October 10, 2016
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Should patients with multiple myeloma receive continuous therapy?

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Click here to read the Cover Story, “ICER report questions value of myeloma regimens, but critics say findings don’t translate to practice.”

POINT

Yes.

All transplant-eligible and transplant-ineligible patients with multiple myeloma should be considered for maintenance/continuous therapy. The continuous and/or maintenance therapy must be well tolerated by the patient with convenient administration — preferably oral or very intermittent subcutaneous or IV. Multiple myeloma is currently not a curable disease. There are a small number of patients whose disease will be well controlled for a long period following primary therapy. However, we are not able to prospectively identify these patients. In the absence of predictive biomarkers, all patients with multiple myeloma can potentially benefit from continuous therapy after primary induction treatment. For transplant-eligible patients, this consists of induction therapy followed by hematopoietic stem cell collection, high-dose therapy with melphalan and infusion of hematopoietic stem cells. Following recovery, administration of maintenance lenalidomide (Revlimid, Celgene) until progression improved PFS in three large studies from the United States (CALGB 100104), France (IFM 05-2) and Italy (GIMEMA RV-MM-PI-209).

Philip L. McCarthy, MD
Philip L. McCarthy

The U.S. study demonstrated an OS benefit. The IFM study did not, and the GIMEMA trial showed a trend toward OS improvement. None of these studies were powered to ask an OS question, and all had PFS as the primary endpoint. A meta-analysis of over 1,200 patients of the three studies demonstrated an OS benefit for lenalidomide maintenance (HR = 0.74; 95% CI, 0.62-0.89). The 26% reduction in risk for death represented an estimated 2.5-year increase in median survival. In a subgroup analysis, all categories benefited, including patients in and not in complete remission. For high-risk cytogenetic patients there was less of a benefit; for a large number of patients, cytogenetic information was not available. For very high-risk patients, a phase 2 study of lower-dose lenalidomide, bortezomib (Velcade, Millennium/Takeda) and dexamethasone, followed by lenalidomide maintenance, demonstrated the role of continuous therapy to control high-risk disease.

There is a risk for second primary cancers with lenalidomide maintenance, and currently we cannot predict who will get these second cancers. The risk is higher in patients who receive lenalidomide maintenance, and the risks for progression and death are higher for those who do not receive maintenance. Thus, continuous therapy with lenalidomide maintenance improves PFS and OS after autologous HSCT for newly diagnosed patients.

For transplant-ineligible patients, continued therapy improved PFS in the FIRST trial, which examined lenalidomide/dexamethasone therapy until progression, lenalidomide/dexamethasone for 18 cycles or melphalan/thalidomide (Thalomid, Celgene)/prednisone for 12 cycles. PFS was superior for continuous lenalidomide/dexamethasone (25.5 months) compared with 18 cycles (20.7 months) or melphalan/prednisone/thalidomide (21.2 months). OS for continuous lenalidomide–dexamethasone was superior compared with melphalan/prednisone/thalidomide (HR = 0.78; 95% CI, 0.64-0.96).

Continuous maintenance therapy after autologous HSCT and after induction therapy for the transplant-ineligible patients can be considered a standard of care. New agents, such as monoclonal antibodies and agents with novel mechanisms of antimyeloma activity that are well tolerated, may be incorporated into long-term disease control strategies. Another important aspect of conducting clinical trials will be the development of early endpoints such as minimal residual disease negativity and immune profiling to determine the best choice of long-term therapy, with the ultimate goal of cure.

References:

Attal M, et al. Abstract 8001. Presented at: ASCO Annual Meeting; June 3-7,2016; Chicago.

Attal M, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1114138.

Benboubker L, et al. N Engl J Med. 2014;doi:10.1056/NEJMoa1402551.

McCarthy PL, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1114083.

Nooka AK, et al. Leukemia. 2014;doi:10.1038/leu.2013.335.

Palumbo A, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1112704.

Sonneveld P, et al. J Clin Oncol. 2013;doi:10.1200/JCO.2012.48.4626.

Philip L. McCarthy, MD, is professor of oncology and internal medicine and director of the blood and marrow transplant program at Roswell Park Cancer Institute, and professor of oncology at University of Buffalo’s Jacobs School of Medicine and Biomedical Sciences. He can be reached at philip.mccarthy@roswellpark.org. Disclosure: McCarthy reports an investigator role in the CALGB 100104 trial.

