Gasparetto Shares Treatment Considerations, Options in 2 Multiple Myeloma Cases

Cristina Gasparetto, MD

Cristina Gasparetto, MD

Cristina Gasparetto, MD, recently sat down withTargeted Oncologyto discuss treatment considerations and options for patients with multiple myeloma based on 2 case scenarios. Gasparetto, an assistant professor of medicine at Duke University School of Medicine and a member of the Duke Cancer Institute, discussed these cases during a live case-based peer perspective event.

Case 1

In the first case, the patient was a 61-year-old Caucasian female who was diagnosed with stage II multiple myeloma in July 2011. Genetic testing showed her to have t(11:14) chromosomal translocation. At the time, she was treated with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone induction therapy followed by autologous stem cell transplantation. She achieved a complete response after transplant. The patient was placed on lenalidomide (Revlimid) maintenance therapy.

In January 2014, routine follow-up showed that her M-protein levels had risen to 1.4 d/dL and her light chain levels continued to rise. Although she has developed mild anemia and her creatinine level was slightly elevated to 1.3 md/dL, she continued to work full time, had no bone pain, and had a normal calcium level.

TARGETED ONCOLOGY:Describe the details of the case and your initial impressions of this patient.

Gasparetto:

This was a patient with standard-risk multiple myeloma. She underwent appropriate induction chemotherapy with a triple regimen with bortezomib, lenalidomide, and dexamethasone, and because of her performance status and her age, she appropriately received consolidation with high-dose therapy and some maintenance. We have solid data now showing that early transplant is still beneficial compared to continuation of therapy and the addition of lenalidomide maintenance also is beneficial, prolonging their progression-free survival (PFS) and overall survival (OS), so the patient was treated appropriately.

Generally, after transplant, patients with standard risk should be on lenalidomide a little bit longer, but progressing after 3 years is still not considered to be a poor prognostic factor. Generally, patients progressing within a year from transplant are then treated more aggressively and they are defined as having high-risk myeloma.

This patient progressed after about 3 years. She doesn’t have the classic clinical progression. She has a little bit more anemia, but she doesn’t have any symptoms. After transplant, some patients will progress with a lot of symptoms—new bone lesions, anemia, elevation of renal functions—and they have a worse outcome. Patients will progress with the rising of the M-spike, like in this patient, and so sometimes after transplant we continue to monitor the patient closely a little bit longer, until we figure out their rate of progression. This patient had an M-spike rising to 1.4, so she clearly meets the definition of relapse.

TARGETED ONCOLOGY:Which patients are candidates for maintenance therapy? What are the options?Gasparetto:Lenalidomide maintenance after transplant is becoming standard of care. We have 3 large randomized studies in the transplant setting showing that adding lenalidomide post-transplant improves PFS, and then we have 1 study showing OS benefit, and then a large analysis presented this year at ASCO showing a survival advantage for patients placed on lenalidomide. So pretty much all patients after transplant should have the option of proceeding to lenalidomide maintenance.

Some patients, unfortunately, can’t tolerate lenalidomide for various reasons—they have an intolerance, or for some patients who have profound renal insufficiency, it’s difficult to address the lenalidomide. For example, patients on dialysis, or patients with another cancer have some issues going on lenalidomide, so an alternative option is bortezomib. We have studies showing that bortezomib is also beneficial post-transplant in prolonging the PFS, but the standard of care remains lenalidomide. We have more data showing clearly it’s better maintenance than bortezomib, but we don’t have a lot of data.

TARGETED ONCOLOGY:What are the treatment options for a patient who is largely asymptomatic with good performance status and developing biochemical relapse and early signs of clinical relapse on lenalidomide?Gasparetto:If a patient is progressing slowly with a biochemical relapse and a rising of the M-spike and the patient doesn’t have many symptoms, sometimes increasing the dose of lenalidomide, adding dexamethasone, and adding a third agent like bortezomib again will be appropriate. Sometimes if the patient is not really symptomatic, we continue to monitor without intervention, and then when we see a more rapid progression, we’ll start treatment.

The problem is, we have a lot of data supporting treatment with 3 drugs versus 2, so if a patient is asymptomatic it’s difficult sometimes to reinitiate treatment with 3 drugs, so taking a little bit more time and watching the patients when appropriate in this situation.

TARGETED ONCOLOGY:In your personal experience, what is the response usually like for carfilzomib/pomalidomide (Pomalyst) in lenalidomide-refractory patients?Gasparetto:Carfilzomib, pomalidomide, and dexamethasone is a very powerful triple combination. We have data from a phase II study published a few years ago in 2013, and the overall response in patients who were refractory to lenalidomide was about 70% with some patients achieving a very good partial response, so the response is very rapid. The combination is clearly effective and overall well tolerated. There is still a study going on escalating the dose of carfilzomib to a higher dose, but for the moment, the data that we have published shows that it’s a very powerful, very effective combination that can be used particularly in patients with clinical relapse after transplant. That would be my choice.

