regimens consisted of melphalan and total body irradiation (TBI) or melphalan alone in the PBSCT group. The alloBMT group received one of four regimens: cyclophosphamide and TBI; cyclophosphamide, VP-16 and 1,3-bis(2-chloroethyl)-1-nitrosourea (CVB); busulfan and cyclophosphamide (BU/CY) and total marrow irradiation (TMI); or melphalan and TBI. Procedure-related mortality was 12.5% for the PBSCT group and 25% for the alloBMT group. With a median follow-up for survivors in the PBSCT and alloBMT groups of 11 months (range, 4-46) and 15 months (range, 2-84 months), respectively, there was no significant difference in median overall survival (33.5 versus 38.6 months, p = 0.7637) or event-free survival (16.7 versus 31 months, p = 0.8450). There was, however, a plateau in survival at 40% in the alloBMT group. No plateau in survival was seen in the PBSCT group. Clinical relapses occurred as late as 39 months posttransplant. Patients have survived up to 28 months postrelapse.

Recent advances in our understanding of the cellular and molecular derangements involved in multiple myeloma are beginning to be translated into novel therapeutic approaches. Growth factors, specifically interleukin-6, appear to be critical for disease progression, and interruption of autocrine and paracrine loops has been achieved, with resultant inhibition of myeloma cell growth. Oncogenes, tumor-suppressor genes, and cell-survival genes have all been found to be dysregulated in some myeloma patients. The implications of acquisition of the multidrug resistance phenotype are just beginning to be understood. High-dose therapeutic regimens with bone marrow or peripheral stem-cell rescue are being studied in an attempt to produce a cure. Autologous marrow and peripheral blood stem-cell transplantation are better suited to the older myeloma patient population than is allogeneic marrow transplantation, and have also yielded promising results.