Symptomatic Relapse and Second-Line Therapy for MM

Ravi Vij, MD:In June 2018, this patient is seen in his doctor’s office, and at that time he is noted to have an increase in his M (monoclonal) protein. Therefore, it is decided to do a further workup. This patient is noted to, over the proceeding few months, have dropped their hemoglobin from 12.9 grams per deciliter to 10.2 grams per deciliter. The patient doesn’t have renal insufficiency or hypercalcaemia, but on closer interrogation he does say he feels more fatigued. So this patient is clearly having the progression of disease at this point.

In the second-line of treatment, we consider a number of factors for deciding the appropriate intervention. The choices are many, so we have to consider what the patient got in the frontline of treatment, how they responded to the frontline of treatment, how they tolerated their treatment, and whether they progressed on treatment or had a treatment-free interval. We also need to know what the pace of relapse of the patient is. In this case, we have a patient who is starting to get somewhat symptomatic. His performance status is somewhat limited. It’s a performance status of 2. Also, he has high-risk chromosomal features with a 17p deletion. So, all these factors do need to be taken into consideration when deciding what treatment to give this patient.

The choices of treatment are informed once again, on the number of clinical trials that we have had the luxury of being able to look at over the years. We have trials looking at 3-drug regimens of Kyprolis (carfilzomib) with Revlimid (lenalidomide) and dexamethasone, ixazomib (Ninlaro) with Revlimid and dexamethasone, and elotuzumab (Empliciti) with Revlimid and dexamethasone, compared with Revlimid and dexamethasone. We’ve had trials that have looked at, more recently, daratumumab (Darzalex) with Revlimid and dexamethasone, comparing it with Revlimid and dexamethasone.

On the other hand, we have trials that have looked at trying to improve on a standard of Velcade-based (bortezomib) treatments. We have had Kyprolis/dexamethasone versus bortezomib/dexamethasone. We’ve had Farydak (panobinostat) with Velcade and dexamethasone, compared with Velcade and dexamethasone. And more recently, in the ASCO meeting in June 2018, we’ve had a trial of bortezomib with pomalidomide (Pomalyst) and dexamethasone, compared with bortezomib and dexamethasone.

We have a lot of different treatment options for patients these days. The way I approach it is that initially, I try to figure out if a patient has a biochemical progression or whether they have true symptomatic progression. For those who have a biochemical progression, I’m inclined to even go and get a PET scan to make sure there is no subclinical disease activity that is starting to emerge that hasn’t rendered the patient symptomatic yet but may do so in the near future. We also go ahead and repeat the bone marrow biopsy to look for both the degree of plasmacytosis and the chromosomal features. For those that are having an indolent disease progression, often we use elotuzumab with lenalidomide and dexamethasone when appropriate. I think that there is some controversy in the field whether elotuzumab would be active in patients who have already had prior lenalidomide, since most people in the United States have and are often on at time of progression as maintenance. But I think that for those who are biochemically progressing and have no other features, it is an appropriate choice of therapy to consider, and if it is not effective, then one can certainly easily move on to something else. For those that have more symptomatic progression, one has to look for alternatives. There, one has to look at, again, how symptomatic a patient is and what the pace of progression is. In an elderly patient like this, with a limited performance status, often these patients find it difficult to come to the doctor’s office to get therapies that are given intravenously or subcutaneously. Those patients want an all-oral option, and I think in this case it is absolutely appropriate to try a 3-drug regimen of ixazomib with lenalidomide and dexamethasone. This patient had only a finite period of lenalidomide. He’s been off lenalidomide for several months now. So, I think that this patient could very well respond and could have the convenience of an all-oral regimen.

We also know ways to run a subset analysis of the trial, the TOURMALINE-MM1 study published inBloodrecently, in which even patients with 17p deletion do well with what may otherwise be perceived as a gentle regimen of ixazomib/lenalidomide, and dexamethasone. In fact, the benefit in the 17p deleted patients was more marked than in the whole population. So, I think that for this patient, I would say that trial of ixazomib with lenalidomide and dexamethasone will certainly be appropriate.

Transcript edited for clarity.

CASE: A 72-year-old Caucasian Man With Relapsed Multiple Myeloma

September 2016

• Patient history: At the age of 72, a Caucasian man was diagnosed with multiple myeloma; R-ISS stage I
• Other relevant history includes hypertension and difficulty walking up stairs
• He was treated with lenalidomide/dexamethasone and achieved a VGPR
• Treatment duration was 9 months; patient subsequently discontinued therapy 12 months ago

June 2018

• On routine follow-up, patient complains of increasing problems with fatigue, and has rising levels of M protein
• Laboratory results:
  • Hb, 9.6 g/dL
  • Ca²⁺9.2 mg/dL
  • Creatinine, 0.8 mg/dL
  • M-protein, 3.0 g/dL
  • 30% plasma cells in bone marrow
• Cytogenetics/FISH: del(17p)
• ECOG PS: 2