Evidence-Based Medicine: Maintenance Therapy in MM

Ajai Chari, MD, PhD:For a patient with high-risk cytogenetics, which we define importantly as deletion 17p—but the percentage matters, and I’ll get back to that—translocation 4;14, translocation 14;16, and while not considered true high-risk, the amplification of chromosome 1, because now we consider standard risk the absence of chromosome 1 amplification.

So the management of these patients, and I wanted to mention specifically, 17p deletion is very important to talk about because we know that both clonal burden and allele burden matter. What does that mean? Having a few cells in deletion 17p is not necessarily high risk, and we’re talking about FISH [fluorescence in situ hybridization] that’s done with CD138 selection. And depending on the studies, at least 20% to perhaps 60% deletion is considered high risk. Small numbers may not be. But let’s just put the semantics aside and say the patient is standard high-risk myeloma. Induction therapy, perhaps carfilzomib, LEN/DEX [lenalidomide/dexamethasone], and perhaps quadruplet. But transplant consolidation is reasonable, although we still haven’t improved outcomes of high risk. And I think one area where we may tweak the maintenance of high-risk patients is with not just lenalidomide but perhaps dual therapy.

The Emory [University] group did a retrospective study showing that combination maintenance therapy with a proteasome inhibitor seemed to improve the outcomes of these patients, and so either bortezomib or off-label use of ixazomib might be something to consider. And in particular, I think a PI, or proteasome inhibitor, might be prudent to use in a patient with 4;14 translocation, which has been better overcome or addressed with proteasome inhibition.

This patient elected to do maintenance therapy, and I do recommend maintenance therapy in all my patients. I think everything we talk to patients about should be a risk/benefit. And so lenalidomide maintenance in both the CALGB and IFM studies published in the sameNew England Journal [of Medicine]showed that PFS [progression-free survival] of nonmaintenance patients is essentially approximately 2 years post-transplant. With the addition of lenalidomide that doubles to nearly 4 years.

Both those regimens use lenalidomide 10 mg continuously, and one of the tradeoffs though is that this additional PFS came at the expense of secondary primary malignancies [SPMs]. So both studies showed that the control arm, which got placebo maintenance, had a 3% to 4% risk of SPMs, and the addition of LEN [lenalidomide] maintenance doubled that to 6% to 8%. So I do recommend for all patients going through maintenance on lenalidomide to keep up with their age-appropriate cancer screening—mammograms, colonoscopies, skins exams—because the tumors that were developing in these patients were of all types—solid, liquid. It’s important to pay attention to the blood counts as well. I think LEN [lenalidomide] maintenance with that discussion of risk/benefit is evidence-based medicine and increases PFS.

The one thing I do a little differently is I don’t do 10 mg continuously. I think it’s nice to give patients that week off, and I think it lets the bone marrow recover a little bit. I’ve seen less fatigue. In my experience I haven’t seen very many secondary malignancies either, so that’s something to consider. The initial studies as mentioned did this continuously.

Transcript edited for clarity.

Case: 56-Year-Old Man With Asymptomatic Relapsed Multiple Myeloma

History:

• In 2015, at the age of 53, an African-American man was diagnosed with multiple myeloma; R-ISS stage I
• Patient was treated with bortezomib + lenalidomide + dexamethasone (VRd) for 4 cycles, followed by ASCT
• Patient achieved a VGPR
• Received lenalidomide maintenance for 2 years

September 2018

• On routine follow-up, no clinical symptoms observed
• Imaging: stable disease
• Laboratory results:
  • Hb, 11.3 g/dL
  • Ca²⁺9.2 mg/dL
  • Creatinine, 0.8 mg/dL
  • M-protein:
    • June: 1.2 g/dL
    • July: 1.4 g/dL
    • August: 1.7 g/dL
• Cytogenetics/FISH: no adverse cytogenetics
• ECOG PS: 0
• Patient was started on ixazomib + lenalidomide + dexamethasone (IRd)