Treatment in medical oncology is gradually shifting from the use of non-specific chemotherapeutic agents towards an era of novel targeted therapy in which drugs and their combinations target specific aspects of the biology of tumor cells. Multiple myeloma (MM) has become one of the best examples in this regard, reflected in the identification of new pathogenic mechanisms, together with the development of novel drugs that are being explored from the preclinical setting to the early phases of clinical development. We review the biological rationale for the use of the most important new agents for treating MM and summarize their clinical activity in an increasingly busy field. First, we discuss data from already approved and active agents (including second- and third-generation- proteasome inhibitors, immunomodulatory agents (IMIDs) and alkylators). Then we focus on agents with novel mechanisms of action, such as monoclonal antibodies (MoAb), cell cycle specific drugs, deacetylase inhibitors, agents acting on the unfolded protein response, signaling transduction pathway inhibitors, and kinase inhibitors.
Among this plethora of new agents or mechanisms some are specially promising: Anti-CD38 MoAb, such as daratumumab, are the first antibodies with clinical activity as single agents in MM. Also the kinesin spindle protein inhibitor Arry-520 is effective in monotherapy as well as in combination with dexamethasone in heavily pretreated patients. Immunotherapy against MM is also being explored, and probably the most attractive example of this approach is the combination of the anti-CS1 MoAb elotuzumab with lenalidomide and dexamethasone, that has produced exciting results in the relapsed/refractory setting.
Patients from groups BA and BB presented with a significantly higher number of adverse prognostic factors, reflecting that we were dealing with high tumor MM cases, as compared with patients from group AA. The number of mononuclear cells, CD34+ cells and CFU-GM cells collected in patients with non-reversible renal insufficiency was similar to those harvested in MM patients with normal renal function. Moreover, neutrophil and platelet engraftments were identical in patients with and without renal failure (days +11 and +12, respectively). By contrast, transplant-related mortality (TRM) was significantly higher in group BB patients (29%) than in groups BA (4.1%) and AA (3.3%). In multivariate analysis only three variables showed independent influence on TRM: poor performance status (ECOG 3), hemoglobin <9.5 g/dl and serum creatinine > or =5 mg/dl. The response to high dose therapy was independent of renal function. Interestingly, 43% of patients from group BB showed an improvement in renal function (creatinine < 2 mg/dl) after transplant. The three-year overall survival from transplantation was 56, 49 and 61% for the BB, BA and AA groups, respectively, with a statistically significant difference favoring group AA (P<0.01). PFS did not differ significantly between the three groups of patients. In multivariate analysis the only unfavorable independent prognostic factors for overall survival were poor performance status either at diagnosis or at transplant, high beta(2)-microglobulin levels, and no response to transplant. According to these results, ASCT is an attractive alternative for MM patients with renal insufficiency, and it should not constitute a criterion for exclusion from transplant unless patients display poor performance status and very high creatinine levels (>5 mg/dl).
We evaluated the clinical results of lenalidomide (Len) as a compassionate salvage therapy in refractory/relapsed multiple myeloma (MM) patients. A nationwide multi-centre, retrospective research study was performed to evaluate clinical data from patients with advanced MM for which compassionate use of lenalidomide was requested. The primary endpoints were the overall response rate (ORR) and the time to progression (TTP). Secondary objectives included safety and overall survival (OS) since starting of lenalidomide therapy. Data collected from the Spanish Compassionate Use Registry included 111 patients treated in 2006-2008. The median (range) number of previous treatment lines was 3 (1-8). The median duration of lenalidomide treatment while on study was of 4.9 months (1-18). Dexamethasone was given concomitantly with Len in 89% of patients. The ORR was 66% (4% of patients had stringent complete, 11% complete and 11% very good partial responses). Median TTP and OS were 13.0 and 17.4 months, respectively. The depth of response was significantly associated with a longer OS. Toxicity, mainly myelosuppression, was predictable and manageable with Len dose adjustments and cytokine support. Lenalidomide as salvage compassionate therapy in refractory/relapsed MM showed, in this series of heavily pre-treated patients, similar efficacy to that reported in pivotal clinical trials with acceptable tolerance.
It has been shown in non-randomized studies that tandem transplant results in an increased CR rate. A randomized trial showed that tandem transplant resulted in a significantly longer EFS and OS in patients failing to achieve CR or near-CR with a single transplant. However, other studies failed to show a survival benefit from a second transplant. The aim of our study was to investigate the feasibility and efficacy in terms of response up-grading and survival from a second transplant intensification in patients with chemosensitive disease who failed to achieve CR or near-CR with a first transplant. Patients diagnosed with MM from Oct 1999 to Dec 2003 younger than 70 years received 6 courses of VBMCP/VBAD chemotherapy and responding patients were intensified with busulphan/melphalan or MEL-200 followed by stem cell support. Patients not achieving CR or near-CR were planned to undergo a second transplant (either a second auto with CVB - cyclophosphamide, etoposide and BCNU - intensification or a dose-reduced intensity “allo” with Fludarabine/MEL-140 conditioning, depending on sibling donor availability). It is of note that 99 (55%) did not receive the second HDT procedure because patient refusal -28 pts-, lack of CD34–17 pts-, progressive disease - 16 pts-, poor PS -15 pts-, physician decision -14 pts-, others -8 pts-. Patients who did not proceed with the second transplant were significantly older (58 vs. 55 yrs, p= 0.001) and had higher serum beta2-microglobulin levels (4.7 vs. 3.5, p=0.02). Fifty nine patients received a second autologous transplant while 23 underwent a “mini-allo”. Twenty-eight percent of the patients given a second autologous transplant achieved an up-graded response (CR or near-CR: 7%, PR: 10% and MR 12%) while 61% showed “no change”, progressive disease or early death. A response up-grade was observed in 43% of patients undergoing a “mini-allo” procedure (CR: 26%, PR: 4%, MR: 3%). The CR rate was significantly higher with the allogeneic procedure (26 vs. 5%, p=0.01). However, there was a trend towards a higher TRM with the “miniallo” procedure (5% vs. 17% (p=0.09). The survival from the second high-dose procedure was not significantly different between the two transplant modalities (2nd auto vs “mini-allo”).
Conclusions.
in about one-half of the patients in whom a tandem transplant is planned the second high-dose procedure is not performed, a dose-reduced intensity allogeneic transplant after an autologous procedure results in a significantly higher CR rate than a tandem autologous transplant, with the current follow-up we found no significant differences in survival between the two transplant modalities.
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