Trial Information

Evaluation of a Method Designed to Improve Outcome of High-Dose Chemotherapy (HDC) and Autologous Hematopoietic Stem Cell Transplantation (AHSCT) for Selected Patients With Myeloma: A Phase I Study Using Total Skeletal Irradiation (TSI) Administered Via Helical Tomotherapy (HT)Plus High-Dose Melphalan and Amifostine Before AHSCT2

While HDC/AHSCT is active most patients eventually relapse; obviously, those with lesser
responses progress as well. Many investigators regard HDC/AHSCT as a "mature" modality a
useful if fixed element in an evolving treatment paradigm that focuses on the introduction
of new (non-HDC/AHSCT) agents with unique mechanisms of action. However, data from several
related sources (including both the syngeneic and second ["tandem" or salvage] AHSCT
experience), suggests that the efficacy of HDC/AHSCT could be improved by obtaining better
cytoreduction of the HDC component, thus prolonging survival and possibly even producing an
increase in cures. However, to do so will require additional attention to the sources of
relapse following HDC/AHSCT, mainly the residual myeloma in the patient, but perhaps also
the inadvertent reinfusion of clonogenic myeloma cells in the AHSCT. For reasons discussed
herein, this study will focus on the former.

We believe that the agents with more potent activity vs. the (multiple) myeloma cancer stem
cell (MM-CSC) and/or their microenvironment are ultimately needed to increase the cure rate
in myeloma. Unfortunately, preliminary data suggest current modalities used in myeloma
therapy are only variably effective vs. these targets, and that newer agents with such
activity are only now becoming available for clinical trials.

The use of these newer agents are most likely to augment, not supplant, current modalities,
lending even more urgency to optimizing existing elements to try to improve the efficacy of
HDC/AHSCT and especially to determine if activity vs. MM-CSC and/or the microenvironment of
these current modalities can be augmented. Radiation seems especially attractive to
re-evaluate, given new, "targeted" methods of administration such as those described herein.
Impetus for this effort comes from the known radiosensitivity of clonogenic myeloma cells
(a population that at least may contain MM-CSC), and especially given the ability of local
radiotherapy to provide local disease control in myeloma, and especially given the ability
of local radiotherapy to cure some patients with solitary plasmacytoma "proving" activity of
radiotherapy vs. MM-CSC in this closely-related diagnosis.

It is important to note that improvement in current modalities may offer better clinical
outcomes even if major effects vs. the MM-CSC and microenvironment interaction are not
produced. We do not currently have the ability to measure such effects; this will not be
part of this trial.