What is the correct philosophy for the treatment of multiple myeloma?

In this issue of Leukemia and Lymphoma, Fenk [1] and colleagues describe a method of treating relapsed multiple myeloma with bortezomib and sequentially adding dexamethasone and, if required, bendamustine. The overall response rate was 84%. We need to ask, “To what end do we sequentially add agents when we could certainly achieve a similar response with the simultaneous administration of all three?” A similar trial design for newly diagnosed patients [2] with multiple myeloma was reported, giving two cycles of bortezomib, adding dexamethasone if a response had not been achieved after two cycles or if a complete response had not been achieved after four cycles.

The strategy was to reduce toxicity associated with therapy. The quality of life assessment in multiple myeloma using the TWiST (time without symptoms and toxicity) tool has demonstrated that quality of life is strongly linked to time on chemotherapy [3]. Total therapy, as pioneered at the University of Arkansas, adds all known active agents in multiple myeloma to effect maximal cytoreduction during induction. There is a consolidation phase where stem cells are collected followed by tandem transplants and maintenance, a strategy derived from lymphoblastic leukemia (ALL). ALL is a curable disease, and if we believe multiple myeloma is currently curable, then aggressive multidrug (presumably more toxic) regimens are justified. But should we think of multiple myeloma the way we think of ALL? Does the biology of myeloma more resemble low-grade lymphoma and chronic lymphatic leukemia, where more is not necessarily better, recurrence is invariable, and long-term survival can be achieved with the administration of lower intensity therapy? Should we be borrowing the philosophy of our colleagues in infectious diseases, dealing with HIV infection, currently incurable? With the development of HAART, AIDS can be converted to a chronic disease compatible with long-term survival. If one believes the latter, attempting to treat the disease with less, rather than more, becomes logical using low-intensity treatment achieving plateau until resistance develops followed by introduction of non-cross-resistant agents to maintain the response.

The question of sequential versus combined agents in myeloma is unsettled. A report on stem cell transplant at relapse [4] produced the same survival as early application of transplant. In Total Therapy 2, it did not matter whether patients received thalidomide as initial induction therapy or whether it was administered at the time of progression. Survival in both groups was the same [5]. One might imagine that the prevalence of peripheral neuropathy, however, would be significantly less in patients that were spared thalidomide until later in the disease course. The same might be considered for early versus late anthracyclines.

The ECOG has taken a low-intensity philosophical approach. One would not attempt to prove that two-drug therapy was superior to six-drug therapy, but if one could achieve equivalent results with minimalist therapy and the goal is “how you live as well as how long you live,” progress will have been made [6]. ECOG has successfully demonstrated lower early mortality in patients who received dexamethasone weekly compared to those who have received it 12 days per cycle, the standard since 1984. The reduced mortality associated with weekly treatment was so striking that the Data Safety Monitoring Board terminated the study early. One-year survival was 98%, superior to any previously reported therapy [7]. A reasonable question is whether transplantation is actually required with the advent of novel agents. High-dose therapy, although clearly effective and capable of prolonging survival compared to standard (by the 1990s' standards) chemotherapy, still produces significant financial burdens, and for those patients who do not live near a large urban medical center, relocation.

Fenk et al. are able to demonstrate that 46% of patients respond with one agent, 40% two agents, and only 14% required all three. The feasibility of inducing a response with this “less is more” approach opens the door for further studies, whose underpinning philosophy is, “utilizing a less toxic approach to achieve survivals associated with other chronic diseases but not necessarily using complete response rates as the standard of care.”

In the context of ongoing research, it remains appropriate to continue the search for a cure as has been demonstrated in recipients of allogeneic T-lymphocytes [8]. Although research into a cure for multiple myeloma must continue, it is now increasingly rational to attempt to exert long-term control with a minimalist approach, two drugs at a time.