Myeloma therapy: 25 years forward--immune modulation then and now.

In 1983, immune modulation was being studied in the laboratory and in the clinic. The development of the clonogenic human myeloma stem-cell assay allowed testing of fresh myeloma bone marrow samples as well as a range of cell lines. Leukocyte interferons were of particular interest at that time. These were heady times: interferons had been on the cover of Time magazine and were clearly the molecules to beat. However, although clinical trials confirmed antimyeloma activity, it was unclear whether the antitumor effect was mediated directly via antiproliferative action on the myeloma cells or indirectly through cells in the microenvironment. Separate studies had shown that MRC-5 fibroblasts as well as macrophages could serve as enhancing “mother” cells for myeloma colony growth. Cocultivation and self-renewal studies revealed a complex interaction between self-renewing myeloma stem cells and modulating microenvironmental accessory cells. Our results indicated synergy between interferons and cytotoxic agents, such as alkylating agents in the antimyeloma activity. Subsequent clinical trials confirmed the therapeutic benefit in patients with myeloma using interferons within combinations as front-line therapy as well as for maintenance. But over time, it also became clear that the benefit was much less than we had hoped. On average, responses increased by approximately 15% and remissions and survival improved by 6 to 12 months at most. For the first time, there was more careful assessment and comparison of prolongation of remission (progression-free survival) versus improvement in overall survival (or not). With multiple studies, it seemed that interferons prolonged remission, but might or might not impact overall survival. Does this sound familiar? These are the exact questions being addressed today with regard to thalidomide as part of the melphalan, prednisone, and thalidomide combination or within the total therapy-2 approach, with or without thalidomide. Interestingly, in our 1983 article using levamisole as an immunomodulating agent for maintenance, the same issue emerged. The alternating combination chemotherapy of vincristine, melphalan, cyclophosphamide, and prednisone (VMCP)/vincristine, cyclophosphamide, doxorubicin, and prednisone or VMCP/vincristine, carmustine, doxorubicin, and prednisone versus melphalan and prednisone produced a significantly longer median survival of 40 months, as compared with 24 months for melphalan and prednisone (P .01). With the addition of levamisole in the maintenance phase, there was a marginally enhanced improvement in survival (P .06). These results with combination chemotherapy provided the best survival results yet obtained by the Southwest Oncology Group and compared favorably with all previously reported myeloma therapy trials, which had median survivals in the 30 to 32 month range. The initial median survival projection of 48 months for patients randomly assigned to VMCP plus levamisole was particularly promising. It was intriguing that levamisole, an agent that influenced lymphocyte and macrophage function, could improve outcomes in myeloma treatment. Fast forward 25 years: surprisingly, the major elements of the discussions and strategic planning are the same, and only the players are different. Now, we have much better immunomodulatory therapy in the form of thalidomide, lenalidomide, and bortezomib. These important new agents have a variety of properties ranging from antimicrobial to antiangiogenic, immunomodulatory, and, of course, proteasome inhibition, which has a multifaceted impact on both cell function and cell-to-cell interactions. Although there has been great enthusiasm to attempt to emulate the success with imatinib as a targeted approach in chronic myelogenous leukemia, the successful agents in myeloma are multifunctional, with a diverse impact on cell functions and pathways. This may indeed be the secret of success. The level of success can be readily grasped by comparing the response rates and survival outcomes in the 1980s with 2008 as evidenced in Table 1, which shows overall survivals then and now. The change is substantial: 2008 survival of more than 96% at 1 year versus 75% to 83% and 2008 survival still around 90% at 2 years versus 48% to 66% (Table 1). The benefit and comparisons are particularly interesting looking at the results with lenalidomide plus low-dose (weekly) dexamethasone compared with the prior results with interferon and levamisole. There is essentially a doubling of survival at 2 years, with preliminary evidence that this survival will be maintained for at least 3 to 4 years. The impact of the new agents was documented by the recent comparative survival data from the Mayo Clinic experience, which showed the improved survival in the 2001 to 2006 timeframe. The research capability was there 25 years ago. We just didn’t have the drugs. We had the capacity to screen thousands of agents, which we did. The self-renewal process was separately assessed to look for agents capable of eliminating myeloma stem cells. Although we identified several promising agents, including bisantrene, these did not prove clinically useful. Ultimately, the clinical observation of JOURNAL OF CLINICAL ONCOLOGY C E L E B R A T I N G 2 5 Y E A R S O F J C O VOLUME 26 NUMBER 29 OCTOBER 1