Paner Details the Current Landscape for Multiple Myeloma

Agne Paner, MD

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 aTargeted Oncologylive 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.¹The 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.²That 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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Case 2

December 2013

• A 77-year-old African American male was diagnosed 24 months ago with stage III multiple myeloma and was not eligible for transplant based on his level of frailty.
• His cytogenetics showed hyperdiploid disease.
• He received treatment with lenalidomide (15 mg daily) and low-dose dexamethasone.
• After 9 cycles of therapy, the M-spike plateaued at 0.6 g/dL; therapy was continued.

December 2015

• Hemoglobin, 11.4 g/dL
• Creatinine, 1.0 mg/dL
• M-protein rose from 0.6 g/dLà1.2 g/dLà1.5 g/dL
• He reported feeling tired, but continued to do well functionally.

TARGETED ONCOLOGY:What was the rationale here for the initial treatment?

The FRIST trial compared lenalidomide and dexamethasone for the upfront treatment of newly diagnosed non—transplant-eligible patients continuously until progression, or the disease, or intolerable toxicity to lenalidomide given over 18 months and to fixed-duration MPT regimen [melphalan, prednisone, and thalidomide]. The trial results showed that PFS was the best in lenalidomide and dexamethasone continuously. One could make an argument, based on the SWOG trial data that we discussed earlier, that even those patients who are not transplant candidates should be treated with a 3-drug combination. It can be dose-adjusted for frailer patients. But even patients who were not transplant-eligible had better PFS with the bortezomib/lenalidomide/dexamethasone combination when compared with those treated with lenalidomide and dexamethasone in the SWOG trial. We don’t have much more information as to why lenalidomide and dexamethasone were chosen, but it is 1 of the treatment options for patients who are not transplant candidates.

The fact that that lenalidomide was given at a 15-mg daily dose suggests that the patient probably had impaired kidney function that called for the dose adjustment. On the other hand, some may argue that in older and frail patients who don’t need rapid disease reduction, it would be reasonable to try a lower dose of lenalidomide and increase the dose if patients tolerate it.

While we don’t have a specific dose of low-dose dexamethasone noted in this case, the dose established by the ECOG trial is considered to be 40 mg once a week.³This trial showed that high-dose dexamethasone versus low-dose dexamethasone caused more toxicity, even though the initial responses were better. Since then, 40 mg weekly of dexamethasone has been considered the standard of care for the majority of regimens in multiple myeloma. In patients older than 75 years, it would be reasonable to further decrease dexamethasone to 20 mg weekly since they have a harder time tolerating the drug, which can cause insomnia, mood alterations, hyperglycemia, and hypertension.

TARGETED ONCOLOGY:Would these symptoms (fatigue, rising M-protein, etc) be considered progression of disease?

We would consider this progression of his disease since he had at least 25% and at least a 0.5 mg/dL increase in his monoclonal protein. His kidney function as well as hemoglobin level seems to be normal, so we would label it as biochemical relapse.

TARGETED ONCOLOGY:Do you continue the patient on lenalidomide or switch to another therapy at this point?

If I think that this patient could tolerate a higher dose of lenalidomide, this again may be an opportunity to increase the dose and add elotuzumab. If I doubt that the patient could tolerate the higher dose, than the better approach would be to switch to a different regimen.

TARGETED ONCOLOGY:What is the rationale for maintaining the immunomodulatory drug (IMiD) beyond progression?

I would only continue an IMiD agent beyond progression if I can increase the dose and combine it with elotuzumab, hoping that we will recapture some of the response. I think the approach of increasing the dose of lenalidomide at the time of progression was not evidence-based; it was an approach that came out of clinical practice.

• Lenalidomide was increased to 25 mg daily, dexamethasone 20 mg was added, and elotuzumab was added (EloRD).

May 2016

• Hospitalized 2 months previously for pneumonia, the patient complained of increasing back pain, fatigue, and weakness.
• Laboratory findings:
  • M-protein, 2.1 g/dL
  • Serum beta-2-microglobulin, 6.2 mg/L
  • Albumin, 2.1 g/dL
  • Creatinine clearance, 32 ml/min
• Skeletal survey showed new compression fracture in the L4/L5 vertebrae.
• Bone marrow biopsy showed 30% involvement by abnormal-appearing plasma cells, confirmed by CD138+ immunohistochemical stain.
• His ECOG performance status was 2

TARGETED ONCOLOGY:What is the rationale for adding elotuzumab?

Elotuzumab is an anti-SLAMF7 monoclonal antibody, and its receptor is expressed in natural killer (NK) cells as well as in plasma cells. Lenalidomide is able to upregulate and NK cells, while elotuzumab activates them. Therefore, there is a synergistic effect between these 2 drugs. Adding elotuzumab would hopefully help to engage more NK cells and recapture some of the response.

TARGETED ONCOLOGY:How long do you wait to determine whether EloRD is working?

