Numerous treatment options are available to multiple myeloma patients, with the therapeutic objective of inducing complete remission (CR) or at least very good partial remission (VGPR).

In the American Society of Hematology's recent Education Program Book, "Hematology," researcher Jean-Luc Harousseau compares treatment regimens with and without a stem cell transplant component. In addition, he examines the mounting belief that complete remission, a potentially unreliable prognostic indicator, should cease to be the therapeutic goal in all situations.

Comparison: Treatment With and Without Stem Cell Transplant

During initial treatment after diagnosis, physicians can administer varying levels of chemotherapy and various combinations of novel agent drugs. Under a high-dose chemotherapy regimen, the drugs completely destroy a patient's bone marrow, and physicians must perform a stem cell transplant after therapy. This procedure replaces the depleted bone marrow with new cells, either harvested from the patient before treatment or from a matched donor. Less damaging therapies with low-dose chemotherapy preserve enough bone marrow that transplant remains unnecessary.

Presently, it is difficult to compare the efficacy of high and low-dose treatment approaches because follow-up remains short in many novel agent studies; treatment duration varies across trials; no randomized comparative trial has yet occurred; and physicians often administer high-dose treatment with transplant only to young patients, who may fare better because of age and health factors unrelated to therapeutic approach.

However, even lacking rigorous comparative studies, and despite the increased success of low-dose chemotherapy with the addition of novel agents, available evidence continues to favor therapy with a transplant component. Regimens of melphalan-prednisone (MP) plus thalidomide (Thalomid) or Velcade, or Revlimid plus dexamethasone, yield impressive CR/VGPR rates of 35 and 45 percent respectively, but these results remain inferior to high-dose treatments that include stem cell transplantation.

A regimen of Velcade-thalidomide-dexamethasone with two rounds of stem cell transplantation increases response rate to almost 80 percent. By administering thalidomide maintenance therapy after transplant, the median progression-free survival can extend to longer than four years, and regimens of novel agents both before and after transplant has yielded overall survival rates of near 90 percent.

Nevertheless, research suggests that prolonged treatment with Revlimid and dexamethasone, even absent transplant, can produce outstanding VGPR and two-year progression-free survival rates. Consequently, a randomized trial comparing extended novel agent treatment versus novel agents plus transplant is necessary. Possibly, some young patients may not need frontline transplantation, and instead transplant could become an option only if relapse occurs after therapy with a non-bone marrow destroying regimen.

Is Complete Remission the Most Reliable Benchmark of Successful Treatment?

Historically, researchers have considered complete remission (CR) to be the ultimate objective when treating multiple myeloma patients. The introduction of novel agents, when combined with a melphalan-prednisone or dexamethasone regimen, has produced not only high CR/VGPR rates, but also high progression-free survival rates.

However, recent studies suggest that CR may not always be a reliable indicator of successful treatment: some patients may do well even without attaining CR, and other patients may achieve CR and nevertheless relapse quickly.

In patients who developed the blood cell disorder monoclonal gammopathy of undetermined significance (MGUS) before progressing to multiple myeloma, research suggests that they can achieve a good prognosis even without CR. Conversely, patients whose myeloma originates from the t(4;14) mutation may accomplish CR but still relapse early. A research group has recently stated that ultimately, meaningful benefit from CR achievement only occurs in the small subgroup of patients (13 percent) with a poor-prognosis gene expression profile.

More likely then, it is the magnitude of treatment response that is significant, and CR is simply a frequent, though not required, element of such response. A patient's multiple myeloma subtype remains a critical prognostic indicator, and in patients with less aggressive disease, VGPR alone might be a sufficient treatment objective.

Researcher Jean-Luc Harousseau, MD, predicts that as treatment becomes more multi-pronged, combining a variety of novel agents and treatment approaches, the quality of response will further improve. Such improved success will, he suggests, "probably justify a new definition of response criteria, as this is already the case in acute and chronic leukemias."

For more information, please see the full article in the American Society of Hematology's 2008 Education Program Book, "Hematology," and related Beacon articles about treatment in the young and in the elderly.