In young patients under age 65, stem cell transplants have greatly reduced remission rates when coupled with novel therapeutic agents (thalidomide, Velcade, and Revlimid).

Unlike elderly patients, younger individuals are usually healthy enough to withstand an intensive course of high-dose chemotherapy. The chemotherapy, while a potent killer of cancerous cells, also destroys bone marrow, therefore necessitating a transplant after treatment. In conjunction with high-dose therapy and transplant, the introduction of novel agents has further improved complete remission (CR), very good partial remission (VGPR), and progression-free survival (PFS) rates.

Of the three novel agents available, researchers first tested thalidomide by administering a thalidomide/dexamethasone (Thal/Dex) combination treatment before stem cell transplantation. Overall, the Thal/Dex regimen yielded superior CR and VGPR rates before transplantation, as compared to traditional high-dose chemotherapy. However, the overall CR rate remained low and Thal/Dex did not provide a meaningful increase in post-transplantation remission rates.

Adding either cyclophosphamide or doxorubicin has improved post-transplant response rates.

Researchers have also tested a combination of Velcade and dexamethasone (Vel/Dex) against traditional high-dose chemotherapy, again finding superior response rates in the novel agent regimen. Compared to traditional therapy, Vel/Dex significantly improved the CR and VGPR response rates both before and after stem cell transplantation. Additionally, Vel/Dex produced fewer incidences of peripheral neuropathy, or nerve damage in the extremities.

In particular, poor-risk cytogenetic patients, who usually experience less favorable treatment outcomes, achieved equivalent CR rates on the Vel/Dex regimen. Researcher Jean-Luc Harousseau, MD, advises, “This regimen could be considered the standard of care to which other regimens should be compared and the backbone of more complex combinations.”

Finally, researchers tested a Revlimid/dexamethasone combination (Rev/Dex), achieving a 56 percent CR/VGPR response rate. The treatment yielded very high progression-free survival and overall survival rates in the short-term.

Despite these promising results, the role of Rev/Dex in conjunction with stem cell transplantation remains unclear, both because robust data is lacking and because Revlimid reduces the number of stem cells available for transplant. Adding other drugs, however, appears to overcome the negative impact of Revlimid on stem cell collection.

Nevertheless, Harousseau emphasizes the need for further studies combining a Revlimid regimen with stem cell transplantation.

Armed with the promising results of novel agents over traditional chemotherapy, researchers have also experimentally combined novel agents into one regimen. In a study of Velcade, thalidomide and dexamethasone (VTD), VTD was clearly superior to Thal/Dex, achieving CR and VGPR rates of 60 and 77 percent, respectively.

A Velcade, Revlimid, dexamethasone combination (VRD) has, in preliminary results, achieved a response rate of almost 100 percent. Researchers are also testing short courses of VTD with chemotherapy (V-DTPACE) with the aim of high response rates but reduced toxicity.

While combining multiple novel agents appears most effective at reducing tumor burden, Harousseau explains that it is still too early to determine whether better tumor reduction will translate into longer progression-free and overall survival.

Researchers have also evaluated adding thalidomide not only before transplantation to reduce tumor burden, but also afterwards as ongoing maintenance therapy. These trials demonstrated significant survival advantages.

Ongoing trials of Velcade and Revlimid are also examining these novel agents as post-transplant maintenance therapies.

“Therefore, when more mature data are available, the standard intensive frontline therapy for younger patients could become induction with novel agents, ASCT [stem cell transplantion] as consolidation, and maintenance with novel agents,” Harousseau concludes.

For more information, please see the full article in the American Society of Hematology's 2008 Education Program Book, Hematology, and a related Beacon article on treatment in elderly patients.