Current First-Line Treatment Options for Transplant-Ineligible Multiple Myeloma

Sagar Lonial, MD, FACP, highlights first-line therapies available for transplant-ineligible newly diagnosed multiple myeloma, with special considerations regarding comorbidities.

Sagar Lonial, MD, FACP: When we talk about treatment options for transplant-ineligible multiple myeloma, we’ve come a long way from the old days of melphalan and prednisone-based combinations. For instance, VMP [bortezomib, melphalan, and prednisone] was one of the first big steps forward, demonstrating improvement over melphalan and prednisone. MPT [melphalan, prednisone, and thalidomide] was another, adding thalidomide to melphalan and prednisone. But many of those were basically put to the wayside due to the FIRST trial, which demonstrated that continuous lenalidomide/dexamethasone was as good if not better than MP-based combinations in transplant-ineligible, frail, older myeloma patients.

What we’ve seen now are trials that have evaluated other potential treatment options in addition to lenalidomide and dexamethasone. Those include regimens such as bortezomib/dexamethasone or the addition of bortezomib with lenalidomide and dexamethasone, as explored in the SWOG-S0777 trial. What’s interesting is that it may not be as simple as just picking your favorite regimen. You do need to think about various comorbidities when making treatment decisions.

For instance, in a patient who [has diabetes] and who may have preexisting peripheral neuropathy, using a bortezomib-based induction may not necessarily offer the best short-term or long-term outcomes, particularly if you’re concerned that the diabetes and neuropathy are at risk for progressing relatively early. For a patient like this, one may want to think about either the doublet regimen of lenalidomide/dexamethasone or the triplet regimen of daratumumab, lenalidomide, and dexamethasone.

It is important to recognize that while carfilzomib has not been extensively studied in the older, frailer patient population as a way to mitigate the risk of peripheral neuropathy, we do have data on using carfilzomib with melphalan and prednisone versus melphalan, prednisone, and bortezomib. In that head-to-head trial, there really was no benefit noted with the addition of carfilzomib, suggesting that there are some cautions about using that agent, particularly in patients with cardiovascular comorbidities.

We also have seen the ALCYONE trial data that looked at bortezomib, melphalan, and prednisone plus or minus daratumumab. What we saw in that trial is that the addition of daratumumab clearly offers significant benefit in terms of PFS [progression-free survival], depth of response, MRD [minimal residual disease] negativity, and overall survival. But, as I mentioned, the use of VMP-based approaches in the United States is uncommon. I would think about this as a vehicle for delivering bortezomib with daratumumab and dexamethasone, and omitting the melphalan, really knowing that most of us don’t use melphalan-based therapies in the United States any longer.

I think it is important to think about comorbidities, including the patient’s ECOG performance status. For instance, do I always want to use a triplet regimen, or are there patients for whom I might just use a doublet? In the truly frail 90-year-old patient, I may use reduced-dose lenalidomide, at 10 mg, with perhaps 4 mg, 8 mg, or 10 mg of dexamethasone. I think it’s important that we recognize that we should dose-adjust both the lenalidomide and the dexamethasone. As you get older, the ability to tolerate even 20 mg of weekly dexamethasone becomes a bit more challenging.

Finally, I think it’s important we think about DVT [deep vein thrombosis] prophylaxis and functional activity as we start to use lenalidomide-based combinations, particularly in the older, frailer population. Patients who are wheelchair-bound or really have limited mobility should be considered for more intensive anticoagulation with a lenalidomide-based induction therapy. That may include the use of DOACs [direct oral anticoagulants] or low-molecular-weight heparin, because aspirin may not be enough prophylaxis for those patients.

Transcript edited for clarity.

Case: A 78-Year-Old Man with Multiple Myeloma

Initial Presentation

  • An active 78-year-old man presents with a year history of progressive fatigue; he feels joint and muscle pain diffusely for about 2 months
  • PMH: suffered a myocardial infarction 4 years ago; LVEF 45%
  • PE: bony tenderness appreciated on the hips and lower back

Clinical Workup

  • Labs: Hb 10.9 g/dL, calcium 10.0 mg/dL, LDH 160 U/L, creatinine 2.1 mg/dL, albumin 3.3 g/dL, beta-2 microgloblulin 5.2 mcg/mL, M-protein 2.6 g/dL, lambda free light chains 4.1 mg/dL
  • Hepatitis B negative
  • Skeletal survey and MRI revealed lytic bone lesions in the left hip, pelvis and L2 vertebrae
  • Bone marrow shows 70% plasma cells IgG k restricted
  • FISH: normal
  • Diagnosis: R-ISS stage II MM
  • ECOG 0


  • Patient is ineligible for ASCT due to comorbidities
  • Initiated treatment with daratumumab + lenalidomide + dexamethasone
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