Frontline Treatment Approaches in Multiple Myeloma

Ravi Vij, MD:The choice of frontline agent for multiple myeloma is driven by our clinical trials. We have had a number of trials over the years that have been done in older patients. The treatment for an elderly patient with multiple myeloma 20 years ago used to be melphalan (Evomela) and prednisone. We went through a series of trials that looked at a 3-drug regimen of melphalan and prednisone with thalidomide (Thalomid) that showed there was certainly improvement in progression-free survival and some improvement in overall survival with these patients. But the fact is, that thalidomide was a difficult drug for older patients to tolerate. We then had trials that looked at 3-drug regimens of melphalan and prednisone with lenalidomide and compared them with melphalan and prednisone with thalidomide, and the results were fairly equivalent.

However, our field has always wanted to try to move away from the use of melphalan in frontline therapy. The drug has some toxicities that may not be the best for older individuals. Also, the drug has somewhat erratic and delayed responses. So, the FIRST trial, that was published in theNew England Journal of Medicinea few years ago, looked at using lenalidomide and dexamethasone and compared it with a standard of melphalan, prednisone, and thalidomide. This trial showed that lenalidomide and dexamethasone, followed by long-term lenalidomide maintenance, improved progression-free survival and the depth of response.

At least based on the trial, the management of this patient was certainly appropriate. It is based on evidence-based medicine. In the future we’re going to have more trials that may change the standard. There are several trials that are pending at this time that are looking at 3-drug combinations and comparing them with the Revlimid, dexamethasone standard. These include trials looking at ixazomib (Ninlaro), then Revlimid and dexamethasone; elotuzumab (Empliciti) with Revlimid and dexamethasone; and also, a trial looking at daratumumab (Darzalex) with lenalidomide and dexamethasone. These may certainly change the standard of care in the years to come.

More recently, we actually had the approval of a 3-drug regimen of Velcade (bortezomib) with melphalan, prednisone, and daratumumab by the FDA for frontline use. Once again, we’ll have to see how that leads to a change in the therapeutic landscape. As I’ve stated, the use of melphalan in frontline therapy is something that we wanted to move away from. Certainly, people are wanting to use our novel drugs in frontline, but this may not be the best mix for the patient.

There are obviously a lot of factors we consider when we decide how to treat a patient frontline. Paramount, I think, still remains whether a patient is transplant-eligible or not. For those who are transplant-eligible, we try to avoid the use of melphalan-based regimens certainly. For this particular patient, the current standard of care—at least based on randomized trials—is lenalidomide and dexamethasone. We know that the 3-drug combinations we have now in the second-line setting and beyond seemed to provide very good results even for patients with adverse-risk chromosomal features. However, we have no data in the frontline setting at this time. So, I think that in the future, our standards may change and the information from chromosomal features and FISH testing may inform our decision, regarding choice of therapy, especially if our choice of therapeutic options multiplies. But at this point, I think that the major use of the chromosome and FISH information is for planning postinduction phase of therapy, especially for the transplant-eligible population.

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