Case 2

In the second case, the patient was a 73-year-old African American male who was diagnosed 24 months ago with stage III IgG kappa multiple myeloma and not eligible for transplant based on his level of frailty. His M-protein was 1.8 g/dl, his creatinine clearance was normal, and his cytogenetics were classified as standard risk. He received treatment with lenalidomide 25 mg daily and low-dose dexamethasone. His M-protein stabilized at 0.2 g/dl. After 1 year, he achieved maximum response and his dose was decreased to 15 mg for tolerability.

Two years later, the patient’s M-protein level rose to 0.8 g/dl, he continued to do well functionally, and lenalidomide was increased to 25 mg daily. Six months after that, the patient complained of increasing back pain, fatigue, and weakness. He was hospitalized 2 months prior for pneumonia. His ECOG performance status was 2. The patient was started on pomalidomide, weekly cyclophosphamide, and low-dose dexamethasone.

Abnormal laboratory findings showed: serum beta-2-microglobulin level, 6.2 mg/L, albumin level of 2.1 g/dL, creatinine clearance of 32 ml/min. A skeletal survey showed lytic lesions in the L4/L5 vertebra. A bone marrow biopsy showed 30% involvement by abnormal appearing plasma cells, confirmed by CD138+ IHC stain.

This patient was a frail older gentleman found not to be a candidate for transplant. We have a large study—the first showing that lenalidomide in combination with dexamethasone continued therapy is well tolerated and effective in this population of patients.

We also have data now showing that maybe going with 3 drugs out of the gate at the time of diagnosis is superior to using 2 drugs. Since this patient [population] is frail, particularly in patients with other comorbidities, it’s difficult to use 3 drugs because of poor tolerability.

This patient received lenalidomide and dexamethasone, which is very appropriate. After another year, lenalidomide was reduced to a lower dose, which is also appropriate considering his renal function was not normal. Then at the time of progression, the lenalidomide was increased, but clearly the patient’s condition continued to deteriorate.

TARGETED ONCOLOGY:What are the up-front treatment options for this patient?Gasparetto:

He clearly became refractory to lenalidomide with new lytic lesions. His creatinine clearance is about 30 ml, so you have to choose now a combination that is appropriate and manageable in the patient in this situation. You have a few options of changing the lenalidomide to pomalidomide, [which] is very appropriate, and pomalidomide/dexamethasone is approved in this setting by the FDA to be used in first relapse in patients with lenalidomide-refractory disease.

Adding a third agent is also very appropriate. The pomalidomide, cyclofosfamide, and dexamethasone was recently published in the results of a phase II randomized study showing that 3 drugs were more effective. The response rate was actually very good, around 70%. The pomalidomide is safe in patients with compromised renal insufficiency. You may need to adjust the dose, decrease to 3 mg for severe renal insufficiency. It’s an oral regimen that can be given to frail patients in these situations.

Patients can progress only with what we call a biochemical relapse where you monitor the M-spike and see if the M-spike is slowly increasing and if the patient is symptomatic. When the M-spike reaches the level of 0.5, it is considered a relapse.

If a patient is asymptomatic you can opt to follow the patient without intervention until you see a more rapid biochemical progression. Also very important is the duration of the first response. If your patient remains in remission for several years and then you have a biochemical relapse, you might not need to intervene right away.

A patient relapsing with symptoms—if you have myeloma causing endocrine damage, new bone lesions, increase of renal dysfunction, more anemia—you need to intervene right away. That is the classic clinical progression, clinical relapse, where you need to initiate therapy immediately because the myeloma is causing the symptoms.

TARGETED ONCOLOGY:How do you define progression? When do you start therapy for relapsed disease?Gasparetto:

If the patient is [experiencing] asymptomatic biochemical relapse, I generally follow the patient monthly, and if the relapse is very slow and the patient is otherwise well, I don’t intervene right away. If I monitor the M-spike and I see that the M-spike is increasing—so I see a more rapid rate of proliferation—then I initiate treatment. Also, if a patient progresses very rapidly after, for example transplant, that’s a different story. If a patient has high-risk myeloma and I see a relapse within a year after transplant, I probably will intervene sooner in this patient.

TARGETED ONCOLOGY:What are the treatment options for a patient developing asymptomatic biochemical relapse? What is your typical approach?Gasparetto: