ONCAlert | 2018 SGO Annual Meeting on Women’s Cancer
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Paner Details the Current Landscape for Multiple Myeloma

Samantha Hitchcock
Published Online:10:30 AM, Thu March 15, 2018

Agne Paner, MD
Agne Paner, MD, recently shared the treatment considerations and decisions she makes when treating patients with multiple myeloma. Paner, an assistant professor of medicine at Rush University Medical Center, Chicago, Illinois, explained her treatment decisions based on 2 case scenarios during a Targeted Oncology live case-based peer perspectives presentation.

Case 1

July 2011
 
  • A 61-year-old Caucasian female was diagnosed with stage II multiple myeloma.
  • Genetic testing showed t(4:16).
  • At the time, she was treated with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVD) induction therapy, followed by autologous stem cell transplantation (ASCT).
  • She achieved a complete remission with RVD and transplant.
  • The patient was placed on lenalidomide maintenance therapy.

TARGETED ONCOLOGY:  Discuss the rationale for the choice of upfront therapy in this patient.

Our first case was a 61-year-old Caucasian woman with stage II myeloma translocation (14:16). She was started on treatment with RVD induction therapy, followed by transplant. She achieved complete remission and then was placed on lenalidomide maintenance.

The 3-drug induction therapy is considered the standard of care for multiple myeloma. This particular regimen of RVD now has phase III trial data supporting its benefit over lenalidomide and dexamethasone alone.1 The SWOG trial showed that newly diagnosed patients with multiple myeloma treated with the 3-drug regimen had better progression-free survival (PFS) and overall survival. And that was the case for both transplant-eligible and non–transplant-eligible patients. The CALGB trial also established lenalidomide maintenance after ASCT. In the United States, lenalidomide is given until the progression of disease or intolerable toxicities.2 That is what our patient received. It is interesting that patients who achieve complete remission after ASCT also benefit from lenalidomide maintenance.

TARGETED ONCOLOGY: What is the role of transplant as part of frontline therapy for myeloma?

ASCT, even in an area with a potent 3-drug induction regimen, continues to have value. The results of the IFM/DFCI 2009 trial, which compared early versus delayed transplant, showed that patients had deeper responses and longer PFS by about 9 months when the transplant was offered as a part of initial treatment, as compared with delaying it to first relapse.

TARGETED ONCOLOGY: What duration would you recommend for lenalidomide maintenance?

For lenalidomide maintenance, I think in the United States we should try to follow the CALGB trial design, in which lenalidomide was continued until progression of the disease or intolerable toxicities.2

TARGETED ONCOLOGY: What is the typical follow-up for this type of patient?

That can vary in different practices, but in lenalidomide maintenance we would recommend that they receive a complete blood count and comprehensive metabolic panel monthly to monitor for potential toxicities. The disease status should be assessed anywhere from monthly to every 3 months, depending on the patient’s condition.

TARGETED ONCOLOGY: Are there certain toxicities that are concerning in this stage?

When it comes to lenalidomide toxicities, cytopenias have to be monitored and the dose has to be adjusted to kidney function. Sometimes patients can also have liver function abnormalities. Fatigue, diarrhea, skin rash, and infection are other common adverse effects. Second primary malignancies are slightly increased in patients on lenalidomide maintenance.

The disease status is followed using monoclonal protein and light chains, so the serum protein electrophoresis with immunofixation and a free light chains assay. For patients who have Bence-Jones proteinuria as their only measurable disease, then urine protein electrophoresis should be followed instead.

August 2016
 
  • On routine follow-up, the patient reported having mild fatigue, but continued to work full-time; she had grade 1 neuropathy.
    • M-protein, 1.4 g/dL
    • Light chain levels continue to rise
    • Hemoglobin, 10.3 g/dL
    • Creatinine, 1.3 mg/dL

TARGETED ONCOLOGY: How do you define progression in multiple myeloma?

Progression in multiple myeloma can be defined either by chemical or clinical relapse. Biochemical relapse is the reappearance of monoclonal protein, if the patient was previously in a complete response. Otherwise, it’s defined as an increase in monoclonal protein by 25% and at least 0.5 mg/dL. This patient, who was in complete remission but now has the appearance of monoclonal protein at 1.4 mg/dL, certainly meets the criteria for biochemical relapse.

To fulfill the criteria for clinical relapse, she should meet CRAB [hypercalcemia, renal failure, anemia, and bone lesions] criteria. She does have hemoglobin of 10.3 g/dL. And if we assume that she had normal hemoglobin when she was in remission, this would be considered 1 of the criteria. Also if there is a worsening kidney function, new bone lesions, or hypercalcemia, all of those would be considered clinical evidence of myeloma relapse, requiring treatment.

