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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).

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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.

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For more than 25 years, melphalan and prednisone has remained as the gold standard treatment for elderly multiple myeloma (MM) patients. Bortezomib has shown significant activity with manageable toxicity in refractory/relapse MM patients. Moreover, in vitro synergy has been reported when bortezomib is combined with cytotoxic agents such as melphalan. Aim: To define the appropriate dose of bortezomib in combination with MP and to analyse the efficacy of V-MP in untreated MM patients ≥ 65 years old. Methods: This is a dose escalation study with two sequential dose levels (Ph 1) and expansion of the cohort at the MTD by 60 patients to further refine estimates of efficacy (Ph 2). In the first cohort, bortezomib (1mg/m2) was administered as a iv bolus to 6 consecutive patients on days 1,4,8,11,22,25,29 and 32 followed by a 10 day rest period in combination with oral melphalan, 9 mg/m2, and prednisone, 60mg/m2, once daily on days 1 to 4. In the 2nd cohort, bortezomib was administered at 1.3mg/m2. MTD was defined as that dose level below which 2/6 patients had a DLT. Patients: 12 patients have been enrolled to date - 6 in cohort 1 and 6 in cohort 2. Results: Toxicity has been manageable. The first cohort at 1 mg/m2 has completed at least two 6-week treatment cycles. There was no DLT in the first cycle. The 2nd cohort has enrolled 6-patients at a dose of 1.3 mg/m2 but none has completed the first cycle yet. In the first cohort, there was one patient with grade 3 neutropenia (ANC = 0,668) observed at Cycle 1 Day 25. During the second cycle, there were no patients with grade 4 therapy-related toxicity and only one grade 3 adverse event (neutropenia) was observed. The most common grade1 or 2 toxicities were nausea, vomiting, rash, constipation, diarrhea, fever, herpes zoster infection, anorexia, neutropenia, anemia and thrombocytopenia. Ocular neuropathic pain (grade 2) developed de novo in 1 patient during the first cycle; one dose of bortezomib was held and the adverse event resolved with analgesic treatment in 4 days. Treatment was continued at a dose of 0,5 mg/m2 at D11 and D22. After this date, bortezomib at 1.0 mg/m2 was restarted. The second cohort is in the first 6-week cycle at present, so observations are limited. One serious adverse event (pulmonary embolism and probably septic shock with death) was observed in this cohort in a patient at day +11. He had normal WBC. Two grade 3 adverse events (leucopenia and neutropenia) were observed in one patient. Other grade 1 or 2 toxicities are similar to those observed in the first cohort. Regarding response, after two cycles of treatment, in the first cohort, 3 out of the 6 patients have experienced >50% reduction in M-protein (two with > 75% reduction) and the others three have experienced either a minor response (1) or stable disease (2). In the second cohort, response data are not available at this time. Conclusion:The combination of V-MP is well tolerated at standard doses of MP with bortezomib 1 mg/m2 with no DLTs in 6-patients. Bortezomib (1.3 mg/m2) is being explored in the second 6-patient cohort in order to define the MTD. So far, no patient has developed DLT. Rapid M-protein responses have been seen. Results will be updated and presented for the 2nd cohort.