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COUNTER

No.

One of the things that has become part of the accepted landscape of multiple myeloma management is the use of maintenance therapy. Although there are a large number of clinical trials currently studying the number of drugs and combinations available, maintenance has become synonymous with low-dose, single-agent lenalidomide (Revlimid, Celgene). Community oncologists and multiple myeloma experts alike use low-dose lenalidomide in almost any situation imaginable: in newly diagnosed and relapsed patients, and in patients who have or have not undergone autologous peripheral blood stem cell transplants. It has been used after almost any imaginable form of therapy.

David S. Siegel, MD, PhD
David S. Siegel

The use of maintenance lenalidomide grew out of a series of three randomized trials done over the past decade that have unequivocally shown that its low-dose administration leads to a dramatic prolongation of PFS relative to a comparable control group of patients not on maintenance therapy. One of these trials — a large intergroup study conducted in the United States by the Alliance for Clinical Trials in Oncology — ultimately showed a modest OS benefit, and a recent meta-analysis confirmed this advantage. There have been no randomized trials justifying maintenance in anything other than newly diagnosed multiple myeloma.

But before we close the book and declare the question answered, we need to reconsider the questions we were asking and whether these trials were designed to answer that question. The question can be presented easily: is there something “magical” about giving low-dose lenalidomide in the aftermath of therapy designed to maximally cytoreduce a patient with myeloma, or will that exposure to something that represents less than our maximal effort to eliminate the disease lead to the selection of resistant subclones that will ultimately lead to greater refractoriness to subsequent therapies? Both of these scenarios are certainly possible and not necessarily mutually exclusive.

Lenalidomide is a remarkable drug. We are only just beginning to understand its mechanism of action, and its effects are wide ranging. It is entirely possible that in the setting of low disease burden, the constant stimulation of the immune system might lead to long-term suppression in ways that are not currently understood. Having acknowledged that, do these trials prove that point? I would say no. The previously mentioned trial — which is the main driver of belief in an OS advantage — does not look at the magic vs. resistance question by its design. Because PFS served as its primary endpoint, the control arm was crossed over to lenalidomide shortly after the trial began. So, both arms ended up progressing while on low-dose lenalidomide. The notion of maintaining naiveté so these patients would have the benefit of more treatment-sensitive relapses was lost. The other two prominent trials — conducted in France and Italy — were not confounded by patient crossover, which could be why they did not show an OS benefit. None of these trials were designed or powered to consider OS as a legitimate endpoint.

The MRC Myeloma IX trial showed that maintenance therapy with thalidomide (Thalomid, Celgene) had only a modest PFS impact. It had no OS impact — an endpoint for which it was designed and powered — and actually showed a statistically significant decrease in OS for patients with high-risk disease. We can argue that thalidomide is not lenalidomide, and that most patients do not have high-risk disease. Yet, thalidomide is a very similar drug that engages the same cereblon receptor as lenalidomide. We also do not know that high-risk patients don’t represent a more compressed timeline that allows us to see trends with greater sensitivity at a more rapid pace. Numerous studies have demonstrated that we do not routinely recognize high-risk patients, and in the community, only a quarter of high-risk patients are identified as such. Academic centers do not do much better. Is it right to give all patients maintenance when there is a hint that it might be counterproductive for the most vulnerable?

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My most metaphysical argument against maintenance is actually an incredibly optimistic one. We have seen multiple myeloma therapy evolve dramatically in a relatively short period of time. We may already have the tools to cure some fraction of patients. We know from randomized trials that responsiveness and durability of response to subsequent therapy lines is reduced. Given that, for a therapy that is of marginal advantage at best, is it justified to select for greater refractoriness in an era in which we are on the cusp of tremendous changes in our treating abilities? I want to hold on to the very optimistic notion that I will be able to cure my patients — if not now, then soon.

References:

Attal M, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1114138.

McCarthy PL, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1114083.

Morgan GJ, et al. Clin Cancer Res. 2013;doi:10.1158/1078-0432.CCR-12-3211.

Palumbo A, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1112704.

David S. Siegel, MD, PhD, is chief of the myeloma division at John Theurer Cancer Center at Hackensack University Medical Center. He can be reached at davids.siegel@hackensackmeridian.org. Disclosure: Siegel reports no relevant financial disclosures.