Experts Disagree on Role of Transplant in Myeloma

Oct 4, 2013

New drugs provide powerful options, but little consensus on standard treatments

New York—There is a profound disagreement over whether early stem cell transplant (SCT) should still be characterized as a standard early intervention for multiple myeloma (MM), even in relatively young patients.

Newer drugs are yielding response rates comparable to transplant, and this development has fundamentally altered traditional approaches to this malignancy. At the 17th International Congress on Hematologic Malignancies, experts debated how these treatments have affected the role of transplant.

“The treatment of multiple myeloma is no longer a 100-yard dash; it is a marathon,” said James R. Berenson, MD, the medical and scientific director of the Institute for Myeloma and Bone Cancer Research in West Hollywood, Calif. According to Dr. Berenson, better-tolerated, newer drug therapies now produce response rates that rival those produced with SCT, while preserving future options when the cancer progresses.

“Patients need to be able to avail themselves of the opportunity to seek the newer therapies. Reducing that ability with too much prior treatment at too high of a dose is detrimental to their long-term outcomes, which not only includes their overall survival but their quality of life,” Dr. Berenson said.

The opposite view, presented by Nikhil C. Munshi, MD, the associate director of the Jerome Lipper Multiple Myeloma Center at the Dana-Farber Cancer Institute (DFCI) in Boston, is drawn from the results of six major trials that have associated up-front SCT with longer progression-free survival (PFS) and overall survival rates than comparator strategies in relatively young patients with MM. Although toxicity is greater with SCT, the survival advantage is observed even in MM of an advanced stage or with adverse cytogenetics. Although it might be reasonable to initiate treatment with newer therapies, such as bortezomib (Velcade, Millennium) and lenalidomide (Revlimid, Celgene), and then employ SCT as second-line therapy, Dr. Munshi is not convinced that the data supports this.

“The question was: Can we delay transplant? And my question is, why?” Dr. Munshi said. Although he acknowledged that there is no well-established survival advantage with employing SCT early rather than late, there is “emerging data” that outcomes overall are better. Generally, SCT can be expected to be attractive early in the development of the disease when patients are healthier, and Dr. Munshi noted that delaying SCT in some cases may be detrimental, especially to those with extensive bone disease, renal dysfunction and aggressive disease, or those near the age for which SCT becomes relatively contraindicated.

The argument for SCT is that it has provided deeper responses than standard-dose therapy, including higher proportions of complete (CR) and molecular responses. In MM, like most other hematologic malignancies, deeper responses track with better outcomes. Although Dr. Munshi acknowledged that the advantage of SCT so far has been predominantly demonstrated against therapies with less activity than those now in widespread use, he said randomized trials using newer agents are needed to overturn the standard. In response, Dr. Berenson, while acknowledging the absence of head-to-head comparisons of SCT and combinations of newer agents, maintained that these newer regimens appear to consistently show greater anti-myeloma activity than that of SCT.

“What about the high CR rates?” Dr. Berenson said. “Well, guess what? The highest CR rates are no longer being achieved among transplant patients but were seen from the results of the trial involving carfilzomib, lenalidomide and dexamethasone. Moreover, I expect we will do even better as we figure out how to best use these newer agents together.”

In regard to carfilzomib (Krypolis, Onyx) in combination with lenalidomide and low-dose dexamethasone (the “CRd regimen”), he specifically cited a recent Phase I/II trial in which 78% of the 36 patients who completed eight or more front-line treatment cycles achieved a near CR or better (Blood 2012;120:1801-1809, PMID: 22665938). The 24-month PFS in this group was 92%. Both numbers are the highest yet reported to date in any clinical trial involving treatment of newly diagnosed MM patients.

However, Dr. Munshi does not discount the potential of combining SCT with newer therapies. He cited two studies that demonstrated further improvement in response by SCT following induction therapies with novel agent combinations that provide high responses. This suggests SCT could further add to the high responses now observed with novel combinations.

The debate about the role of early SCT could be at least partially resolved with data generated from an ongoing trial known as Intergroupe Francophone du Myelome (IFM)/DFCI 2009 that Dr. Munshi has been closely involved in developing. In the trial, which has completed enrollment, patients between the ages of 18 and 65 with MM and no prior therapy were randomized to receive lenalidomide, bortezomib and dexamethasone (RVD) with or without SCT (see page 19). The primary outcome is PFS. Relative toxicity will be evaluated as a secondary end point even though quality-of-life comparisons are not a part of the formal design.

The trial has the potential to establish whether SCT adds benefit when combined with newer agents, but Dr. Berenson is already impressed with the response rates with newer agents without SCT. He is convinced that SCT diminishes the options available to patients who are unable to tolerate treatments necessary to overcome their disease as it progresses over time. In addition to newer agents, patients now have access to combinations of these agents in multiple effective maintenance treatments such as lenalidomide and steroids, better supportive-care approaches and other viable strategies that prolong survival when first-line therapies become ineffective.

“After failing their initial treatment, patients are no longer going over a cliff like they were in the 1990s when treatment options were so limited,” Dr. Berenson said. “We do not know what is ahead of us, but we do know that survival is now very long, so to compromise the patient’s ability to receive the many effective treatment options now available—and what I hope may be curative therapy in the future—because of the toxicity from high-dose therapy, is also important to consider.”

As a result of these specific concerns, Dr. Berenson reported that he is no longer recommending SCT for any of his patients even as a second-line strategy. Although conventional wisdom supports the perspective of Dr. Munshi, whose approach is based on trials uniformly accepted as establishing the standards of clinical practice for MM, Dr. Berenson does not appear to be alone in his position. During a panel discussion that followed the debate, Ola Landgren, MD, PhD, the chief of the MM section at the National Cancer Institute (NCI) in Bethesda, Md., also suggested that the data generated by newer agents has changed practice at the NCI.

“In our clinical trials, we no longer transplant up front,” Dr. Landgren said. Based on the kinds of deep responses achieved with chemotherapy alone, he indicated that the toxicity of SCT no longer appears warranted at least as an initial treatment approach.

Although Dr. Munshi does not disagree that the activity of the newer agents is very promising, he countered that SCT would be an added consolidation component of this long-term strategy, further improving outcomes.

The IFM/DFCI trial has the potential to determine whether chemotherapy alone is as good or better for long-term outcome as SCT plus chemotherapy, but equivocal results could be problematic for resolving this debate if further studies with CRd or other emerging agents suggest that these offer superior activity to those being employed in the IFM/DFCI study. Importantly, the goals in the current era differ from those when MM survival was measured in months. As survival rates increase, the most aggressive regimen may no longer be the best initial option if other options can preserve a good quality of life over a longer period.

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