Achievement of maximal disease response to thalidomide is limited by patient tolerance more often than disease resistance

Forty patients with progression of multiple myeloma following prior treatment (average 2 prior regimens, range 1-4) including autologous stem cell transplantation, (18 patients) who had an easily measurable monoclonal protein were treated with thalidomide therapy in escalating dosage as tolerated. Thalidomide therapy was continued until one of the following events occurred: either 1 ) disease progression during thalidomide therapy or 2) the individual's inability to tolerate continuation of the remission-associated dosage of thalidomide. At that point, the combination of moderate dose thalidomide, 200 mg daily, and dexamethasone therapy, (40 mg administered on day 1-4 and day 14-17 of each month), was offered, as an alternative to thalidomide alone. Of the 40 patients who were treated with thalidomide monotherapy, 30 responded. (75%) The median duration of thalidomide therapy at the time of this writing among these responders is 6 months, but 15 of the 30 or half of the patients are still taking thalidomide monotherapy and remain in remission using it. Moreover, a change in therapy to dexamethasone and thalidomide occurred in 17 patients. Of these who changed 5 were primarily thalidomide resistant. Only 3 (10%) of the 30 responders were changed because of disease progression occurring on thalidomide monotherapy. The remaining twelve (40%) changed to the DT combination because they could not tolerate continued exposure to the side effects associated with the remission achieving dosage of thalidomide and sought to lower their thalidomide dosage. Of the 17 treated with DT, 13 responded. Twelve of these 13 had not shown dexamethasone resistance previously. One of 4 dexamethasone resistant patients responded well to the DT regimen. In summary the likelihood of response to thalidomide, defined as a sustained, greater than 25 % drop in monoclonal protein is high among relapsed patients, but achievement of maximal response or maximal duration of response is limited, not by drug efficacy, but by tolerance of optimal dosing. Analogs achieving equivalent TNF alpha inhibition with diminished neurotoxicity should substantially impact on remission duration and survival in myeloma.