Phase I Study of Bortezomib and ¹⁵³Sm-Lexidronam Combination for Refractory and Relapsed Multiple Myeloma.

Background: Multiple myeloma (MM) is a highly radiosensitive B-cell malignancy and radiation therapy is an effective treatment for these patients. Recent preclinical studies have demonstrated that the bone-seeking radionuclide, Samarium Sm¹⁵³ lexidronam (Sam) in combination with the proteasome inhibitor, bortezomib (Velcade [Vel]), can synergistically inhibit proliferation of myeloma cell lines in vitro and reduce MM growth in mice bearing murine MM without significant myelotoxicity. These results provide the basis for a new targeted therapeutic approach for refractory and relapsed MM patients involving combining Vel with Sam to improve the anti-MM effects of these agents without increasing their toxicity.

Aims: The primary objective of this dose escalation Phase I study is to determine safety and tolerability as well as the response rate as determined by Blade criteria of Vel + Sam treatment for patients with relapsed or refractory MM.

Methods: MM patients who had failed ≥2 prior treatments will be enrolled on this Phase I dose-escalation trial which involves six cohorts with three patients each. Previous treatment with Vel is allowed. Dose escalations in parallel arms are as follows:

A complete treatment cycle is 8 weeks, and patients are to receive a maximum of 4 cycles. Vel is given on days 1, 4, 8 and 11 followed by a 45-day rest period. Sam is administered only on day 3. The cycle is repeated on Day 57 if disease is stable or improved and platelets and neutrophils recover to at least Grade 1 toxicity (may be delayed for up to four weeks). Dose limiting toxicity (DLT) is defined as cycle 1 Grade 4 hematologic or Grade ≥3 non-hematologic toxicity.

Results: Eighteen patients have been enrolled to date in cohorts 1 through 5. Three patients have been treated in cohorts 1, 2, 4, and 5, and 6 patients have been entered in cohort 3. Fifteen patients are evaluable for response and the other 3 patients have not yet completed a treatment cycle. Of 15 evaluable patients, 3 patients including one Velcade-refractory patient have shown responses [immunofixation+ complete response {IF+ CR} (n=2) and minor response (n=1)], 3 have stable disease, and 9 patients showed progressive disease. One Velcade-refractory patient with progressive disease initially showed a transient IF+ CR. Two patients developed transient Grade 4 thrombocytopenia. One of these episodes occurred during Cycle 1 in a patient in cohort 3; and, as a result, cohort 3 has been expanded to a total of 6 patients. Four patients showed transient Grade 3 neutropenia. Only two patients showed treatment emergent neuropathy one of which resolved while on study. To date, seven patients remain on study and one patient has completed 4 cycles of therapy.

Conclusions: Early results from this dose escalation Phase I trial evaluating the combination of Vel and Sam are encouraging and demonstrate responses in relapsed and refractory MM patients. The trial continues to enroll subjects. Updated results from this study will be presented at the meeting.