Bortezomib Combo Keeps on Giving in Myeloma

Martin Dreyling, MD


October 12, 2012

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Prognostic Markers: A Complicated Picture

Hello, I am Martin Dreyling, Professor of Medicine at the University of Grosshadern in Munich, Germany. Welcome to this edition of Medscape Oncology Insights on hematologic malignancies. I will highlight for you several of the important studies in blood cancers presented at the 2012 Annual Congress of the European Society for Medical Oncology (ESMO).

The first highlight for me was the overview of the molecular biology programs in leukemia and lymphoma, presented by Elias Campo.[1]We have to realize that life is becoming more difficult. It is not sufficient to have 1 prognostic marker, now that we have to cover full cell programs as risk and predictive factors. Elias gave a very nice example, which is SOX11.

SOX11 as a factor is intensively discussed in mantle cell lymphoma, and in the initial series, we could see that cases that did not express SOX11 had a more indolent course. Recently, our Swedish colleagues[2] showed that SOX11 was a negative prognostic factor. To bring all of these data together, we have to look for additional secondary alterations, such as p53, and p53 in the setting of SOX11 helps to decide the prognostic relevance of this marker.

In the third presentation, Michele Ghielmini[3] gave an overview on the individual treatment strategies in different lymphoma subtypes, specifically the molecular targeted therapies. It is worthwhile to realize that there are 2 major roads to follow. One strategy is the use of intensified antibodies. These are, for example, toxin-labeled antibodies, which have shown quite satisfying response rates in recent studies. The second strategy is small molecules, targeting specifically the B cell-receptor pathway. The latter pathway in particular will play a crucial role in the further development of clinical care of our patients.

AML: Flow Cytometry Aids Prediction

Let us move to the scientific presentations. I will start with acute myeloid leukemia (AML) as a paradigm of how molecular markers influence our clinical procedures. Dr. Sharawat from New Delhi, India,[4] presented data on a series of more than 150 patients with AML, and they investigated known risk factors, such as stem cell factor expression and FLT3. They applied flow cytometry analysis, which enabled them to detect CD117 as well as CD135 as negative prognostic factors. Flow cytometry analysis is simple, standardized, and easy to apply, so this might be a practical approach that will lead to further improvement in our treatments.

In another presentation focused on molecular markers embedded in molecular treatments, the Ulm group and Lars Bullinger[5] presented data on a phase 1-2 study in acute myeloid leukemia that used belinostat, which is an HDAC [histone deacetylase] inhibitor, in addition to anthracyclines (idarubicin). In this small series, it could be shown very convincingly that gene profiling predicted sensitivity to this targeted approach. Just by identifying a low number -- approximately a dozen -- of molecular markers, they could predict whether the patient is going to respond or not respond to this treatment. Crucial members of this panel are, in fact, well-known players in the field of AML -- MLL and p53.

ATLL: Poor Prognosis Data From Japan

With the rare disease adult T-cell leukemia/lymphoma, it is fair to say that in Europe we have much less experience compared with our Japanese colleagues. Dr. Katsuya[6] gave an overview of the clinical course of more than 150 patients who were treated in Japan during the last decade. In a previously published study focusing on the different clinical courses of the disease, it was easy to differentiate between an acute and a smoldering form of disease.[7] In contrast, in the current series, this could be not reproduced. Even the so-called "smoldering" disease had a poor outcome, with a median overall survival in the range of 3-3.5 years.

How can we explain these results? It is not absolutely certain, but we can say that this series was based on chemotherapy only. The future is going in the direction of molecularly targeted approaches or more intelligent approaches, an example of which was recently published by our French colleagues, who provided very promising data combining interferon plus an antiviral strategy.[8]

ALCL: First-line Brentuximab Is Promising

Let's move on to anaplastic T-cell lymphoma (ALCL). Michelle Fanale from the MD Anderson Cancer Center presented first data[9] from a phase 1 trial in first-line treatment of this disease. Anaplastic T-cell lymphoma is divided into 2 groups: ALK [anaplastic lymphoma kinase]-positive and ALK-negative disease. However, the clinical problems are the ALK-negative cases. Crizotinib, which is a major player now in the care of lung cancer, does not play a major role here, but we have a specific antibody that targets CD30, which is expressed by these cells.

In this first phase 1 first-line treatment study, the researchers combined this very promising compound (which has so far been tested only in relapsed disease in monotherapy) and combined it with the standard first-line treatment (CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisolone]). They started with 2 cycles of brentuximab, then stepped in with 6 cycles of CHOP and finished up with 8 additional applications of brentuximab.

What was the outcome of this phase 1 trial? First of all, and of greatest importance, it was feasible. This treatment was very well tolerated, and side effects were moderate, specifically the well-known polyneuropathy. Second, in this first series of 30 patients, 10 had achieved ongoing complete remissions, and specifically in this high-risk patient group, most (10 of 30) were ALK-negative.

These are quite satisfying results. Of course, this has to be confirmed in a randomized trial, which is just being planned.

Multiple Myeloma: Bortezomib Not Affected by Previous Treatments

The final topic is multiple myeloma. We had an excellent presentation by Heinz Ludwig,[10] who represented the Austrian group. He presented data from a phase 2 trial investigating the combination of bendamustine, bortezomib, and dexamethasone. This was a phase 2 trial with 74 patients, and the overall response rate was in the range of 60%. Even patients who had previously been treated with bortezomib achieved a 76% response rate. In contrast, patients treated previously with lenolidomide achieved only a response rate in the range of 44%-60%.

What are the consequences of these data? Bendamustine, at least in Germany, is a well-known approach to the treatment of multiple myeloma. If you combine it with the molecular approach, you have to reduce the dose to about 70 mg/m2. Finally, what is probably the most important thing with respect to the therapeutic algorithm in multiple myeloma is that it is possible to re-expose patients initially treated with bortezomib to another combination -- for example, bendamustine, bortezomib, and dexamethasone -- and again achieve promising durations of remission of 12 or 13 months, as long as the patient initially responded to the bortezomib.

Tailoring Therapy to Response and Comorbidity

That has very important consequences for the therapeutic algorithm, and these ideas were discussed by Dr. Mohty,[11] who just recently moved from Nantes to Paris. He very nicely showed the different treatment options for this kind of disease and emphasized that we not only have to keep in mind the individual line of treatment, but we also have to have an overall strategy. Of course, this overall strategy has been also guided by the patient's performance status.

The comorbidity index was discussed by Dr. Kim from Seoul,[12] and it is very important in our daily clinical care that we individualize these approaches to our patients. This is the best meaning of personalized medicine.

Closing Remarks

With that, I will conclude. Thank you for joining me for this edition of Medscape Oncology Insights. This is Martin Dreyling, reporting from ESMO 2012 in Vienna.