Tailoring Initial Treatment for Newly Diagnosed, Transplantation-Eligible Multiple Myeloma

High-dose melphalan (Alkeran) and autologous stem cell transplantation are commonly incorporated into the initial line of therapy for patients newly diagnosed with multiple myeloma. This option is usually offered to patients less than 70 years old who have no major comorbidities. Selected older patients and those with mild to moderate organ dysfunction may also be reasonable candidates. An important goal of induction therapy is to achieve remission; a complete response predicts longer survival after transplantation. The regimens for initial therapy that are based on level 1 evidence and consensus include bortezomib (Velcade)/dexamethasone, bortezomib/doxorubicin/dexamethasone, bortezomib/thalidomide (Thalomid)/dexamethasone, and lenalidomide (Revlimid)/low-dose dexamethasone. Recent studies have provided guidance for choosing among these regimens for patients with cytogenetic abnormalities, renal disease, and other negative prognostic indicators. There is evidence from phase III studies that use of thalidomide/dexamethasone and bortezomib-based induction regimens can translate into significantly better survival after transplantation compared with the older chemotherapy regimens.

Supported by an educational grant from Millennium Pharmaceuticals, Inc.

In nearly all cases, multiple myeloma is ultimately fatal. However, the 5-year survival rate has improved significantly, from 26% in 1975 through 1977 to 37% in 1999 through 2005 (P < .05).[1] Survival has particularly improved in myeloma patients younger than 60 years old, beginning in the mid-1990s.[2] In addition to early deaths, late deaths years after initial treatment have been reduced in this age group.

The improvement in US survival rates began after routine use of autologous stem cell transplantation (ASCT) in the mid-1990s and the advent of thalidomide (Thalomid), bortezomib (Velcade), and lenalidomide (Revlimid).[3] Therefore, consideration of ASCT after induction therapy with one or more of these agents has become the standard of care for front-line myeloma treatment. Transplantation is usually offered to patients younger than 70 years old who have no major comorbidities, but more advanced age and renal dysfunction are not necessarily barriers.[4] Another aspect of eligibility for ASCT, not inconsequential, is the patient’s willingness to undergo the procedure after the benefits and risks have been carefully explained. Patients do not need to decide about transplantation upon diagnosis, but those who wish to reserve it as an option for relapsed/refractory disease should either undergo a stem cell harvest early in the course of initial therapy or not be exposed to oral melphalan (Alkeran)-containing regimens or extensive radiation.

There are three goals of induction therapy for transplantation-eligible myeloma patients. The first is to achieve response. Patients who are being considered for treatment have active, symptomatic myeloma, and improvement in symptoms and related organ dysfunction is essential to proceeding to transplantation. A number of studies suggest that the degree (or depth) of response prior to transplantation corresponds to improved outcome. High rates of complete response (CR) or near-CR (nCR) after induction often translate into high CR/nCR rates after transplantation (see, for example, Alegre[5] and Oakervee[6]). Moreover, studies suggest that > 90% disease reduction to induction, ie, very good partial response (VGPR), may predict prolonged event-free survival (EFS)/progression-free survival (PFS) and/or prolonged overall survival (OS) after transplantation.[5,7-9] Indeed, a meta-analysis of 21 studies of transplantation in front-line myeloma showed that the association between response to induction and long-term OS was statistically significant.[10] An important caveat is that if a patient has partial response (PR) to a course of induction therapy, it is not clear that changing or prolonging therapy in an attempt to achieve CR or VGPR is better than simply proceeding to transplantation.

Another consideration in choosing the induction therapy regimen is the need to avoid jeopardizing subsequent stem cell collection. As mentioned above, this requires minimizing alkylating agents, notably melphalan, and minimizing the extent and dose of any radiation therapy. Finally, of course, the regimen must minimize other toxicities that may preclude ASCT, such as cardiac, pulmonary, or renal side effects. Some commentators have suggested that a goal of induction therapy is to provide a less contaminated stem cell product. Although that seems logical, there is little evidence that the degree of bone marrow involvement at the time of stem cell harvest relates to ultimate outcome.

Incorporation of the new agents into multidrug combinations has been very encouraging, and a number of promising regimens for induction therapy have been reported in the past few years. What follows is a description of the new standards for induction therapy in transplantation-eligible multiple myeloma patients and a review of the evidence that clinicians can use to choose among the newly established options.

New Standards for Induction Therapy in Transplantation Candidates

TABLE 1

NCCN-Proposed Multiple Myeloma Induction Therapies Prior to Transplantation

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