By Rafat Abonour, MD

2008-12-09

A large number of studies have been presented at this meeting addressing the biology and therapy of multiple myeloma (MM). The race to better understand the pathophysiology of the disease and land the “R-CHOP” with hope for cure led to an unprecedented number of clinical trials with new agents and newer combinations.

As we are still working with currently approved proteasome inhibitors and IMiDs, newer agents in these classes are evolving as powerful tools in refractory diseases. In addition, we are discovering newer mechanisms of action for these agents (abstract #846). The Little Rock group presented data showing that bortezomib induces osteoblast differentiation leading to bone mineralization. The same group showed that rapid activation of proteasome genes and their corresponding proteins in MM cells within 48 hours of a single bortezomib test-dose exposure is an indicator of poor clinical outcome (abstract #733). This intriguing observation after appropriate validation may lead to better dosing with bortezomib or using different agents in these high-risk patients. The University of Pittsburgh group (abstract #845) showed that neutropenia associated with IMiDs is related to down-regulation of PU.1, a key transcription factor involved in granulocyte differentiation. Their findings show that IMiDs do not induce neutropenia by marrow suppression but rather by a transient blockade of maturation, which might be overcome by application of G-CSF.

Among the several new combinations presented was the Mayo Clinic study of lenalidomide, cyclophosphamide, and dexamethasone (RCD) (abstract #91) in newly diagnosed patients. In 53 patients enrolled, overall response rate was 78 percent, and 48 percent had more than very good partial response (VGPR). Myelosuppression was a significant toxicity leading to new dosing for cyclophosphamide. The EVOLUTION study increased the heat by adding bortezomib to the RCD combination. Side effects were predictable and easily manageable (abstract #93). Preliminary response rates were seen in all treated subjects with more than 68 percent having a VGPR. A similar but sequential combination of bortezomib, thalidomide, cyclophosphamide, and dexamethasone was reported by Dr. William Bensinger (abstract #94). In 44 eligible patients, 56 percent achieved more than VGPR.

From across the Atlantic came the Dutch cooperative group HOVON, a randomized phase III study in elderly patients with multiple myeloma treated with MPT versus MP (abstract #157). Is thalidomide important? The quality of the responses seen in the thalidomide-treated group was clearly better. However, OS was not different, perhaps because a substantial number of the MP patients received thalidomide as the second-line therapy.

The number of new agents being tested grows rapidly. The MMRC reported positive results on a novel proteasome inhibitor carfilzomib. Another new IMiD was studied in 37 patients by the Mayo group. Pomalidomide was highly active even in lenalidomide-refractory patients and well tolerated. Results of a clinical trial with perifosine, an oral novel signal transduction modulator with multiple pathway effects, including inhibition of Akt and activation of JNK, led to durable responses in 40 percent of patients. Finally, vorinostat, a histone deacytylate inhibitor, when combined with bortezomib, appeared to overcome resistance to single-agent bortezomib.

Several transplant studies were presented. So what is the best induction regimen? Replacing vincristine with bortezomib (PAD) in the VAD induction regimen showed that VGPR was better in the PAD before and after high-dose chemotherapy. A more complicated three-arm regimen showed that the thalidomide-bortezomib combination was associated with higher complete remission. Dr. Palumbo updated the trial of  bortezomib-doxorubicin-dexamethasone as induction prior to reduced-intensity autologous transplantation followed by lenalidomide as consolidation/maintenance in elderly patients (abstract #159). This Italian version of total therapy resulted in 95 percent VGPR and 40 percent CR.

Yes, indeed this is only a dizzying sample of what is being presented about MM. However, we all agree that we are witnessing incredible and magical responses even in a group of patients that we had little to offer a few years ago. The search is on for a cure.

Dr. Abonour indicated no relevant conflicts of interest.

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