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New Agents for R/R Myeloma
How I Adapt My Clinical Practice to New Approaches for Relapsed/Refractory Multiple Myeloma

Released: January 23, 2017

Expiration: January 22, 2018

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In the era of novel agents, the survival of patients with MM has been prolonged 3-fold to 4-fold not only because of the improved frequency, extent, and duration of response to initial therapy, but also because of the many new options that have been shown to extend survival even in patients with relapsed disease. The benefits of these new combination approaches include both their impressive efficacy, as well as a lower rate of serious adverse events. We are now seeing not only extended PFS and OS in patients with MM, but enhanced quality of life as well.

Treatment for Relapsed/Refractory MM
First, it can be difficult to determine when to switch therapy or initiate a new treatment in the relapsed or refractory setting. Of importance, in patients with relapsed/refractory MM, it is not always necessary to wait for the appearance of CRAB features—hypercalcemia, renal dysfunction, anemia, and bone disease—to initiate new treatment. Once a persistent M-protein rise is seen, intervention is needed to prevent the development of additional clinical sequelae.

The management of patients with relapsed MM depends on both specific clinical features, such as the presence of renal dysfunction, cardiac disease, or other clinical comorbidities, and the characteristics of the disease, for example, whether is the patient has high-risk or a p53-deleted MM. Choice of treatment is also influenced by previous therapies, in particular whether there is resistance to any class of drugs.

Triplet vs Doublet Regimens
Today, there are many different options for treating relapsed MM. However, one important principle for management of relapsed disease is that triplet regimens are preferable to doublets in patients who can tolerate the more aggressive therapy. For initial management of newly diagnosed MM, the combinations of bortezomib/lenalidomide/dexamethasone (VRd) and cyclophosphamide/bortezomib/dexamethasone (CyBorD or VCD), are commonly used in the United States and are thought to be superior to lenalidomide/dexamethasone (Rd) alone. Similarly, in the relapsed setting, treatment often consists of an immunomodulatory agent, either lenalidomide or pomalidomide, combined with a proteasome inhibitor (PI) or, more recently, a monoclonal antibody and dexamethasone. The first-generation PI bortezomib can be used for relapsed disease but more often a second-generation PI, either carfilzomib or ixazomib, are better options in this setting. The monoclonal antibodies daratumumab (an anti-CD38 antibody) and elotuzumab (an anti-SLAMF7 antibody) are now also approved in this setting.

My Preferred Triplets After 1-3 Previous Regimens
For patients with relapsed MM who have received 1-3 previous therapies, options that I often recommend include carfilzomib/lenalidomide/dexamethasone (KRd), bortezomib/pomalidomide/dexamethasone (VPomD), or carfilzomib/pomalidomide/dexamethasone (KPomD), depending on the characteristics of the previous treatment. KRd, in particular, is very active compared with Rd alone, based on data from the phase III ASPIRE trial. However, the use of carfilzomib might be limited in patients who have a history of cardiac or pulmonary disease, as related adverse events have been reported with this agent, albeit with a low incidence.

Select Treatment Options for Indolent Disease
In patients with relatively indolent disease at relapse, the combination of elotuzumab/lenalidomide/dexamethasone (ERd) was found to be superior to Rd alone. Likewise, combination of the oral second-generation boronic acid–based PI ixazomib with Rd (IRd) has shown similar advantage compared with Rd alone. Both ERd and IRd regimens can be used for patients with indolent relapse, and IRd is the first all-oral triplet combination and is the preferred options for patients who prefer an all-oral treatment approach.

The randomized trials with KRd, ERd, and IRd included only those patients not refractory to lenalidomide, and we do not know how active these combinations are in lenalidomide-refractory MM. Many patients in the United States receive lenalidomide and/or bortezomib as part of their initial management (either VRd or VCD) and, therefore, may be resistant to one or both of these agents at relapse. Because of this, I often recommend using the second-generation immunomodulatory drug pomalidomide, as discussed above, usually together with a second-generation PI.

New Options With Daratumumab
The monoclonal antibody daratumumab, which targets CD38 on malignant cells, was initially approved as a single agent for patients with advanced, high-risk MM and at least 3 previous lines of therapy, based on a 30% response rate in the phase II SIRIUS trial. Excitingly, recent data from phase III clinical trials of daratumumab combined with either bortezomib/dexamethasone, the CASTOR trial, or with Rd, the POLLULX trial, in patients with 1-3 previous therapies has shown superior efficacy vs double therapy alone. In both cases, the addition of daratumumab markedly increased the extent and frequency of response and reduced the chances of progression or death related to MM by approximately two thirds. As a result, the approval of daratumumab was expanded in 2016 to include both of these combinations for patients with relapsed MM and at least 1 previous therapy. Daratumumab may also be of benefit in combination with pomalidomide and dexamethasone as salvage therapy, according to a recent retrospective analysis.

But How to Choose?
Optimal choice of treatment for relapsed MM is guided by characteristics of both the patient and disease. Although triplet therapies are often used, the doses and schedules of those drugs may need to be modified for elderly patients. Please review this recent ClinicalThought on the selection of therapy for elderly patients with relapsed/refractory MM from Suzanne Lentzsch, MD, PhD, for more information on the use of doublet therapy for patients who are particularly frail and/or elderly.

We discussed many different treatment options for patients with relapsed/refractory MM, and there is no one correct approach for many of these patients. Pomalidomide is an oral agent that has shown activity in lenalidomide-refractory patients, can be given to patients with renal dysfunction, and is effective in patients with del(17p)/p53. Carfilzomib also can be useful in the context of high-risk MM but, as mentioned, should be avoided in patients with heart or lung comorbidities. Ixazomib is a novel, all-oral PI that has shown activity in patients who have received 1-3 previous treatments. The monoclonal antibodies elotuzumab and daratumumab have activity even in patients with del(17p), high-risk disease, and/or multiple relapses, likely because immunotherapies do not rely on the p53 pathway for their mechanism of action.

To help you select optimal treatment for your patients with MM, my colleagues (Shaji Kumar, MD; Suzanne Lentzsch, MD, PhD; Sagar Lonial, MD; and G. David Roodman, MD, PhD) and I have created an interactive treatment decision aid, available here, along with other online activities and several more commentaries from MM experts. This tool is designed to help you rapidly select individualized treatment options based on your patient’s specific disease characteristics and overall fitness by offering recommendations from each of the experienced faculty listed above specifically for the case you enter into the tool.

Which of these advances are you excited to use in your clinical practice? Share your thoughts in the comment box below.

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You have a 63-year-old patient who was diagnosed with MM after x-rays and MRIs reveal multiple, diffuse bone lesions. FISH shows t(4;14) cytogenetics. He received VCD induction, followed by ASCT and maintenance lenalidomide, and achieved a sustained CR. Twenty months following his ASCT, he complains of bone pain and exam reveals increasing M-protein, diffuse focal lesions by PET/CT, and persistence of t(4;14) cytogenetics but no del(17p). How would you treat this patient?
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