The Impact of Withholding Immunomodulatory Drugs for Stem Cell Mobilization On Disease Activity in Multiple Myeloma.

Novel agents, such as lenalidomide, thalidomide, and bortezomib, are being used with increased frequency in combination with dexamethasone as induction regimens for frontline treatment of multiple myeloma, especially in patients who are eligible for high dose chemotherapy with autologous stem cell transplantation (ASCT). The current standard of care is to allow a “washout” period of at least 28 days from the end of induction therapy to the time of stem cell mobilization and subsequent transplant. It has been generally observed that disease progression is imminent in the majority of patients within a few months once an immunomodulatory agent is discontinued. We report our experience in disease progression during this “washout” period. Based on previous data of treatment-free intervals, we hypothesize that the patients who received bortezomib-containing regimens would have a lower incidence of disease progression from the end of induction therapy to the time of transplant.

We conducted a retrospective chart review of patients who received high dose chemotherapy with ASCT from January 2006 to July 2009. Inclusion criteria required a period of at least 28 days between the end of induction therapy to transplant; treatment with a single novel agent and dexamethasone; and the presence of secretory disease. Patients were divided into three groups: Group 1 included patients who received bortezomib and dexamethasone (B; n=12); Group 2 included patients who received thalidomide and dexamethasone (T; n=10); and Group 3 included patients who received lenalidomide and dexamethasone (L; n=13). Determination of progressive disease (PD) versus stable disease (SD) was defined as follows: > 25% increase and a minimum of 500 mg increase in the serum M protein level. In addition, a second group of “near PD” (nPD) included those patients with > 25% increase but did not yet have a 500 mg increase in the serum M protein level. For patients with an unknown or non-quantifiable serum M protein level, the involved immunoglobulin measurement was used.

A total of 35 patients were included in three arms of analysis as shown in Table 1. In Group 1 (B), 50% (n=6) had stable disease, 17% (n=2) had progressive disease, and 33% (n=4) had near progressive disease. In Group 2 (T), 50% (n=5) had stable disease, 20% (n=2) had progressive disease, and 30% (n=3) had near progressive disease. In Group 3 (L), 54% (n=7) had stable disease, 8% (n=1) had progressive disease, and 38% (n=5) had near progressive disease. Ten patients in Group 3 (L) received cyclophosphamide to aid in stem cell mobilization. The median number of days from the end of induction to the time of transplant (i.e. washout period) was 75 days in Group 1 (B), 80.5 days in Group 2 (T), and 72.7 days in Group 3 (L).

It was incidentally noted that the patients across all treatment groups who had SD at the time of transplant had a slighter higher rate of achieving CR after ASCT than those who had PD or nPD.

We conclude that even a short period (> 28 days) without therapy may be associated with disease progression in a significant number of patients. In our small sample size, this did not appear to differ according to the induction regimen, which disproves our original hypothesis that the bortezomib treated group would have a lower incidence of disease progression from the end of induction to the time of transplant. Further data, including the impact on survival, is being accumulated. Larger prospective trials, however, are needed for more in depth analysis.

This observation would support the Arkansas group approach to continue some form of therapy throughout induction, stem cell mobilization, and until transplant (Blood, 2008; 112: 3115). In the setting of continued immunomodulatory agent therapy right up to stem cell mobilization, the use of cyclophosphamide, combination chemotherapy (i.e. the Arkansas approach) or plerixifor may be required to improve stem cell yield pre-transplant.

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