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Elderly Pts with R/R MM
My Treatment Approach for Very Elderly Patients With Multiple Comorbidities and Relapsed Myeloma

Released: December 13, 2016

Expiration: December 12, 2017

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Case 1: Elderly Patient With Cardiac and Renal Dysfunction Who Relapsed on Lenalidomide/Dexamethasone
Your 85-year-old patient has a long history of congestive heart failure and was diagnosed with MM 2 years ago with hemoglobin 8.7 g/dL, serum creatinine 2.0 mg/dL, and serum calcium 9.0 mg/dL, along with 50% bone marrow plasma cells, IgGκ 7 g/dL, t(4:14) translocation, and multiple compression fractures. He received lenalidomide plus dexamethasone (Rd) with monthly zoledronic acid during this time but developed progressive disease while receiving this treatment.

Rationale for Treatment Selection Following Progression
First, because he has multiple compression fractures, I would continue the patient on monthly zoledronic acid.

For treatment of his relapsed MM, I would recommend bortezomib and dexamethasone (Vd). Because the patient progressed on his previous lenalidomide-based regimen, I would recommend a class switch to a proteasome inhibitor–based therapy. Furthermore, this patient has congestive heart failure, and there are some data suggesting that lenalidomide can worsen congestive heart failure. The patient also has an increased creatinine level, which would make bortezomib ideal since the patient would not require a dose reduction or adjustment due to the increased creatinine with this agent.

I would not use a more aggressive triplet therapy for second‑line treatment for this patient, since he is 85 years of age and seems to be frail. Triplet combinations such as carfilzomib plus Rd or carfilzomib plus pomalidomide/dexamethasone (PomD) may be too difficult for this patient to tolerate. Carfilzomib has a higher risk of inducing shortness of breath and congestive heart failure, so given his current comorbidities, I would avoid any medication that might worsen his heart function. Often, in older patients, pomalidomide is also not well tolerated, and again, I think a class switch is important for this patient. I would also not consider panobinostat plus Vd due to the high risk of grade 3/4 thrombocytopenia and diarrhea.

When considering the newly available monoclonal antibodies, I would probably not elect to use elotuzumab plus Rd—the currently approved combination—because I think a class switch to a proteasome inhibitor is important. Single-agent daratumumab may be a consideration for some clinicians, but it is not approved for first-line relapse. Recently, daratumumab was also approved in combination with either Vd or Rd for patients who have received at least 1 previous therapy, based on the POLLUX and CASTOR trials. Daratumumab plus Vd was well tolerated but did show grade 3/4 hypertension in a small number of patients (7%).

Finally, you could consider a triplet approach with bortezomib/cyclophosphamide/dexamethasone (VCD) for this patient, although data from the UPFRONT trial comparing Vd, bortezomib/thalidomide/dexamethasone (VTD), and bortezomib/melphalan/prednisone (VMP) showed no difference between these 3 regimens. This may be due to the fact that the doublet was better tolerated, and patients could receive the full dose of bortezomib. So, based on the available data for this elderly patient with cardiac and renal dysfunction who progressed on IMiD-based treatment, I would recommend a switching classes to doublet therapy with Vd.

Case 2: Elderly Patient With Comorbidities Who Relapsed With High-Risk Disease
Let’s talk about another case example: An 80-year-old man with a history of hypertension, diabetes, congestive heart failure, chronic renal dysfunction, and peripheral neuropathy is diagnosed with MM (hematocrit 30%, serum creatinine 2.5 mg/dL, calcium 8.0 mg/dL, serum IgGκ 8.5 g/dL, compression fracture at L3-4, 70% bone marrow plasma cells, and FISH analysis t11;14). He is treated with lenalidomide/dexamethasone for 18 months and achieves a good PR but developed new diffuse bone lesions, with serum creatinine 4.0 mg/dL and 60% bone marrow plasma cells with del(17p) cytogenetics.

Rationale for Treatment Selection
Although this patient is younger than the first example, he has substantial comorbidities, including diabetes and peripheral neuropathy in addition to cardiac and renal risk factors. This patient progressed while on lenalidomide and, importantly, also has high-risk cytogenetics. Again, I would recommend switching to a proteasome inhibitor–based therapy but would consider triplet therapy for a patient with high risk features if he could tolerate it.

For this patient, I would probably start with cyclophosphamide/bortezomib/dexamethasone since it is generally well tolerated in patients with congestive heart failure, and dose adjustment would not be necessary with the patient’s renal dysfunction. Since this patient also has peripheral neuropathy, he should be closely monitored if given bortezomib, and bortezomib should be administered subcutaneously. Because this patient has high-risk cytogenetics, other triplet treatment options could also be considered, including daratumumab plus Rd, daratumumab plus Vd, elotuzumab plus Rd, carfilzomib plus Rd, or ixazomib plus Rd. Again, given the fact that carfilzomib is associated with an increased risk of congestive heart failure, I would first consider daratumumab, elotuzumab, or ixazomib as part of a combination approach instead of carfilzomib.

As mentioned above, daratumumab was recently approved in combination with Vd or Rd for patients who have received at least 1 previous therapy, based on the POLLUX and CASTOR trials. This combination did not seem to increase rate of peripheral neuropathy compared with Vd alone but did result in an increased rate of grade 3/4 hypertension (7% vs 0.8%, respectively).

Elotuzumab plus Rd has shown good efficacy in patients who have received 1-3 previous therapies, and the adverse event profile did not significantly change with the addition of elotuzumab. Ixazomib plus Rd is another good option for this patient, and I would be less concerned about peripheral neuropathy with ixazomib, because according to results from the TOURMALINE MM1 study, there is no significant increase in grades 3/4 peripheral neuropathy with ixazomib plus Rd compared with Rd alone.

Some clinicians may also consider a pomalidomide-based regimen, as there are data showing that pomalidomide can be effective in patients who are resistant to lenalidomide-based treatment, but again, I would be more in favor of completely doing a class switch for this patient.

Summary
It can be difficult to select an effective treatment regimen for elderly patients with multiple comorbidities. In patients with MM who relapse on Rd, a class switch to a proteasome inhibitor would be the most appropriate option. Choosing between doublet or triplet therapy depends on existing comorbidities as well as age and cytogenetic risk. Vd can be a good option for some patients with multiple comorbidities since it is well tolerated in patients with congestive heart failure and no dose adjustments are needed with impaired renal function. In patients with high-risk MM, a more aggressive triplet therapy is a more appropriate option.

A New Tool to Help Guide MM Treatment Decisions
To help you address the challenges associated with treatment decisions for your patients with MM, my colleagues (Kenneth Anderson, MD; Shaji Kumar, MD; Sagar Lonial, MD; and G. David Roodman, MD, PhD) and I have created an Interactive Treatment Decision Tool, 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.

Please share your questions or thoughts on your current management approaches for elderly patients with MM in the comment box below.

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Let’s consider the second case discussion: an 80-year-old man with a history of hypertension, diabetes, congestive heart failure, chronic renal dysfunction, and peripheral neuropathy who was initially treated with Rd for 18 months and achieved a good PR before progressing with new diffuse bone lesions, serum creatinine 4.0 mg/dL, and 60% bone marrow plasma cells with del(17p) cytogenetics. In your current clinical practice, how would you treat this patient?
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