I think most of the regimens show response after 2 cycles of therapy. Two months later, the patient is admitted to the hospital and now meets the criteria for clinical progression of the disease and his monoclonal protein has further increased, so I would switch his treatment to the next line of therapy.

TARGETED ONCOLOGY:What are the options for this patient when symptomatic disease progression occurs?

The options are numerous, and the decision has to be made based on many factors: the logistics of the regimen, patient comorbidities, renal function, presence of neuropathy, heart function, ejection fraction, and history of COPD or asthma. In this patient, we could treat him with a daratumumab-based combination. If he does not have neuropathy, we could treat him with daratumumab and bortezomib. He has never had bortezomib, so that would be the most reasonable option to explore in this patient. Alternatively, he could be treated with bortezomib in combination with cyclophosphamide and dexamethasone. He has not had exposure to acylating agents either. Alternatively, ixazomib-based or carfilzomib-based regimens could also be considered.

TARGETED ONCOLOGY:Why would you prefer daratumumab-based regimen?

We don’t have a comparison between daratumumab and bortezomib with dexamethasone on one hand, and cyclophosphamide and bortezomib with dexamethasone on the other. But we do have data on daratumumab and bortezomib with dexamethasone combination versus bortezomib and dexamethasone in a first or later relapse, from the so-called CASTOR trial.⁴Patients who were treated with the 3-drug regimen had much improved response rates and PFS compared with patients who received bortezomib and dexamethasone alone.

TARGETED ONCOLOGY:What supportive care measures are necessary for this patient with this regimen?

I think we need to address his bone health. At the start of treatment, patients who have multiple myeloma should receive bone-modifying therapies. That would be bisphosphonates or, in patients with impaired kidney function or who are at risk of worsening kidney function, it could be denosumab. If patients discontinued the bisphosphonates after 1 or 2 years, they should consider restarting them at the time of relapse. We should also think about antibacterial and antiviral prophylaxis, because patients who receive treatment with proteasome inhibitors, as well as with daratumumab, have a higher risk of shingles reactivation. Therefore, they should be treated with acyclovir at 400 mg twice a day as long as they are on the therapy, as well as for 3 to 6 months after the completion of therapy. Bacterial prophylaxis is less well defined, but certainly could be considered in some patients who are starting treatment for multiple myeloma, especially if they have a history of infections or if they have low levels of immunoglobulins.

• The patient was treated with daratumumab, weekly subcutaneous bortezomib, and dexamethasone.

TARGETED ONCOLOGY:What other toxicities would be of concern with the daratumumab, bortezomib, and dexamethasone regimen?

We should be watchful for infusion reactions. They can happen in nearly half of patients and usually they will happen during the first or second infusion. They are unlikely to happen afterwards. Patients should receive premedication with steroids. One should keep in mind that infusion reactions with daratumumab can be delayed; therefore, patients should also get 4 mg of dexamethasone or an equivalent low-dose steroid directly after the infusion as well as the next day. For patients who have baseline COPD or asthma, they should be reminded to use an inhaler if they notice shortness of breath. In patients with poor ejection fraction, we tend to split the first dose into 2 days, since it is a 1-liter infusion. Also, Singulair [montelukast sodium] should be considered for infusion reaction prevention. One study showed that infusion reactions can be decreased by one-third if patients use Singulair for prevention.

When it comes to adverse effects of daratumumab, it’s important to remember that it interferes with type and cross blood transfusions. Patients should have this type of screening done before they have treatment with this particular monoclonal antibody. Daratumumab is an immunoglobulin G monoclonal antibody and it can actually bind CD38 expressed on the red cells.

TARGETED ONCOLOGY:What should be considered when scheduling daratumumab infusions?

One consideration should be splitting the dose in those patients who may not be able to tolerate a 1-liter infusion in 1 day. We also try not to treat patients on Fridays because of possible delayed infusion reactions. Also, if patients do develop infusion reactions and we cannot complete infusion on the same day at the clinic, we bring them in to complete infusion the next day, so we try to have at least a 1-day cushion before the weekend.

References:

1. Durie B, Hoering A, Rajkumar V, et al. Bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT): results of the randomized phase III trial SWOG S0777. Presented at: American Society of Hematology 57thAnnual Meeting & Exposition; December 5-8, 2015; Orlando, FL. Abstract 25.
2. Holstein SA, Jung SH, Richardson PG, et al. Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomized, double-blind, phase 3 trial.Lancet Haematol. 2017;4(9):e431-e442. doi: 10.1016/S2352-3026(17)30140-0.
3. Rajkumar SV, Jacobus S, Callander NS, et al; Eastern Cooperative Oncology Group. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial.Lancet Oncol.2010;11(1):29-37. doi: 10.1016/S1470-2045(09)70284-0.
4. Palumbo A, Chanan-Khan AAA, Weisel K, et al. Phase III randomized controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study.J Clin Oncol. 2016;34(18 suppl; abstr LBA4). meetinglibrary.asco.org/record/135751/abstract.