Myeloma Staging and Up-front Treatment Options

Paul G. Richardson, MD:So, this is a very interesting patient, the second case. He’s a 77-year-old gentleman, African American, who was diagnosed approximately 2 years ago with advanced stage III multiple myeloma. Now, as we think about staging in multiple myeloma, it’s relevant to sort of revisit this a little bit. Obviously, by Durie-Salmon criteria, this particular patient had advanced bone disease, so he meets the [stage III] category by Durie-Salmon. But his stage III classification here was built on the ISS staging, which was built upon the height of the beta-2 microglobulin, and the level of the serum albumin. And the rule of thumb here is simply 3.5: if the beta-2 microglobulin is above 3.5, that’s obviously stage II versus stage I. If it’s above 5.5, it’s actually stage III. And in the same context, if the albumin is less than 3.5, that’s also stage II.

   So, there are three stages to the ISS staging. They’re based upon the height of the beta-2 microglobulin and the serum albumin. Stage I would be less than 3.5 and higher than 3.5 for the albumin. Stage II would be greater than 3.5 for the beta-2 but less than 5.5, with an albumin less than 3.5. And then stage III is 5.5 and above.

   Now, what’s been recently incorporated into our risk assessment is another laboratory prone to LDH, and I think the takeaway message is that the high LDH is not a good thing. Now, as we think about risk and profiling, and our sort of categorization of risk at the bedside and community practice, cytogenetics obviously is key. And the most important aspect of cytogenetics is fluorescence in situ hybridization (FISH). Now, obviously, at specialist centers now, we have access to gene expression profiling, which helps us understand risk. I think these tools remain early in their use. And like [the] plasma cell labeling index, which is used for example at the Mayo Clinic, these tools are not necessarily available broadly. I think some of them show great promise. For example, the 70- and 100-gene models do seem to have consistent validation to be used clinically.

   But having said that, they remain, I think, early in terms of their development. And, for example, at our center, whilst we require standard cytogenics and FISH studies, we don’t routinely do gene expression profiling unless it’s part of a clinical trial. So, that tends to be our approach to this staging concept. So, clinical staging, Durie-Salmon, ISS, use of cytogenetics, including FISH, to help quantify, or rather, get an idea of prognostication.

   So, this gentleman who’s 77 years old, as I mentioned, had stage III myeloma by virtue of his ISS staging, was clearly not a candidate for autologous stem cell transplant with his age. He was also frail. Moreover, his cytogenetics at the time were classified as intermediate. What that means: he didn’t have the classical high-risk features with t(4;14), t(14;16), or 17p deletion. But there were other features that were relevant that made him said to be considered intermediate. Now, what does that mean? Well, that means, in my book anyway, that you have standard risk and high risk. And I think intermediate risk is something of a misnomer, a rather difficult group to classify. Personally, in my own practice, I think of standard risk and high risk.

   In any event, the choice of lenalidomide as initial treatment, given his frailty, was quite reasonable. I think that lenalidomide/dexamethasone is an excellent choice for an older patient who is frail. But it’s important to remember that randomized data have shown that lenalidomide/dexamethasone compared with lenalidomide/bortezomib/dexamethasone has been shown to be inferior. RVD (lenalidomide, bortezomib, dexamethasone) has resulted in a greater progression-free survival and overall survival in a prospective randomized trial compared with RD (lenalidomide/dexamethasone). And this was also reflected by significant differences in response rate.

   Now, in an elderly patient who’s 77 years old, the use of bortezomib may be more challenging. Having said that, the use of bortezomib weekly, subcutaneously, and at low dose in an older, frailer patient has actually been explored by our own group and others; [this is the] so-called RVD light regimen. And in that setting, we’ve seen excellent results. And my colleague, Dr. Jacob Laubach, has led this particular effort in partnership with our colleagues at Mass General, with Dr. Betsy O’Donnell. And what he and Betsy have shown is that the use of RVD light, for example, is a highly efficacious and well-tolerated regimen in older, frailer patients. I think the choice in our gentleman, of RVD, given his frailty and his relatively intermediate cytogenetic risk profile with all the caveats that I just alluded to, with his ISS stage III, is reasonable. My own bias, however, would be to have added weekly bortezomib to his management earlier, I think, because that may have helped, given some of the other features of this disease.

Case Scenario 2:

December 2013

• The patient is a 77-year old African American male who was diagnosed 24 months ago with stage III multiple myeloma and not eligible for transplant based on his level of frailty. His cytogenetics were classified as intermediate risk.
• He received treatment with lenalidomide (15 mg daily) and low-dose dexamethasone.

December 2015

• IgA monoclonal protein spike seen on SPEP. M-protein level has risen to 0.6 g/dl.
• He continued to do well functionally.
• Lenalidomide was increased to 25 mg daily.

May 2016

• The patient now complains of increasing back pain, fatigue and weakness. He was hospitalized two months ago for pneumonia.
• Abnormal laboratory findings show:
  • Serum beta-2-microglobulin level, 6.2 mg/L
  • Albumin level of 2.1 g/dL.
  • Creatinine clearance of 32 ml/min
• Skeletal survey shows lytic lesions in the L4/L5 vertebrae.
• Bone marrow biopsy shows 30% involvement by abnormal appearing plasma cells, confirmed by CD138+ IHC stain.
• ECOG performance status is 2.
• The patient was started on pomalidomide, weekly cyclophosphamide, and low-dose dexamethasone.