TARGETED ONCOLOGY: Would there be a difference in your next steps based on whether it is biological or clinical relapse?

If patients have a clinical relapse, meeting CRAB criteria, they should be started on a next-line therapy. In patients who have biochemical relapse only, it is controversial if they should be treated or observed. If the patient is asymptomatic and has indolent disease, he or she can be monitored closely since some of these patients will take months or years to develop symptoms. On the other hand, patients who are known to have aggressive disease, either based on their cytogenetics or aggressive presentation at the diagnosis, as well as patients who have rapidly rising monoclonal proteins, should get started on treatment before their symptoms appear.

TARGETED ONCOLOGY: When do you suggest starting therapy for relapse disease for this patient?

She did have slight worsening of kidney function and hemoglobin. We decided that it may be worthwhile to increase her lenalidomide to a therapeutic dose and add elotuzumab (Empliciti) at this point. Elotuzumab is only approved by the FDA in combination with lenalidomide. If patients become refractory to lenalidomide, they lose the opportunity to be treated with elotuzumab. This would be 1 situation where we can still apply it and use it in a patient with a biochemical relapse. Alternatively, the patient could be closely monitored and started on a second-line therapy when they develop symptoms.

The list of the available therapies for patients in their first relapse is truly long. There is no 1 standard of care regarding how these patients should be treated, but the data that emerged in the last 2 years showed that patients treated with a 3-drug regimen combination have longer PFS and better response rates compared with treatment with a doublet in relapsed setting. The preference in patients who can tolerate 3-drug regimens would be a combination of either a daratumumab (Darzalex)-based, a carfilzomib (Kyprolis)-based, or a ixazomib-based regimen.

If we consider that the patient is refractory to lenalidomide at the time of relapse and maintenance therapy, daratumumab could be combined with bortezomib or pomalidomide. Carfilzomib can also be given at a higher dose of 56 mg/m2, or could be combined with pomalidomide or cyclophosphamide.

In patients who have had a long PFS after their first ASCT, if they remained in remission for 3 years on maintenance therapy, they should also be considered a second ASCT.

TARGETED ONCOLOGY: Why is a second ASCT an option for the second line and how would it compare against some of the other options?

It has not been directly compared with 3-drug combination regimens. The way the studies were designed for 3-drug combinations, the majority of the drugs were continued until progression of the disease or intolerable toxicities. The second ASCT was not a part of the trial design. However, I think the 3-drug combinations and ASCT are not mutually exclusive. On the contrary, they could be complementary. Three-drug regimens could be used for re-induction followed by ASCT. It is yet another treatment option for people who have chronic relapsing disease.

What we do know about second ASCT is that if it is done in earlier lines of therapy, it tends to give longer PFS, as opposed to postponing it to later lines of therapy. Also, as patients continue to relapse, and get older, their overall health may no longer allow them to undergo ASCT. For those 2 reasons, a second ASCT ideally should be considered in the early relapse setting.

TARGETED ONCOLOGY: How would tolerance to previous therapy and other factors go into your choice of therapy?

Certain comorbidities may favor using one regimen over another; the convenience of the treatment is another factor. Ixazomib-based triplet regimens are the only ones that are in pill form. For patients who place great value on having more time away from the clinic, or for patients who are not able to travel for intravenous infusions, that could be a preferred option. 

Daratumumab- and carfilzomib-based regimens both require intravenous infusions and require at least weekly trips to the clinic. On the other hand, they give rather impressive response and PFS rates, and they could be preferred for patients who have a more aggressive disease. Daratumumab is overall well tolerated, but it can cause infusion reactions that cause reactive airway symptoms. Therefore, patients with asthma and chronic obstructive pulmonary disease (COPD) are at a higher risk of infusion reaction. Carfilzomib is overall well tolerated, but has certain adverse effects to watch out for, such as increased blood pressures, small risk of worsening ejection fraction, or renal failure. Those effects happen in 5% to 10% of patients. The major drawback of carfilzomib is actually its twice-a-week infusion schedule, which requires patients to travel to infusion centers frequently.

Neuropathy is a well-known adverse effect of bortezomib, and it usually determines whether you would use bortezomib again at the time of the relapse, such as in the daratumumab/bortezomib/dexamethasone regimen, or if you would consider the so-called CyBorD regimen (bortezomib/Cytoxan/dexamethasone). 

Cytopenias are an adverse effect that can be seen with all of these regimens. And it usually tends to be worse in the first couple of cycles. Once the disease volume decreases, it becomes less of an issue. So it is not necessarily an adverse effect that differentiates these regimens, but it is one, in general, to be aware of.

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