THAL in refractory MM[18
A phase-I/II study of dose-escalated THAL (maximum daily dose of 800 mg/d) was conducted in 1998. Of 169 patients with advanced and refractory MM enrolled, 67% had CA; 76% had received one and 53% two prior transplants. PR status was achieved by 30%, including 10% who entered CR. Median durations of OS and EFS were 20 months and 6 months, respectively; at 72 months, nearly 20% of the patients are currently alive, and 10% remain event-free 7 years after treatment initiation.
Bortezomib–thalidomide–dexamethasone (VTD) salvage therapy[21
A phase-I/II trial of this combination was performed between March 2002 and December 2004. A starting dose of 1.0 mg/m2 of bortezomib was administered on days 1, 4, 8, and 11, with a cycle length of 21 days. THAL was added with the second cycle at a starting dose of 50 mg/day, with dose escalation to 100 mg, 150 mg, and 200 mg in cohorts of ten patients, with the possibility of added DEX pulsing after cycle 2 in case PR status was not achieved. Bortezomib was then increased to 1.3 mg/m2 in subsequent patient cohorts, using the same THAL dose escalation scheme and allowing for addition of DEX pulsing. The trial accrued 85 patients, 76% of whom had CA, and of whom 92% had had one and 65% two prior autotransplants. Eventually, 61% achieved PR status, including 7% who achieved CR. The dose-limiting toxicity of the combination was peripheral neuropathy grade 3, which was observed when THAL was increased to 150 mg with bortezomib 1.3 mg/m2. The median durations of EFS and OS were 9 months and 22 months, respectively, but were shorter in the presence of CA (data not shown); at 3 years, 30% of patients are alive and 10% are event-free.
Phase-II evaluation of rapidly recycled high-dose DT-PACE (HD-DTPACE) with PBSC boost[41
Due to dose- and time-interval–limiting mucosal toxicity, MEL200 cannot be rapidly recycled, so that relapse may occur prior to the ‘timely’ administration of second transplant within 2–3 months after the first. Achieving similar CR rates in high- and low-risk MM is deceiving as far as long-term success of therapy is concerned because, in high-risk MM, the depth of tumor mass reduction is likely to be less profound, and tumor re-growth may proceed sooner. Thus, it appears worthwhile to test the hypothesis that rapidly recycled non-normal stem-cell-toxic HD-DTPACE (with scheduled PBSC boosts after each cycle to avoid cumulative myelotoxicity) can produce more profound net tumor cytoreduction without significant re-growth between cycles. Off-protocol pilot data in 30 patients, mostly with CA, are summarized in . Of 16 patients receiving one cycle, five achieved CR, two near-CR, and eight PR; of eight receiving two cycles, one achieved CR, three near-CR and three PR; of three patients receiving three cycles, two achieved near-CR and two PR; all three receiving four cycles achieved near-CR. Thus, among all 30 patients treated, the rates of CR, near-CR and PR were 20%, 27% and 43%, respectively. There were no deaths in this series of patients.
Characteristics of patients and response to high-dose dexamethasone (DEX), thalidomide (THAL), cisplatin, doxorubicin, cyclophosphamide, etoposide (HD-DTPACE). See text for details.
Fractionated MEL-VTD as salvage transplant regimen[42
There is synergistic interaction between MEL and immunomodulatory agents, THAL and lenalidomide, as well as the proteasome inhibitor bortezomib.[43
] To date, we have applied, in an off-protocol setting, MEL-VTD as follows: bortezomib administered at 1.0 or 1.3 mg/m2
on days 1, 4, and 7 along with THAL at 100 or 200 mg/day for 7 days, DEX at 20 or 40 mg on the days of and after bortezomib administration, and MEL at 50, 60, 70, 80, 90, or 100 mg/m2
after each bortezomib dose, for total MEL doses of 150, 180, 210, 240, 270 or 300mg/m2
(). Despite highly unfavorable patient and disease features (CA present in 69% of all 94 patients), MEL-VTD promoted high frequencies of near-CR and CR in almost 70%, with frequent resolution of MRI-FL. Toxicities – especially grade >2 stomatitis – were noted in fewer than 10% of subjects. Tandem MEL300-VTD transplants were given to 11 patients, including two who had previously been exposed to a total dose of 400 mg/m2
as part of an original MEL200-based tandem transplant regimen (total, 1000 mg/m2
Melphalan (MEL) plus Velcade (bortezomib), thalidomide, and dexamethasone (M-VTD) regimen and response.
An important component of a currently accruing formal trial of MEL300-VTD is a pharmacogenomic approach evaluating the 24-hour versus baseline GEP changes after a MEL test dose of 10 mg/m2. Repeat analysis 48 hours after the first of three therapeutic MEL100 doses will allow us to link test-dose- and therapeutic-dose-induced GEP changes with clinical outcome. By examining both plasma-cell and MAG expression changes, we hope to identify MEL-unique and prognostically relevant tumor and stromal cell gene alterations as a prelude to future routine in vivo drug sensitivity testing.
The Arkansas experience with more than 3000 transplants for MM (‘ARK 3000’)[44
We performed MEL200-based transplants in more than 3000 patients with MM (‘ARK3000’). Three treatment groups were distinguished: (1) TT-P, comprising patients on TT protocols for newly diagnosed disease that included protocol-based induction therapy; (2) non-TT-P, comprising patients receiving other protocol-based transplants in case of prior treatment; and (3) non-P, comprising patients given off-protocol transplants due to protocol ineligibility or patient/physician preference. As expected, the TT-P group had more favorable baseline features in terms of CA, B2M, CRP, and albumin, compared with previously treated patients; pre-transplant CR was higher, and a second transplant was completed more frequently. Post-transplant outcomes (OS, EFS and CR duration not shown) with TT-P were superior to outcomes after non-TT-P, which in turn were better than those in the non-P group (). Multivariate analyses of pre-transplant parameters and type of treatment intervention revealed TT protocol therapies to be independent favorable features for OS, EFS and CR duration (). As shown in , five subgroups could be discerned that exhibited distinctly different OS according to the number of favorable parameters: absence of CA of chromosome 13 or hypodiploidy (CA13/hypo), low B2M, low CRP, high albumin, and high platelet count.
Figure 5 (a) Survival from first transplantation among the ‘Arkansas 3000’ group of patients according to whether they were treated on Total Therapy (TT) protocols (TT-P), other protocols for previously treated patients (non-TT-P), or off-protocol (more ...)
Multivariate analysis of pre-transplant parameters and treatment regimen associated with overall survival (OS), event-free survival (EFS) and complete response (CR) duration.
Among 251 patients receiving a third transplant, 120 with at least 3 years elapsing since their second transplant enjoyed a subsequent survival of almost 2 years as opposed to 8 months among the reminder. Their better outcome was accounted for by more favorable laboratory features, such as lower incidences of CA (especially the CA13/hypodiploidy variety) at any time or within 6 months from first transplant and LDH elevation prior to first transplant. Thus, further stem-cell-supported therapies should be considered for the further management of patients with durable preceding remissions, especially when new agent-associated toxicities such as neuropathy become overwhelming or pancytopenia develops that precludes administration even of the modestly myelosuppressive lenalidomide. We have also applied MEL-based transplants in the setting of treatment-induced myelodysplasia (t-MDS) or acute leukemia, provided that PBSCs had been collected at a time when no MDS-associated CAs (MDS-CA) were present on bone-marrow examination. Maintaining further transplant options requires collection of adequate PBSC quantities, in our practice a minimum of 20 x 106 CD34/kg.